WO2022076565A1 - Salicylanilide analogs for use in the treatment of coronavirus - Google Patents

Abstract

Provided herein, inter alia, are methods for treating coronavirus infection in a mammal with salicylanilide analogs. Additionally, provided herein are methods of treating coronavirus infection in a mammal with salicylanilide analogs in combination with one or more other compounds useful in the treatment of SARS-CoV-2 infection.

Description

SALICYLANILIDE ANALOGS FOR USE IN THE TREATMENT OF CORONAVIRUS

[001] This application claims the benefit of priority of US Provisional Patent Application No. 63/088,711, filed October 7, 2020, which is incorporated by reference herein for all purposes.

[002] Throughout this application various publications, patents, and/or patent applications are referenced. The disclosures of the publications, patents and/or patent applications are hereby incorporated by reference in their entireties into this application in order to more fully describe the state of the art to which this disclosure pertains.

TECHNICAL FIELD

[003] The present disclosure provides methods for treating coronavirus infections comprising administering an effective amount of salicylanilide analogs.

BACKGROUND

[004] Salicylanilide analogs have been prepared for the first time in 1966 and described in GB Patent No. 1,183,641. Salicylanilide analogs have been found to be useful, for example, in the treatment of parasitic disease (GB Patent No. 1,183,641), liver fluke infections (U.S. Patent No. 3,914,418), dengue virus infections (International Publication No. WO 2019222349), topical prevention or treatment of a skin infection or an inflammatory skin condition international Publication No. WO 2019038443), enteric toxigenic pathogen infections (U.S. Publication No. 2020/0046659), and infections caused by Gram-positive bacteria such as Staphylococcus (U.S. Patent No. 10,758,553).

[005] Additionally, salicylanilide analogs have been found to be useful, for example, in the treatment of adenovirus infections (Marrugal -Lorenzo et al. (2019) Scientific Reports 9: 17 1-10), and broad range of antiviral infections, including rhinoviruses and influenza virus (Jurgeit et al. (2012) plospathogens 8: 10 el002976).

[006] Coronaviruses are a group of viruses that causes diseases in birds, mammals and humans. The diseases include respiratory infections and enteric infections which can be mild or lethal. Coronaviruses are viruses in the subfamily Orthocoronavirinae, in the family Coronaviridae , in the order Nidovirales. The genus Coronavirus includes avian infectious bronchitis virus, bovine coronavirus, canine coronavirus, human coronavirus 299E, human coronavirus OC43, murine hepatitis virus, rat coronavirus, and porcine hemagglutinating encephalomyelitis virus. The genus Torovirus includes Berne virus and Breda virus. Coronaviruses are enveloped viruses having a positive-sense single-stranded RNA genome and a nucleocapsid of helical symmetry. The genomic size of coronaviruses ranges from approximately 26 to 32 kilobases, which is believed to be the largest for an RNA virus.

[007] The name “coronavirus" is derived from the Latin corona and the Greek korone (e.g., "garland” or “wreath"), meaning crown or halo. The corona reference relates to the characteristic appearance of virions (the infective form of the virus) by electron microscopy, which have a fringe of large, bulbous surface projections creating an image reminiscent of a royal crown or of the solar corona. This morphology is created by the viral spike (S) peplomers, which are proteins that population the surface of the virus and determine host tropism. Proteins that contribute to the overall structure of all coronaviruses are the spike (S), envelope (E), membrane (M) and nucleocapsid (N). In the specific case of the SARS coronavirus, a defined receptor-binding domain on S mediates the attachment of the virus to its cellular receptor, angiotensin-converting enzyme 2 (ACE2). Some coronaviruses (specifically the members of Betacoronavirus subgroup A) also have a shorter spike-like protein called hemagglutinin esterase (HE). It is interesting to note that the 2019-2020 China pneumonia outbreak in Wuhan was traced to a novel coronavirus, labeled 2019-nCoV by the World Health Organization (WHO) and is also known as SARS-CoV- 2, which causes Coronavirus disease 2019, or COVID-19. There is a need in the art for methods for preventing or treating coronavirus-related viral infections in human and animal subjects. Accordingly, the embodiments described herein are provided in an effort to meet this need and/or provide other benefits, or at least provide the public with a useful choice.

[008] The present disclosure provides a method for treating coronavirus infection comprising administering an effective amount of salicylanilide analogs.

BRIEF SUMMARY OF THE INVENTION

[009] In an aspect, provided herein is a method of treatment of coronavirus infection in a mammal, including administering to the mammal an effective dose of a compound of formula (I), (II), or (III):

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof.

[0010] Each R¹ and R^3a is independently hydrogen, halogen, haloalkyl, -OH, C1-C5 alkoxy, -NO2, -CN, or C1-C5 alkyl.

[0011] Each R⁴ and R⁵ is independently H or C1-C5 alkyl.

[0012] Each R² and R³ is independently hydrogen, -OH, halogen, -NO2, haloalkyl, C1-C5 alkoxy,

C1-C5 alkyl, -NH2, C1-C5 alkylamino, or C1-C5 alkylthio.

[0013] L¹ is -O-, -S-, -C(O)-, -NH-, -N(H)C(O)- or -C(O)N(H).

[0014] n is 0 to 4.

[0015] m is 0 to 4.

[0016] v is O to 5.

[0017] x is O to 5.

[0018] z is 0 to 4. [0019] In an aspect, provided herein is a method of treatment of coronavirus infection in a mammal, including administering to the mammal an effective dose of a compound of formula (I), (II), or (III):

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof, in combination with one or more other compounds useful in the treatment of SARS-CoV- 2 infection, wherein:

[0020] Each R¹ and R^3a is independently hydrogen, halogen, haloalkyl, -OH, C1-C5 alkoxy, -NO2, -CN, or C1-C5 alkyl.

[0021] Each R⁴ and R⁵ is independently H or C1-C5 alkyl.

[0022] Each R² and R³ is independently hydrogen, -OH, halogen, -NO2, haloalkyl, C1-C5 alkoxy,

C1-C5 alkyl, -NH2, C1-C5 alkylamino, or C1-C5 alkylthio.

[0023] L¹ is -O-, -S-, -C(O)-, -NH-, -N(H)C(O)- or -C(O)N(H).

[0024] n is 0 to 4. [0025] m is 0 to 4.

[0026] v is O to 5.

[0027] x is O to 5.

[0028] z is 0 to 4.

BRIEF DESCRIPTION OF THE DRAWINGS

[0029] FIG. 1 A shows the SARS-CoV-2 titer in Vero cells treated with compound 30.

[0030] FIG. IB shows the SARS-CoV-2 titer in Vero cells treated with compound 17.

[0031] FIG. 2A shows Log reduction of compounds 17, 23, 26, 30, 44, and 50 at 20 pM, after 24 hours.

[0032] FIG. 2B shows Log reduction of compounds 17 and 30 at 20 pM, after 24 hours.

[0033] FIG. 3 A compares cell viability and neutralization of viral activity as a function of drug concentration for compound 30.

[0034] FIG. 3B compares cell viability and neutralization of viral activity as a function of drug concentration for compound 17 (niclosamide).

[0035] FIG. 4A shows the treatment schedule of the prophylactic mouse model of SARS-CoV-2.

[0036] FIG. 4B shows weight loss in mice monitored throughout the duration of dosing schedule with compound 30, vehicle (negative control), or EIDD-2801 (molnupiravir; positive control).

[0037] FIG. 4C shows the impact of orally administered compound 30, vehicle (negative control), or EIDD-2801 (molnupiravir; positive control) on the viral titers in the lungs of mice on Day 4.

