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

[0001] This application is a divisional application of a Chinese patent application with the application number 202180017553.6 (PCT international application number PCT / US2021 / 012959), the invention name "Compounds for Chronic Disorders", and the filing date January 11, 2021. Background Art

[0002] A chronic condition is a human health condition or disease that persists or otherwise has a long-term effect, or is a disease that develops over time. The term chronic is typically applied when the course of the condition lasts for more 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 immunodeficiency syndrome.

[0003] Cancer, also known as malignancy, is the abnormal growth of cells. Cancer develops when the body's normal control mechanisms stop working. Instead of dying, old cells grow uncontrollably, forming new abnormal cells. These extra cells may form large masses of tissue, called tumors. Some cancers, such as leukemia, do not form tumors.

[0004] There are more than 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 and stage of the cancer. The goal of therapy is to kill as many cancer cells as possible while minimizing damage to nearby normal cells.

[0006] The three main treatments are:

[0007] · Surgery: directly removing the tumor;

[0008] · Chemotherapy: using chemicals to kill cancer cells;

[0009] · Radiation therapy: using X-rays to kill cancer cells.

[0010] The main unresolved problems of metastatic cancer are recurrence after an objective response to chemotherapy, drug-induced side effects of first-line chemotherapy, and delayed response to second-line treatment. Unfortunately, there are few options available for use as third-line treatment. Thus, there is a growing need to find new chemopreventive agents that can effectively prevent and / or manage chronic conditions such as cancer.

[0011] Natural products, such as flavonoids, can be used for the prevention or treatment of chronic disorders. However, due to their reduced solubility and bioavailability, natural products are not effective substitutes for current therapeutic agents. Thus, there is a need in the art for the development of novel drugs that provide increased bioavailability, solubility, and tissue distribution capabilities for targeted delivery. Such agents can be active against a variety of chronic conditions and, in some embodiments, can exhibit anti-cancer or anti-viral activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] In conjunction with the drawings, the foregoing and other information of the present disclosure, as well as other features, will become more apparent from the following description and the appended claims. It should be understood that these drawings only depict several embodiments in accordance with the present disclosure and should not be considered as limiting its scope. The present disclosure will be described with additional features and details by using the drawings.

[0013] Figure 1 Depicts the spectrum of Compound I

[0014] a. Mass spectrum

[0015] b. IR spectrum

[0016] c. 1 1H NMR spectrum

[0017] d. 13 13C NMR spectrum

[0018] Figure 2 Depicts the spectrum of Compound II

[0019] a. Mass spectrum

[0020] b. IR spectrum

[0021] c. 1 1H NMR spectrum

[0022] d. 13 13C NMR spectrum

[0023] Figure 3 Depicts the spectrum of Compound III

[0024] a. Mass spectrum

[0025] b. IR spectrum

[0026] c. 1 1H NMR spectrum

[0027] d. 13 13C NMR spectrum

[0028] Figure 4 Depicts the spectrum of Compound IV

[0029] a. Mass spectrum

[0030] b. IR spectrum

[0031] c. 1 1H NMR spectrum

[0032] d. 13 13C NMR spectrum

[0033] Figure 5 depicts the spectrum of Compound V

[0034] a. Mass spectrum

[0035] b. IR spectrum

[0036] c. 1 1H NMR spectrum

[0037] d. 13 13C NMR spectrum

[0038] Figure 6 depicts the spectrum of Compound VI

[0039] a. Mass spectrum

[0040] b. IR spectrum

[0041] c. 1 1H NMR spectrum

[0042] d. 13 13C NMR spectrum

[0043] Figure 7 depicts the spectrum of Compound VII

[0044] a. Mass spectrum

[0045] b. IR spectrum

[0046] c. 1 1H NMR spectrum

[0047] d. 13 13C NMR spectrum

[0048] Figure 8 depicts the spectrum of Compound VIII

[0049] a. Mass spectrum

[0050] b. IR spectrum

[0051] c. 1 1H NMR spectrum

[0052] d. 13 13C NMR spectrum

[0053] Figure 9 depicts the spectrum of Compound IX

[0054] a. Mass spectrometry

[0055] b. IR spectrum

[0056] c. 1 H NMR spectrum

[0057] d. 13 C NMR spectrum

[0058] Figure 10A Depicts the anti - cancer activity of Compound I on different cell lines.

[0059] A: Effect of the molecule on different cancer cell lines;

[0060] B: Effect of the molecule on normal cell lines;

[0061] C: Comparison with other standard drugs:

[0062] Abbreviations

[0063] MCF - 7 (human breast cancer cells);

[0064] MDAMB 231 (triple - negative breast cancer cell line);

[0065] PANC - 1 (human pancreatic cancer cell line);

[0066] HT - 29 (human colon cancer cell line);

[0067] T - ALL (T - cell acute lymphoblastic leukemia);

[0068] HDF (human dermal fibroblasts);

[0069] AC - 16 (human cardiomyocytes);

[0070] HBMSC (human bone marrow mesenchymal stem cells);

[0071] MCF - 12A (human normal breast cells);

[0072] CRL2989 (human normal pancreatic cells);

[0073] NCM 60 (normal colon epithelial cell line)

[0074] Figure 10B Depicts apoptosis induction and mitochondrial membrane potential of the control and Compound I.

[0075] Figure 11 Depicts a series of graphs for elucidating the mechanism of action of the compounds of the present disclosure (e.g., Compound I) that inhibit histone deacetylase (HDAC) activity.

[0076] Figure 12 A series of charts depicting the formation of neuron cell types induced by Compound I.

[0077] a. Neuron differentiation of human stem cells – molecules

[0078] b. Oncogene expression analysis of molecules

[0079] Figure 13 Depicts the inhibition of cancer stem cell markers by Compound I.

[0080] Figure 14 Depicts the cancer cell kinetics and treatment of conventional drugs and the compounds of the present invention.

[0081] Figure 15 Depicts the breakthroughs achieved by the compounds of the present disclosure.

[0082] Figure 16 Depicts cancer stem cells and receptors.

[0083] Figure 17 Depicts the abnormal signal transduction pathways in cancer stem cells and shows cancer stem cells as targets.

[0084] Figure 18 Depicts the genes targeted by the compounds of the present disclosure for various types of cancer.

[0085] Figure 19 Depicts the evaluation of the cytotoxicity of an anti-cancer agent by measuring the IC50 against a set of normal cell lines, which were untreated with Compound 1 ( Figure 19 A) and treated in combination with Compound I ( Figure 19 B).

[0086] Figure 20 Depicts in vivo studies in a stage IV translocation tumor model comparing conventional drugs with Compound I of the present disclosure.

[0087] Figure 21 Provides a PANC-1 mouse xenograft model for evaluating the efficacy of Compound I compared to gemcitabine.

[0088] Figure 22 Depicts the steps in the coronavirus replication pathway targeted by the compounds of the present disclosure.

[0089] Figure 23 Depicts how the binding of an ACE-2 inhibitor disrupts the interaction between the virus and the receptor.

[0090] Figure 24A Depicts the molecular binding site of Nsp15.

[0091] Figure 24B depicts a model showing the binding of a small molecule to Nsp15.

[0092] Figure 24C depicts a model showing the binding site residues proposed to interact with the compounds of the present disclosure.

[0093] Figure 25 Panel A depicts normal Vero cells and Vero cells infected with SARS-CoV-2 at an MOI of 0.1, treated with different doses of the indicated antiviral drugs for 48 h. The viral yield in the cell supernatant was then quantified by qRT-PCR.

[0094] Figure 25 Panel B depicts a graph representing the average % inhibition of viral yield and the cytotoxicity of the drug (e.g., Compound I). The experiments were performed in triplicate.

[0095] Figure 25 Panel C depicts immunofluorescence microscopy of virus infection after treatment with Compound I. At 48 h post-infection, the infected cells were fixed and then incubated with rabbit serum against the nucleoprotein (NP) of SARS-related CoV as the primary antibody and Alexa 488-labeled goat anti-rabbit IgG as the secondary antibody. The cell nuclei were stained with Hoechst dye. Scale bar, 20 μm.

[0096] Figure 25 Panel D depicts Western blot analysis of nucleoprotein (NP) expression at 24 h post-infection (p.i.) in cells infected with SARS-CoV-2 at an MOI of 0.1.

[0097] Figure 25 Panel E depicts a graph representing nucleoprotein (NP) expression normalized to GAPDH. The viral yield in the infected cell supernatant was quantified by qRT-PCR. The experiments were performed in triplicate.

[0098] Figure 25 Panels F - H depict graphs showing a reduction in viral RNA found in the supernatant and cell pellet from samples treated with 1 μM Compound I.

[0099] Figure 26 Panel A depicts a cell viability assay of calu-3 cells treated with different concentrations of Compound I.

[0100] Figure 26 Panel B depicts a plaque reduction percentage assay in calu-3 cells treated with different concentrations of Compound I.

[0101] Figure 27Panel A depicts 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, based on the weight of Compound I.

[0102] Figure 27 Panel B depicts the results of a tissue distribution study from 0.5 h to 96 h in the heart, lungs, muscle, spleen, tibia, and femur of nude mice administered a single dose of 10 mg / kg, based on the weight of Compound I.

[0103] Figure 28 Panel A- Figure 28 Panel E is a graph showing the effects on organ weights ( Figure 28 Panel A- Figure 28 Panel B), liver weights ( Figure 28 Panel C), and body weights ( Figure 28 Panel D-2 Figure 8 Panel E) of male and female Wistar rats after oral administration of various amounts of Compound I.

[0104] Figure 28 Panel F- Figure 28 Panel I is a graph showing the effects on hematological parameters (urea, creatinine, etc.) when male and female Wistar rats are orally administered various amounts of Compound I.

[0105] Figure 28 Panel J- Figure 28 Panel K is a graph showing the effects on electrolytes when male and female Wistar rats are orally administered various amounts of Compound I.

[0106] Figure 28 Panel L- Figure 28 Panel O is a graph showing the effects on liver function of male and female Wistar rats after oral administration of various amounts of Compound I.

[0107] Figure 28 Panel P- Figure 28 Panel Q is a graph showing the effects on renal function of male and female mice after oral administration of various amounts of Compound I.

[0108] Figure 29 depicts histopathological studies of organ samples of the liver, kidney, skeletal muscle, heart, and spleen from male ( Figure 29 Panel A) and female rats s( Figure 29 Panel B). Tissue samples were collected on the last day of the treatment period. SUMMARY OF THE INVENTION

[0109] The present disclosure relates to compounds having anti-cancer and anti-viral activity. The compounds can be used to treat subjects suffering from chronic disorders. The compounds have a structure of Formula 1A

[0110]

[0111] or any of its derivatives, its pharmaceutically acceptable salts, or combinations thereof.

[0112] Wherein:

[0113] R1 is H, OH, or alkoxy;

[0114] R2 is alkoxy or OH;

[0115] R3 is alkoxy or OH;

[0116] X is C1-C 15 alkyl, C2-C 15 alkenyl, C2-C 15 alkynyl, or an aralkyl chain, each independently substituted by at least one alkoxy, OH, =NH, or oxo group;

[0117] Y is H or alkyl; and

[0118] X is in the ortho position to R2, or in the para position to R1. Detailed Description

[0119] Definition

[0120] "Alkyl" or "alkyl group" refers to a fully saturated straight-chain or branched-chain hydrocarbon chain having one to fifteen carbon atoms, and which is attached to the remainder of the molecule by a single bond. Unless otherwise specifically stated in the specification, the alkyl group may be optionally substituted.

[0121] "Alkenyl" or "alkenyl group" refers to a straight-chain or branched-chain hydrocarbon chain having two to fifteen carbon atoms and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the remainder of the molecule by a single bond. Unless otherwise specifically stated in the specification, the alkenyl chain may be optionally substituted.

[0122] "Alkenylene" or "alkenylene chain" refers to a straight-chain or branched-chain divalent hydrocarbon chain group having two to twelve carbon atoms and having one or more carbon-carbon double bonds. The alkenylene chain is attached to the remainder of the molecule by a single bond and to the radical by a single bond. Unless otherwise specifically stated in the specification, the alkenylene chain may be optionally substituted.

[0123] "Alkoxy" refers to a group having the formula -OR a wherein R a is an alkyl, alkenyl, or alkynyl group having one to twelve carbon atoms as defined above. Unless otherwise specifically stated in the specification, the alkoxy group may be optionally substituted.

[0124] "Arylalkyl" or "aryl-alkyl" means a group having the formula -R b -R c wherein R b is an alkylene or alkenylene group as defined above, and R c is one or more aryl groups as defined above, such as, for example, benzyl, diphenylmethyl, etc. Unless specifically stated otherwise in the specification, an arylalkyl group may be optionally substituted.

[0125] "Oxo" means the following groups having a double bond to an oxygen atom.

[0126] As used herein, the term "substituted" 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: halogen atoms such as F, Cl, Br, and I; oxygen atoms in groups such as hydroxy groups, alkoxy groups, and ester groups; sulfur atoms in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; nitrogen atoms in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamine groups; silicon atoms in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other atoms. "Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced by a higher order bond (such as a double bond 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 groups. For example, "substituted" includes any of the above groups in which one or more hydrogen atoms are replaced by, for example: -NR 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" also refers to any of the above groups in which one or more hydrogen atoms are replaced by: -C(=O)R g 、-C(=O)OR g 、-C(=O)NR g R h 、-CH2SO2R g 、-CH2SO2NR g R h 。In the above, R g and R h are the same or different and independently are hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic group, N-heterocyclic group, heterocyclic group alkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. "Substituted" further refers to any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino group, cyano group, hydroxyl group, imino group, nitro group, oxo group, thio group, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylamino group, thioalkyl group, aryl group, aralkyl group, cycloalkyl group, cycloalkenyl group, cycloalkynyl group, cycloalkylalkyl group, haloalkyl group, haloalkenyl group, haloalkynyl group, heterocyclic group, N-heterocyclic group, heterocyclic group alkyl, heteroaryl group, N-heteroaryl group, and / or heteroarylalkyl group. In addition, each of the aforementioned substituents may also be optionally substituted by one or more of the above substituents.

[0127] As used herein, the symbol (which may hereinafter be referred to as an "attachment bonding point") represents an attachment point between two chemical entities, where one is depicted as attached to the attachment point and the other is not depicted as attached to the attachment point. For example, represents that the chemical entity "XY" is bonded to another chemical entity via an attachment bonding point. In addition, the specific attachment point to an undescribed chemical entity can be specified by inference. For example, the compound CH3-R 3 , where R 3 is H or means that when R 3 is "XY", the attachment bonding point is the same bond as the bond described as being attached to CH3 for R 3 .

