[0001] The disclosure is directed to antimicrobial, sulfur-containing compounds and methods of using them. BACKGROUND

[0002] Surgical site infections continue to be a risk factor in orthopedic surgery, as well as in stent and shunt implantation procedures. Particularly problematic are those infections caused by gram-negative bacteria, since standard cephalosporin prophylactic treatment does not treat gram- negative infections. Biofilm formation is also a significant risk factor in any implantation procedure. Biofilms are highly resistant to antibiotics and immune responses, as such, inhibiting biofilm formation can be critical to preventing post-surgical infection.

[0003] Small molecule antimicrobial compounds that are safe and effective are needed. SUMMARY

[0004] The disclosure is directed to compounds of formula I, as well as any stereoisomers of formula I:

wherein R ¹ is H, C _1-6 alkyl, or C _1-6 haloalkyl; R ² is H, C _1-6 alkyl, or C _1-6 haloalkyl; R ³ is H, C _1-6 alkyl, or C _1-6 haloalkyl; R ⁴ is H, C _1-6 alkyl, or C _1-6 haloalkyl; R ⁵ is H, C _1-6 alkyl, or C _1-6 haloalkyl; R ⁶ is H, C _{1- 6} alkyl, or C _1-6 haloalkyl; R ⁷ is H, C _1-6 alkyl, or C _1-6 haloalkyl; R ⁸ is H, C _1-6 alkyl, or C _1-6 haloalkyl; and n is 0, 1, or 2. Pharmaceutical compositions comprising a compound of formula I are also described, as well as medical devices that comprise a compound of formula I. Methods of using the compounds of formula I as antimicrobial agents is also described. DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0005] The disclosure may be more fully appreciated by reference to the following description, including the following definitions and examples. In this document, the terms“a” or “an” are used to include one or more than one and the term“or” is used to refer to a nonexclusive “or” unless otherwise indicated. In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. When a range of values is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent“about,” it will be understood that the particular value forms another embodiment. All ranges are inclusive and combinable. Further, reference to values stated in ranges includes each and every value within that range. Certain features of the disclosed compositions and methods which are described herein in the context of separate aspects may also be provided in combination in a single aspect. Alternatively, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single aspect, may also be provided separately or in any subcombination.

[0006] The term "alkyl," when used alone or as part of a substituent group, refers to a straight- or branched-chain alkyl group having from 1 to 6 carbons atoms (“C _1-6 ”), in the chain. Examples of alkyl groups include methyl (Me, C ₁ alkyl) ethyl (Et, C ₂ alkyl), n-propyl (C ₃ alkyl), isopropyl (C ₃ alkyl), butyl (C ₄ alkyl), isobutyl (C ₄ alkyl), sec-butyl (C ₄ alkyl), tert-butyl (C ₄ alkyl), pentyl (C ₅ alkyl), isopentyl (C ₅ alkyl), tert-pentyl (C ₅ alkyl), hexyl (C ₆ alkyl), isohexyl (C ₆ alkyl), and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.

[0007] When a range of carbon atoms is used herein, for example, C _1-6 , all ranges, as well as individual numbers of carbon atoms are encompassed. For example,“C _1-3 ” includes C _1-3 , C _1-2 , C _2-3 , C ₁ , C ₂ , and C ₃ .

[0008] The term "halogen" represents chlorine, fluorine, bromine, or iodine. The term "halo" represents chloro, fluoro, bromo, or iodo.

[0009] The term“haloalkyl” refers to an alkyl moiety wherein one or more of the hydrogen atoms has been replaced with one or more halogen atoms. One exemplary substitutent is fluoro. Preferred haloalkyl groups of the disclosure include trihalogenated alkyl groups such as

trifluoromethyl groups. [0010] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized

pharmacopoeia for use in animals, e.g., in humans.

[0011] “Subject” refers to an animal, including, but not limited to, a primate (e.g., human, monkey, chimpanzee, gorilla, and the like), rodents (e.g., rats, mice, gerbils, hamsters, ferrets, and the like), lagomorphs, swine (e.g., pig, miniature pig), equine, canine, feline, and the like. The terms “subject” and“patient” are used interchangeably herein when referencing, for example, a mammalian subject, such as a human patient.

[0012] “Treating” or“treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment“treating” or“treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment,“treating” or“treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment,“treating” or“treatment” refers to delaying the onset of the disease or disorder.