[0038] FIGS. 5A-D show the cytokine levels of mice treated with compound 30, vehicle (negative control), or EIDD-2801 (molnupiravir; positive control). FIG. 5 A shows the impact of compound 30 or EIDD-2801 on IL-6. FIG. 5B shows the impact of compound 30 or EIDD-2801 on G-CSF. FIG. 5C shows the impact of compound 30 or EIDD-2801 on MCP-1. FIG. 5D shows the impact of compound 30 or EIDD-2801 on eotaxin.

DETAILED DESCRIPTION OF THE INVENTION

[0039] Unless defined otherwise, technical and scientific terms used herein have meanings that are commonly understood by those of ordinary skill in the art unless defined otherwise. Generally, terminologies pertaining to techniques of cell and tissue culture, molecular biology, immunology, microbiology, genetics, transgenic cell production, protein chemistry and nucleic acid chemistry and hybridization described herein are well known and commonly used in the art. The methods and techniques provided herein are generally performed according to conventional procedures well known in the art and as described in various general and more specific references that are cited and discussed herein unless otherwise indicated. See, e.g., Sambrook et al. Molecular Cloning: A Laboratory Manual, 2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989) and Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates (1992). A number of basic texts describe standard antibody production processes, including, Borrebaeck (ed) Antibody Engineering, 2nd Edition Freeman and Company, NY, 1995; McCafferty et al. Antibody Engineering, A Practical Approach IRE at Oxford Press, Oxford, England, 1996; and Paul (1995) Antibody Engineering Protocols Humana Press, Towata, N.J., 1995; Paul (ed.), Fundamental Immunology, Raven Press, N.Y, 1993;

Coligan (1991) Current Protocols in Immunology Wiley/Greene, NY; Harlow and Lane (1989) Antibodies: A Laboratory Manual Cold Spring Harbor Press, NY; Stites et al. (eds.) Basic and Clinical Immunology (4th ed.) Lange Medical Publications, Los Altos, Calif., and references cited therein; Coding Monoclonal Antibodies: Principles and Practice (2nd ed.) Academic Press, New York, N.Y., 1986, and Kohler and Milstein Nature 256: 495-497, 1975. All of the references cited herein are incorporated herein by reference in their entireties. Enzymatic reactions and enrichment/purification techniques are also well known and are performed according to manufacturer's specifications, as commonly accomplished in the art or as described herein. The terminology used in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are well known and commonly used in the art. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.

[0040] Before describing the present teachings in detail, it is to be understood that the disclosure is not limited to specific compositions or process steps, as such may vary. It should be noted that, as used in this specification and the appended claims, the singular form “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, reference to “a conjugate” includes a plurality of conjugates and reference to “a cell” includes a plurality of cells and the like. It is understood the use of the alternative (e.g., “or”) herein is taken to mean either one or both or any combination thereof of the alternatives.

[0041] The term “and/or” used herein is to be taken mean specific disclosure of each of the specified features or components with or without the other. For example, the term “and/or” as used in a phrase such as “A and/or B” herein is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Likewise, the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0042] As used herein, the term “about” refers to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, “about” or “approximately” can mean within one or more than one standard deviation per the practice in the art. Alternatively, “about” or “approximately” can mean a range of up to 10% (i.e., ±10%) or more depending on the limitations of the measurement system. For example, about 5 mg can include any number between 4.5 mg and 5.5 mg. Furthermore, particularly with respect to biological systems or processes, the terms can mean up to an order of magnitude or up to 5-fold of a value. When particular values or compositions are provided in the instant disclosure, unless otherwise stated, the meaning of “about” or “approximately” should be assumed to be within an acceptable error range for that particular value or composition. In some embodiments, “about” encompasses variation within 10%, 5%, 2%, 1%, or 0.5% of a stated value.

[0043] Numeric ranges are inclusive of the numbers defining the range. Measured and measurable values are understood to be approximate, taking into account significant digits and the error associated with the measurement. Also, all ranges are to be interpreted as encompassing the endpoints in the absence of express exclusions such as “not including the endpoints”; thus, for example, “ranging from 1 to 10” includes the values 1 and 10 and all integer and (where appropriate) non-integer values greater than 1 and less than 10.

[0044] The term “coronavirus infection” refers to a human or animal that has cells that have been infected by a coronavirus. The infection can be established by performing a detection and/or viral titration from respiratory samples, or by assaying blood-circulating coronavirusspecific antibodies. The detection in the individuals infected with coronavirus is made by conventional diagnostic methods, such as molecular biology (e.g., PCR), which are known to those skilled in the art.

[0045] The use of “comprise”, “comprises”, “comprising”, “contain”, “contains”, “containing”, “include”, “includes”, and “including” and their grammatical variants, as used herein are intended to be non-limiting so that one item or multiple items in a list do not exclude other items that can be substituted or added to the listed items. It is to be understood that both the foregoing general description and detailed description are exemplary and explanatory only and are not restrictive of the teachings. Unless specifically noted in the above specification, embodiments in the specification that recite “comprising” various components are also contemplated as “consisting of’ or “consisting essentially of’ the recited components; embodiments in the specification that recite “consisting of’ various components are also contemplated as “comprising” or “consisting essentially of’ the recited components; and embodiments in the specification that recite “consisting essentially of’ various components are also contemplated as “consisting of’ or “comprising” the recited components (this interchangeability does not apply to the use of these terms in the claims).

[0046] The section headings used herein are for organizational purposes only and are not to be construed as limiting the desired subject matter in any way. In the event that any literature incorporated by reference contradicts any term defined in this specification, this specification controls. While the present teachings are described in conjunction with various embodiments, it is not intended that the present teachings be limited to such embodiments. On the contrary, the present teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those of skill in the art. The features of any embodiment described herein can be combined with the features of any one or more other embodiments described herein, provided that the embodiments are not inconsistent with each other.

Definitions

[0047] The terms "effective amount", “therapeutically effective amount” or “effective dose” or related terms may be used interchangeably and refer to an amount of the therapeutic agent that when administered to a subject, is sufficient to affect a measurable improvement or prevention of a disease or disorder associated with coronavirus infection. For example, administering an effective dose sufficient to inhibit the proliferation and/or replication of the coronavirus, and/or the development of the viral infection within the subject. Therapeutically effective amounts of the therapeutic agents provided herein, when used alone or in combination with an antiviral agent, will vary depending upon the relative activity of the therapeutic agent, and depending upon the subject and disease condition being treated, the weight and age and sex of the subject, the severity of the disease condition in the subject, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. In one embodiment, a therapeutically effective amount will depend on certain aspects of the subject to be treated and the disorder to be treated and may be ascertained by one skilled in the art using known techniques. In addition, as is known in the art, adjustments for age as well as the body weight, general health, sex, diet, time of administration, drug interaction, and the severity of the disease may be necessary.

[0048] The terms “subject” and “patient” as used herein refer to human and non-human animals, including vertebrates, mammals and non-mammals. In one embodiment, the subject can be human, non-human primates, simian, ape, murine (e.g., mice and rats), bovine, porcine, equine, canine, feline, caprine, lupine, ranine or piscine.

[0049] The term “administering”, “administered” and grammatical variants refers to the physical introduction of a therapeutic agent to a subject, using any of the various methods and delivery systems known to those skilled in the art. Exemplary routes of administration for the formulations disclosed herein include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, for example by injection or infusion. The phrase “parenteral administration” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, as well as in vivo electroporation. In one embodiment, the formulation is administered via a non-parenteral route, e.g., orally. Other non-parenteral routes include a topical, epidermal or mucosal route of administration, for example, intranasally, vaginally, rectally, sublingually or topically. Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.

