Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
  • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
  • C07D493/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
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  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• • A—HUMAN NECESSITIES
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  • A61K31/33—Heterocyclic compounds
  • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
  • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
• • A—HUMAN NECESSITIES
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
  • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K31/33—Heterocyclic compounds
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  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/428—Thiazoles condensed with carbocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
• • A—HUMAN NECESSITIES
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4965—Non-condensed pyrazines
  • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
• • A—HUMAN NECESSITIES
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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
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  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• MRSA Methicillin-resistant Staphylococcus aureus
• vancomycin-resistant Enterococcus multidrug resistant Streptococci pneumoniae, Neisseria gonorrhoeae, and Mycobacterium tuberculosis
• pan-resistant Klebsiella pneumoniae Pseudomonas aeruginosa and Acinetobacter baumannii
• Goldston et al. Suicide Life Threat. Behav. 2010, 40(3), 245-256; Nicasio et al. Pharmacotherapy 2008, 28 (2), 235-249 There is also a need for new therapeutic agents to treat biodefense pathogens.
• Spectinomycin is an aminocyclitol antibiotic that specifically inhibits bacterial protein synthesis by binding to 30S ribosome at a unique site that is highly conserved across bacterial pathogens (Carter et al. Nature 2000, 407(6802), 340-348; Borovinskaya et al. ACS Chem. Biol. 2007, 2 (8), 545-552; Wirmer et al. Meth. Enzmol. 2006, 415, 180-202). Although spectinomycin is potent in cell free assays its clinical use is restricted to second line treatment for Neisseria gonorrhoeae infections (McCormack et al.
• the invention in one aspect, relates to aryl substituted aminomethyl spectinomycin analogs useful as antibacterial agents, methods of making same,
• compositions comprising same, and methods of treating bacterial infections using same.
• compositions comprising one or more compounds of Formula I, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a pharmaceutically acceptable carrier.
• pharmaceutical compositions comprising an effective amount of at least one compound according to Formula I or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a pharmaceutically acceptable carrier.
• the pharmaceutical compositions of the present invention comprise a therapeutically effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a pharmaceutically acceptable carrier.
• Also disclosed are methods for treating an infectious disease, in particular a bacterial infection, in a human subject comprising the step of administering to the human subject a therapeutically effective amount of at least one compound according to Formula I, or a pharmaceutically acceptable salt, solvate, or polymorph thereof.
• Also disclosed are methods for treating an infectious disease, particularly a bacterial infection, in a vertebrate animal comprising the step of administering to the vertebrate animal a therapeutically effective amount of at least one compound of Formula I, or a
• Also disclosed are methods for treating a human subject for a disorder associated with exposure to a biodefense pathogen comprising the step of administering to the human subject an effective amount of at least one compound according to Formula I, or a pharmaceutically acceptable salt, solvate, or polymorph thereof.
• Also disclosed are methods for inhibiting protein synthesis in at least one bacterial cell comprising the step of contacting the bacterial cell with an effective amount of at least one compound according to Formula I, or a pharmaceutically acceptable salt, solvate, or polymorph thereof.
• kits comprising at least one compound according to Formula I, or a pharmaceutically acceptable salt, solvate, or polymorph thereof; and one or more of: (a) at least one agent known to inhibit microbial ribosomal activity; (b) at least one agent known to have antimicrobial activity; (c) at least one agent known to treat an infectious disease; (d) instructions for treating an infectious disease; (e) instructions for administering the compound in connection with treating a microbial infection; or (f) instructions for administering the compound with at least one agent known to treat an infectious disease.
• Figure 1 shows the chemical structure of spectinomycin and spectinomycin analogs, specifically, (A) spectinomycin, which also shows the generally accepted ring numbering and nomenclature system; (B) trospectomycin; and (C) spectinamides as disclosed in US
• Figure 2 is a computer generated model depicting the interaction of a compound of the invention with bacterial RNA and ribosomal protein.
• Each of panels A, B, and C shows compound 2 docked into bacterial ribosome at RNA helix 34 of the 30S ribosomal subunit, and the loop of interacting ribosomal protein RspE, which is a binding site for the aryl side chain of compound 2.
• the figure shows the amino acid differences and docking results for compound 2 to ribosomes of different bacterial species, namely (A) E. coli, (B) M.
• Figure 3 shows data showing the anti-5 1 . pneumoniae activity of a representative compound in a mouse model of lung infection.
• the graph shows the overall survival at various times following intranasal bacterial challenge (5. pneumoniae D39x). Mice were treated with a 5 mg/kg dose b.i.d. of spectinomycin (indicated as "SPC" in the figure) or compound 2 (the compound number refers to the compound number and associated structure shown in Table 1), or vehicle.