[0013] An "effective amount" means an amount or dose sufficient to generally bring about the desired therapeutic benefit in patients in need of such treatment for the designated disease, disorder, or condition. Effective amounts or doses of the compounds of the present disclosure may be ascertained by routine methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the compound, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician. An example of a dose is in the range of from about 0.001 to about 200 mg of compound per kg of subject's body weight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day, in single or divided dosage units (e.g., BID, TID, QID). For a 70-kg human, an illustrative range for a suitable dosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about 2.5 g/day. [0014] “Compounds of the present disclosure,” and equivalent expressions, are meant to embrace formula I as described herein, which expression may include the pharmaceutically acceptable salts, where the context so permits.

[0015] It is to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed“isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers,” for example, diastereomers and enantiomers.

[0016] Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images of each other are termed“enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R-and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a“racemic mixture.” The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

[0017] The present disclosure is directed to compounds of formula I, as well as the stereoisomers thereof:

wherein

R ¹ is H, C _1-6 alkyl, or C _1-6 haloalkyl;

R ² is H, C _1-6 alkyl, or C _1-6 haloalkyl;

R ³ is H, C _1-6 alkyl, or C _1-6 haloalkyl;

R ⁴ is H, C _1-6 alkyl, or C _1-6 haloalkyl;

R ⁵ is H, C _1-6 alkyl, or C _1-6 haloalkyl; R ⁶ is H, C _1-6 alkyl, or C _1-6 haloalkyl;

R ⁷ is H, C _1-6 alkyl, or C _1-6 haloalkyl;

R ⁸ is H, C _1-6 alkyl, or C _1-6 haloalkyl; and

n is 0, 1, or 2.

[0018] According to the disclosure, R ¹ is H, C _1-6 alkyl, or C _1-6 haloalkyl. In some aspects, R ¹ is H. In other aspects, R ¹ is C _1-6 alkyl, for example, C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, or C ₆ alkyl. In yet other aspects, R ¹ is C _1-6 haloalkyl, for example, C ₁ haloalkyl, C ₂ haloalkyl,

C ₃ haloalkyl, C ₄ haloalkyl, C ₅ haloalkyl, or C ₆ haloalkyl.

[0019] According to the disclosure, R ² is H, C _1-6 alkyl, or C _1-6 haloalkyl. In some aspects, R ² is H. In other aspects, R ² is C _1-6 alkyl, for example, C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, or C ₆ alkyl. In yet other aspects, R ² is C _1-6 haloalkyl, for example, C ₁ haloalkyl, C ₂ haloalkyl,

C ₃ haloalkyl, C ₄ haloalkyl, C ₅ haloalkyl, or C ₆ haloalkyl.

[0020] According to the disclosure, R ³ is H, C _1-6 alkyl, or C _1-6 haloalkyl. In some aspects, R ³ is H. In other aspects, R ³ is C _1-6 alkyl, for example, C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, or C ₆ alkyl. In yet other aspects, R ³ is C _1-6 haloalkyl, for example, C ₁ haloalkyl, C ₂ haloalkyl,

C ₃ haloalkyl, C ₄ haloalkyl, C ₅ haloalkyl, or C ₆ haloalkyl.

[0021] According to the disclosure, R ⁴ is H, C _1-6 alkyl, or C _1-6 haloalkyl. In some aspects, R ⁴ is H. In other aspects, R ⁴ is C _1-6 alkyl, for example, C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, or C ₆ alkyl. In yet other aspects, R ⁴ is C _1-6 haloalkyl, for example, C ₁ haloalkyl, C ₂ haloalkyl,

C ₃ haloalkyl, C ₄ haloalkyl, C ₅ haloalkyl, or C ₆ haloalkyl.

[0022] According to the disclosure, R ⁵ is H, C _1-6 alkyl, or C _1-6 haloalkyl. In some aspects, R ⁵ is H. In other aspects, R ⁵ is C _1-6 alkyl, for example, C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, or C ₆ alkyl. In yet other aspects, R ⁵ is C _1-6 haloalkyl, for example, C ₁ haloalkyl, C ₂ haloalkyl,

C ₃ haloalkyl, C ₄ haloalkyl, C ₅ haloalkyl, or C ₆ haloalkyl.

[0023] According to the disclosure, R ⁶ is H, C _1-6 alkyl, or C _1-6 haloalkyl. In some aspects, R ⁶ is H. In other aspects, R ⁶ is C _1-6 alkyl, for example, C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, or C ₆ alkyl. In yet other aspects, R ⁶ is C _1-6 haloalkyl, for example, C ₁ haloalkyl, C ₂ haloalkyl,

C ₃ haloalkyl, C ₄ haloalkyl, C ₅ haloalkyl, or C ₆ haloalkyl.