[0128] "Pharmaceutically acceptable salts" includes, where appropriate, pharmaceutically acceptable base addition salts and acid addition salts, such as metal salts (e.g., alkali metal and alkaline earth metal salts), ammonium salts, organic amine addition salts, amino acid addition salts, and sulfonates. Acid addition salts include inorganic acid addition salts, such as hydrochlorides, sulfates, and phosphates; and organic acid addition salts, such as alkyl sulfonates, aryl sulfonates, acetates, maleates, fumarates, tartrates, citrates, and lactates. Other examples of acid addition salts include acetates, benzenesulfonates (besylates), benzoates, camphorsulfonates, citrates, ethylenesulfonates, fumarates, gluconates, glutamates, hydrobromides, hydrochlorides, isethionates, lactates, maleates, malates, mandelates, mesylates, mucates, nitrates, palmitates, pantothenates, phosphates, succinates, sulfates, tartrates, p-toluenesulfonates, and the like. Examples of metal salts are alkali metal salts, such as lithium, sodium, and potassium salts; alkaline earth metal salts, such as magnesium and calcium salts, aluminum and zinc salts. Examples of ammonium salts are ammonium salts and tetramethylammonium salts. Examples of organic amine addition salts are salts containing morpholine and piperidine. Examples of amino acid addition salts are salts containing glycine, phenylalanine, glutamate, and lysine. Sulfonates include mesylates, toluenesulfonates, and benzenesulfonates. When a compound contains an acidic side chain, suitable pharmaceutically acceptable base addition salts include metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, glucosamine (N-methylglucosamine), and procaine.

[0129] The term "therapeutically effective" as applied to a dosage or amount means that the amount of a compound or pharmaceutical formulation is sufficient to produce a desired clinical benefit upon administration to a patient in need.

[0130] In the following detailed description, reference is made to the accompanying drawings, which form a part of the description. In the drawings, like reference numerals generally identify like components unless the context otherwise indicates. The illustrative embodiments described in the detailed description, the drawings, and the claims are not meant 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. It will be readily understood that aspects of the present disclosure, as generally described herein and illustrated in the drawings, can be arranged, substituted, combined, separated, and designed in a variety of different configurations, all of which are explicitly contemplated herein.

[0131] Generally speaking, the present invention discloses novel therapeutic compounds for treating chronic disorders, including cancer.

[0132] In some embodiments, the present invention discloses compounds having the structure of Formula 1A,

[0133]

[0134] or any of its derivatives, its pharmaceutically acceptable salts, or combinations thereof.

[0135] Wherein:

[0136] R1 is H, OH, or alkoxy;

[0137] R2 is alkoxy or OH;

[0138] R3 is alkoxy or OH;

[0139] X is a C1-C 15 alkyl, C2-C 15 alkenyl, or aralkyl chain, each independently substituted by at least one alkoxy, OH, =NH, or oxo group;

[0140] Y is H or alkyl; and

[0141] X is in the ortho position to R2 or the para position to R1.

[0142] In some embodiments of the compounds having Formula 1A,

[0143] R1 is H.

[0144] R2 is -OH;

[0145] R3 is C1-C3 alkoxy; and

[0146] X is a C4-C8 alkenyl substituted by 2 oxo groups.

[0147] Y is C1-C3 alkyl.

[0148] In some embodiments, the compounds having Formula 1A have the structure of Formula 1

[0149]

[0150] or any of its derivatives, its pharmaceutically acceptable salts, or combinations thereof.

[0151] Wherein:

[0152] R1 is H, alkoxy, or OH;

[0153] R2 is alkoxy or OH;

[0154] R3 is alkoxy or OH;

[0155] X is a C1-C 15 alkyl, C2-C 15 alkenyl, or aralkyl chain, each independently substituted by at least one alkoxy, OH, =NH, or oxo group.

[0156] In some embodiments of Formula 1, X is

[0157] (i) C6-C 10 alkenyl substituted with four substituents independently selected from the group consisting of oxo, -OH, and C1-C3 alkoxy;

[0158] (ii) C8-C 12 alkenyl substituted with oxo and C1-C3 alkoxy;

[0159] (iii) C4-C8 alkenyl substituted with two oxo groups;

[0160] (iv) C2-C6 alkenyl substituted with oxo and C1-C3 alkoxy;

[0161] (v) C1-C6 alkyl substituted with =NH;

[0162] (vi) C2-C3 alkenyl substituted with –OH;

[0163] (vii) C8-C 12 alkenyl substituted with oxo and two C1-C3 alkoxy groups; or

[0164] (viii) an aralkyl group 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.

[0165] In some embodiments of Formula 1,

[0166] R1 is H;

[0167] R2 is C1-C3 alkoxy;

[0168] R3 is C1-C3 alkoxy; and

[0169] X is C6-C 10 alkenyl substituted with oxo, -OH, and two C1-C3 alkoxy groups;

[0170] In some embodiments of Formula 1,

[0171] R1 is H;

[0172] R2 is C1-C3 alkoxy;

[0173] R3 is C1-C3 alkoxy; and

[0174] X is C8-C 12 alkenyl substituted with oxo and C1-C3 alkoxy;

[0175] In some embodiments of Formula 1,

[0176] R1 is OH;

[0177] R2 is C1-C3 alkoxy;

[0178] R3 is C1-C3 alkoxy; and

[0179] X is a C4-C8 alkenyl group substituted with two oxo groups;

[0180] In some embodiments of Formula 1,

[0181] R1 is C1-C3 alkoxy;

[0182] R2 is OH;

[0183] R3 is C1-C3 alkoxy; and

[0184] X is a C4-C8 alkenyl group substituted with 2 oxo groups;

[0185] In some embodiments of Formula 1,

[0186] R1 is H;

[0187] R2 is OH;

[0188] R3 is OH; and

[0189] X is a C1-C6 alkyl group substituted with =NH;

[0190] In some embodiments of Formula 1,

[0191] R1 is OH;

[0192] R2 is C1-C3 alkoxy;

[0193] R3 is C1-C3 alkoxy; and

[0194] X is a C2-C3 alkenyl group substituted with OH.

[0195] In some embodiments of Formula 1,

[0196] R1 is H;

[0197] R2 is C1-C3 alkoxy;

[0198] R3 is C1-C3 alkoxy; and

[0199] X is a C8-C 12 alkenyl group substituted with oxo and two C1-C3 alkoxy groups.

[0200] In some embodiments of Formula 1,

[0201] R1 is OH;

[0202] R2 is C1-C3 alkoxy;

[0203] R3 is C1-C3 alkoxy; and

[0204] X is an aralkyl group containing a C6-C8 alkyl group and a C6 aryl group, wherein the alkyl group is substituted with oxo, and the aryl group is substituted with two C1-C3 alkoxy groups.

[0205] In some embodiments, the compound having formula 1A has the structure of formula 2

[0206]

[0207] or any of its derivatives, its pharmaceutically acceptable salts or combinations thereof.

[0208] wherein

[0209] R1 is H or OH;

[0210] R2 is alkoxy or OH;

[0211] R3 is alkoxy or OH; and

[0212] R4 is C1-C 15 alkyl, C2-C 15 alkenyl, aralkyl, each of which is substituted with at least one alkoxy, -OH or oxo.

[0213] In some embodiments of formula 2, R4 is:

[0214]

[0215] In some embodiments of formula 2, R1 is H;

[0216] R2 is OCH3;

[0217] R3 is OCH3; and R4 is In some embodiments of formula 2, R1 is H;

[0218] R2 is OCH3;

[0219] R3 is OCH3; and R4 is. In some embodiments of formula 2, R1 is OH;

[0220] R2 is OCH3;

[0221] R3 is OCH3; and R4 is In some embodiments of formula 2, R1 is OH;

[0222] R2 is OCH3;

[0223] R3 is OCH3; and R4 is In some embodiments of Formula 2, R1 is H;

[0224] R2 is OCH3;

[0225] R3 is OCH3; and

[0226] R4 is

[0227] In some embodiments, Formula 1A has the structure of Formula 3

[0228]

[0229] or any of its derivatives, its pharmaceutically acceptable salts, or combinations thereof.

[0230] Wherein:

[0231] R1 is H, alkoxy or OH;

[0232] R2 is alkoxy or OH;

[0233] R3 is alkoxy or OH; and

[0234] R5 is C1-C 12 alkyl or C2-C 12 alkenyl, which is independently substituted by 1 or 2 substituents selected from the group consisting of =NH or oxo.

[0235] In some embodiments of Formula 3,

[0236] R1 is H;

[0237] R2 is OH;

[0238] R3 is OH; and

[0239] R5 is =NH.

[0240] In some embodiments, R5 is in the ortho position to R2.

[0241] In some embodiments of Formula 3,

[0242] R1 is -OC2H5;

[0243] R2 is OH;

[0244] R3 is -OCH3; and

[0245] R5 is

[0246] In some embodiments of Formula 3, R5 is in the para position to R1.

[0247] In some embodiments, a compound having Formula 1A has the structure of Formula 4

[0248]

[0249] or any of its derivatives, its pharmaceutically acceptable salts, or combinations thereof.

[0250] Wherein:

[0251] R1 is OH;

[0252] R2 is C1-C3 alkoxy;

[0253] R3 is C1-C3 alkoxy; and

[0254] R6 is C(CH2)OH.

[0255] In some embodiments of Formula 4,

[0256] R1 is OH;

[0257] R2 is OCH3;

[0258] R3 is OCH3; and

[0259] R6 is C(CH2)OH.

[0260] In some embodiments, the present invention provides a pharmaceutical composition comprising one or more of the above-described compounds and a pharmaceutically acceptable carrier.

[0261] In some embodiments of the present disclosure, pharmaceutically acceptable carriers include gum arabic, animal oils, benzyl alcohol, benzyl benzoate, calcium stearate, carbomer, cetearyl alcohol, cetyl alcohol, cholesterol, cyclodextrin, dextrose, diethanolamine, emulsifying wax, ethylene glycol palmitostearate, glycerin, glyceryl monostearate, glyceryl stearate, glyceryl monooleate, glyceryl monostearate, hydrate, histidine, hydrochloric acid, hydroxypropyl cellulose, hydroxypropyl-β-cyclodextrin (HPBCD), hypromellose (hydroxypropyl methylcellulose (HPMC)), lanolin, lanolin alcohol, lecithin, medium-chain triglycerides, metal soaps, methylcellulose, mineral oil, sodium dihydrogen phosphate, monoethanolamine, oleic acid, polyethylene glycol (PEG 3350, PEG 4000, PEG6000), 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 dihydrogen phosphate, disodium hydrogen phosphate, sorbitan esters, stearic acid, stearyl alcohol, sunflower oil, tragacanth gum, triethanolamine, vegetable oils, water, xanthan gum, or combinations thereof.

[0262] Any chemical structure of Formulas 1A - 4 can be prepared according to the exemplary synthetic routes disclosed herein.

[0263] In one embodiment, the exemplary Compound I of Formula 1A can be prepared by Scheme I provided below.

[0264]

[0265] Chemical synthesis: In a dry three-necked flask, acetylacetone (5 mmol, 0.51 ml) and boron oxide (3.5 mmol, 0.244 g) were dissolved in anhydrous ethyl acetate and stirred at 40 °C for 30 min. Then the corresponding aldehyde (10 mmol) and tributyl borate (10 mmol, 2.4 ml) were added and stirred for another 30 min. n-Butylamine (7.5 mmol) was dissolved in anhydrous ethyl acetate and then added over a 15 min period. The mixture was heated to 40 °C and maintained for 24 h. Then 5 ml of HCl (10%) was added and heated to 60 °C for an additional hour. The aqueous phase was extracted several times with ethyl acetate, the organic layer was dried over Na2SO4, and the solvent was distilled off. The insoluble precipitate (partial product) was filtered out and recrystallized from the residue from various solvents. Purification was carried out by column chromatography (eluent toluene / ethyl acetate 8:2) and crystallization from ethanol (80%).

[0266] Next, the synthesized compounds of Formula 1A-4 were subjected to molecular characterization to determine the structure of the compounds.

[0267] Characterization:

[0268] 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 Formula 1A-4 were elucidated as Compounds I to IX in Table 1 below.

[0269] Table 1

[0270]

[0271]

[0272]

[0273]

[0274] In some embodiments, the compounds of Formula 1A-4 and Compounds I-IX may encompass cis isomers, trans isomers, or cis and trans isomers. In some embodiments, the compounds of Formula 1A-4 and Compounds I-IX may be a mixture of cis and trans isomers. In some embodiments, the compounds of Formula 1A-4 and Compounds I-IX may be cis isomers (i.e., Z-isomers). In some embodiments, the compounds of Formula 1A-4 and Compounds I-IX may be trans-isomers (i.e., E-isomers).

[0275] In some embodiments, the compounds of Formulas 1A - 4 and Compounds I - IX can encompass R or S stereoisomers as well as mixtures of stereoisomers (e.g., mixtures of diastereomers). In some embodiments, the compounds of Formulas 1A - 4 can be racemic mixtures or enantiomerically pure.

[0276] In some embodiments, the compounds of Formulas 1A - 4 and Compounds I - IX are enantiomerically pure (e.g., comprising the R or S enantiomer), diastereomerically pure, or comprise a mixture of stereoisomers (e.g., a racemic mixture or a mixture of diastereomers). In some embodiments, the compounds of Formulas 1A - 4 are racemic mixtures. In some embodiments, the compounds of Formulas 1A - 4 are enantiomerically pure. In some embodiments, the compounds of Formula 1A - 4 are diastereomerically pure.

[0277] In some embodiments, an enantiomerically pure compound is a compound having an enantiomeric excess (ee) 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%.

[0278] In some embodiments, a diastereomerically pure compound is a compound having a diastereomeric excess (de) 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%.

[0279] The compounds of the present invention can be used to perform or provide any of the biological functions described herein.

[0280] Drug composition

[0281] The present disclosure also includes pharmaceutical compositions that comprise a therapeutically effective amount of one or more of the compounds disclosed herein. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of one or more compounds of Formulas 1A, 2, 3, and / or 4, or a pharmaceutically acceptable salt thereof. In other embodiments, the pharmaceutical composition comprises a therapeutically effective amount of one or more compounds selected from Table 1, or a pharmaceutically acceptable salt thereof.