• SPC spectinomycin
• compound 2 the compound number refers to the compound number and associated structure shown in Table 1
• Ranges can be expressed herein as from “about” one particular value, and/or to "about” another particular value. When such a range is expressed, another aspect 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 aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as "about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10" is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.
• the terms “about” and “at or about” mean that the amount or value in question can be the value designated some other value approximately or about the same. It is generally understood, as used herein, that it is the nominal value indicated ⁇ 10% variation unless otherwise indicated or inferred. The term is intended to convey that similar values promote equivalent results or effects recited in the claims. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art.
• an amount, size, formulation, parameter or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is understood that where "about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.
• references in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed.
• X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.
• a weight percent (wt. %) of a component is based on the total weight of the formulation or composition in which the component is included.
• the terms "optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
• the term "subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian.
• the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent.
• the term does not denote a particular age or sex. Thus, adult and juvenile subjects, whether male or female, are intended to be covered.
• the subject is a mammal.
• a patient refers to a subject afflicted with a disease or disorder.
• patient includes human and veterinary subjects.
• antimicrobial activity refers to the ability of a spectinomycin analog or derivative described herein to modify a function or metabolic process of a target microorganism, for example so as to at least partially affect replication, vegetative growth, toxin production, survival, viability in a quiescent state, or other attribute.
• Bacteria to be inhibited or killed using the compositions and method described herein can include gram-negative and gram-positive bacteria, in addition to organisms classified in orders of the class Mollicutes and the like, such as species of the Mycoplasma and Acholeplasma genera.
• Examples of gram-positive bacteria include, but are not limited to, Staphylococcus aureus, Staphylococcus epidermis, Streptococcus agalactiae, Group A streptococcus, Streptococcus pyogenes, Enter ococcus faecalis, Group B gram-positive streptococcus, Corynebacterium xerosis, and Listeria monocytogenes.
• gram-negative bacteria include, but are not limited to, Escherichia coli, Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella, Hemophilus influenza, Neisseria gonorrhoeae, Chlamydia trachomatis, Vibrio cholerae, Vibrio parahemolyticus and Helicobacter pylori.
• fungi can include yeasts, such as Candida albicans.
• viruses can include measles virus, herpes simplex virus (HSV-1 and -2), herpes family members (HIV, hepatitis C, vesicular, stomatitis virus (VSV), visna virus, and cytomegalovirus (CMV).
• HSV-1 and -2 herpes simplex virus
• HSV herpes family members
• VSV vesicular, stomatitis virus
• VSV vesicular virus
• visna virus cytomegalovirus
• protozoa can include Giardia.
• multidrug-resistant tuberculosis As used herein, the terms “multidrug-resistant tuberculosis,” “multidrug-resistant TB,” and “MDR TB,” which can be used interchangeably, refer to a form of tuberculosis that is resistant to two or more of the primary drugs (isoniazid and rifampin) used for the treatment of tuberculosis. These terms refer not only to this particular type of the primary drugs (isoniazid and rifampin) used for the treatment of tuberculosis. These terms refer not only to this particular type of the primary drugs (isoniazid and rifampin) used for the treatment of tuberculosis. These terms refer not only to this particular type of the primary drugs (isoniazid and rifampin) used for the treatment of tuberculosis. These terms refer not only to this particular type of the primary drugs (isoniazid and rifampin) used for the treatment of tuberculosis. These terms refer not only
• tuberculosis disease but also to the Mycobacterium tuberculosis that are associated with the disease.
• treatment refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder.
• This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder.
• this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.
• the term covers any treatment of a subject, including a mammal (e.g. , a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e.
• the subject is a mammal such as a primate, and, in a further aspect, the subject is a human.
• subject also includes domesticated animals (e.g. , cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, chickens, turkeys, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.).
• domesticated animals e.g. , cats, dogs, etc.
• livestock e.g., cattle, horses, pigs, sheep, goats, chickens, turkeys, etc.
• laboratory animals e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.
• the phrase "treating or inhibiting a microbial infection” means to inhibit the replication of the particular microorganism causing the infection, to inhibit transmission of the microorganism, or to prevent the microorganism from establishing itself in its host, and to ameliorate or alleviate the symptoms of the disease caused by the infection.
• the treatment is considered therapeutic if there is a reduction in microorganism load, microorganism replication, microorganism counts or cell numbers, decrease in mortality, decrease in symptoms of the infection, such as a fever, and/or morbidity of a subject.
• the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.
• the term “diagnosed” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein.
• administering refers to any method of providing a pharmaceutical preparation to a subject.
• Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra- arterial administration, intramuscular administration, and subcutaneous administration.
• Administration can be continuous or intermittent.
• a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition.
• a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.
• the terms “effective amount” and “amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition.
• a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects.
• the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or
• a preparation can be administered in a "prophylactically effective amount"; that is, an amount effective for prevention of a disease or condition.
• dosage form means a pharmacologically active material in a medium, carrier, vehicle, or device suitable for administration to a subject.
• a suitable dosage form can comprise a compound according to Formula I, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, in combination with a pharmaceutically acceptable excipient, such as a preservative, buffer, saline, or phosphate buffered saline.
• Dosage forms can be made using conventional pharmaceutical manufacturing and compounding techniques.
• Dosage forms can comprise inorganic or organic buffers (e.g., sodium or potassium salts of phosphate, carbonate, acetate, or citrate) and pH adjustment agents (e.g., hydrochloric acid, sodium or potassium hydroxide, salts of citrate or acetate, amino acids and their salts) antioxidants (e.g., ascorbic acid, alpha- tocopherol), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxyethylene9-10 nonyl phenol, sodium
• cryo/lyo stabilizers e.g., sucrose, lactose, mannitol, trehalose
• osmotic adjustment agents e.g., salts or sugars
• antibacterial agents e.g., benzoic acid, phenol, gentamicin
• antifoaming agents e.g., polydimethylsilozone
• preservatives e.g., thimerosal, 2-phenoxyethanol, EDTA
• polymeric stabilizers and viscosity-adjustment agents e.g., polyvinylpyrrolidone, poloxamer 488, carboxymethylcellulose
• co-solvents e.g., glycerol, polyethylene glycol, ethanol
• a dosage form formulated for injectable use can have a disclosed compound according to Formula I, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, suspended in sterile saline solution for injection together with a preservative.
• encapsulate in a nanocarrier or “encapsulate in a synthetic nanocarrier” both refer to enclosing at least a portion of a substance within a synthetic nanocarrier.
• the substance can be enclosed completely within a synthetic nanocarrier.
• most or all of a substance that is encapsulated is not exposed to the local environment external to the synthetic nanocarrier. In the context where some of a substance is not exposed to the local environment external to the synthetic nanocarrier, this can mean that no more than 50%, 40%, 30%, 20%, 10% or 5% is exposed to the local environment.
• Encapsulation is distinct from adsorption, which places most or all of a substance on a surface of a synthetic nanocarrier, and leaves the substance exposed to the local environment external to the synthetic nanocarrier.
• synthetic nanocarrier refers to a discrete object that is not found in nature, and that possesses at least one dimension that is less than or equal to 5 microns in size.
• a synthetic nanocarrier can be, but is not limited to, one or a plurality of lipid-based nanoparticles, polymeric nanoparticles, metallic nanoparticles, surfactant-based emulsions, dendrimers, buckyballs, nanowires, peptide or protein-based particles (such as albumin nanoparticles) and/or nanoparticles that are developed using a combination of nanomaterials such as lipid-polymer nanoparticles.
• Synthetic nanocarriers may be a variety of different shapes, including but not limited to spheroidal, cuboidal, pyramidal, oblong, cylindrical, toroidal, and the like. Synthetic nanocarriers according to the invention comprise one or more surfaces. Exemplary synthetic nanocarriers include: (1) the biodegradable nanoparticles disclosed in U.S. Pat. No.
• synthetic nanocarriers may possess an aspect ratio greater than 1:1, 1:1.2, 1:1.5, 1:2, 1:3, 1:5, 1:7, or greater than 1:10.
• kit means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. As used herein, "instruction(s)” means documents describing relevant materials or methodologies pertaining to a kit.
• kits may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents.
• Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can comprise one or multiple documents, and are meant to include future updates.
• therapeutic agent include any synthetic or naturally occurring biologically active compound or composition of matter which, when administered to an organism (human or nonhuman animal), induces a desired pharmacologic,
• immunogenic, and/or physiologic effect by local and/or systemic action encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like.
• therapeutic agents include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment.
• the term "therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, an
• the agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas.
• the term therapeutic agent also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro- drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.
• pharmaceutically acceptable describes a material that is not biologically or otherwise undesirable, i. e. , without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.
• derivative refers to a compound having a structure derived from the structure of a parent compound (e.g. , a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds.
• exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.
• a pharmaceutically acceptable carrier refers to aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as powders for reconstitution into injectable solutions or dispersions just prior to use.
• a pharmaceutically acceptable carrier will be sterile or sterilizable, e.g., where the
• the pharmaceutically acceptable carrier is advantageously selected so as not to significantly decrease or neutralize the active ingredient.
• suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
• Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
• compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption.
• adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
• Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the inject
• Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or
• microemulsions which are compatible with body tissues.
• the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use.
• Suitable inert carriers can include sugars such as lactose.
• at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.
• bacteria as used herein is intended to encompass all variants of bacteria, for example, prokaryotic organisms and cyanobacteria. Accordingly, bacterial infections to be treated using the compositions and methods described herein include, but are not limited to, infections caused by gram-positive bacteria such as, but not limited to, Bacillus cereus, Bacillus anthracis, Bacillus cereus, Bacillus anthracis, Clostridium botulinum, Clostridium difficle, Clostridium tetani, Clostridium perfringens, Cory neb acteria diptheriae,
• infections caused by gram-negative bacteria such as, but not limited to, Bacteroides sp., Bordetella pertussis, Brucella sp., Chlamydia trachomatis, Chlamydia sp., Campylobacter infections, enterohaemorrhagic Escherichia coli ⁇ EHEC/E.
• coli 0157 : 17 enteroinvasive Escherichia coli (EIEC), enterotoxigenic Escherichia coli (ETEC), Haemophilus influenzae, Helicobacter pylori, Klebsiella pneumoniae, Legionella sp., Moraxella catarrhalis, Neisseria gonnorrhoeae, Neisseria meningitidis, Proteus sp., Pseudomonas aeruginosa, Salmonella sp., Shigella sp., Vibrio cholera and Yersinia; infections caused by acid fast bacteria including, but not limited to, Mycobacterium tuberculosis, Mycobacterium avium-intracellulare, Mycobacterium johnei, Mycobacterium leprae, atypical bacteria, Mycoplasma, Rickettsia, Spirochetes, Treponema pallidum, Borrelia recurrentis, Bor
• bacterial infections and situations in which such bacterial infections can occur that are not necessarily specific to a particular bacterial species, but encompassed by the term "bacterial infection,” as used herein, include bacterial wound infections, such as in burn wound patients; mucosal infections, enteric infections, bacteremia and septic conditions, pneumonia, trachoma, onithosis, trichomoniasis and salmonellosis, especially in veterinary practice; urinary tract infections; post-surgery infections on or caused by invasive devises; endocarditis by intravenous administration of contaminated drug solutions; bacterial infections in patients with acquired immunodeficiency syndrome, cancer chemotherapy, steroid therapy, hematological malignancies, organ transplantation, renal replacement therapy, and other situations with severe neutropenia; community- acquired respiratory tract infections; meningitis; folliculitis and infections of the ear canal caused by contaminated waters; malignant otitis externa in the elderly and diabetics; osteomyelitis of the caleaneus in children; eye infections commonly associated with
• biological sample refers to a cell or population of cells or a quantity of tissue or fluid from a subject or source, such as an environmental source or a food source, for example.
• the sample is isolated from or removed from a subject, but, in some embodiments, the term “biological sample” can also refer to cells or tissue analyzed in vivo, i.e. without removal from the subject. Often, a “biological sample” will contain cells from the animal, but the term can also refer to non-cellular biological material.
• biological sample encompasses cellular, tissue or fluid extracts, including, but not limited to, skin, plasma, serum, spinal fluid, lymph fluid, synovial fluid, urine, tears, blood cells, organs, tumors, and also to samples of in vitro cell culture constituents
• Samples can comprise cellular or tissue explants obtained from an individual or organism during a medical procedure or intervention, such as a surgical procedure or biopsy. Samples from environmental sources are also included among
• samples to which the compositions and methods described herein can be applied.
• spectinomycin and “SPC” can be used interchangeably, and refer to a compound having a structure represented by a formula:
• spectinomycin can also be referred to as (2 «,4a «,5a «,65',75',8«,95',9a «,10a5')-4a,7,9-trihydroxy-2-methyl-6,8- bis(methylamino)decahydro-4H-benzo[b]pyrano[2,3-e][l,4]dioxin-4-one, Actinospectacin, Trobicin, Togamycin, Spectam, espectinomicina, spectinomycine, spectinomicina, and actinospectacina. It is understood that the core spectinomycin tricyclic ring structure has the following numbering c
• 3 '-aminomethyl-3 '-hydroxy spectinomycin As used herein, "3 '-aminomethyl-3 '-hydroxy spectinomycin,” “3 '-aminomethyl-3 '- hydroxy spectinomycin,” and “mSPC” can be used interchangeably, and refer to a compound having a structure represented by a formula:
• di-benzyloxy carbonyl-3 '- ⁇ R) -methylene mSPC refers to a compound having a structure represented by a formula:
• di-benzyloxy carbonyl-3 ' -(R) -methylene mSPC includes specific examples of the above compound, e.g. such a specific example of a di-benzyloxy carbonyl- 3 ' -(R) -methylene mSPC is a compound having a structure represented by a formula:
• di-benzyloxy carbonyl-3 ' - deoxo- 3 ' - (R) - mSPC oxide refers a compound having a structure rep
• a residue of a chemical species refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species.