[0024] According to the disclosure, R ⁷ is H, C _1-6 alkyl, or C _1-6 haloalkyl. In some aspects, R ⁷ is H. In other aspects, R ⁷ is C _1-6 alkyl, for example, C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, or C ₆ alkyl. In yet other aspects, R ⁷ is C _1-6 haloalkyl, for example, C ₁ haloalkyl, C ₂ haloalkyl,

C ₃ haloalkyl, C ₄ haloalkyl, C ₅ haloalkyl, or C ₆ haloalkyl.

[0025] According to the disclosure, R ⁸ is H, C _1-6 alkyl, or C _1-6 haloalkyl. In some aspects, R ⁸ is H. In other aspects, R ⁸ is C _1-6 alkyl, for example, C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, or C ₆ alkyl. In yet other aspects, R ⁸ is C _1-6 haloalkyl, for example, C ₁ haloalkyl, C ₂ haloalkyl,

C ₃ haloalkyl, C ₄ haloalkyl, C ₅ haloalkyl, or C ₆ haloalkyl.

[0026] According to the disclosure, n is 0, 1, or 2. In some aspects, n is 0. In other aspects, n is 1. In the aspects wherein n is 1, the compounds of formula I include a sulfoxide moiety. As those of skill in the art will appreciate, sulfoxide moieties may exist as either the R or S stereoisomer. In some aspects, n is 2. In the aspects wherein n is 2, the compounds of formula I include a sulfone moiety.

[0027] In some preferred aspects of the disclosure, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are each H and n is 0, 1, or 2. In some preferred aspects of the disclosure, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are each H and n is 0. In some preferred aspects of the disclosure, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are each H and n is 1. In some preferred aspects of the disclosure, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are each H and n is 2.

[0028] In some preferred aspects of the disclosure, at least one of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ is C _1-6 alkyl and the others are H or C _1-6 haloalkyl and n is 0. In some preferred aspects of the disclosure, at least one of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ is C _1-6 alkyl and the others are H or C _1-6 haloalkyl and n is 1. In some preferred aspects of the disclosure, at least one of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ is C _1-6 alkyl and the others are H or C _1-6 haloalkyl and n is 2.

[0029] In some aspects of the disclosure, one of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ is C _{1- 6} alkyl and the others are H and n is 0. In some aspects of the disclosure, one of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ is C _1-6 alkyl and the others are H and n is 1. In some aspects of the disclosure, one of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ is C _1-6 alkyl and the others are H and n is 2.

[0030] In some aspects of the disclosure, two of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are C _{1- 6} alkyl and the others are H and n is 0. In some aspects of the disclosure, two of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are C _1-6 alkyl and the others are H and n is 1. In some aspects of the disclosure, two of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are C _1-6 alkyl and the others are H and n is 2.

[0031] In some aspects of the disclosure, three of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are C _{1- 6} alkyl and the others are H and n is 0. In some aspects of the disclosure, three of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are C _1-6 alkyl and the others are H and n is 1. In some aspects of the disclosure, three of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are C _1-6 alkyl and the others are H and n is 2.

[0032] In some aspects of the disclosure, four of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are C _{1- 6} alkyl and the others are H and n is 0. In some aspects of the disclosure, four of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are C _1-6 alkyl and the others are H and n is 1. In some aspects of the disclosure, four of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are C _1-6 alkyl and the others are H and n is 2.

[0033] In some aspects of the disclosure, five of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are C _{1- 6} alkyl and the others are H and n is 0. In some aspects of the disclosure, five of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are C _1-6 alkyl and the others are H and n is 1. In some aspects of the disclosure, five of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are C _1-6 alkyl and the others are H and n is 2.

[0034] In some aspects of the disclosure, six of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are C _{1- 6} alkyl and the others are H and n is 0. In some aspects of the disclosure, six of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are C _1-6 alkyl and the others are H and n is 1. In some aspects of the disclosure, six of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are C _1-6 alkyl and the others are H and n is 2.

[0035] In some aspects of the disclosure, seven of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are C _{1- 6} alkyl and the other is H and n is 0. In some aspects of the disclosure, seven of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are C _1-6 alkyl and the other is H and n is 1. In some aspects of the disclosure, seven of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are C _1-6 alkyl and the other is H and n is 2.

[0036] In some aspects of the disclosure, each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are C _{1- 6} alkyl and n is 0. In some aspects of the disclosure, each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are C _{1- 6} alkyl and n is 1. In some aspects of the disclosure, each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are C _{1- 6} alkyl and n is 2.