[0282] In various aspects, a compound of Formulas 1A - 4 (including the compounds in Table 1) or a pharmaceutically acceptable salt thereof can be administered at about 0.001 mg / kg to about 100 mg / kg body weight (e.g., about 0.01 mg / kg to about 10 mg / kg or about 0.1 mg / kg to about 5 mg / kg).

[0283] The concentration of the compounds disclosed in a pharmaceutically acceptable mixture will vary depending on several factors, including the dosage of the compound to be administered, the pharmacokinetic characteristics of the one or more compounds used, and the route of administration. The agent can be administered in a single dose or in repeated doses. A dosage regimen using the compounds of the invention is selected based on a variety of factors including the type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or its salt employed. Treatment can be once daily or more frequently, depending on many factors including the overall health of the patient, and the formulation and route of administration of the one or more compounds selected.

[0284] The compounds or pharmaceutical compositions disclosed herein can be manufactured and / or administered in single or multiple unit dosage forms.

[0285] In some embodiments, the compounds of the present disclosure (compounds having Formulas 1-4, and Table 1) are administered to a patient suffering from a chronic condition. In the context of some embodiments of the present invention, the term "chronic disorder" refers to, but is not limited to, acute lymphoblastic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute myelogenous leukemia, adrenocortical carcinoma, AIDS-related lymphoma, anal cancer, appendiceal cancer, basal cell carcinoma, bladder cancer, brain cancer, brainstem glioma, breast cancer, bronchial adenoma / carcinoid tumor, Burkitt lymphoma, carcinoid tumor, cerebellar or cerebral astrocytoma, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic or chronic lymphoblastic leukemia, chronic myelogenous leukemia 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 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, glioma of the brainstem, hairy cell leukemia, head and neck cancer, heart cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, hypothalamic and visual pathway glioma, intraocular melanoma, islet cell carcinoma, Kaposi sarcoma, laryngeal cancer, leukemia, lip and oral cavity cancer, liposarcoma, lymphoma, male breast cancer, malignant mesothelioma, medulloblastoma, melanoma, Merkel cell skin cancer, mesothelioma, metastatic squamous neck cancer, oral cavity cancer, multiple endocrine neoplasia syndrome, multiple myeloma, multiple myeloma / plasmacytoma, mycosis fungoides, myelodysplastic / myeloproliferative diseases, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-melanoma skin cancer, non-small cell lung cancer, oligodendroglioma, oral cavity cancer, oropharyngeal cancer, osteosarcoma and malignant fibrous histiocytoma, ovarian cancer, ovarian germ cell tumor, ovarian epithelial cancer (surface epithelial-stromal tumor), ovarian low malignant potential tumor, pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, nasopharyngeal cancer, pheochromocytoma, pineal astrocytoma, pineal germ cell tumor, pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary adenoma, plasmacytoma, pleuropulmonary blastoma, primary cancer, 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, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, supratentorial primitive neuroectodermal tumor, testicular cancer, laryngeal 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 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 dementia, spinal cord ischemia, spinal cord injury, ischemic stroke, cerebral infarction, spinal cord injury, and cancer-related brain and spinal cord injury, multi-infarct dementia, Alzheimer's disease, other cognitive impairments, depression, onychomycosis (fungal infection of the nails), gingivitis and periodontal disease (gum disease), obesity and diabetes. The compounds disclosed herein are also good candidates for severe acute respiratory syndrome (SARS) and coronavirus disease 2019 (COVID-19) and various cancers with KRAS oncogene mutations.

[0286] 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 cancer. In some embodiments, 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.

[0287] In some embodiments, the chronic condition is a viral infection, such as SARS or COVID-19.

[0288] In certain embodiments, the methods, compounds, and compositions described herein are administered in combination with one or more of the following: other antibody molecules, chemotherapy, other anti-cancer therapies (e.g., targeted anti-cancer therapies, gene therapy, viral therapy, RNA therapy, bone marrow transplantation, nanotherapy, or oncolytic cell drugs), cytotoxic agents, immune-based therapies (e.g., cytokines or cell-based immunotherapies), surgery (e.g., lumpectomy or mastectomy), or radiation therapy, or a combination of any of the foregoing.

[0289] Alternatively, or in combination with the foregoing, the methods and compositions described herein can be administered in combination with one or more of the following: vaccines (e.g., therapeutic cancer vaccines); or other forms of cellular immunotherapy.

[0290] 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 co-therapy). Alternatively or additionally, the combination further includes a VEGF inhibitor (e.g., a VEGF inhibitor as disclosed herein).

[0291] Non-limiting examples of additional therapeutic agents that can be combined with the methods disclosed herein include: taxol, imatinif, doxorubicin, paclitaxel, fluorouracil (5-FU), and vinblastine.

[0292] In some embodiments, the methods and compositions described herein can be administered in combination with one or more antiviral agents.

[0293] Non-limiting examples of additional therapeutic agents (e.g., antiviral agents) that can be used in combination with the methods disclosed herein include: remdesivir, lopinavir / ritonavir, favilavir, chloroquine, hydroxychloroquine, azithromycin, or combinations thereof.

[0294] Numbered embodiments:

[0295] 1. A compound having Formula 1A,

[0296]

[0297] or a pharmaceutically acceptable salt thereof,

[0298] wherein:

[0299] R1 is H, OH, or an alkoxy group;

[0300] R2 is an alkoxy group or OH;

[0301] R3 is an alkoxy group or OH;

[0302] X is a C1-C 15 alkyl, C2-C 15 alkenyl, C2-C 15 alkynyl, or an aralkyl chain, each independently substituted with at least one alkoxy group, OH, ═NH, or an oxo group;

[0303] Y is H or an alkyl group; and

[0304] X is located ortho to R2 or para to R1.

[0305] 2. The compound according to embodiment 1, wherein:

[0306] R2 is a C1-C3 alkoxy group.

[0307] 3. The compound according to embodiment 1 or 2, wherein:

[0308] R3 is a C1-C3 alkoxy group.

[0309] 4. The compound according to embodiments 1-3, wherein:

[0310] X is a C1-C 15 alkyl or C2-C 15 alkenyl, each independently substituted with 1, 2, 3, or 4 substituents selected from the group consisting of an alkoxy group, OH, ═NH, or an oxo group.

[0311] 5. The compound according to any one of Embodiments 1-4, wherein:

[0312] R1 is H or OH.

[0313] 6. The compound according to any one of Embodiments 1-5, wherein:

[0314] Y is H.

[0315] 7. The compound according to any one of Embodiments 1-5, wherein:

[0316] R1 is H;

[0317] R2 is -OH;

[0318] R3 is C1-C3 alkoxyl;

[0319] X is a C4-C8 alkenyl group substituted by two oxo groups; and

[0320] Y is C1-C3 alkyl.

[0321] 8. The compound according to Embodiment 1, which has the structure of Formula 1

[0322]

[0323] or a pharmaceutically acceptable salt thereof,

[0324] wherein:

[0325] R1 is H, alkoxyl or OH;

[0326] R2 is alkoxyl or OH;

[0327] R3 is alkoxyl or OH; and

[0328] X is C1-C 15 alkyl, C2-C 15 alkenyl, C2-C 15 alkynyl or aralkyl chain, each of which is independently substituted by at least one alkoxyl, OH, =NH or oxo group;

[0329] 9. The compound according to Embodiment 8, wherein:

[0330] R1 is H or OH;

[0331] R2 is C1-C3 alkoxyl or OH;

[0332] R3 is C1-C3 alkoxyl or OH; and

[0333] X is C1-C 12 alkyl, C2-C 12an alkenyl, or an aralkyl, each independently substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of an alkoxy group, OH, ═NH, and an oxo group.

[0334] 10. The compound according to embodiment 8 or 9, wherein X is:

[0335] (i) a C6-C 10 alkenyl substituted with four substituents independently selected from the group consisting of an oxo group, -OH, and a C1-C3 alkoxy group;

[0336] (ii) a C8-C 12 alkenyl substituted with an oxo group and a C1-C3 alkoxy group;

[0337] (iii) a C4-C8 alkenyl substituted with 2 oxo groups;

[0338] (iv) a C2-C6 alkenyl substituted with an oxo group and a C1-C3 alkoxy group;

[0339] (v) a C1-C6 alkyl substituted with ═NH;

[0340] (vi) a C2-C3 alkenyl substituted with –OH;

[0341] (vii) a C8-C 12 alkenyl substituted with an oxo group and two C1-C3 alkoxy groups; and

[0342] (viii) an aralkyl comprising a C6-C8 alkyl and a C6 aryl, wherein the alkyl is substituted with an oxo group and the aryl is substituted with two alkoxy groups.

[0343] 11. The compound according to embodiments 8-10, wherein R2 is an alkoxy group.

[0344] 12. The compound according to embodiment 11, wherein R2 is a C1-C3 alkoxy group.

[0345] 13. The compound according to embodiment 12, wherein R2 is –OCH3.

[0346] 14. The compound according to embodiments 8-13, wherein R3 is an alkoxy group.

[0347] 15. The compound according to embodiment 14, wherein R3 is a C1-C3 alkoxy group.

[0348] 16. The compound according to embodiment 15, wherein R3 is –OCH3.

[0349] 17. The compound according to embodiment 8 or 9, wherein:

[0350] R1 is H;

[0351] R2 is C1-C3 alkoxy;

[0352] R3 is C1-C3 alkoxy; and

[0353] X is C6-C 10 alkenyl substituted with oxo, -OH or two C1-C3 alkoxy groups;

[0354] 18. The compound according to embodiment 8 or 9, wherein

[0355] R1 is H;

[0356] R2 is C1-C3 alkoxy;

[0357] R3 is C1-C3 alkoxy; and

[0358] X is C8-C 12 alkenyl substituted with oxo and C1-C3 alkoxy;

[0359] 19. The compound according to embodiment 8 or 9, wherein

[0360] R1 is OH;

[0361] R2 is C1-C3 alkoxy;

[0362] R3 is C1-C3 alkoxy; and

[0363] X is C4-C8 alkenyl substituted with two oxo groups.

[0364] 20. The compound according to embodiment 8 or 9, wherein

[0365] R1 is C1-C3 alkoxy;

[0366] R2 is OH;

[0367] R3 is C1-C3 alkoxy; and

[0368] X is C4-C8 alkenyl substituted with two oxo groups.

[0369] 21. The compound according to embodiment 8 or 9, wherein

[0370] R1 is H;

[0371] R2 is OH;

[0372] R3 is OH; and

[0373] X is C1-C6 alkyl substituted with =NH.

[0374] 22. The compound according to embodiment 8 or 9, wherein

[0375] R1 is OH;

[0376] R2 is C1-C3 alkoxy;

[0377] R3 is C1-C3 alkoxy; and

[0378] X is C2-C3 alkenyl substituted by OH.

[0379] 23. The compound according to embodiment 8 or 9, wherein

[0380] R1 is H;

[0381] R2 is C1-C3 alkoxy;

[0382] R3 is C1-C3 alkoxy; and

[0383] X is C8-C 12 alkenyl substituted by oxo and two C1-C3 alkoxy groups.

[0384] 24. The compound according to embodiment 8 or 9, wherein

[0385] R1 is OH;

[0386] R2 is C1-C3 alkoxy;

[0387] R3 is C1-C3 alkoxy; and

[0388] X is aralkyl containing C6-C8 alkyl and C6 aryl, wherein the alkyl is substituted by oxo and the aryl is substituted by two alkoxy groups.

[0389] 25. The compound according to embodiment 1, which has the structure of formula 2

[0390]

[0391]

[0392] or a pharmaceutically acceptable salt thereof;

[0393] wherein:

[0394] R1 is H or OH;

[0395] R2 is alkoxy or OH;

[0396] R3 is alkoxy or OH; and

[0397] R4 is C1-C 15 alkyl, C2-C 15 alkenyl, C2-C15 An alkynyl group or an aralkyl group, each of which is substituted by at least one alkoxy group, -OH or oxo.

[0398] 26. The compound according to embodiment 25, wherein R4 is selected from the group consisting of:

[0399]

[0400] 27. The compound according to embodiment 25 or 26, wherein R2 is an alkoxy group.

[0401] 28. The compound according to embodiment 27, wherein R2 is a C1-C3 alkoxy group.

[0402] 29. The compound according to embodiment 28, wherein R2 is -OCH3.

[0403] 30. The compound according to embodiments 25-29, wherein R3 is an alkoxy group.

[0404] 31. The compound according to embodiment 30, wherein R3 is a C1-C3 alkoxy group.

[0405] 32. The compound according to embodiment 31, wherein R3 is -OCH3.

[0406] 33. The compound according to embodiment 25 or 26, wherein

[0407] R1 is H;

[0408] R2 is an alkoxy group;

[0409] R3 is an alkoxy group; and

[0410] R4 is

[0411] 34. The compound according to embodiment 25 or 26, wherein

[0412] R1 is H;

[0413] R2 is an alkoxy group;

[0414] R3 is an alkoxy group; and

[0415] R4 is

[0416] 35. The compound according to embodiment 25 or 26, wherein

[0417] R1 is OH;

[0418] R2 is an alkoxy group;

[0419] R3 is an alkoxy group; and

[0420] R4 is

[0421] 36. A compound according to embodiment 25 or 26, wherein

[0422] R1 is OH;

[0423] R2 is an alkoxy group;

[0424] R3 is an alkoxy group; and

[0425] R4 is

[0426] 37. A compound according to embodiment 25 or 26, wherein

[0427] R1 is H;

[0428] R2 is an alkoxy group;

[0429] R3 is an alkoxy group; and

[0430] R4 is

[0431] 38. A compound according to embodiment 1, having the structure of formula 3

[0432]

[0433] or a pharmaceutically acceptable salt thereof,

[0434] wherein:

[0435] R1 is H, an alkoxy group or OH;

[0436] R2 is an alkoxy group or OH;

[0437] R3 is an alkoxy group or OH; and

[0438] R5 is C1-C 12 alkyl or C2-C 12 alkenyl, independently substituted with 1 or 2 substituents selected from the group consisting of =NH and oxo.

[0439] 39. A compound according to embodiment 38, wherein R5 is =NH.

[0440] 40. A compound according to embodiment 38 or 39, wherein R5 is in the ortho position to R2.

[0441] 41. A compound according to any one of embodiments 38-40, wherein R2 is OH.