• an ethylene glycol residue in a polyester refers to one or more -OCH2CH2O- units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester.
• a sebacic acid residue in a polyester refers to one or more -OCO(CH2)sOCO- moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.
• the term "substituted" is contemplated to include all permissible substituents of organic compounds.
• the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds.
• Illustrative substituents include, for example, those described below.
• the permissible substituents can be one or more and the same or different for appropriate organic compounds.
• the heteroatoms, such as nitrogen can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
• substitution or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g. , a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).
• a 1 ,” “A 2 ,” “A 3 ,” and “A 4 " are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.
• aliphatic or "aliphatic group,” as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e. , unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
• alkyl as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s- butyl, i-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like.
• the alkyl group can be cyclic or acyclic.
• the alkyl group can be branched or unbranched.
• the alkyl group can also be substituted or unsubstituted.
• the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein.
• a "lower alkyl” group is an alkyl group containing from one to four carbon atoms, e.g., methyl, ethyl, propyl, butyl.
• alkyl group can also be a CI alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl.
• alkyl is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group.
• halogenated alkyl or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g. , fluorine, chlorine, bromine, or iodine.
• the term "monohaloalkyl” specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine.
• a single halide e.g. fluorine, chlorine, bromine, or iodine.
• polyhaloalkyl specifically refers to an alkyl group that is independently substituted with two or more halides, i.e. , each halide substituent need not be the same halide as another halide substituent, nor do the multiple instances of a halide substituent need to be on the same carbon.
• alkoxyalkyl specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below.
• aminoalkyl specifically refers to an alkyl group that is substituted with one or more amino groups.
• hydroxyalkyl specifically refers to an alkyl group that is substituted with one or more hydroxy groups.
• cycloalkyl refers to both unsubstituted and substituted cycloalkyl moieties
• the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an "alkylcycloalkyl.”
• a substituted alkoxy can be specifically referred to as, e.g. , a "halogenated alkoxy”
• a particular substituted alkenyl can be, e.g. , an "alkenylalcohol,” and the like.
• cycloalkyl as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms.
• examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like.
• heterocycloalkyl is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
• the cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted.
• the cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.
• polyalkylene group as used herein is a group having two or more CH 2 groups linked to one another.
• the polyalkylene group can be represented by the formula — (CH 2 ) a — , where "a" is an integer of from 2 to 500.
• Alkoxy also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as— OA 1 — OA 2 or — OA 1 — (OA 2 ) a — OA 3 , where "a” is an integer of from 1 to 200 and A 1 , A 2 , and A 3 are alkyl and/or cycloalkyl groups.
• alkenyl as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond.
• the alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.
• groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described here
• cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl,
• heterocycloalkenyl is a type of cycloalkenyl group as defined above, and is included within the meaning of the term
• cycloalkenyl where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
• the cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted.
• the cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
• alkynyl as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond.
• the alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.
• cycloalkynyl as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound.
• examples of cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like.
• heterocycloalkynyl is a type of cycloalkenyl group as defined above, and is included within the meaning of the term
• cycloalkynyl where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
• the cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted.
• the cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
• aromatic group refers to a ring structure having cyclic clouds of delocalized ⁇ electrons above and below the plane of the molecule, where the ⁇ clouds contain (4n+2) ⁇ electrons.
• aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages 477-497, incorporated herein by reference.
• aromatic group is inclusive of both aryl and heteroaryl groups.
• aryl as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like.
• the aryl group can be substituted or unsubstituted.
• the aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde,— NH 2 , carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
• biasing is a specific type of aryl group and is included in the definition of "aryl.”
• the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon- carbon bond.
• biaryl can be two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.
• aldehyde as used herein is represented by the formula— C(0)H.
• amine or “amino” as used herein are represented by the formula— NA ] A 2 , where A 1 and A 2 can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
• a specific example of amino is— NH 2 .
• alkylamino as used herein is represented by the formula— NH(-alkyl) where alkyl is a described herein.
• Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl) amino group, hexylamino group, and the like.
• dialkylamino as used herein is represented by the formula— N(-alkyl) 2 where alkyl is a described herein.