[0050] “Treating” is to be understood broadly and encompasses any beneficial effect, including, e.g., delaying, slowing, or arresting the worsening of symptoms associated with pulmonary inflammatory disease or remedying such symptoms, at least in part. Treating also encompasses bringing about any form of improved patient function, as discussed in detail below. In some embodiments, treatment also means prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those who already have the disease or disorder, as well as those who tend to have the disease or disorder or who should prevent the disease or disorder.

[0051] The term “synergistic effect” refers to a situation where the combination of two or more agents produces a greater effect than the sum of the effects of each of the individual agents. The term encompasses not only a reduction in symptoms of the disorder to be treated, but also an improved side effect profile, improved tolerability, improved patient compliance, improved efficacy, or any other improved clinical outcome.

[0052] The term a “sub-therapeutic amount” of an agent or therapy is an amount less than the effective amount for that agent or therapy as a single agent, but when combined with an effective or sub-therapeutic amount of another agent or therapy can produce a result desired by the physician, due to, for example, synergy in the resulting efficacious effects, or reduced side effects.

[0053] Combination therapy or “in combination with” refer to the use of more than one therapeutic agent to treat a particular disorder or condition. By “in combination with,” it is not intended to imply that the therapeutic agents must be administered at the same time and/or formulated for delivery together, although these methods of delivery are within the scope of this disclosure. A therapeutic agent can be administered concurrently with, prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks before), or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks after), one or more other additional agents. The therapeutic agents in a combination therapy can also be administered on an alternating dosing schedule, with or without a resting period (e.g., no therapeutic agent is administered on certain days of the schedule). The administration of a therapeutic agent “in combination with” another therapeutic agent includes, but is not limited to, sequential administration and concomitant administration of the two agents. In general, each therapeutic agent is administered at a dose and/or on a time schedule determined for that particular agent.

[0054] A “pharmaceutically acceptable vehicle” for therapeutic purposes is a physical embodiment that can be administered to a subject. Pharmaceutically acceptable vehicles include pills, capsules, caplets, tablets, oral fluids, injection fluids, sprays, aerosols, troches, dietary supplements, creams, lotions, oils, solutions, pastes, powders, steam, Or it may be a liquid, but is not limited to these. An example of a pharmaceutically acceptable vehicle is a buffered isotonic solution such as phosphate buffered saline (PBS).

[0055] “ TCID50” as used herein, refers to tissue culture infective dose assay used to quantify the virus infectivity in the process solutions of a viral clearance study. This endpoint dilution assay quantifies the amount of vims required to kill 50% of infected hosts. It is a measure of infectious virus titer. The viral titer derived from the viral infectivity assays is represented by logio/ml values. The calculated ratio of the viral titer in the starting material and in the relevant product fraction defines the viral reduction, called logio reduction factor (LRF).

[0056] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0057] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0058] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di- and multivalent radicals. The alkyl may include a designated number of carbons (e.g., C1-C10 means one to ten carbons). Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2- propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-). An alkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. An alkyl moiety may be fully saturated. An alkenyl may include more than one double bond and/or one or more triple bonds in addition to the one or more double bonds. An alkynyl may include more than one triple bond and/or one or more double bonds in addition to the one or more triple bonds.

[0059] The term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, - CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term “alkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.

[0060] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) (e.g., O, N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: -CH2- CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH₃)-CH3, -CH2-S-CH2-CH3, -CH2-S-CH2, - S(O)-CH3, -CH₂-CH₂-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH₃)3, -CH₂-CH=N-OCH₃, -CH=CH- N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to

8 optionally different heteroatoms (e.g., O, N, S, Si, or P). The term “heteroalkenyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one double bond. A heteroalkenyl may optionally include more than one double bond and/or one or more triple bonds in additional to the one or more double bonds. The term “heteroalkynyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one triple bond. A heteroalkynyl may optionally include more than one triple bond and/or one or more double bonds in additional to the one or more triple bonds.

[0061] Similarly, the term “heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as - C(O)R', -C(O)NR', -NR'R", -OR', -SR', and/or -SO2R'. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R" or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R" or the like.

[0062] The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1 -cyclohexenyl, 3 -cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1 -(1,2, 5, 6- tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1- piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively. [0063] In embodiments, the term “cycloalkyl” means a monocyclic, bicyclic, or a multicyclic cycloalkyl ring system. In embodiments, monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic. In embodiments, cycloalkyl groups are fully saturated. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fused bicyclic rings. In embodiments, bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form (CEbjw , where w is 1, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. In embodiments, fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. In embodiments, cycloalkyl groups are optionally substituted with one or two groups which are independently oxo or thia. In embodiments, the fused bicyclic cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted by one or two groups which are independently oxo or thia. In embodiments, multicyclic cycloalkyl ring systems are a monocyclic cycloalkyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. In embodiments, the multicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. In embodiments, multicyclic cycloalkyl ring systems are a monocyclic cycloalkyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl. Examples of multi cyclic cycloalkyl groups include, but are not limited to tetradecahydrophenanthrenyl, perhydrophenothiazin- 1-yl, and perhydrophenoxazin- 1-yl.

[0064] In embodiments, a cycloalkyl is a cycloalkenyl. The term “cycloalkenyl” is used in accordance with its plain ordinary meaning. In embodiments, a cycloalkenyl is a monocyclic, bicyclic, or a multicyclic cycloalkenyl ring system. In embodiments, monocyclic cycloalkenyl ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups are unsaturated (i.e., containing at least one annular carbon carbon double bond), but not aromatic. Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. In embodiments, bicyclic cycloalkenyl rings are bridged monocyclic rings or a fused bicyclic rings. In embodiments, bridged monocyclic rings contain a monocyclic cycloalkenyl ring where two non adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form (CHzjw, where w is 1, 2, or 3). Representative examples of bicyclic cycloalkenyls include, but are not limited to, norbornenyl and bicyclo[2.2.2]oct 2 enyl. In embodiments, fused bicyclic cycloalkenyl ring systems contain a monocyclic cycloalkenyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged or fused bicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkenyl ring. In embodiments, cycloalkenyl groups are optionally substituted with one or two groups which are independently oxo or thia. In embodiments, multicyclic cycloalkenyl rings contain a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. In embodiments, the multicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. In embodiments, multicyclic cycloalkenyl rings contain a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl.

[0065] In embodiments, a heterocycloalkyl is a heterocyclyl. The term “heterocyclyl” as used herein, means a monocyclic, bicyclic, or multicyclic heterocycle. The heterocyclyl monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S where the ring is saturated or unsaturated, but not aromatic. The 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N and S. The 5 membered ring can contain zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. The heterocyclyl monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocyclyl monocyclic heterocycle. Representative examples of heterocyclyl monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3- dioxanyl, 1,3-dioxolanyl, 1, 3 -di thiol any 1, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The heterocyclyl bicyclic heterocycle is a monocyclic heterocycle fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocycle, or a monocyclic heteroaryl. The heterocyclyl bicyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system. Representative examples of bicyclic heterocyclyls include, but are not limited to, 2,3- dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-l-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-lH- indolyl, and octahydrobenzofuranyl. In embodiments, heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5 or 6 membered monocyclic heterocyclyl ring fused to a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl is optionally substituted by one or two groups which are independently oxo or thia. Multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. The multicyclic heterocyclyl is attached to the parent molecular moiety through any carbon atom or nitrogen atom contained within the base ring. In embodiments, multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl. Examples of multicyclic heterocyclyl groups include, but are not limited to lOH-phenothiazin- 10-yl, 9,10-dihydroacridin-9-yl, 9,10- dihydroacridin- 10-yl, lOH-phenoxazin- 10-yl, 10,1 l-dihydro-5H-dibenzo[b,f]azepin-5-yl, l,2,3,4-tetrahydropyrido[4,3-g]isoquinolin-2-yl, 12H-benzo[b] phenoxazin- 12-yl, and dodecahydro-lH-carbazol-9-yl.