[0037] [0037] The compounds of the disclosure will have antimicrobial properties. That is, compounds of the disclosure can inhibit the growth of a bacteria, fungus, virus, and/or parasite, if used in an effective concentration, as compared to a suitable control. For example, the compounds of the disclosure are useful against Bacillus species including B. subtilis, Enterobactericea family including Escherichia. coli, Proteus. mirabilis, Yersinia pestis, Salmonella typhi, Salmonella enteritidis, Klebsiella, Staphylococcus and Strepococcus species including Staph. aureus, methicillin-resistant Staph aureus, Staph faecalis, Strep. pneumonia, Strep. pyogenes, V. cholerae, Staphylococcus, Providencia, Citrobacter, Hafnia, and Aeromonas. The compounds of the disclosure are also useful against Mycobacterium tuberculosis and Candida albicans. [0038] The compounds of the disclosure are useful against gram negative pathogens such as Escherichia coli, Pseudomonas aeruginosa, Neisseria gonorrhoeae, Chlamydia trachomatis, and Yersinia pestis. The compounds of the disclosure are also particularly useful against gram negative pathogens that comprise FimH.

[0039] The compounds of the disclosure are useful against gram positive pathogens such as the Streptococcus genus of bacteria and the Staphylococcus genus of bacteria, for example, Staphylococcus epidermidis and Staphylococcus aureus.

[0040] The compounds of the disclosure are useful against fungi, for example, Tinea versicolor and fungi of the Microsporun, Candida Trichophyton, and Epidermophyton genera.

[0041] The compounds of the disclosure are useful against viruses, for example, influenza.

[0042] The compounds of the disclosure are useful against parasites, for example, Entamoeba histolytica, pinworms, tapeworms, flukes, roundworms, and hookworms.

[0043] The compounds of the disclosure will be used to treat a bacterial, fungal, parasitic, and/or viral infection in a subject. According to these methods, an effective amount of a compound of the disclosure is administered to the subject. The compounds of the disclosure are used, alone or in combination with one or more additional active ingredients, for example, other antimicrobial agents, to formulate pharmaceutical compositions of the disclosure. A pharmaceutical composition of the disclosure comprises: (a) an effective amount of at least one compound in accordance with the disclosure; and (b) a pharmaceutically acceptable carrier/excipient.

[0044] Delivery forms of the pharmaceutical compositions containing one or more dosage units of the active agents may be prepared using suitable pharmaceutical excipients and

compounding techniques known or that become available to those skilled in the art. The

compositions may be administered in the inventive methods by a suitable route of delivery, e.g., oral, parenteral, rectal, topical, or ocular routes, or by inhalation.

[0045] The preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories. Preferably, the compositions are formulated for intravenous infusion, topical administration, or oral administration.

[0046] For oral administration, the compounds of the disclosure can be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension. To prepare the oral compositions, the compounds may be formulated to yield a dosage of, e.g., from about 0.05 to about 100 mg/kg daily, or from about 0.05 to about 35 mg/kg daily, or from about 0.1 to about 10 mg/kg daily. For example, a total daily dosage of about 5 mg to 5 g daily may be accomplished by dosing once, twice, three, or four times per day.

[0047] Oral tablets may include a compound according to the disclosure mixed with pharmaceutically acceptable carriers/excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral carriers/excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

[0048] Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, compounds of the disclosure may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the compound of the disclosure with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.

[0049] Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain:

pharmaceutically-acceptable carriers/excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.

[0050] The compounds of this disclosure may also be administered by non-oral routes. For example, the compositions may be formulated for rectal administration as a suppository. For parenteral use, including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the compounds of the disclosure may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms will be presented in unit-dose form such as ampules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses may range from about 1 to 1000 .mu.g/kg/minute of compound, admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.

[0051] For topical administration, the compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering the compounds of the disclosure may utilize a patch formulation to affect transdermal delivery.

[0052] Compounds of the disclosure may alternatively be administered in methods of this disclosure by inhalation, via the nasal or oral routes, e.g., in a spray formulation also containing a suitable carrier.

[0053] The compounds of the disclosure can also be used with medical devices intended for implantation within a subject. For example, the compounds of the disclosure can be used with stents, shunts, catheters, fracture fixation devices, spinal implants, and joint prostheses. These devices can be fabricated from any suitable material, for example, a biocompatible metal, alloy, polymer, ceramic, or combination thereof.