• Representative examples include, but are not limited to, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl) amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl) amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N- ethyl-N-propylamino group and the like.
• esters as used herein is represented by the formula— OC(0)A 1 or— C(0)OA ⁇ where A 1 can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
• polyester as used herein is represented by the formula— (A 1 0(0)C-A 2 -C(0)0) a — or— (A 1 0(0)C-A 2 -OC(0)) a — , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and "a” is an integer from 1 to 500.
• Polyyester is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.
• ether as used herein is represented by the formula A ] OA 2 , where A 1 and
• a 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein.
• polyether as used herein is represented by the formula— (A 1 0-A 2 0) a — , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and "a" is an integer of from 1 to 500.
• Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.
• halo halogen
• halide halogen
• pseudohalide pseudohalogen
• pseudohalo pseudohalogen
• pseudohalo pseudohalo
• functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.
• heteroalkyl refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups.
• heteroaryl refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group.
• heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions.
• the heteroaryl group can be substituted or unsubstituted.
• the heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.
• Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl.
• heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo [d] oxazolyl, benzo[if]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[l,2-b]pyridazinyl, imidazo[l,2-a]pyrazinyl, benzo[c][l,2,5]thiadiazolyl, benzo[c][l,2,5]oxadiazolyl, and pyrido [2,3 -bjpyrazinyl .
• heterocycle or “heterocyclyl,” as used herein can be used
• Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3- oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole, including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4-t
• heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2- C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl.
• a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like.
• a C5 heterocyclyl comprises a group which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl,
• heterocyclyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocyclyl ring.
• bicyclic heterocycle or "bicyclic heterocyclyl,” as used herein refers to a ring system in which at least one of the ring members is other than carbon.
• Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring.
• Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6- membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms.
• Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[l,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-l,4-benzodioxinyl, 3,4-dihydro-2H- chromenyl, lH-pyrazolo[4,3-c]pyridin-3-yl; lH-pyrrolo[3,2-b]pyridin-3-yl; and 1H- pyrazolo[3,2-b]pyridin-3-yl.
• heterocycloalkyl refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems.
• the heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted.
• heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
• ketone as used herein is represented by the formula A 1 C(0)A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
• nitro as used herein is represented by the formula— NO2.
• nitrile or "cyano” as used herein is represented by the formula— CN.
• sil as used herein is represented by the formula— SiA 1 A 2 A 3 , where A 1 , A 2 , and A 3 can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
• sulfo-oxo as used herein is represented by the formulas— S(0)A 1 , — S(0) 2 A ⁇ — OS(0) 2 A ⁇ or— OS(0) 2 OA ⁇ where A 1 can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
• a 1 can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
• sulfonyl is used herein to refer to the sulfo-oxo group represented by the formula— S(0) 2 A 1 , where A 1 can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
• sulfone as used herein is represented by the formula A 1 S(0) 2 A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
• sulfoxide as used herein is represented by the formula
• a 1 S(0)A 2 where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl,
• cycloalkenyl alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
• R 1 ,” “R 2 ,” “R 3 ,” “R n ,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above.
• R 1 is a straight chain alkyl group
• one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like.
• a first group can be incorporated within second group or, alternatively, the first group can be pendant (i. e. , attached) to the second group.
• an alkyl group comprising an amino group the amino group can be incorporated within the backbone of the alkyl group.
• the amino group can be attached to the backbone of the alkyl group.
• the nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.
• compounds of the invention may contain "optionally substituted" moieties.
• substituted whether preceded by the term “optionally” or not, means that one or more hydrogen of the designated moiety are replaced with a suitable substituent.
• an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
• Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
• individual substituents can be further optionally substituted (i.e. , further substituted or unsubstituted).
• stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein.