[0442] 42. A compound according to any one of embodiments 38 - 41, wherein R3 is OH.

[0443] 43. A compound according to any one of embodiments 38 - 42, wherein R1 is H.

[0444] 44. A compound according to embodiment 38, wherein R5 is:

[0445]

[0446] 45. A compound according to embodiment 38 or 44, wherein R3 is an alkoxy group.

[0447] 46. A compound according to any one of embodiments 38, 44 or 45, wherein R3 is a C1 - C3 alkoxy group.

[0448] 47. A compound according to embodiment 38 or any one of 44 - 46, wherein R3 is -OCH3.

[0449] 48. A compound according to embodiment 38 or any one of 44 - 47, wherein R1 is an alkoxy group.

[0450] 49. A compound according to embodiment 38 or any one of 44 - 48, wherein R1 is a C1 - C3 alkoxy group.

[0451] 50. A compound according to embodiment 38 or any one of 44 - 49, wherein R1 is -OC2H5.

[0452] 51. A compound according to embodiment 38 or any one of 44 - 50, wherein R2 is -OH.

[0453] 52. A compound according to any one of embodiments 44 - 51, wherein R5 is in the para position to R1.

[0454] 53. A compound according to embodiment 1, which has the structure of Formula 4;

[0455]

[0456] or a pharmaceutically acceptable salt thereof;

[0457] wherein:

[0458] R1 is OH;

[0459] R2 is a C1 - C3 alkoxy group;

[0460] R3 is a C1 - C3 alkoxy group; and

[0461] R6 is C(CH2)OH.

[0462] 54. The compound according to embodiment 53, wherein

[0463] R1 is OH;

[0464] R2 is OCH3;

[0465] R3 is OCH3; and

[0466] R6 is C(CH2)OH.

[0467] 55. A pharmaceutical composition comprising the compound according to any one of embodiments 1 - 54 and a pharmaceutically acceptable carrier.

[0468] 56. A method for treating a chronic disorder in a patient in need thereof, the method comprising administering the compound according to embodiments 1 - 54 or the pharmaceutical composition according to embodiment 55.

[0469] 57. The method according to claim 56, wherein the chronic disorder is acute lymphoblastic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute myelogenous leukemia, adrenocortical carcinoma, AIDS-related lymphoma, anal cancer, appendiceal cancer, basal cell carcinoma, bladder cancer, brain cancer, brainstem glioma, breast cancer, bronchial adenoma / carcinoid tumor, Burkitt lymphoma, carcinoid tumor, cerebellar or cerebral astrocytoma, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia or chronic lymphoid leukemia, chronic myelogenous leukemia or chronic myeloid leukemia, chronic myeloproliferative disorder, colon cancer, cutaneous T-cell lymphoma, desmoplastic small round cell tumor, endometrial carcinoma, ependymoma, esophageal cancer, Ewing 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, glioma of the brainstem, hairy cell leukemia, head and neck cancer, heart cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, hypothalamic and visual pathway glioma, intraocular melanoma, islet cell cancer, Kaposi sarcoma, laryngeal cancer, leukemia, lip and oral cavity cancer, liposarcoma, lymphoma, male breast cancer, malignant mesothelioma, medulloblastoma, melanoma, Merkel cell skin cancer, mesothelioma, metastatic squamous neck cancer, oral cavity cancer, multiple endocrine neoplasia syndrome, multiple myeloma, multiple myeloma / plasmacytoma, mycosis fungoides, myelodysplastic / myeloproliferative disease, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-melanoma skin cancer, non-small cell lung cancer, oligodendroglioma, oral cavity cancer, oropharyngeal cancer, osteosarcoma and malignant fibrous histiocytoma, ovarian cancer, ovarian germ cell tumor, ovarian epithelial cancer (surface epithelial-stromal tumor), ovarian low malignant potential tumor, pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, nasopharyngeal cancer, pheochromocytoma, pineal astrocytoma, pineal germ cell tumor, pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary adenoma, plasmacytoma, pleuropulmonary blastoma, primary cancer, primary central nervous system lymphoma, primary liver cancer, prostate cancer, rectal cancer, renal cell cancer, renal pelvis and ureter cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Sézary syndrome, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, supratentorial primitive neuroectodermal tumor, testicular cancer, laryngeal 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 macroglobulinemia, Wilms tumor, Parkinson's disease and Parkinson disorder, Huntington's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Shy-Drager syndrome (Shy-Dragersyndrome), progressive supranuclear palsy, Lewy body dementia, spinal cord ischemia, spinal cord injury, ischemic stroke, cerebral infarction, spinal cord injury, and cancer-related brain and spinal cord injury, multi-infarct dementia, Alzheimer's disease, other cognitive impairments, depression, onychomycosis (of the nails Fungal infection https: / / en.wikipedia.org / wiki / Nail_(anatomy)), gingivitis and periodontal diseases (gum diseases), obesity, diabetes, SARS, COVID-19, or cancers with KRAS oncogene mutations.

[0470] 58. The method according to embodiment 56 or 57, wherein the chronic disorder is cancer.

[0471] 59. The method according to embodiment 58, wherein the cancer is colon cancer, prostate cancer, breast cancer, or leukemia.

[0472] 60. The method according to embodiment 58 or 59, wherein the cancer has a KRAS oncogene mutation.

[0473] 61. The method according to embodiment 56 or 57, wherein the chronic disorder is SARS or COVID-19.

[0474] Example

[0475] Example 1. Anti-cancer activity study (Figure 10)

[0476] The cell proliferation, apoptosis, and cell cycle arrest of the synthesized compounds of Formulas 1-4 were evaluated. The production of reactive oxygen species and calcium was measured using MTT assay and flow cytometry, respectively. The expression of apoptosis- and proliferation-related proteins was determined by Western blotting. The effect of the molecule on the expression of apoptosis-related mRNA in cancer cells was detected by RT-PCR.

[0477] The molecule induces apoptosis and cell cycle arrest in pancreatic cancer cell lines (PANC)

[0478] When pancreatic cancer cells (PANC) were treated with Compound I at different doses (1-100 μg / mL) for 24 and 48 h, cell viability was significantly reduced in a time- and dose-dependent manner. Compared with the standard 5-fluorouracil (10 μM) that showed a 30.21 ± 0.21% reduction in live cells at 3 h, exposure of PANC cells to 10 μg / mL resulted in a reduction of about 65.5 ± 0.88% in live cells. After 24 hours of exposure, the IC 50Values were 5.74 ± 0.02 μg / ml and 5.21 ± 0.19 μM for 5-FU. Most importantly, these molecules showed an 85.29% ± 0.98 increase in protection against normal pancreatic cells, with an IC 50 of 109.24 μg / ml, while 5-FU showed 40.32 ± 0.98% toxicity at 6 h. Changes in cell morphology were detected by cell membrane blebbing, chromatin condensation, and the formation of apoptotic bodies ( Figure 10A ).

[0479] In vitro studies showed that the disclosed compounds potentially target proteins involved in the G2 / M checkpoint ( Figure 10A and 10B ), as it has been shown to induce arrest in this checkpoint in breast, pancreatic, and other cancers, which prevents cells from passing through this checkpoint and entering mitosis.

[0480] Cell growth inhibition was demonstrated by inducing apoptosis through the intrinsic pathway (caspases 3 and 9) in a caspase-dependent manner, which led to subsequent loss of mitochondrial potential (ΔΨm) ( Figure 10B ), increased ROS production, and DNA damage, thus causing cell cycle arrest in the G0 / G1 phase in a dose- and time-dependent manner.

[0481] The novel molecules are 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, thus inducing mitotic arrest, altering the expression of cell cycle-related proteins, and disrupting microtubules.

[0482] Example 2. Molecules inhibit histone deacetylase (HDAC) activity

[0483] Next, the expression of class I HDACs during pancreatic tumorigenesis was detected. Briefly, different concentrations of Compound I were added and incubated for 24 h. Western blot analysis confirmed that the protein expression of class I HDACs was decreased in a dose-dependent manner compared to the control (p < 0.05). Compound I significantly inhibited HDAC1, HDAC2, HDAC3, and HDAC8 from class I. Collectively, these data suggest that the inhibition of class I HDACs by the molecule is sufficient to induce cell death in the PANC cell line. These results indicate that the molecule is an effective HDAC inhibitor. The inhibition of class I HDACs is associated with the upregulation of histone H3 acetylation and p21 mRNA and protein expression, which is related to anti-proliferative activity. It has also been reported that HDAC6 functions as an α-tubulin deacetylase, regulating tubulin stability. Since α-tubulin and histone H3 are common downstream targets of HDACs, the relationship between protein expression and molecular function was further investigated. The effect of Compound I on histone H3 acetylation in PANC cells was studied using Western blot analysis. Compared to the control group, Compound I induced stronger hyperacetylation of histone H3, which was consistent with its effective inhibitory effect on class I HDAC1, but acetyl-α-tubulin was not detected.

[0484] Mechanism of action ( Figure 11 )

[0485] Without being bound by any particular theory, the compounds disclosed herein may exhibit one or more of the following mechanisms of action:

[0486] ■ May induce cell cycle arrest and senescence changes, induce mitotic arrest, and alter the expression of cell cycle-related proteins, and disrupt microtubules by targeting STAT-3, β-catenin / Wnt signaling, MAPK, JAK-1 / 2 / 3, aurora kinase A.

[0487] ■ Cause loss of mitochondrial membrane potential, cytochrome c release, upregulation of Bax, downregulation of Bcl-2, and cleavage of caspase-3, thus showing activation of mitochondrial-mediated apoptosis.

[0488] ■ Multi-targeted kinase inhibitors inhibit the proliferation of a variety of human cancer cells and cancer stem cells in vitro and in vivo through multiple pathways.

[0489] ■ Histone deacetylase (HDAC) inhibitors and histone methyltransferase (HMT) inhibitors.

[0490] ■ Downregulate the levels of HDAC2 and HDAC3 at the mRNA and protein levels, and also have the potential to downregulate the level of KLF4, which plays an important role in stem cell formation.

[0491] ■Compared with the standard drug suberoylanilide hydroxamic acid (SAHA), the hTERT level was down-regulated.

[0492] To elucidate the potential mechanism of the anti-proliferative effect, the cell cycle distribution and apoptosis of PANC cells were investigated. Early apoptosis was observed as early as 6 hours by the binding of annexin V-fluorescein to the cell membrane. Compounds I-IX activated the intrinsic apoptotic pathway by inducing caspase-3 and caspase-9. The involvement of the intrinsic pathway in mitochondria could be seen, where mitochondrial permeability and cytochrome c release increased significantly, while the mitochondrial membrane potential decreased. Apoptosis was confirmed at the protein level, including Bax, Bcl-2, and survivin, and the disruption of the cell cycle was used for the final verification of apoptosis. Propidium iodide / annexin V double staining showed a pre-apoptotic cell population in cells treated with PANC at 3 h. In addition, we observed that fluorescence-activated cell sorting (FACS) analysis indicated that the molecular-induced cell cycle arrest was related to the regulation of important checkpoint control proteins p21 WAF1 / KIP1 , p27 KIP1 , p53, and cyclin A, resulting in G0 / G1 arrest in the PANC cell line, down-regulating the expression of cyclin D3, cyclin E1, CDK2, CDK4, and CDK6, and up-regulating the expression of p21, p27, and p53 via HDAC inhibition.

[0493] Example 3. Neurogenesis and neuronal development - Molecular-induced formation of neuronal cell types in human umbilical cord stem cells ( Figure 12 )

[0494] At the beginning of the induction, the HUMSC cultures phenotypically showed large and thin flat cell bodies with large nuclei. MSCs treated with the molecule showed morphological changes within 48–72 h. At this time, the MSC population showed spherical refractive cell bodies with dendritic processes and slender axon-like processes extending from the cell body, which are typical features of neurons. After 72 h of treatment, the proportion of neuron-like cells reached a peak, where the cell bodies shrank and the processes further extended. The MSCs maintained this morphology during the induction.

[0495] Example 4. KRAS degradation

[0496] In short, the present disclosure provides compounds capable of modulating G12C mutant KRAS proteins. In some cases, the compounds act as electrophiles and are capable of forming covalent bonds with cysteine residues at the positions of mutant proteins K-Ras4B G12C / G12D / G12V-GTP / GDP, K-Ras4B G13D-GTP / GDP, K-Ras4B Q61H-GTP / GDP. Methods of using such compounds to treat various diseases or disorders, such as cancer, are also provided. Additional mechanistic studies have shown that the compound AB-REV-001 can block the formation of guanosine triphosphate (GTP) with the KRAS complex in vitro. In addition, AB-REV-001 inhibits the KRAS downstream signaling pathways RAF / MEK / ERK and RAF / PI3K / AKT.

[0497] Example 5. Cancer Stem Cell Inhibition

[0498] Cancer stem cells (CSCs) are thought to exhibit unique self-renewal, proliferation, and differentiation capabilities and thus play important roles in all aspects of cancer. CSCs have important effects on tumor progression, drug resistance, recurrence, and metastasis in different types of malignancies. 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 due to their hypoxic microenvironment and location away from the vasculature, the effects of conventional therapeutic agents on CSCs are limited, which hinders the efficacy of anti-CSC drugs ( Figure 14 ). However, the disclosed compounds can overcome this limitation and can penetrate to deeper locations and disrupt CSCs. Thus, in an embodiment, the present invention provides a method of inhibiting cancer stem cell survival and / or self-renewal, comprising administering to the cancer stem cells an effective amount of a compound disclosed herein, such as compound I ( Figure 13 ).

[0499] Figure 17Describes the abnormal signal transduction pathways in CSCs and strategies for targeting CSCs. The signal transduction pathways of CSCs play important roles in self-renewal, drug resistance, tumor recurrence, and distant metastasis. Signal transduction pathways such as Notch, Wnt, and Hedgehog signaling, as well as downstream effectors, including transcription factor - catenin (-cat), signal transducer and activator of transcription 3 (STAT3), and Nanog, play key roles in CSC characteristics. After interacting with xCT, CD44 variant (CD44v) enhances glutathione synthesis and the ability to defend against reactive oxygen species (ROS). Due to this abnormal state, CSCs acquire a unique phenotype. The best way to eradicate CSCs is to identify the molecules responsible for the specific characteristics of CSCs rather than those of normal cells. Target 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).