[0066] The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(Ci-C4)alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3 -bromopropyl, and the like.

[0067] The term “acyl” means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0068] The term “aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. The term “heteroaryl” refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term “heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6- fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1- naphthyl, 2-naphthyl, 4-biphenyl, 1 -pyrrolyl, 2-pyrrolyl, 3 -pyrrolyl, 3 -pyrazolyl, 2-imidazolyl, 4- imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4- isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3- thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2- benzimidazolyl, 5-indolyl, 1 -isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3- quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An “arylene” and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen.

[0069] A fused ring heterocyloalkyl-aryl is an aryl fused to a heterocycloalkyl. A fused ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl. A fused ring heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl. A fused ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl. Fused ring heterocycloalkyl-aryl, fused ring heterocycloalkyl-heteroaryl, fused ring heterocycloalkyl- cycloalkyl, or fused ring heterocycloalkyl-heterocycloalkyl may each independently be unsubstituted or substituted with one or more of the substitutents described herein.

[0070] Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different.

Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g. substituents for cycloalkyl or heterocycloalkyl rings). Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g. all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring. When referring to a spirocyclic ring system, substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.

[0071] The symbol ■” denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.

[0072] he term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom. [0073] The term “alkylsulfonyl,” as used herein, means a moiety having the formula -S(O2)-R', where R' is a substituted or unsubstituted alkyl group as defined above. R' may have a specified number of carbons (e.g., “C1-C4 alkylsulfonyl”).

[0074] The term “alkylarylene” as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene group has the formula:

[0075] An alkylarylene moiety may be substituted (e.g. with a substituent group) on the alkylene moiety or the arylene linker (e.g. at carbons 2, 3, 4, or 6) with halogen, oxo, -N3, -CF3, -CCI3, - CBn, -CI3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CH3 -SO3H, , -OSO3H, - SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted C1-C5 alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl). In embodiments, the alkylarylene is unsubstituted.

[0076] Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “cycloalkyl,” “heterocycloalkyl,” “aryl,” and “heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0077] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR', =0, =NR', =N-0R', -NR'R", -SR', -halogen, -SiR'R'R'", -OC(O)R', - C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)₂R', -NR- C(NR'R"R"')=NR"", -NR-C(NR'R")=NR"', -S(O)R', -S(O)₂R', -S(O)₂NR'R", -NRSO2R', -NR'NR"R"', -ONR'R", -NR'C(O)NR"NR"'R"", -CN, -NO2, -NR'SO₂R", -NR'C(O)R", - NR'C(O)-OR", -NR'OR", in a number ranging from zero to (2m'+l), where m' is the total number of carbon atoms in such radical. R, R', R", R'", and R"" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R'", and R"" group when more than one of these groups is present. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e g., -CF3 and -CH2CF3) and acyl (e g., -C(O)CH₃, -C(O)CF₃, -C(O)CH₂OCH₃, and the like). [0078] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: -OR', -NR'R", -SR', -halogen, - SiR'R'R'", -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'- C(O)NR"R"', -NR"C(O)₂R', -NR-C(NR'R"R"')=NR"", -NR-C(NR'R")=NR"', -S(O)R', -S(O)₂R', - S(O)₂NR'R", -NRSOzR', -NR'NR"R'", -ONR'R", -NR'C(O)NR"NR'"R"", -CN, -NO₂, -R', -N3, - CH(Ph)₂, fluoro(Ci-C₄)alkoxy, and fluoro(Ci-C₄)alkyl, -NR'SO₂R", -NR'C(O)R", -NR'C(O)- OR", -NR'OR", in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R", R'", and R"" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R'", and R"" groups when more than one of these groups is present.

[0079] Substituents for rings (e.g. cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent). In such a case, the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings). When a substituent is attached to a ring, but not a specific atom (a floating substituent), and a subscript for the substituent is an integer greater than one, the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different. Where a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent), the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency. Where a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms. Where the ring heteroatoms are shown bound to one or more hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency.

[0080] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ringforming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ringforming substituents are attached to non-adjacent members of the base structure.

[0081] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR')q-U-, wherein T and U are independently -NR-, -O-, - CRR'-, or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O) -, - S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR')s-X'- (C"R"R"')d-, where s and d are independently integers of from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R", and R'" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0082] As used herein, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0083] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those that are known in art to be too unstable to synthesize and/or isolate. The present disclosure is meant to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[0084] As used herein, the term “isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.

[0085] The term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.

[0086] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.

[0087] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0088] “Analog,” or “analogue” is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called “reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.

[0089] Descriptions of compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.

[0090] As used herein, the term “salt” refers to acid or base salts of the compounds used in the methods of the present invention. Illustrative examples of acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.

[0091] The term “pharmaceutically acceptable salts” is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0092] Thus, the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids. The present disclosure includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g. methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art.

[0093] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0094] In addition to salt forms, the present disclosure provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Prodrugs of the compounds described herein may be converted in vivo after administration. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent.

[0095] Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure. Methods of Use

[0096] In an aspect, provided herein is a method of treatment of coronavirus infection in a mammal, including administering to the mammal an effective dose of a compound of formula (I), (II) or (III):

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof. Each R¹ and R^3a is independently hydrogen, halogen, haloalkyl, -OH, C1-C5 alkoxy, -NO2, -CN, or Ci- C5 alkyl. Each R⁴ and R⁵ is independently H or C1-C5 alkyl. Each R² and R³ is independently hydrogen, -OH, halogen, -NO2, haloalkyl, C1-C5 alkoxy, C1-C5 alkyl, -NH2, C1-C5 alkylamino, or C1-C5 alkylthio. L¹ is -O-, -S-, -C(O)-, -NH-, -N(H)C(O)- or -C(O)N(H). n is 0 to 4, m is 0 to 4, v is 0 to 5, x is 0 to 5, and z is 0 to 4.

[0097] In an aspect, provided herein is a method of treatment of coronavirus infection in a mammal, including administering to the mammal an effective dose of a compound of formula (I), (II) or (III):

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof, in combination with one or more other compounds useful in the treatment of SARS-CoV-2 infection. Each R¹ and R^3a is independently hydrogen, halogen, haloalkyl, -OH, C1-C5 alkoxy, -NO2, -CN, or C1-C5 alkyl. Each R⁴ and R⁵ is independently H or C1-C5 alkyl. Each R² and R³ is independently hydrogen, -OH, halogen, -NO2, haloalkyl, C1-C5 alkoxy, C1-C5 alkyl, -NH2, C1-C5 alkylamino, or C1-C5 alkylthio. L¹ is -O-, -S-, -C(O)-, -NH-

, -N(H)C(O)- or -C(O)N(H). n is 0 to 4, m is 0 to 4, v is 0 to 5, x is 0 to 5, and z is 0 to 4.

[0098] In embodiments, R¹ is -I, -Br, -F, or -Cl. In embodiments, R¹ is -I. In embodiments, R¹ is -Cl. In embodiments, R¹ is-F. In embodiments, R¹ is -Br.

[0099] In embodiments, R² is hydrogen, halogen, C1-C5 alkoxy, or haloalkyl. In embodiments, R² is hydrogen. In embodiments, R² is halogen. In embodiments, R² is C1-C5 alkoxy. In embodiments, R² is haloalkyl.

[00100] In embodiments, R² is -I, -Br, -F, or -Cl. In embodiments, R² is -I. In embodiments, R² is -Cl. In embodiments, R² is-F. In embodiments, R² is -Br. [00101] In embodiments, R² is halo(Ci-Cs) alkyl. In embodiments, R² is halo(Ci) alkyl. In embodiments, R² is halo(C2) alkyl. In embodiments, R² is halo(C3) alkyl. In embodiments, R² is halo(C4) alkyl. In embodiments, R² is halo(C5) alkyl.