• each R° may be substituted as defined below and is independently hydrogen, Ci- 6 aliphatic, -CH 2 Ph, -0(CH 2 )o iPh, -CH 2 -(5-6 membered heteroaryl ring), or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3—12— membered saturated, partially unsaturated, or
• Suitable monovalent substituents on R° are independently halogen, -(CH 2 ) 0 2 R e , -(haloR*), -(CH 2 ) 0 2 OH, -(CH 2 ) 0 2 OR e , -(CH 2 y 2 CH(OR') 2 ; -O(haloR'), -CN, -N 3 , -(CH 2 y 2 C(0)R e , -(CH 2 )o- 2 C(0)OH, -(CH 2 ) 0 - 2 C(O)OR e , -(CH 2 ) 0 - 2 SR e , -(CH 2 )o 2 SH, -(CH 2 )o 2 NH 2 , -(CH 2 ) ⁇ 2 NHR*, -(CH 2 ) ⁇ 2 NR* 2 , -N0 2 ,
• each R* is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently selected from Ci ⁇ aliphatic, -CH 2 Ph, -0(CH 2 )o iPh, or a 5- 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• Suitable divalent substituents that are bound to vicinal substitutable carbons of an "optionally substituted” group include: -0(CR * 2 ) 2 - 3 0-, wherein each independent occurrence of R * is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• Suitable substituents on the aliphatic group of R * include halogen,
• each R" is unsubstituted or where preceded by "halo” is substituted only with one or more halogens, and is independently Ci-4 aliphatic, -CH 2 Ph, -0(CH 2 )o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R ⁇ , -NR ⁇ 2 , -C(0)R ⁇ , -C(0)OR ⁇ , -C(0)C(0)R ⁇ , -C(0)CH 2 C(0)R ⁇ ,
• each R ⁇ is independently hydrogen, Ci-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ , taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• Suitable substituents on the aliphatic group of R ⁇ are independently halogen,
• each R" is unsubstituted or where preceded by "halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH 2 Ph, -0(CH 2 )o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• leaving group refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons.
• suitable leaving groups include halides and sulfonate esters, including, but not limited to, triflate, mesylate, tosylate, and brosylate.
• hydrolysable group and “hydrolysable moiety” refer to a functional group capable of undergoing hydrolysis, e.g. , under basic or acidic conditions.
• hydrolysable residues include, without limitation, acid halides, activated carboxylic acids, and various protecting groups known in the art (see, for example, "Protective Groups in Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999).
• organic residue defines a carbon containing residue, i.e. , a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove.
• Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc.
• Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
• an organic residue can comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.
• radical for example an alkyl
• substituted alkyl can be further modified (i substituted alkyl) by having bonded thereto one or more "substituent radicals.”
• the number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein.
• Organic radicals contain one or more carbon atoms.
• An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1- 12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms.
• an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms.
• Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical.
• an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthyl radical.
• an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like.
• organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di- substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide,
• dialkylcarboxamide substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein.
• organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.
• Inorganic radicals contain no carbon atoms and therefore comprise only atoms other than carbon.
• Inorganic radicals comprise bonded combinations of atoms selected from hydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, and halogens such as fluorine, chlorine, bromine, and iodine, which can be present individually or bonded together in their chemically stable combinations.
• Inorganic radicals have 10 or fewer, or preferably one to six or one to four inorganic atoms as listed above bonded together. Examples of inorganic radicals include, but not limited to, amino, hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonly known inorganic radicals.
• the inorganic radicals do not have bonded therein the metallic elements of the periodic table (such as the alkali metals, alkaline earth metals, transition metals, lanthanide metals, or actinide metals), although such metal ions can sometimes serve as a pharmaceutically acceptable cation for anionic inorganic radicals such as a sulfate, phosphate, or like anionic inorganic radical.
• Inorganic radicals do not comprise metalloids elements such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gas elements, unless otherwise specifically indicated elsewhere herein.
• a specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
• a 50:50 mixture of enantiomers is referred to as a racemic mixture.
• Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula.
• one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane).
• the Cahn-Inglod-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.
• Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance.
• the disclosed compounds of the present invention can be isotopically-labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature.
• isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 35 S, 18 F and 36 CI, respectively.
• Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
• Certain isotopically-labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e. , 3 H, and carbon-14, i.e. , 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i. e.
• Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.
• the compounds described in the invention can be present as a solvate.
• the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate.
• the compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution.
• one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the invention to form solvates and hydrates.
• the invention includes all such possible solvates.
• co-crystal means a physical association of two or more molecules which owe their stability through non-covalent interaction.
• One or more components of this molecular complex provide a stable framework in the crystalline lattice.
• the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g. "Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?" Almarasson, O., et. al., The Royal Society of Chemistry, 1889-1896, 2004.
• Examples of co-crystals include p- toluenesulfonic acid and benzenesulfonic acid.
• ketones with an a-hydrogen can exist in an equilibrium of the keto form and the enol form.
• amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form.
• pyrazoles can exist in two tautomeric forms, N 1 - unsubstituted, 3-A 3 and N ⁇ unsubstituted, 5-A 3 as shown below.
• the invention includes all such possible tautomers.
• a structure of a compound can be represented by a formula:
• n is typically an integer. That is, R" is understood to represent five independent substituents, R" (a) , R" (b) , R" (c) , R" (d) , R" (e) .
• independent substituents it is meant that each R substituent can be independently defined. For example, if in one instance R" (a) is halogen, then R" (b) is not necessarily halogen in that instance.
• Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art.