[0500] It has been demonstrated that the compounds of the present disclosure selectively target cancer stem cells in the tumor microenvironment and disrupt CSCs by regulating genes involved in self-renewal and differentiation. The compounds of the present disclosure inhibit the expression of genes in the following cancers ( Figure 18 ):

[0501] Breast cancer: CD44+CD24- / low lineage-, ALDH-1 high

[0502] Liver cancer: CD133+, CD49f+, CD90+

[0503] Colorectal cancer: CD133+, CD44+, CD166+, EpCAM+, CD24+

[0504] Pancreatic cancer: CD133+, CD44+, EpCAM+, CD24+

[0505] Leukemia: CD34+CD38-

[0506] Lung cancer: CD133+, ABCG2 高

[0507] Leukemia: CD34+, CD38-, HLA-, DR-, CD71-, CD90-, CD117-, CD123+

[0508] A decrease in the expression of stem cell surface markers is visible within 1 hour and up to 15 hours. No cancer stem cell markers were observed after 24 hours of treatment compared to other standard drugs.

[0509] Example 6: In vitro cancer research with Compound I

[0510] Chemotherapy is a drug treatment that uses powerful chemicals to kill rapidly growing cells in the body. However, the treatment exhibits adverse side effects, which can range from simple gastritis and hair loss to severe bone marrow suppression, cardiotoxicity, etc. In terms of cytotoxicity, the effects of combining Compound I of the present invention with chemotherapy drugs were studied. As detailed below, if cells are treated with Compound I of the present invention before the chemotherapy drug, the cytotoxicity of the chemotherapy drug (e.g., docetaxel, paclitaxel, Pazobanib, Endoxon, etoposide, doxorubicin, Dacromycin, Avastin, gemcitabine, cisplatin, and oxaliplatin) is significantly reduced.

[0511] The cytotoxicity of anticancer agents was studied using a set of separate human normal cell lines and in combination with Compound I of the present invention. The cytotoxic effects were 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 hepatocytes (THLE2), human cardiomyocytes (AC-16), human intestinal epithelial cells (HIEC-6), human neuronal cells (SHSY-5Y), human vascular endothelial cells (HuVEC), human lung epithelial cells (Calu-3), human lung fibroblasts (MRC 5).

[0512] According to the data, after treatment with anticancer agents at different concentrations (1 - 500 μM), compared with the control, the normal cells were significantly reduced (p > 0.05), and morphological changes were observed. The IC50 values of doxorubicin, Gemicitanib, 5-FU, cisplatin, Lenolidamide, irinotecan, chloroquine, hydroxychloroquine, vincristine, and vinblastine were found to be from 12.90 μM - 40.50 μM( Figure 19 A). Compared with the negative control, a significant level of apoptosis was observed in all treated normal cell lines, which shows its unique characteristics.

[0513] Next, cells were treated with an anticancer agent in combination with Compound I of the present invention. After the combination treatment, an increase in cell viability was observed, and no signs of cell rounding, granulation, and cell shrinkage were observed, indicating that treatment of normal cells with Compound I reduced the toxic effects induced by the anticancer agent. It was found that the IC50 increased compared to treatment with the anticancer agent alone. The average treatment in all cell lines showed an IC50 > 100 μM, which shows the cytoprotective effect of Compound I( Figure 19B). No significant apoptosis was observed in the combination study, indicating that Compound I reduced the cytotoxicity produced by chemotherapeutic agents. Even at the highest concentration, no significant cytotoxic effect was observed in normal cell lines.

[0514] Example 7: In Vivo Cancer Study with Compound I

[0515] Metastasis research

[0516] In vivo studies showed that tumor growth could be inhibited in a xenograft nude mouse model with an improved therapeutic window compared to standard drug therapy. Notably, no tumor recurrence or relapse was observed in the follow-up study after 6 months.

[0517] Compared to other standard drugs, the compounds of the present disclosure showed in vivo efficacy with 90% TGI (tumor growth inhibition) in triple-negative breast cancer, pancreatic cancer model, liver cancer model, and colon cancer model, without any mortality growth inhibition ( Figure 20 ).

[0518] In addition, compared to gemcitabine and 5-fluorouracil treatments, the compounds of the present disclosure significantly disrupted the surrounding ECM tissue, resulting in increased quiescence, apoptosis, enhanced chemosensitivity, reduced invasiveness, decreased metastatic spread, and a 6-fold reduction in in vivo tumor volume and cancer progression.

[0519] When the compounds of the present disclosure were administered singly in combination with a standard drug regimen, further anti-cancer effects were demonstrated, showing a significant inhibition of in vivo tumor recurrence.

[0520] Pancreatic cancer xenograft model (PANC-1)

[0521] Study Design: A PANC-1 xenograft mouse model was conducted according to the experimental design described in A of Figure 21 . Tumor volume was monitored for 30 days after single administration of PBS (vehicle control), 25 mg / kg gemcitabine, and 10 mg / kg Compound I.

[0522] Results: As shown in B of Figure 21 , from day 5 to day 30, the tumor volume steadily increased in mice (n = 12) treated with 25 mg / kg gemcitabine. In contrast, the tumor volume decreased in mice treated with 10 mg / kg Compound I during the same period. This result was confirmed by imaging studies, showing no tumor detected in mice treated with Compound I ( Figure 21 C).

[0523] The reduction in tumor volume was converted to an increased survival rate in mice treated with Compound I ( Figure 21 D).

[0524] Comparison with standard drugs

[0525] Compared with the current standard-of-care drugs (Table 1 below): Revlimid, Avastin, Herceptin, 5-fluorouracil, and gemcitabine, the compounds of the present disclosure are up to 50 times more effective in reducing the number of tumor spheres and up to 100 times more effective in reducing the CSC population and preventing tumor recurrence.

[0526] Compared with standard drugs for treating stage IV cancer such as Revlimid (100% mortality), Avastin (60% mortality), Herceptin (60% mortality), 5-fluorouracil (70% mortality), and gemcitabine (50% mortality), no significant toxicity and mortality were observed in vital organs.

[0527] Furthermore, when administered in combination with standard drugs, the compounds of the present disclosure reduce mortality and enhance the sensitivity to tumor cells, thereby improving the therapeutic effect.

[0528] Table 1: 9 Breakthrough Small Molecules vs. Standard Drugs

[0529]

[0530] Downregulation of metastatic genes and signaling pathways

[0531] Compared with 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.

[0532] Without being bound to any particular theory, the multi-tyrosine kinase inhibitors can induce apoptosis and inhibit the invasion of cancer cells by inhibiting activated NF-κB, Akt, ERK2, Tyk2, and PKC. Without being bound to theory, these compounds also attenuate migration and invasion by inhibiting the PI3K / Akt / mTOR signaling pathway. Without being bound to any particular theory, the compounds effectively inhibit metastasis, angiogenesis, and cancer cell invasion via ERK1 / 2-, Akt / NF-κB / mTOR-, and p38 MAPK-dependent NF-κB signaling pathways.

[0533] Regulation of epithelial-mesenchymal transition (EMT)

[0534] All nine compounds disclosed herein inhibit tumor growth in xenograft mouse models and modulate the expression of mesenchymal and epithelial markers. They repress the expression of mesenchymal genes such as fibronectin, vimentin, N-cadherin, TWIST, and SNAIL, and increase the expression of epithelial genes such as occludin and E-cadherin via specific targeting of the canonical WNT / β-catenin / Hedgehog and TGFβ / BMP-SMAD pathways.

[0535] Immunomodulation

[0536] 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 the conversion of APCs to CD4+ and CD8+ by capturing, internalizing, processing, and presenting tumor antigens via class I and class II MHC molecules.

[0537] In vivo tumors treated with the molecules further showed reduced ECM deposition and impaired CD31 + Endothelial cells, α-SMA + Cancer-associated fibroblasts, and F4 / 80 + Infiltration of macrophages, indicating that the treatment produced a suppressive tumor microenvironment, which in turn inhibited tumor growth, invasion, and metastasis.

[0538] Example 8: Targeting lung cancer stem cells

[0539] Compound I has a significant effect on targeting specific lung cancer stem cells and induces apoptosis and inhibits metastasis without damaging normal cells, which contributes to cancer therapy. Compound I is an orally bioavailable multi-tyrosine-kinase inhibitor with 120 target proteins, which induces apoptosis and inhibits the invasion of lung cancer stem cells without toxicity to normal cells. During the entire study period, no discomfort or signs of any cardiovascular or respiratory disorders were observed in the animals after administration.

[0540] Example 9: Compounds of the present disclosure as inhibitors of ACE-2 and Nsp15

[0541] Objective: To determine whether the compounds of the present disclosure (e.g., Compound I) are potential inhibitors of ACE-2 and Nsp15, which are proteins responsible for the entry and replication of viruses such as SARS-CoV-2 in human cells.

[0542] Background: To infect a human host, a virus must be able to enter individual human cells. The virus uses the host cell machinery to produce copies of itself, which then spill over and spread to new cells. Studies have shown that SARS-CoV-2 attaches to target cells through the interaction between its spike protein (S) and the host cell protein angiotensin-converting enzyme-2 (ACE-2, a transmembrane enzyme found on the cell surface). This interaction on the host cell surface is very important because it initiates the infection process ( Figure 22 ). Therefore, drugs that modulate the biological activity of ACE-2 are considered potential candidates for treating this viral infection.

[0543] Another protein identified from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that may play a role in viral progression is Nsp15 ( Figure 22 ). Nsp15 has 89% identity with the protein of the early outbreak of SARS-CoV. Analysis of SARS-CoV has shown that inhibition of Nsp15 can slow down viral replication. The newly mapped protein is conserved in coronaviruses and is essential in its life cycle and virulence. Initially, Nsp15 was thought to be directly involved in viral replication, but it has recently been proposed that it may help viral replication by interfering with the host's immune response.

[0544] Results: To evaluate the potential of the compounds of the present disclosure to target ACE-2 and Nsp15, studies were conducted using in silico methods and molecular docking. From these analyses, it was found that Compound I has a high binding affinity for all the tested viral proteins ( Figure 22-2 4). Specifically, Figure 21 the affinity of Compound I for the ACE-2 binding site was shown, which leads to the disruption of the interaction between the virus and the receptor. It was also found that Compound I has an affinity for the Nsp15 binding site, as shown in Figure 24A -C.

[0545] Summary: The present disclosure provides small molecule inhibitors that target S-ACE-2, which mediates the entry of SARS-CoV-2 into human cells. In addition, the compounds of the present disclosure also target Nsp15, which can slow down viral replication. Therefore, the compounds of Formulas 1-4 have the potential to be developed into effective drugs against COVID-19.

[0546] Example 10: In vitro antiviral activity of Compound I in Vero cells

[0547] Study design: Standard assays were performed to measure the effects of Compound I on the cytotoxicity, virus yield, and infection rate of SARS-CoV-2 ( Figure 25)。First, the cytotoxicity of Compound I was tested on Vero cells. Then, in the presence of different concentrations of Compound I, Vero cells were infected with SARS-CoV-2( Figure 25 isolate A) at a multiplicity of infection (MOI) of 0.1 PFU / cell, with DMSO used as a vehicle. The efficacy was evaluated by quantifying the viral copy number in the cell supernatant via quantitative real-time RT-PCR (qRT-PCR), and the visualization of viral nucleoprotein (NP) expression was confirmed by immunofluorescence assay 48 h post-infection (p.i.)( Figure 25 isolate C). In addition, after infection, the cells were exposed to the test compound to further evaluate its potential as a prophylaxis and treatment against coronaviruses. The protective effect of Compound I in the lung epithelial (Calu-3) cell line was also evaluated.

[0548] 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 h( Figure 25 isolate B), followed by the addition of different concentrations of Compound I (0.001 μM, 0.01 μM, 1 μM, 3 μM, 5 μM, respectively). Based on the evaluation of the data obtained from the dose-response curve, it was found that Compound I effectively exhibited antiviral activity, with an IC50 of 1 μM( Figure 25 isolate B, blue line, representing the average % inhibition of the virus), and a CC50 of >15 μM( Figure 25 isolate B, red line, representing the cytotoxicity of the drug).

[0549] To further determine the effectiveness of Compound I, cells infected with SARS-CoV-2 were treated with serial dilutions of Compound I, and the supernatant and cell pellet were collected 2 h post-infection for real-time RT-PCR( Figure 25 isolate F- Figure 25 isolate H).

[0550] At 24 h, compared with the vehicle DMSO, the viral RNA (indicating released virions) present in the supernatant of the samples treated with Compound I was reduced by 100%. Similarly, a 99% reduction in cell-associated viral RNA was observed with Compound I treatment (indicating unreleased and unpackaged virions). At 36 h, this effect increased to a reduction in viral RNA in the Compound I treatment, which showed statistical significance when compared to the control samples, indicating that Compound I treatment led to an effective loss of essentially all viral material at 36 h.

[0551] At 48 h, a decrease in viral RNA was observed in both the supernatant and cell pellet of the samples treated with 1 μM Compound I, corresponding to a 99% decrease in viral RNA in these samples compared to the control samples. Similarly, no toxicity was observed with Compound I at any of the tested concentrations.

[0552] After treatment with Compound I, immunofluorescence microscopy of virus-infected cells was performed. Specifically, Vero cells were infected with SARS-CoV-2 at an MOI of 0.1 and treated with 1 μM and 1 μM of Compound I. At 48 h p.i., the infected cells were fixed and then probed with rabbit serum against the NP of SARS-related CoV as the primary antibody and Alexa 488-labeled goat anti-rabbit IgG as the secondary antibody, respectively. The cell nuclei were stained with Hoechst dye. Scale bar, 20 μm. The staining results showed that the viral load measured by nucleoprotein expression was significantly reduced in Vero cells treated with either dose of Compound I ( Figure 25 Panel C). These results were confirmed by Western blot analysis of the infected cells at 24 h p.i. ( Figure 25 Panel D) and quantified by normalization to GAPDH ( Figure 25 Panel E).

[0553] Example 11: In vitro activity of Compound I in lung epithelial cells

[0554] The antiviral activity of Compound I against SARS-CoV-2 was re-evaluated in Calu-3 cultures. A dose-dependent decrease in replication was observed at 0.1 - 5 μM, and the mean IC50 value was 0.01 μM (SARS-CoV-2) as compared to untreated controls. To determine whether Compound I was able to inhibit replication, we first evaluated the antiviral activity and cytotoxicity in the continuous human lung epithelial cell line, Calu-3 cells. Compound I inhibited SARS-CoV-2 replication in the cells with a mean half-maximal effective concentration (IC50) value of 1.5 μM ( Figure 25 Panel B). Importantly, we did not observe any cytotoxicity at concentrations up to 100 μM, thus demonstrating that the 50% cytotoxic concentration (i.e., CC50) of Compound I in Calu-3 cells exceeded 100 μM. Collectively, these results suggest that substantial inhibition of SARS-CoV-2 replication will be achieved at low micromolar concentrations in lung epithelial cells.