[00102] In embodiments, R² is fluoro(Ci-C5) alkyl. In embodiments, R² is chloro(Ci-C5) alkyl. In embodiments, R² is iodo(Ci-C5) alkyl. In embodiments, R² is bromo(Ci-C5) alkyl.

[00103] In embodiments, R² is fluoro(Ci) alkyl. In embodiments, R² is chloro(Ci) alkyl. In embodiments, R² is iodo(Ci) alkyl. In embodiments, R² is bromo(Ci) alkyl.

[00104] In embodiments, R² is fluoro(C2) alkyl. In embodiments, R² is chloro(C2) alkyl. In embodiments, R² is iodo(C2) alkyl. In embodiments, R² is bromo(C2) alkyl.

[00105] In embodiments, R² is fluoro(C3) alkyl. In embodiments, R² is chloro(C3) alkyl. In embodiments, R² is iodo(C3) alkyl. In embodiments, R² is bromo(C3) alkyl.

[00106] In embodiments, R² is fluoro(C4) alkyl. In embodiments, R² is chloro(C4) alkyl. In embodiments, R² is iodo(C4) alkyl. In embodiments, R² is bromo(C4) alkyl.

[00107] In embodiments, R² is fluoro(C5) alkyl. In embodiments, R² is chloro(C5) alkyl. In embodiments, R² is iodo(Cs) alkyl. In embodiments, R² is bromo(C5) alkyl.

[00108] In embodiments, R² is -CF3, -CI3, CBn, or -CCh. In embodiments, R² is -CF3. In embodiments, R² is -CI3. In embodiments, R² is -CBn. In embodiments, R² is -CCh.

[00109] In embodiments, R² is C1-C5 alkoxy. In embodiments, R² is methoxy, ethoxy, propoxy, butoxy, or pentoxy. In embodiments, R² is methoxy. In embodiments, R² is ethoxy. In embodiments, R² is propoxy. In embodiments, R² is butoxy. In embodiments, R² is pentoxy.

[00110] In embodiments, R³ is hydrogen or halogen. In embodiments, R³ is hydrogen. In embodiments, R³ is halogen.

[00111] In embodiments, R³ is -Cl. In embodiments, R³ is -F. In embodiments, R³ is -Br. In embodiments, R³ is -I.

[00112] In embodiments, R⁴ is hydrogen or C1-C5 alkyl. In embodiments, R⁴ is hydrogen. In embodiments, R⁴ is C1-C5 alkyl.

[00113] In embodiments, R⁴ is methyl, ethyl, propyl, butyl, or pentyl. In embodiments, R⁴ is methyl. In embodiments, R⁴ is ethyl. In embodiments, R⁴ is propyl. In embodiments, R⁴ is butyl. In embodiments, R⁴ is pentyl.

[00114] In embodiments, R⁵ is hydrogen or C1-C5 alkyl. In embodiments, R⁵ is hydrogen. In embodiments, R⁵ is C1-C5 alkyl. [00115] In embodiments, R⁵ is methyl, ethyl, propyl, butyl, or pentyl. In embodiments, R⁵ is methyl. In embodiments, R⁵ is ethyl. In embodiments, R⁵ is propyl. In embodiments, R⁵ is butyl. In embodiments, R⁵ is pentyl.

[00116] In embodiments, R^3a is hydrogen, halogen or haloalkyl. In embodiments, R^3a is hydrogen. In embodiments, R^3a is halogen. In embodiments, R^3a is haloalkyl.

[00117] In embodiments, R^3a is -Cl. In embodiments, R^3a is -F. In embodiments, R^3a is -Br. In embodiments, R^3a is -I.

[00118] In embodiments, R^3a is halo(Ci-Cs) alkyl. In embodiments, R^3a is halo(Ci) alkyl. In embodiments, R^3a is halo(C2) alkyl. In embodiments, R^3a is halo(C3) alkyl. In embodiments, R^3a is halo(C4) alkyl. In embodiments, R^3a is halo(C5) alkyl.

[00119] In embodiments, R^3a is fluoro(Ci-C5) alkyl. In embodiments, R^3a is chloro(Ci-C5) alkyl. In embodiments, R^3a is iodo(Ci-C5) alkyl. In embodiments, R^3a is bromo(Ci-C5) alkyl.

[00120] In embodiments, R^3a is fluoro(Ci) alkyl. In embodiments, R^3a is chloro(Ci) alkyl. In embodiments, R^3a is iodo(Ci) alkyl. In embodiments, R^3a is bromo(Ci) alkyl.

[00121] In embodiments, R^3a is fluoro(C2) alkyl. In embodiments, R^3a is chloro(C2) alkyl. In embodiments, R^3a is iodo(C2) alkyl. In embodiments, R^3a is bromo(C2) alkyl.

[00122] In embodiments, R^3a is fluoro(C3) alkyl. In embodiments, R^3a is chloro(C3) alkyl. In embodiments, R^3a is iodo(C3) alkyl. In embodiments, R^3a is bromo(C3) alkyl.

[00123] In embodiments, R^3a is fluoro(C4) alkyl. In embodiments, R^3a is chloro(C4) alkyl. In embodiments, R^3a is iodo(C4) alkyl. In embodiments, R^3a is bromo(C4) alkyl.

[00124] In embodiments, R^3a is fluoro(C5) alkyl. In embodiments, R^3a is chloro(C5) alkyl. In embodiments, R^3a is iodo(Cs) alkyl. In embodiments, R^3a is bromo(C5) alkyl.

[00125] In embodiments, R^3a is -CF3, -CI3, CBn, or -CCI3. In embodiments, R^3a is -CF3. In embodiments, R^3a is -CI3. In embodiments, R^3a is -CBn. In embodiments, R^3a is -CCI3.

[00126] In embodiments, n is 0. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4.

[00127] In embodiments, m is 0. In embodiments, m is 1. In embodiments, m is 2. In embodiments, m is 3. In embodiments, m is 4.

[00128] In embodiments, v is 0. In embodiments, v is 1. In embodiments, v is 2. In embodiments, v is 3. In embodiments, v is 4. In embodiments, v is 5. [00129] In embodiments, x is 0. In embodiments, x is 1. In embodiments, x is 2. In embodiments, x is 3. In embodiments, x is 4. In embodiments, x is 5.

[00130] In embodiments, z is 0. In embodiments, z is 1. In embodiments, z is 2. In embodiments, z is 3. In embodiments, z is 4.

[00131] In embodiments, L¹ is -O-, -S-, or -C(O)-. In embodiments, L¹ is -O-. In embodiments, L¹ is -S-. In embodiments, L¹ is -C(O)-.

[00132] In embodiments, provided herein is a method of treatment of coronavirus infection in a mammal, including administering to the mammal an effective dose of a compound having the structure:

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof.

[00133] In embodiments, provided herein is a method of treatment of coronavirus infection in a mammal, including administering to the mammal an effective dose of a compound having the structure:

niclosamide (17) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof.

[00134] In embodiments, provided herein is a method of treatment of coronavirus infection in a mammal, including administering to the mammal an effective dose of a compound having the structure:

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof.

[00135] In embodiments, coronavirus infection is HCoV-OC43, HCoV-HKUl, HCoV-229E, HCoV-NL63, MERS-CoV, SARS-CoV or SARS-CoV-2 infection.

[00136] In embodiments, coronavirus infection is MERS-CoV, SARS-CoV or SARS-CoV-2 infection.

[00137] In embodiments, coronavirus infection is (COVID-19) SARS-CoV-2 infection.