[0054] In some embodiments, the device is impregnated with a compound of formula I. In other embodiments, the device is at least partially coated with a compound of formula I. Preferably, the concentration of the compound is effective to inhibit the growth of a bacteria, fungus, virus, and/or parasite relative to a control device., i.e., relative to a device that is not impregnated with or at least partially coated with a compound of formula I.

[0055] In some aspects, the device comprises one or more pores or recesses on an outer surface of the device. In these aspects, a compound of formula I may be disposed within one or more of the pores or recesses on the outer surface of the device. Preferably, the disposed amount is effective to inhibit the growth of a bacteria, fungus, virus, and/or parasite relative to a control device.

[0056] According to embodiments of the disclosure, a compound of formula I may be compounded, or otherwise combined with a biocompatible polymer matrix. In certain embodiments the polymer matrix may be biodegradable. In certain embodiments of the disclosure a medical device may be fabricated from a biodegradable polymer matrix. In other aspects, the device may be at least partially coated, preferably on an outer surface of the device, with a biodegradable polymer matrix. In those aspects of the disclosure comprising a biodegradable polymer, a compound of the disclosure can be dissolved within the biodegradable polymer matrix. In other aspects, a compound of the disclosure can be disposed as discrete particles within the biodegradable polymer matrix.

Suitable biodegradable polymers can include, for example, poly(alpha-hydroxy esters) including poly(lactic acid) and polyglycolic acid , polyphosphazenes, polyanhydrides, polyacetals, poly(ortho esters), polyphosphoesters, polycaprolactone, polyurethanes, polycarbonates, polyamides, polydioxanes, polyoxalates, polylactones, polyethylene glycol, collagen, alginate, hyaluronic acid, chitosan and polysaccharides.

[0057] Also according to the disclosure of methods comprising implanting a medical device and locally delivering, at the implantation site, an effective amount of a compound of the disclosure. Other methods comprise implanting a medical device and locally delivering, at the implantation site, a pharmaceutical composition comprising an effective amount of a compound of the disclosure. The medical devices that can be used in these methods may be any implantable medical device, including the devices described herein.

[0058] Some of these methods further comprise a step of removing a pre-existing implant from the implantation site before the implanting or delivering steps. In some of these aspects, the implantation site may contain an active colony of one or more pathogens.

[0059] In other embodiments, the methods may further comprise administering an additional therapeutic agent, either locally to the implantation site or systemically, for example, orally or intravenously. The additional therapeutic agent may be administered before the compound of the disclosure is delivered. Alternatively, the additional therapeutic agent may be administered after the compound of the disclosure is delivered. EXAMPLES

[0060] Exemplary compounds useful in methods of the disclosure will now be described by reference to the illustrative synthetic schemes for their general preparation below and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product.

Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Unless otherwise specified, the variables are as defined above in reference to Formula (I). Reactions may be performed between the melting point and the reflux temperature of the solvent, and preferably between 0 °C and the reflux temperature of the solvent. Reactions may be heated employing conventional heating or microwave heating. Reactions may also be conducted in sealed pressure vessels above the normal reflux temperature of the solvent.

[0061] The compounds of the disclosure can be prepared using methods known to those of skill in the art, in combination with the present disclosure. For example, compounds of the disclosure can be prepared according to the following schemes.

Scheme 1

Compounds of the disclosure can be tested using assays known in the art. Compounds of the disclosure are tested according to the following protocol:

One mL of a 10 mg/mL stock solution of the test compound in sterile phosphate buffered saline (PBS) will be prepared. The 10 mg/mL stock solution will be diluted in Iso-Sensitest Broth (ISB, Thermo Fisher CM0473) to give 10 mL of a 256 μg/mL solution. Fourteen (14) additional 1:2 dilutions in ISB of the 256 μg/mL solution will be prepared such that there will be 5 mL of each diluted test compound solution. The concentration range of the serial dilutions will be from 256- 0.016 μg/mL. One mL of each diluted solution will be aliquoted into each of three sterile culture tubes.

An overnight culture of Staphylococcus aureus grown in ISB will be diluted to 0.5

McFarland units with ISB. The 0.5 MacFarland unit culture will be further diluted at 1:150 with ISB to give 75 mL of diluted culture. One mL of the diluted culture will be aliquoted into each of the prepared sterile tubes containing the diluted test compound. The tubes will be gently mixed and incubated at 37 °C with gentle shaking for 18 hours.

The cultures will be visually inspected after the overnight incubation. The Minimum Inhibitory Concentration of the test compound will be the lowest test compound dilution at which there is no visible bacterial growth as determined by solution turbidity with the naked eye.