[0555] Example 12: Effect of Compound I on the viral infection stage

[0556] It is hypothesized that compound I inhibits early replicating SARS-CoV-2 by inhibiting viral RNA synthesis. To test this hypothesis and determine at which stage of the viral replication cycle compound I inhibits SARS-CoV-2, Vero cells were infected with a multiplicity of infection (MOI) of 0.1 PFU / cell, resulting in a single-cycle infection, and were treated with 1 μM compound I at 2-h intervals from 2 h before to 10 h after infection. Maximum inhibition was observed when compound I was added between 2 h before and 2 h after infection. Less inhibition was detected when compound I was added between 6 and 8 h after infection, and no inhibition was observed when compound I was added 10 h after infection. These results demonstrate that compound I inhibits SARS-CoV-2 in the early stage of infection. Since viral RNA is synthesized in the early stage of infection and compound I is associated with the inhibition of viral RNA synthesis, the cellular level of viral RNA was next determined by real-time quantitative PCR (qPCR) after treatment with compound I. Treatment with increasing concentrations of compound I led to a decrease in the viral RNA level, which was observed to be associated with a decrease in the titer. These results suggest that compound I inhibits SARS-CoV-2 in the early post-infection period by interfering with viral RNA replication.

[0557] In a normal epithelial cell SARS-CoV-2 infection model of human lung epithelial cells (calu-3 cell line), compound I was studied to observe whether it could also inhibit SARS-CoV-2 replication in human cells. These results showed that compound I was able to inhibit SARS-CoV-2 replication at the same concentration as in Vero cells (IC50 10 μM compound I-treated cells = <102 TCID50 / ml), indicating that the antiviral activity of compound I is not cell-type dependent ( Figure 26 of A). As for other coronaviruses, the expression of the SARS-CoV genome is mediated by the translation of genomic RNA and a set of “nested” subgenomic messenger RNAs, which are generated by a unique mechanism involving discontinuous transcription during RNA synthesis. To determine whether compound I acts by blocking viral RNA synthesis in the case of SARS-CoV-2, Calu-3 cells were infected with SARS-CoV-2 shortly after the viral adsorption period and were treated with different concentrations (1.5 and 10 μM) of compound I. Total RNA was extracted 24 h post-infection (p.i.) and analyzed by RT-PCR. As Figure 26As shown in B of , treatment with Compound I led to a dose-dependent decrease in intracellular SARS-CoV-2 RNA levels, achieving more than 95% inhibition over the control at a concentration of Compound I that did not affect RNA synthesis in uninfected cells. Viral genomic RNA was quantified by quantitative reverse transcription polymerase chain reaction (qRT-PCR) in the clarified supernatant. As with the effect on the infectious titer, a dose-dependent decrease was found in viral genomic RNA, and the IC50 was similarly calculated to be 5 μM. Overall, these data demonstrate that Compound I has effective antiviral effects against two genetically distinct emerging CoVs.

[0558] Example 13: Immune Response of the Compounds of the Present Disclosure

[0559] Compound I has the ability to activate CD4+ helper T cells and CD8+ cytotoxic T cells and generate an immune response in vivo to defend against viral infection. Specifically, Compound I increased the number and activity of cytotoxic T cells and promoted the activation of macrophages, NK cells, and DCs, which promoted the conversion of APCs to CD4+ and CD8+ via the capture, internalization, processing, and presentation of antigens through class I and II MHC molecules.

[0560] Example 14: Proposed Mechanism of Action in the Lung

[0561] In a xenograft animal model of stage 4 metastatic breast cancer, Compound I reduced the production of cytokines (tumor necrosis factor α [TNF-α] and interleukin-6 [IL-6]) and chemokines (CXCL10, CCL2, CCL3, CCL5), and was associated with the migration of natural killer cells and macrophages and was observed in the lung. From the data collected in the QPCR gene expression study, on day 7, histopathological evidence showed normal lung pathology, no pneumonia was observed, and a decrease in the expression of cytokines (TNF-α, IL-6, interferon γ [IFN-γ], IL-2, and IL-5), chemokines (CXCL9, CXCL10, CCL2, CCL3, and CCL5), and receptors (CXCR3, CCR2, and CCR5) was detected in the lung, which was associated with the influx of T lymphocytes. No signs of clinical disease and histopathological evidence of diseases characterized by bronchiolitis, interstitial pneumonia, diffuse alveolar damage, and fibrotic scars were observed.

[0562] Example 15: Enhancement of Hydroxychloroquine by Reducing Side Effects in COVID-19 Treatment

[0563] Coronavirus disease (COVID-19) is an infectious disease caused by the virus SARS-CoV-2. This disease causes respiratory illness, the symptoms of which include coughing, fever, and in more severe cases, difficulty breathing. Currently, a drug that may be effective in treating COVID-19 is hydroxychloroquine. However, hydroxychloroquine drugs can cause severe side effects, including cardiovascular diseases, eye damage, mild or severe bronchospasm, and can also affect mental health. The effect of the 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 the compound I of the present invention helps to enhance hydroxychloroquine by reducing side effects in the treatment of COVID-19 ( Figure 20 and 21 ).

[0564] Example 16: Pharmacokinetics (PK), Tissue Distribution and Toxicity

[0565] The pharmacokinetics and toxicity of compound I in vivo were studied in a nude mouse model

[0566] PK research :

[0567] Data analysis showed that the average plasma concentration of compound I was significantly higher than that of the control group during the entire 6 h sampling period. After intravenous administration, compound I was widely distributed in several tissues, including the hippocampus, heart, lung, stomach, liver, mammary gland, kidney, spleen, femur, and tibia ( Figure 27 of A- Figure 27 of B). Compared with the control group, the maximum plasma concentration (Cmax) of the treatment group increased by 29-fold, and the area under the curve (AUC) increased by 28-fold (p>0.05).

[0568] Notably, compound I was widely distributed in several organs, and especially those with high porosity, which is consistent with its pharmacodynamic activity in these organs. In addition, when compared with the control, it was found that the distribution volume of compound I was significant after IV administration, which means good tissue distribution. The tissue distribution in the current study showed that compound I reached appropriate pharmacodynamic activity levels in the hippocampus, femur, tibia, and mammary gland at 10 mg / kg IV, which is relevant to the prevention and treatment goals of neurodegenerative diseases and other chronic diseases ( Figure 27 of B). No toxicity was observed.

[0569] At 1 h, 2 h, 4 h, and 24 h after administration, the tissue-to-plasma ratio of Compound I was recorded in animals. At 60 min, the highest levels of Compound I were found in the lung, brain, stomach, liver, mammary gland, and small intestine, all of which are highly perfused organs, followed by the spleen and heart. Compound I was detected in most organs until 72 h, but not in the femur and kidney. The ratio in most organs continued to increase up to 4 h. Interestingly, from 1, 2, and 24 h after dosing, the tissue-to-plasma ratio of Compound I in the hippocampus and brain increased significantly and continuously. No discomfort or any signs of cardiovascular or respiratory disorders were observed in the animals after administration and throughout the study period. The monitored body weight did not change during the 7-day period after drug administration.

[0570] PK Results: Pharmacokinetic studies conducted with the compounds disclosed herein revealed prolonged persistence in the systemic blood circulation, and no renal toxicity, cardiotoxicity, and hepatotoxicity were observed compared to other standard drugs that showed severe cardiotoxicity, hepatotoxicity, gastrointestinal toxicity, and respiratory disorders.

[0571] Summary: When compared to the administration of standard drugs, the novel molecules of the present disclosure showed enhanced pharmacokinetics, biodistribution, and tolerance. In vivo biodistribution studies showed that the accumulation of the novel molecules in tumors of the animal model was significantly higher than that in other organs analyzed (P < 0.01).

[0572] Acute oral toxicity study :

[0573] Experimental Design: Acute toxicity assays were conducted according to the Organization for Economic Co-operation and Development (OECD) Guideline 423 (OECD, 2001a). A total of 60 mice with body weights between 27 and 37 g were randomly divided into six experimental groups of 10 mice each (5 males and 5 females per group). After an overnight fast, Compound I was administered to each treatment group as a single dose of 200 mg / kg, 500 mg / kg, 1000 mg / kg, or 2000 mg / kg by oral gavage. The control group was treated with the same volume of distilled water. After dosing, all animals were observed for mortality and changes in general behavior during the initial 30 min, and then at 2 h, 4 h, 6 h, 10 h, and 24 h after treatment. Toxicity symptoms such as hypoactivity, piloerection, dyspnea, tremors, and convulsions were evaluated after the administration of different doses. The LD50 value was determined according to the method described in OECD Guideline 423 (OECD, 2001a). During the remaining experimental period, the animals were observed at least once a day during the 14-day post-dosing period. Body weights were measured at the start of treatment and on days 4, 7, 11, and 14 after administration. On day 14, the mice were sacrificed under anesthesia, and the vital organs (heart, kidney, lung, spleen, and liver) were removed for macroscopic examination.

[0574] Sub-toxicity study :

[0575] Experimental design: A subchronic toxicity study was conducted according to the OECD test guideline 408 (OECD, 2008) for the test chemical. A total of 48 male and female Wister rats with body weights between 170 and 240 g were randomly divided into four groups (n = 6 males and 6 females / group). Rats in the treatment groups received compound I orally at doses of 200 mg / kg / day, 500 mg / kg / day, 1000 mg / kg / day, 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 administered orally with the same volume of distilled water (vehicle). During the experiment, the body weights of all groups were measured once a week. The mortality, changes in behavioral patterns, changes in physical appearance, and disease symptoms of the animals were also visually observed. At the end of the treatment period, all rats were fasted overnight (12 h–16 h) and then anesthetized with urethane by intraperitoneal injection (1 mL / 100 g body weight). Blood samples were collected for the measurement of hematological (EDTA-2K coated tubes) and biochemical (dry tubes) parameters. After euthanasia, the rats were sacrificed and the organs were removed for autopsy, organ weight measurement, and histopathological examination.

[0576] Urinalysis: Urinalysis was performed in all rat groups during the last week of the treatment period. Fresh urine was collected from all animals overnight to determine the levels of specific gravity, pH, white blood cells, nitrite, protein, glucose, ketone, blood, urobilinogen, and bilirubin. Urine samples were analyzed using an automated urinalysis analyzer and test strips.

[0577] Hematology and Serum Biochemistry: For hematological studies, all animals were fasted overnight but allowed free access to water. The rats were then anesthetized and blood samples were collected from the abdominal aorta. Whole blood was collected in EDTA tubes (containing potassium salt of ethylenediaminetetraacetic acid) and immediately processed for hematological analysis. The parameters measured 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. To measure biochemical parameters, the dry tubes containing the collected blood were centrifuged at 3000 rpm for 15 min at 5 °C to obtain serum. Serum samples were analyzed using an automated biochemical analyzer. Clinical biochemical 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). Serum electrolytes such as calcium (Ca2+) + ), sodium (Na + ), potassium (K ˉ ) and chloride (Cl

[0578] were also determined.

[0579] Autopsy and Organ Weights: Gross autopsy was performed on all rat groups, including examination of thoracic organs, external surface organs, and all internal organs. Careful macroscopic examination of the vital organs was carried out to detect any type of abnormality. Thereafter, various organs (including heart, liver, kidney, stomach, lung, spleen, adrenal gland, thymus, epididymis, testis, uterus, and ovary) were surgically removed, washed 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) ÷ Body weight of the rat on the day of sacrifice (g)] × 100.

[0579] Histopathology: The main organs (lungs, heart, liver, kidneys) and reproductive organs (testes and ovaries) were removed for histopathological examination. After weighing, the organs were quickly fixed in 10% buffered formalin (pH 7.4). After fixation, the tissue specimens were dehydrated in a graded series of ethanol (70%-100%), rinsed in toluene, and finally embedded in paraffin. Thereafter, 5-μm-thick sections were prepared using a microtome (Leica) and stained with hematoxylin and eosin (H&E) before microscopic examination. The microscopic features of the organs of the treatment group were compared with those of the control group, and micrographs were recorded.

[0580] Statistical analysis: All data were expressed as mean ± standard deviation (SD). Statistical significance between the control and treatment groups was determined by one-way analysis of variance (ANOVA), followed by Dunnett's post hoc test. GraphPad Prism version 6.0 for Windows was used for statistical analysis. Data analysis from the male and female groups was performed separately, and differences were considered statistically significant at p < 0.05.

[0581] Toxicity results:

[0582] General signs and behavioral analysis

[0583] ■ Clinical signs and symptoms are important observational indicators for monitoring the toxic effects of drugs on organs (Jothy et al., 2011). In our current study, in the acute and subacute toxicity studies of a specific oral dose of Compound I, no treatment-related deaths were observed in animals of either sex.

[0584] ■ During the 14-day (acute) and 28-day (subacute) observation periods, the animals did not show any adverse changes in body behavior, food, and water consumption.

[0585] ■ No obvious or gross abnormalities were observed in all animals in both groups (acute and subacute toxicity). Therefore, the median lethal dose (LD50) of the drug can be considered to be greater than 2,000 mg / kg.

[0586] ■ According to the Globally Harmonized Classification System (GHS), substances with an LD50 > 2,000 mg are considered relatively safe (Miyagawa, 2010). Therefore, according to the GHS, Compound I can be classified as Category 5.

[0587] Effect of Compound I on body weight and organ weight ( Figure 28 of A- Figure 28 of E)

[0588] ■ Exposure to potentially toxic drugs will lead to a sharp decline in the body weight of rats (Teo et al., 2002). Changes in body weight and relative organ weight are indicators for the toxicity and health assessment of experimental animals (Piao et al., 2013).

[0589] ■ The body weights of rats in the control group and the treatment group are as Figure 28 shown in Figure 28 E of

[0590] . In this study, all rats in each dose group showed continuous body weight gain during the experiment, indicating that Compound I did not cause any harmful effects on body weight in the acute and subacute toxicity groups.

[0590] ■ In addition, there was no significant difference in the percentage of body weight gain compared between the treatment group and the control group.