[00138] In embodiments, the effective dose of the compound of formula (I), (II) or (III) is from about 0.01 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 75 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, from about 0.01 mg/kg to about 20 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.01 mg/kg to about 5 mg/kg, from about 0.01 mg/kg to about 1 mg/kg, from about 0.1 mg/kg to about 100 mg/kg, from about 0.1 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 25 mg/kg, or from about 0.1 mg/kg to about 10 mg/kg.

[00139] In embodiments, the effective dose of the compound of formula (I), (II) or (III) is about 0.01 mg/kg, about 0.02 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 5 mg/kg, about 10 mg/kg, about 25 mg/kg, about 50 mg/kg, about 100 mg/kg, about 200 mg/kg, or about 500 mg/kg.

[00140] In embodiments, the effective dose of the compound of formula (I), (II) or (III) is about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 40 mg/kg, about 50 mg/kg, about 75 mg/kg, or about 100 mg/kg.

[00141] In embodiments, the compound of formula (I), (II) or (III) is administered at a concentration of about 0.1 mM, about 0.5 mM, about 1 mM, about 2.5 mM, about 5 mM, about 7.5 mM, about 10 mM, about 15 mM, about 20 mM, about, 25 mM, about 30 mM, about 50 mM, about 100 mM, about 200 mM, or about 500 mM.

[00142] In embodiments, therapeutic compositions of the present disclosure may be administered with a pharmaceutically acceptable diluent, carrier, or excipient, in unit dosage form. Administration can be parenteral (e.g., intravenous, subcutaneous), oral, or topical, as nonlimiting examples.

[00143] The composition can be in the form of a pill, tablet, capsule, liquid, or sustained release tablet for oral administration; or a liquid for intravenous, subcutaneous, or parenteral administration; gel, lotion, ointment, cream, or a polymer or other sustained release vehicle for local administration.

[00144] Methods well known in the art for making formulations are found, for example, in "Remington: The Science and Practice of Pharmacy" (20th ed., ed. A. R. Gennaro A R., 2000, Lippincott Williams & Wilkins, Philadelphia, Pa.). Formulations for parenteral administration may, for example, contain excipients, sterile water, saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes. Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylenepolyoxypropylene copolymers may be used to control the release of the compounds. Nanoparticulate formulations (e.g., biodegradable nanoparticles, solid lipid nanoparticles, liposomes) may be used to control the biodistribution of the compounds. Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. The concentration of the compound in the formulation varies depending upon a number of factors, including the dosage of the drug to be administered, and the route of administration.

[00145] Compounds described herein may be optionally administered as a pharmaceutically acceptable salt, such as non-toxic acid addition salts or metal complexes that are commonly used in the pharmaceutical industry. Examples of acid addition salts include organic acids such as acetic, lactic, pamoic, maleic, citric, malic, ascorbic, succinic, benzoic, palmitic, suberic, salicylic, tartaric, methanesulfonic, toluenesulfonic, or trifluoroacetic acids or the like; polymeric acids such as tannic acid, carboxymethyl cellulose, or the like; and inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid phosphoric acid, or the like. Metal complexes include zinc, iron, and the like.

[00146] Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose and sorbitol), lubricating agents, glidants, and anti-adhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc).

[00147] Formulations for oral use may also be provided as chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium.

[00148] A therapeutically effective dose refers to a dose that produces the therapeutic effects for which it is administered. The exact dose will depend on the disorder to be treated and may be ascertained by one skilled in the art using known techniques.

[00149] It will be understood, however, that the specific dose level and frequency of dosage for any particular subject can be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

[00150] In embodiments the mammal is a dog, a cat or a human. In embodiments, the mammal is a dog. In embodiments, the mammal is a cat. In embodiments, the mammal is a human.

[00151] In embodiments, provided herein are methods of treating SAR.S-CoV-2 infection in a subject, comprising administering to the subject having SARS-CoV-2 infection a therapeutically effective amount of a combination comprising a salicylanilide analog and one or more other compounds useful in the treatment of SARS-CoV-2 infection. In embodiments, the salicylanilide analog is a compound of Formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof. In embodiments, the salicylanilide analog is a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In embodiments, the salicylanilide analog is a compound of Formula (II) or a pharmaceutically acceptable salt thereof. In embodiments, the salicylanilide analog is a compound of Formula (III) or a pharmaceutically acceptable salt thereof.

[00152] In embodiments, the salicylanilide analog is administered in combination with one or more other compounds useful in the treatment of SARS-CoV-2 infection. The one or more other compounds may be administered before, simultaneously with, or after the salicylanilide analog. The one or more other compounds may be provided in the same composition as the salicylanilide analog or in separate compositions. In embodiments, the other compound useful in the treatment of SARS-CoV-2 infection is a therapeutic antibody. In embodiments, the other compound useful in the treatment of SARS-CoV-2 infection is a therapeutic peptide or protein. In embodiments, the other compound useful in the treatment of SARS-CoV-2 infection is a therapeutic peptide. In embodiments, the other compound useful in the treatment of SARS-CoV-2 infection is a therapeutic protein. In embodiments, the therapeutic peptide has a length of 50 or fewer amino acids and/or the therapeutic protein has a length of 51 or greater amino acids. In embodiments, the other compound useful in the treatment of SARS-CoV-2 infection is a small molecule antiviral.

[00153] In embodiments, the salicylanilide analog can be combined with a therapeutic antibody. In embodiments, the therapeutic antibody is a neutralizing antibody. In embodiments, the salicylanilide analog is a compound of Formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof.

[00154] In embodiments, the salicylanilide analog can be combined with a small molecule antiviral. In embodiments, the salicylanilide analog can be combined with a therapeutic peptide. In embodiments, the salicylanilide analog can be combined with a therapeutic protein. In embodiments, the salicylanilide analog is a compound of Formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof. [00155] In embodiments, compound of Formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof and a therapeutic antibody are administered sequentially, and in any order.

[00156] In one embodiment, compound of Formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof and a therapeutic antibody are administered concomitantly.

[00157] In embodiments, compound of Formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof and a neutralizing antibody are administered sequentially, and in any order.

[00158] In one embodiment, compound of Formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof and a neutralizing antibody are administered concomitantly.

[00159] In embodiments, compound of Formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof and a small molecule anti-viral are administered sequentially, and in any order.

[00160] In one embodiment, compound of Formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof and a small molecule anti-viral are administered concomitantly.

[00161] In embodiments, compound of Formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof and a therapeutic peptide or a protein are administered sequentially, and in any order.

[00162] In one embodiment, compound of Formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof and a therapeutic peptide or a protein are administered concomitantly.

[00163] The disclosure will be further understood by the following non-limiting examples.

Examples

[00164] As used herein, the symbols and conventions used in these processes, schemes and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society, the Journal of Medicinal Chemistry, or the Journal of Biological Chemistry.

Example 1

Synthesi s of 3 , 5 -dichloro-A-(4-(4-chlorophenoxy)-3 , 5 -bi s(trifluoromethyl)phenyl)-2- hydroxybenzamide (30)

[00165] Compound 30 was prepared as shown in Scheme 1 below.

[00166] Compound 2. Compound 1 (1 g, 3.41 mmol) was added to a solution of H2SO4 (2.1 ml)/HNCh (1.5 ml). The mixture was heated at 70 °C for 2 h and then cooled to room temperature. The mixture was then poured into ice water and extracted with ethyl acetate (300 mL). The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the crude compound 2 as a solid, which was used for next reaction directly without purification.

[00167] Compound 3. 4-chlorophenol (438 mg, 3.41 mmol) was dissolved in DMF (10ml) and added to compound 2 (about 3.41 mmol), followed by addition of K2CO3 (470 mg, 3.4 mmol). The mixture was stirred at room temp for 1 h and quenched with water. The mixture was extracted with ethyl acetate (300 mL). The organic layer was then washed with IN aqueous NaOH, brine, dried over Na2SO4, filtered, and concentrated to afford crude compound 3 as a brown oil, which was used for next reaction directly without purification.

[00168] Compound 4. Compound 3 (about 3.41 mmol) was dissolved in EtOH (5 mL). Zn dust (2.2 g) and ammonium formate (2 g) was added. The mixture was stirred at 40 °C for 1 h. LCMS shows the formation of the product. The mixture was filtered through Celite and washed with ethyl acetate (300 mL). The organic layer was washed with brine and concentrated to give a residue, which was purified by silica gel column chromatography eluting with 10% EtOAc/hexane to give the product as an oil (280 mg).

[00169] Compound 30. A mixture of compound 4 (142 mg, 0.39 mmol), 3,5-dichlorosalicyclic acid (105 mg, 0.5 mmol) and P(OMe)i (155 mg, 0.5 mmol) in toluene (3 mL) was heated at 110 °C for 12 h. The mixture was then cooled to room temp and concentrated to give a residue, which as purified by silica gel column chromatography (10% EtOAC/hexane) to give the product compound 30 as a white solid (106 mg). 1H NMR (400 MHz, acetone-d6) 6 6.88-6.93 (m, 2H), 7.35-7.39 (m, 2H), 7.73 (d, J = 2.5 Hz, 1H), 8.10 (d, J = 2.5 Hz, 1H), 8.59 (s, 2H), 10.5 (s, 1H). MS(ESI): 543 (M+H).

Example 2

[00170] In vitro Efficacy Testing of compounds 17, 23, 26, 30, 44, and 50 against SARS-CoV-2 [00171] Vero cells were inoculated with MOI 0.05 of SARS-CoV-2 premixed with indicated doses of test compounds (0.05 mL/well). At least three wells were used as a negative control and were mock-infected and three wells were served as a virus control and were infected. All control wells were untreated with test compounds. After 1 hour of incubation at 37C@5%CO2, wells were washed 3 times with dilution media and 0.5 mL of media containing the indicated compound doses (2.5 uM, 5 uM, 10 uM, or 20 uM) was added back to each well. 0.5 mL of dilution media per a well was added to untreated wells. Cells were incubated at 37C@5%CO2 and samples collected at 0 and 24 hours post-infection. Collected 100 uL timepoint media was replaced with equal amount of compound doses or dilution media (untreated wells). Samples were stored at -80°C till the day of analysis. The SARS-CoV-2 titer in Vero cells via 50% tissue culture infectious disease dose assay (TCID50) was performed for each sample collected at 0 and 24 hours post infection. Results of this assay demonstrated that compound 30 displayed the best efficacy in reducing viral infectivity among compounds tested. Results of the SARS-CoV-2 titer in Vero cells via TCID50 for compound 30 are shown in FIG. 1 A. Results of the SARS-CoV-2 titer in Vero cells via TCID50 for compound 17 (niclosamide) are shown in FIG. IB.

[00172] Log reduction was calculated from the TCID50 data obtained for each compound at 20pM. FIGS. 2A and 2B show the log reduction of antiviral compounds 17, 23, 26, 30, 44, and 50 (at 20 pM) against SARS-CoV-2 after 24 hours post infection. Example 3

[00173] In vitro cytotoxicity and efficacy testing of compounds 17 (niclosamide) and 30.

[00174] Efficacy testing was carried out as described above in example 2, but with a 72-hour post infection period. Toxicity was evaluated using an ATP -based cell viability assay with a 72 hour exposure period to the drugs. Cytotoxicity testing was carried out as follows: Vero cells were cultured according to the manufacturer’s protocol. The cells were adhered to wells in opaque 96- well plates by incubating 2xl0⁴ cells per well in 100 pL of Dulbecco’s modified Eagle medium (DMEM) containing 7% fetal bovine serum (FSB) at 37°C in a 5% CO2 humidifying chamber for 24 hours. After discarding the media, the cells were then treated with either compound 30 or compound 17 (niclosamide) in the range 0.024-25 pM in DMEM. After 72 hours of incubation, an ATP -based assay was performed at 37°C in a 5% CO2 humidifying chamber for 10 min using the Cell Titer Gio luminescent cell viability assay kit (Promega, Madison, WI) per the manufacturer’s instructions. The data was normalized to a positive control (DMEM with cells only and no drug), and the background using a negative control (0.2 mM digitonin in DMEM with cells) was subtracted. These assays were performed in duplicate.

[00175] Compound 30 (FIG. 3 A) and 17 (niclosamide) (FIG. 3B) showed best activity against the virus with comparable ICsos at 0.74 pM. Compound 17 (niclosamide) (FIG. 3B) showed about 5- fold greater toxicity (EC50 = 0.25 +/- 0.011 pM) than compound 30 (FIG. 3 A) EC50 = 1.22 +/- 0.031 pM. Moreover, therapeutic index of compound 30 is significantly better (1.65) than that of compound 17 (niclosamide) (0.34).

Example 4

[00176] Prophylactic mouse model of SARS-CoV-2 infection and quantification of viral titers and cytokine levels.

[00177] B6Cg-Tg(K18-ACE2)2Prlmn/J female mice (7-9 weeks of age) were used. Mice were maintained in pathogen-free conditions and handling conforming to the requirements of the National Institutes of Health and the Scripps Research Institute Animal Research Committee. SARS-CoV-2 strain USA-WA1/2020 (BEI Resourced NR-52281) was grown on Vero cells using complete DMEM containing 10% FBS and lx PenStrep. Mice were treated orally twice a day, for a total of 5 days, either with vehicle, molnupiravir (EIDD-2801; 500 mg / kg) or compound 30 (5 mg/kg) starting 24 hours pre infection, mice were infected intranasally with 10⁴ PFU / 50 pl PBS. Weight loss was measured daily. Three independent trials were run with n=5 mice.

[00178] Lungs were collected in 1 ml complete DMEM and processed with mini-bead beater bead homogenizer. Supernatants were titrated on Vero cells; an overlay of 1% methyl cellulose was added and plates were incubated in 37°C for 3 days. Cells were fixed with PFA/PBS 4 % and stained with crystal violet. Multiplex ELISA (Biorad; Hercules, CA) was performed to detect cytokines in BALF according to manufacturer’s instructions. Data is expressed as mean +/- SEM. An unpaired, one-tailed Student’s t-test was calculated using GraphPad Prism to perform a statistical comparison between groups. A statistical comparison of two groups was performed by two-way ANOVA. Non-linear regression curve-fitting of cell viability and viral activity was calculated using the log(inhibitor) vs response (variable slope) method in GraphPad Prism.

[00179] In this study molnupiravir (also known as EDD-2801/MK-4482), which is a prodrug of the antiviral ribonucleoside analogue P-D-N4-hydroxy cytidine (NHC; EIDD-1931) was used as a positive control. Molnupiravir was chosen based on its ability to treat infections caused by multiple RNA viruses including SARS-CoV-2 (Rosenke et al. (2021) Nat. Commun. 12: 1-8; Stuyver et al. (2003) Antimicrob. Agents Chemother. 47:244-254). Three groups of transgenic hACE-2 mice (n=5) were infected as described above and then treated orally, as described above, with either vehicle (negative control), molnupiravir (EIDD-2801, positive control), or compound 30. (Day 0). The oral doses were administered twice a day at 12-hr intervals for a total of five days. Twenty-four hours after the first dose, all three groups were intranasally infected with 10,000 plaque-forming units (PFU) of SARS-CoV-2 on Day 1 (FIG. 4A).