[0591] Relative organ weight (ROW)

[0592] ■ The relative organ weights (ROW) of the liver, brain, kidney, heart, and spleen in two tests are shown. When evaluated against the control group, the differences in ROW between the control group and the treatment group were statistically significant.

[0593] ■ No significant changes were observed in all organs, so it can be determined that the administration of Compound I did not cause any side effects on vital organs.

[0594] Effect of Compound I on food and water intake.

[0595] ■ The figure depicts the effect of Compound I on food and water intake in subacute treatment.

[0596] ■ When compared with the control group, single daily administration of Compound I at the study dose for 28 days resulted in no significant changes in food and water intake (P>0.05).

[0597] Effect of Compound I on hematological parameters ( Figure 28 shown in Figure 28 F to

[0598] I of

[0598] ).

[0599] ■The reference values of RBC, WBC, PCV, MCH, and MCHC are 7 - 10×10^6 / μl, 6 - 18×10^3 / μl, 35% - 64%, 14.3 - 19.5 pg, and 26.2 - 40 g / dl, respectively. In the current study, when compared with the control group, the mean values of hematological parameters in both groups (acute and subacute toxicity studies), such as WBC, RBC, PCV, and hemoglobin in the treatment group, did not show significant changes (Loha et al., 2019).

[0600] ■This result indicates that Compound I may not have any toxic substances that can cause conditions such as anemia or other abnormalities.

[0601] ■An increase in the release of WBC is an obvious biomarker of stress and also helps to protect the body against some inflammatory conditions, such as bacterial infections, leukemia, and massive bleeding.

[0602] ■The results obtained from this study indicate that, relative to the control group, Compound I did not cause any significant changes in the WBC count level or its subtypes (including neutrophils, lymphocytes, monocytes, and eosinophils) at any dose. This suggests that Compound I is non-toxic.

[0603] The effect of Compound I on biochemical parameters ( Figure 28 of L- Figure 28 of Q)

[0604] ■Biochemical evaluation is crucial for assessing the safety of drugs on liver and kidney functions. Data on biochemical parameters for the control and treatment groups are presented in Figure 28 of L- Figure 28 of Q. In this study, all measured biochemical parameters in the acute and subacute study groups did not show any significant changes.

[0605] ■In the current work, the potential hepatotoxicity of Compound I was evaluated by measuring the enzyme activities of aminotransferases (ALAT and ASAT) - see Figure 28 of L- Figure 28 of M.

[0606] ■Abnormal elevations in aminotransferase activities (ALAT and ASAT) are often associated with hepatotoxicity [Fortson et al., 1985].[[]END]]

[0607] ■The results indicate that, when compared with the control group, the biochemical parameters of the treatment group with the highest dose (2000 mg / kg body weight) reached were not directly affected (p > 0.05).

[0608] ■These findings are consistent with the findings of acute toxicity, which showed no clinical symptoms or behavioral changes in mice treated with similar doses.

[0609] ■ However, when compared with the control group, there was no effect on the aminotransferase activity in the treatment group (p > 0.05).

[0610] ■ In both sexes of the animals, at the doses of 200 mg / kg, 500 mg / kg, 1000 mg / kg and 2000 mg / kg, the plasma level changes of AST, ALT, and ALP activities were not significant, which clearly indicated that Compound I did not cause damage to the liver.

[0611] Renal function tests ( Figure 28 of J - Figure 28 of K)

[0612] ■ The potential toxic effects of the drug on renal function were also evaluated by measuring the urea and creatinine concentrations, as any significant changes in these parameters may be involved in induced nephrotoxicity [Mukinda et al., 2010; Gnanamani, A et al., 2008].[[]END]]

[0613] ■ The retention of creatinine, electrolytes, urea, and uric acid in the body is an indicator of renal damage. Changes in the levels of some electrolytes (such as Na+, K+, Cl−, and Mg2+) can also be signs of kidney injury.

[0614] ■ Our findings showed that when compared with the control group, in both sexes of rats, at all doses, there were no significant differences in the levels of creatinine, electrolytes, urea, or uric acid, and Compound I also had no effect on serum electrolytes (Na+, Ca2+, Mg2+, and Cl−). ( Figure 28 of J - Figure 28 of K).

[0615] ■ In addition, when compared with the control group, there were no significant differences in the levels of total protein, albumin, conjugated bilirubin, and bilirubin.

[0616] ■ This provided further support for the safety of Compound I at these doses, as renal function was not altered.

[0617] Histopathological studies ( Figure 29 of A - Figure 29 of B)

[0618] ■ On the last day of the treatment period, histopathological analyses were performed on organ samples of the liver, kidney, pancreas, heart, lung, stomach, and reproductive organs of male and female rats, and the results of some of these tissues were tabulated in Figure 29 of A - Figure 29 of B.

[0619] Liver cancer:

[0620] ■ In the compound I treatment group, multiple sections of the livers of male rats showed normal hepatocytes as well as normal portal triads, sinusoids, and central vein systems.

[0621] ■ Sections of the livers of female rats from the treatment group showed nearly normal cellular architecture and normal hepatocytes. There were also portal triads of normal appearance, including branches of the hepatic portal vein, interlobular bile ducts, and hepatic arteries. Sections of the livers of male and female rats from the control group showed normal hepatic architecture.

[0622] Kidney:

[0623] ■ Multiple sections taken from renal biopsies of male and female rats in the treatment group showed nearly normal size and shape of glomeruli, tubules, loops, and blood vessels.

[0624] ■ There was no strong evidence of acute tubular necrosis and glomerular changes in the compound I treatment group. Sections of renal biopsies of male and female rats in the control group showed normal findings.

[0625] Pancreas (not shown):

[0626] ■ Sections of the pancreases of male and female rats in the control treatment group showed normal architecture, while in the compound I treatment group, few abnormalities were observed in the architecture of pancreatic acini and islets of Langerhans.

[0627] Heart:

[0628] ■ Sections of the hearts taken from male and female rats were normal in rats in the control treatment group as well as in rats treated with compound I. However, no significant changes were observed in male rats.

[0629] Lung (not shown):

[0630] ■ In male and female rats, multiple sections of the lungs in the control treatment group showed normal cellular architecture, alveoli, and lymphatics. In the compound I treatment group, no lymphocytic infiltration was observed in male and female rats.

[0631] Stomach (not shown)

[0632] ■ In the control treatment group, sections of the stomachs of rats of both sexes showed normal findings. In the compound I treatment group, female rats showed normal cellular architecture with normal mucosa, submucosa, outer muscular layer, and serosa, while male rats showed normal cellular architecture and no polyp formation or hyperplastic changes were observed.

[0633] Reproductive organs (not shown)

[0634] For both the control group and the compound I treatment group, sections of the reproductive organs (i.e., testes in males and ovaries in females) showed normal pathology.

[0635] Example 17: Expected Recovery of COVID-19 Patients after Administration of Compound I

[0636] Dose: 250 mg of Compound I administered orally, B.I.D., for 7 days

[0637] Day 01 :

[0638] The orally bioavailable pharmaceutical Compound I is absorbed in the intestine and distributed throughout the body. It targets the SARS-CoV-2 virus entry, inhibits replication and proteolytic processes, and shuts down the protein production machinery for the virus to enter host cells.

[0639] Day 02 :

[0640] Compound I stimulates the body's own immune system by acting as an immunomodulator, increasing the production of anti-inflammatory cytokines and interferons, and inhibiting lysosomal activity in host cells targeted against antiviral infection. The elevated levels of circulating IL-6 will be reduced, which is associated with controlled levels of lung elasticity and defense against more severe bronchoalveolar inflammation.

[0641] Day 03 :

[0642] The induced immune response inhibits further viral replication, promotes the clearance of the virus from the respiratory tract, induces tissue repair, and triggers an extended adaptive immune response against the virus, thereby slowing the progression of the disease. After treatment, peripheral lymphocytes will increase, C-reactive protein will decrease, and over-activated cytokine-secreting immune cells (CXCR3+CD4+T cells, CXCR3+CD8+T cells, CXCR3+NK cells) will decrease within 3 - 5 days, thus reducing the cytokine storm induced by SARS-CoV-2.

[0643] Days 04-06 :

[0644] Overall, treatment with Compound I inhibits SARS-CoV-2 virus particles that invade the respiratory mucosa and infect other cells, which in turn triggers a series of immune responses and the generation of cytokine storms in the body, which may be related to the critical condition of COVID-19 patients. After administration of Compound I, the lung function and symptoms of the patient will improve within 4 - 5 days, and the lung damage caused by the excessive immune response to SARS-CoV-2 can be alleviated.

[0645] Summary

[0646] Compound I has shown significant inhibitory effects on many key proteins of coronaviruses similar to SARS-CoV ( Figure 22)。This compound inhibits viral enzymes (including protease ACE-2 receptor and viral replication protein Nsp15), thereby greatly reducing the infection and replication of the virus in host cells. In vivo studies in mice further showed that it is not toxic to normal cells, and there is no disease recurrence in the health and normal functions of the animals after 9 months of administration. Without being bound by theory, it is believed that the molecule of the present invention has the ability to activate CD4+ helper T cells and CD8+ cytotoxic T cells, and generates an immune response in vivo to defend against viral infection.

[0647] In addition, dose-dependent inactivation of SARS-CoV-2 was observed upon direct exposure to Compound I, and a 50% reduction (IC50) was achieved at 1 μM. Collectively, these data support the further development of Compound I for the treatment of CoV and suggest a new mechanism of interaction of Compound I with the CoV replication complex, which may elucidate key aspects of replication. As explained above, pharmacokinetic studies investigated the concentration of Compound I at different time intervals after oral administration or intravenous injection. In tissue distribution, Compound I was found to be mainly concentrated in the heart, lungs, liver, and other organs. In the gastrointestinal tract, a large amount of Compound I accumulated in the stomach, indicating that Compound I can be absorbed through gastric tissue and distributed throughout the body. In addition, less than 2% of Compound I was excreted in urine or feces, suggesting that approximately 98% of Compound I was absorbed or distributed to vital organs. In summary, our current findings will provide a more complete understanding of the in vivo biological effects of Compound I.

[0648] As can be understood from the above, for the purpose of illustration, various embodiments of the present disclosure have been described herein, and various modifications can be made without departing from the scope and spirit of the present disclosure. Therefore, the various embodiments disclosed herein are not intended to be limiting, and the true scope and spirit are indicated by the appended claims.

[0649] In summary, the present invention relates to the following aspects:

[0650] 1. A novel compound exhibiting anti-cancer and anti-viral activities for treating a subject suffering from a chronic disorder, said compound comprising a structure according to Formula 1A,

[0651]

[0652] or any of its derivatives, its pharmaceutically acceptable salts, or combinations thereof.

[0653] Wherein:

[0654] R1 is H, OH, or an alkoxy group;

[0655] R2 is an alkoxy group or OH;

[0656] R3 is an alkoxy group or OH;

[0657] X is a C1-C 15 alkyl, C2-C 15 alkenyl or aralkyl chain, each independently substituted by at least one alkoxy, OH, =NH or oxo group;

[0658] Y is H or alkyl; and

[0659] X is in the ortho position to R2, or the para position to R1.

[0660] 2. The compound according to item 1, wherein:

[0661] R1 is H;

[0662] R2 is -OH;

[0663] R3 is a C1-C3 alkoxyl;

[0664] X is a C4-C8 alkenyl substituted by two oxo groups; and

[0665] Y is a C1-C3 alkyl.

[0666] 3. The compound according to item 1, which has the structure of formula 1

[0667]

[0668] or any of its derivatives, its pharmaceutically acceptable salts or combinations thereof.

[0669] Wherein:

[0670] R1 is H, alkoxy or OH;

[0671] R2 is alkoxy or OH;

[0672] R3 is alkoxy or OH;

[0673] X is a C1-C 15 alkyl, C2-C 15 alkenyl, or aralkyl chain, each independently substituted by at least one alkoxy, OH, =NH or oxo group.

[0674] 4. The compound according to item 3, wherein X is:

[0675] (i) A C6-C 10 alkenyl substituted by four substituents, said substituents being independently selected from the group consisting of oxo, -OH and C1-C3 alkoxy;

[0676] (ii) A C8-C 12 alkenyl substituted by oxo and C1-C3 alkoxy;

[0677] (iii) C4-C8 alkenyl substituted by two oxo groups;

[0678] (iv) C2-C6 alkenyl substituted by oxo and C1-C3 alkoxy;

[0679] (v) C1-C6 alkyl substituted by =NH;

[0680] (vi) C2-C3 alkenyl substituted by -OH;

[0681] (vii) C8-C 12 alkenyl substituted by oxo and two C1-C3 alkoxy groups; and

[0682] (viii) An aralkyl containing C6-C8 alkyl and C6 aryl, wherein the alkyl is substituted by oxo and the aryl is substituted by two alkoxy groups.

[0683] 5. The compound according to item 3 or 4, wherein:

[0684] R1 is H;

[0685] R2 is C1-C3 alkoxy;

[0686] R3 is C1-C3 alkoxy; and

[0687] X is a C6-C 10 alkenyl substituted by oxo, -OH and two C1-C3 alkoxy groups.

[0688] 6. The compound according to item 3 or 4, wherein

[0689] R1 is H;

[0690] R2 is C1-C3 alkoxy;

[0691] R3 is C1-C3 alkoxy; and

[0692] X is a C8-C 12 alkenyl substituted by oxo and C1-C3 alkoxy.

[0693] 7. The compound according to item 3 or 4, wherein

[0694] R1 is OH;

[0695] R2 is C1-C3 alkoxy;

[0696] R3 is C1-C3 alkoxy; and

[0697] X is a C4-C8 alkenyl substituted by two oxo groups.

[0698] 8. The compound according to item 3 or 4, wherein

[0699] R1 is C1-C3 alkoxy;

[0700] R2 is OH;

[0701] R3 is C1-C3 alkoxy; and

[0702] X is a C4-C8 alkenyl group substituted by two oxo groups.

[0703] 9. The compound according to item 3 or 4, wherein

[0704] R1 is H;

[0705] R2 is OH;

[0706] R3 is OH; and

[0707] X is a C1-C6 alkyl group substituted by =NH.

[0708] 10. The compound according to item 3 or 4, wherein

[0709] R1 is OH;

[0710] R2 is C1-C3 alkoxy;

[0711] R3 is C1-C3 alkoxy; and

[0712] X is a C2-C3 alkenyl group substituted by OH.

[0713] 11. The compound according to item 3 or 4, wherein

[0714] R1 is H;

[0715] R2 is C1-C3 alkoxy;

[0716] R3 is C1-C3 alkoxy; and

[0717] X is a C8-C alkenyl group substituted by oxo and two C1-C3 alkoxy groups 12 alkenyl.

[0718] 12. The compound according to item 3 or 4, wherein

[0719] R1 is OH;

[0720] R2 is C1-C3 alkoxy;

[0721] R3 is C1-C3 alkoxy; and

[0722] X is an aralkyl group containing a C6-C8 alkyl group and a C6 aryl group, wherein the alkyl group is substituted by oxo, and the aryl group is substituted by two C1-C3 alkoxy groups.

[0723] 13. The compound according to item 1, which has the structure of formula 2

[0724]

[0725] or any of its derivatives, its pharmaceutically acceptable salts, or a combination thereof.

[0726] Wherein:

[0727] R1 is H or OH;

[0728] R2 is alkoxy or OH;

[0729] R3 is alkoxy or OH; and

[0730] R4 is C1-C 15 alkyl, C2-C 15 alkenyl or aralkyl, each of which is substituted by at least one alkoxy group, -OH or oxo.

[0731] 14. The compound according to item 13, wherein R4 is selected from the group consisting of:

[0732]

[0733] 15. The compound according to item 13 or 14, wherein R1 is H;

[0734] R2 is OCH3;

[0735] R3 is OCH3; and

[0736] R4 is

[0737] 16. The compound according to item 13 or 14, wherein R1 is H;

[0738] R2 is OCH3;

[0739] R3 is OCH3; and

[0740] R4 is.

[0741] 17. The compound according to item 13 or 14, wherein R1 is OH;

[0742] R2 is OCH3;

[0743] R3 is OCH3; and

[0744] R4 is

[0745] 18. The compound according to item 13 or 14, wherein R1 is OH;

[0746] R2 is OCH3;

[0747] R3 is OCH3; and

[0748] R4 is

[0749] 19. The compound according to item 13 or 14, wherein R1 is H;

[0750] R2 is OCH3;

[0751] R3 is OCH3; and

[0752] R4 is

[0753] 20. The compound according to item 1, which has the structure of formula 3

[0754]

[0755] or any of its derivatives, its pharmaceutically acceptable salts or combinations thereof.

[0756] Wherein:

[0757] R1 is H, alkoxy or OH;

[0758] R2 is alkoxy or OH;

[0759] R3 is alkoxy or OH; and

[0760] R5 is C1-C 12 alkyl or C2-C 12 alkenyl, which is independently substituted by 1 or 2 substituents selected from the group consisting of =NH and oxo.

[0761] 21. The compound according to item 20, wherein

[0762] R1 is H;

[0763] R2 is OH;

[0764] R3 is OH; and

[0765] R5 is =NH, wherein

[0766] R5 is in the ortho position to R2.

[0767] 22. The compound according to item 20, wherein

[0768] R1 is -OC2H5;

[0769] R2 is OH;

[0770] R3 is -OCH3;

[0771] R5 is wherein

[0772] R5 is in the para position to R1.

[0773] 23. The compound according to item 1, which has the structure of formula 4;

[0774]

[0775] or any of its derivatives, its pharmaceutically acceptable salts or combinations thereof.

[0776] wherein:

[0777] R1 is OH;

[0778] R2 is C1-C3 alkoxy;

[0779] R3 is C1-C3 alkoxy; and

[0780] R6 is C(CH2)OH.

[0781] 24. The compound according to item 23, wherein

[0782] R1 is OH;

[0783] R2 is OCH3;

[0784] R3 is OCH3; and

[0785] R6 is C(CH2)OH.

[0786] 25. A pharmaceutical composition comprising the compound according to any one of items 1-24 and a pharmaceutically acceptable carrier.

[0787] 26. A method for treating a chronic disorder in a patient in need thereof, the method comprising administering the compound according to items 1-24 or the pharmaceutical composition according to item 25.

[0788] 27. The method according to item 26, wherein the chronic disorder is acute lymphoblastic leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related lymphoma, anal cancer, appendiceal cancer, basal cell carcinoma, bladder cancer, brain cancer, brainstem glioma, breast cancer, bronchial adenoma / carcinoid tumor, Burkitt lymphoma, carcinoid tumor, cerebellar or cerebral astrocytoma, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic or chronic lymphocytic leukemia, chronic myelogenous leukemia or chronic myeloid leukemia, chronic myeloproliferative disorder, colon cancer, cutaneous T-cell lymphoma, desmoplastic small round cell tumor, endometrial uterine cancer, ependymoma, esophageal cancer, Ewing 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, glioma of the brainstem, hairy cell leukemia, head and neck cancer, heart cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, hypothalamic and visual pathway glioma, intraocular melanoma, islet cell carcinoma, Kaposi sarcoma, laryngeal cancer, leukemia, lip and oral cavity cancer, liposarcoma, lymphoma, male breast cancer, malignant mesothelioma, medulloblastoma, melanoma, Merkel cell skin cancer, mesothelioma, metastatic squamous neck cancer, oral cavity cancer, multiple endocrine neoplasia syndrome, multiple myeloma, multiple myeloma / plasmacytoma, mycosis fungoides, myelodysplastic / myeloproliferative disease, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-melanoma skin cancer, non-small cell lung cancer, oligodendroglioma, oral cavity cancer, oropharyngeal cancer, osteosarcoma and malignant fibrous histiocytoma, ovarian cancer, ovarian germ cell tumor, ovarian epithelial cancer (surface epithelial-stromal tumor), ovarian low malignant potential tumor, pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, nasopharyngeal cancer, pheochromocytoma, pineal astrocytoma, pineal germ cell tumor, pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary adenoma, plasmacytoma, pleuropulmonary blastoma, primary cancer, 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, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, supratentorial primitive neuroectodermal tumor, testicular cancer, laryngeal 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 macroglobulinemia, Wilms tumor, Parkinson's disease and Parkinson disorder, Huntington's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Shy-Drager syndrome, progressive supranuclear palsy, dementia with Lewy bodies, spinal cord ischemia, spinal cord injury, ischemic stroke, cerebral infarction,Spinal cord injury, as well as cancer-related brain and spinal cord injuries, multi-infarct dementia, Alzheimer's disease, other cognitive impairments, depression, onychomycosis (fungal infection of the nails), gingivitis and periodontal diseases (gum diseases), obesity, diabetes, viral infections, or cancers with KRAS oncogene mutations.

[0789] 28. The method according to item 26 or 27, wherein the chronic disorder is cancer.

[0790] 29. The method according to item 28, wherein the cancer is colon cancer, prostate cancer, breast cancer or leukemia.

[0791] 30. The method according to item 28 or 29, wherein the cancer has a KRAS oncogene mutation.

[0792] 31. The method according to item 26 or 27, wherein the chronic disorder is a viral infection.

[0793] 32. The method according to item 31, wherein the viral infection is SARS or COVID-19.

[0794] 33. The method according to any one of items 28 - 30, the method further comprising administering an effective amount of a chemotherapeutic agent to the patient in need after administering the compound according to items 1 - 24 or the pharmaceutical composition according to item 25.

[0795] 34. The method according to item 33, wherein the chemotherapeutic agent is selected from the group consisting of: docetaxel, paclitaxel, pazopanib, endostatin, etoposide, doxorubicin, dacomycin, avastin, gemcitabine, cisplatin and oxaliplatin.

[0796] 35. The method according to item 33 or 34, wherein administering the compound according to items 1 - 24 or the pharmaceutical composition according to item 25 to the patient in need reduces and / or reverses the side effects associated with administering a chemotherapeutic agent to the patient in need.

[0797] 36. The method according to item 35, wherein the side effects associated with administering a chemotherapeutic agent to the patient in need include one or more of gastritis, hair loss, bone marrow suppression and cardiotoxicity.

[0798] 37. The method according to item 31 or 32, the method further comprising administering an effective amount of an additional antiviral agent to the patient in need.

[0799] 38. The method according to item 36, wherein the additional antiviral agent is chloroquine or hydroxychloroquine.

[0800] 39. The method according to item 37, wherein administering to a patient in need a compound according to items 1-24 or a pharmaceutical composition according to item 25 reduces and / or reverses the toxic side effects associated with administering chloroquine or hydroxychloroquine to a patient in need.

[0801] 40. The method according to item 38, wherein the toxic side effects associated with administering chloroquine or hydroxychloroquine to a patient in need include one or more of cardiovascular diseases, eye damage, mild or severe bronchospasm, and mental health conditions.

Claims

1. A compound of formula 1 or any of its derivatives, its pharmaceutically acceptable salts, or combinations thereof, wherein: R1 is H, alkoxy, or OH; R2 is alkoxy or OH; R3 is alkoxy or OH; X is selected from: (i) C6-C 10 alkenyl substituted by four substituents, said substituents being independently selected from the group consisting of oxo, -OH and C1-C3 alkoxy; (ii) C8-C 12 alkenyl groups substituted with oxo and C1-C3 alkoxy groups; (iii) a C4-C8 alkenyl group substituted with two oxo groups; (iv) a C2-C6 alkenyl group substituted with oxo and C1-C3 alkoxy; (v) a C1-C6 alkyl group substituted with =NH; (vi) a C2-C3 alkenyl group substituted with -OH; and (vii) C8-C 12 alkenyl substituted with an oxo group and two C1-C3 alkoxy groups.

2. The compound according to claim 1, wherein: R1 is H; R2 is C1-C3 alkoxy; R3 is C1-C3 alkoxy; and X is a C6-C 10 10 alkenyl group substituted with oxo, -OH, and two C1-C3 alkoxy groups.

3. The compound according to claim 1, wherein R1 is H; R2 is C1-C3 alkoxy; R3 is C1-C3 alkoxy; and X is an C8-C alkenyl group substituted by oxo and C1-C3 alkoxy 12 groups.

4. The compound according to claim 1, wherein R1 is OH; R2 is C1-C3 alkoxy; R3 is C1-C3 alkoxy; and X is a C4-C8 alkenyl group substituted with two oxo groups.

5. The compound according to claim 1, wherein R1 is C1-C3 alkoxy; R2 is OH; R3 is C1-C3 alkoxy; and X is a C4-C8 alkenyl group substituted with two oxo groups.

6. The compound according to claim 1, wherein R1 is H; R2 is OH; R3 is OH; and X is a C1-C6 alkyl group substituted with =NH.

7. The compound according to claim 1, wherein R1 is OH; R2 is C1-C3 alkoxy; R3 is C1-C3 alkoxy; and X is a C2-C3 alkenyl group substituted with OH.

8. The compound according to claim 1, wherein R1 is H; R2 is C1-C3 alkoxy; R3 is C1-C3 alkoxy; and X is an C8-C alkenyl group substituted with an oxo group and two C1-C3 alkoxy groups. 12 alkenyl group.

9. The compound according to claim 1, having the structure of formula 2 or any of its derivatives, its pharmaceutically acceptable salts, or combinations thereof, wherein: R1 is H or OH; R2 is alkoxy or OH; R3 is alkoxy or OH; and R4 is selected from the group consisting of:

10. The compound according to claim 9, wherein R1 is H; R2 is OCH3; R3 is OCH3; and R4 is 11. The compound according to claim 9, wherein R1 is H; R2 is OCH3; R3 is OCH3; and R4 is 12. The compound according to claim 9, wherein R1 is OH; R2 is OCH3; R3 is OCH3; and R4 is 13. The compound according to claim 9, wherein R1 is H; R2 is OCH3; R3 is OCH3; and R4 is 14. The compound according to claim 1, having the structure of formula 3 or any of its derivatives, its pharmaceutically acceptable salts, or combinations thereof, wherein: R1 is H, alkoxy, or OH; R2 is alkoxy or OH; R3 is alkoxy or OH; and R5 is C1-C 12 alkyl or C2-C 12 alkenyl, which is independently substituted by 1 or 2 substituents selected from the group consisting of =NH and 15. The compound according to claim 14, wherein R1 is H; R2 is OH; R3 is OH; and R5 is =NH, wherein R5 is in the ortho position to R2.

16. The compound according to claim 14, wherein R1 is -OC2H5; R2 is OH; R3 is -OCH3; R5 is wherein R5 is in the para position to R1.

17. The compound according to claim 1, which has the structure of Formula 4; or any of its derivatives, its pharmaceutically acceptable salts or combinations thereof, wherein: R1 is OH; R2 is C1-C3 alkoxy; R3 is C1-C3 alkoxy; and R6 is C(CH2)OH.

18. The compound according to claim 17, wherein R1 is OH; R2 is OCH3; R3 is OCH3; and R6 is C(CH2)OH.

19. The compound according to claim 1, wherein the compound is 20. The compound according to claim 1, wherein the compound is 21. The compound according to claim 1, wherein the compound is 22. The compound according to claim 1, wherein the compound is 23. The compound according to claim 1, wherein the compound is 24. The compound according to claim 1, wherein the compound is 25. The compound according to claim 1, wherein the compound is 26. The compound according to claim 1, wherein the compound is 27. The compound according to claim 1, wherein the compound is 28. A pharmaceutical composition comprising the compound according to any one of claims 1-27 and a pharmaceutically acceptable carrier.

29. Use of the compound according to any one of claims 1-27 or the pharmaceutical composition according to claim 28 in the preparation of a medicament for the treatment of cancer.

30. The use according to claim 29, wherein the cancer is breast cancer, leukemia, colon cancer, pancreatic cancer, liver cancer, prostate cancer or lung cancer.

31. The use according to claim 29, wherein the cancer has a KRAS oncogene mutation.

32. Use of the compound according to any one of claims 1-27 or the pharmaceutical composition according to claim 28 in the preparation of a medicament for the treatment of viral infections, wherein the viral infection is SARS or COVID-19.

33. Intermediate compounds selected from the following: wherein R is H or alkoxy.

34. A method for measuring the in vitro antiviral activity of compound I in Vero cells, comprising: First, testing the cytotoxicity of compound I on Vero cells; Then, infecting Vero cells with SARS-CoV-2 at a multiplicity of infection (MOI) of 0.1 PFU / cell in the presence of different concentrations of compound I, using DMSO as a vehicle; Evaluating the efficacy by quantifying the viral copy number in the cell supernatant via quantitative real-time RT-PCR (qRT-PCR), and confirming the visualization of viral nucleoprotein (NP) expression by immunofluorescence analysis 48 h post-infection (p.i.).

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