[00180] The non-treated group (vehicle) averaged a 10% weight loss by Day 4 while the treated groups (compound 30 and EIDD-2801) displayed no clinical signs and maintained healthy weights throughout the course of the experiment (FIG. 4B). Lung viral titer results revealed that mice treated with compound 30 averaged approximately 10-fold lower viral titers than the vehicle, with EIDD-2801 displaying no measurable titer levels (FIG. 4C).

[00181] Concentrations of various cytokines in the bronchoalveolar lavage fluids from the three treatment groups of mice were examined. Specifically, the effect of compound 30 on the interleukin-6 (IL-6), monocyte chemoattractant protein- 1 (MCP-1), granulocyte-macrophage colony-stimulating factor (G-CSF) and eotaxin concentrations were examined due to their upregulation in and predictive value for severe cases of COVID-19 in patients (Xi et al. (2021) Virol. J. 18: 1-7). Compound 30 reduced IL-6, MCP-1 and G-CSF levels by 8-, 3.5- and 10-fold, respectively, relative to untreated mice (FIGS. 5A-C). Moreover, with respect to IL-6 and MCP- 1, the reduction of cytokine concentrations was on par with EIDD-2801 (FIG. 5 A and FIG. 5C). However, a significant difference in the concentration of eotaxin was not observed in the three groups of mice (FIG. 5D).

[00182] The findings from the SARS-CoV-2 mouse model illustrate that compound 30 can partially suppress viral replication in the host. More importantly, compound 30 was able to prevent elevation of key contributors of inflammation typically found in the more advanced stages of COVID-19. Noteworthy was that compound 30 was dosed approximately 100-fold less than EIDD-2801. These results suggest that salicylanilide analogs could present a dual mechanism of action against SARS-CoV-2. One that both inhibits viral replication and attenuates the production of a subset of inflammatory cytokines.

[00183] The results show that compound 30, which is orally available, can reduce viral titers, weight loss associated with viral infection, as well as lung inflammation in a mouse model.

[00184] The complete disclosures of all publications cited herein are incorporated herein by reference in their entireties as if each were individually set forth in full herein and incorporated.

[00185] Various modifications and alterations to the embodiments disclosed herein will become apparent to those skilled in the art without departing from the scope and spirit of this disclosure. Illustrative embodiments and examples are provided as examples only and are not intended to limit the scope of the present invention.

Claims

CLAIMS:

1. A method of treatment of coronavirus infection in a mammal, comprising administering to the mammal an effective dose of a compound of formula (I), (II) or (III):

U) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof, wherein: each R¹ and R^3a is independently hydrogen, halogen, haloalkyl, -OH, C1-C5 alkoxy, -NO2, -CN, or C1-C5 alkyl; each R⁴ and R⁵ is independently H or C1-C5 alkyl; each R² and R³ is independently hydrogen, -OH, halogen, -NO2, haloalkyl, C1-C5 alkoxy, C1-C5 alkyl, -NH2, C1-C5 alkylamino, or C1-C5 alkylthio;

L¹ is -O-, -S-, -C(O)-, -NH-, -N(H)C(O)- or -C(O)N(H); n is 0 to 4; m is 0 to 4; v is 0 to 5; x is 0 to 5; and z is 0 to 4.

2. The method of claim 1, wherein L¹ is O.

3. The method of claim 1 or 2, wherein R⁴ is H.

4. The method of any one of claims 1-3, wherein R⁵ is H.

5. The method of any one of claims 1-4, wherein R¹ is halogen.

6. The method of claim 5, wherein R¹ is -Cl.

7. The method of any one of claims 1-6, wherein R² is halogen, C1-C5 alkoxy, or haloalkyl.

8. The method of claim 7, wherein R² is -Cl, -OCH3, or -CF3.

9. The method of any one of claims 1-8, wherein R³ is halogen or C1-C5 alkoxy.

10. The method of claim 9, wherein R³ is -Cl or -OCH3.

11. The method of any one of claims 1-10, wherein R^3a is haloalkyl.

12. The method of claim 11, wherein R^3a is -CF3.

13. The method of claim 1, wherein the compound of formula (I) is selected from the group consisting of:

(30) (50) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof.

14. The method of claim 1, wherein the compound of formula (II) is:

niclosamide (17) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof.

15. The method of claim 1, wherein the compound of formula (III) is:

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof.

16. The method of any one of claims 1-15, wherein the coronavirus infection is selected from the group consisting of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and COVID-19 (SARS-CoV-2) infection.

17. The method of claim 16, wherein the coronavirus infection is COVID-19 (SARS-CoV-2) infection.

18. The method of any one of claims 1-17, wherein the compound of formula (I), (II) or (III) is administered at a concentration of about 0.1 pM, about 0.5 pM, about 1 pM, about 2.5 pM, about 5 pM, about 7.5 pM, about 10 pM, about 15 pM, about 20 pM, about, 25 pM, about 30 pM, about 50 pM, about 100 pM, about 200 pM, or about 500 pM.

19. The method of claim 1, wherein the effective dose of the compound of formula (I), (II) or (III) is about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 40 mg/kg, about 50 mg/kg, about 75 mg/kg, or about 100 mg/kg.

20. A method of treatment of coronavirus infection in a mammal, comprising administering to the mammal an effective dose of a compound of formula (I), (II) or (III):

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof, in combination with one or more other compounds useful in the treatment of SARS-CoV-

2 infection, wherein: each R¹ and R^3a is independently hydrogen, halogen, haloalkyl, -OH, C1-C5 alkoxy, -NO2, -CN, or C1-C5 alkyl; each R⁴ and R⁵ is independently H or C1-C5 alkyl; each R² and R³ is independently hydrogen, -OH, halogen, -NO2, haloalkyl, C1-C5 alkoxy,

C1-C5 alkyl, -NH2, C1-C5 alkylamino, or C1-C5 alkylthio;

L¹ is -O-, -S-, -C(O)-, -NH-, -N(H)C(O)- or -C(O)N(H); n is 0 to 4; m is 0 to 4; v is 0 to 5; and x is 0 to 5.

21. The method of claim 20, wherein the other compound useful in the treatment of SARS- CoV-2 infection is a therapeutic antibody.

22. The method of claim 20, wherein the other compound useful in the treatment of SARS- CoV-2 infection is a therapeutic peptide or protein.

23. The method of claim 20, wherein the other compound useful in the treatment of SARS- CoV-2 infection is a small molecule anti-viral.

24. The method of any one of claims 20-23, wherein L¹ is O.

25. The method of any one of claims 20-24, wherein R⁴ is H.

26. The method of any one of claims 20-25, wherein R⁵ is H.

27. The method of any one of claims 20-26, wherein R¹ is halogen.

28. The method of claim 27, wherein R¹ is -Cl.

29. The method of any one of claims 20-28, wherein R² is halogen, C1-C5 alkoxy, or haloalkyl.

30. The method of claim 29, wherein R² is -Cl, -OCH3, or -CF3.

31. The method of any one of claims 20-30, wherein R³ is halogen or C1-C5 alkoxy.

32. The method of claim 31, wherein R³ is -Cl or -OCH3.

33. The method of any one of claims 20-32, wherein R^3a is haloalkyl.

34. The method of claim 33, wherein R^3a is -CF3.

35. The method of claim 20, wherein the compound of formula (I) is selected from the group consisting of:

(23) (26)

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof.

36. The method of claim 20, wherein the compound of formula (II) is:

niclosamide (17) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof.

37. The method of claim 20, wherein the compound of formula (III) is:

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof.

38. The method of any one of claims 20-37, wherein the coronavirus infection is selected from the group consisting of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and COVID-19 (SARS-CoV-2) infection.

39. The method of claim 38, wherein the coronavirus infection is COVID-19 (SARS-CoV-2) infection.