• the starting materials and reagents used in preparing the disclosed compounds of the present invention and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St.
• compositions of the invention Disclosed are the components to be used to prepare the compositions of the invention as well as the compositions themselves to be used within the methods disclosed herein.
• these and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary.
• compositions disclosed herein have certain functions.
• the invention relates to compounds according to Formula I useful as antibacterial agents. More specifically, in one aspect, the present invention relates to compounds that are aryl substituted aminomethyl spectinomycin analogs using for treating bacterial infections.
• each disclosed derivative can be optionally further substituted. It is also contemplated that any one or more derivative can be optionally omitted from the invention. It is understood that a disclosed compound of the present invention can be provided by the disclosed methods. It is also understood that the disclosed compounds of the present invention can be employed in the disclosed methods of using.
• the invention relates to a compound having a structure represented by
• n is an integer selected from 0, 1 , and 3. In a further aspect, n is an integer selected from 0, 1 , and 2. In a still further aspect, n is an integer selected from 0, 2, and 3. In yet further aspect, n is an integer selected from 1 , 2, and 3. In an even further aspect, n is an integer selected from 0 and 1. In a still further aspect, n is an integer selected from 0 and 2. In a yet further aspect, n is an integer selected from 0 and 3. In an even further aspect, n is an integer selected from 1 and 2. In a still further aspect, n is an integer selected from 1 and 3. In a yet further aspect, n is an integer selected from 2 and 3. In an even further aspect, n is 0. In a still further aspect, n is 1. In a yet further aspect, n is 2. In an even further aspect, n is 3.
• the invention relates to a compound having a structure represented by a formula:
• a compound can have a structure represented by a formula:
• a compound can have a structure represented by a formula:
• a compound can have a structure represented by a formula:
• a c sented by a formula :
• a compound can have a structure represented by a formula:
• a compound can have a structure represented by a formula:
• a compound can have a structure represented by a formula:
• a compound can have a structure represented by a formula:
• each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen,— F,—CI, —Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl,— CH 2 F,— CHF 2 ,— CF3, -CH2CI, -CHCI2, -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH2CH2CI, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH3, -OCH 2 CH 3 , -OCH 2 F, -OCHF 2 , -OCF3, -OCH 2 Cl, -OCHCl 2 ,
• a compound can have a structure represented by a formula:
• each of R 3a , R 3b , R 3c , R 3d , and R 3e are independently selected from hydrogen,— F, —CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl,— CH 2 F,— CHF 2 ,— CF3, -CH 2 C1, -CHC1 2 , -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH3, -OCH 2 CH 3 , -OCH 2 F, -OCHF 2 , -OCF3, -OCH 2 Cl, -OCHCl 2 , -OCCI3, -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 , -0CH 2 CH 2
• a compound can have a structure represented by a formula:
• a compound can have a structure represented by a formula:
• R 3c is selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 F,
• a compound can have a structure represented by a formula:
• R 3c is selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH3, -OCH 2 CH 3 , -OCH 2 F,
• a compound can have a structure represented by a formula:
• a compound can have a structure represented by a formula:
• a compound can have a structure represented by a formula:
• R 3b is selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH3, -OCH 2 CH 3 , -OCH 2 F,
• a compound can have a structure represented by a formula:
• a compound can have a structure represented by a formula:
• a compound can have a structure represented by a formula:
• R 3a is selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH2CI, -CHCI2, -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH2CH2CI, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH3, -OCH 2 CH 3 , -OCH 2 F,
• a compound can have a structure represented by a formula:
• a compound can have a structure represented by a formula:
• each of R 3b and R 3c is selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH3, -OCH 2 CH 3 ,
• each of R 3a and R 3c is selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH3, -OCH 2 CH 3 , -OCH 2 F, -OCHF 2 , -OCF3, -OCH 2 Cl, -OCHCl 2 , -OCCI3, -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 , -0CH 2 CH 2 C1, -0CH 2 CHC1 2 , -(C
• each of R 4a , R 4b , and R 4c is selected from hydrogen, halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3
• each of R 4a , R 4b , and R 4c is selected from hydrogen,— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CCb, -OCH3, -OCH 2 CH 3 , -OCH 2 F, -OCHF 2 , -OCF3, -OCH 2 Cl, -OCHCl 2 , -OCCI3, -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 , -0CH 2 CH 2 C1, -0CH 2 CHC1
• each of R 4a , R 4b , and R 4c is selected from hydrogen, halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3
• each of R 4a , R 4b , and R 4c is selected from hydrogen,— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CCb, -OCH3, -OCH 2 CH 3 , -OCH 2 F, -OCHF 2 , -OCF3, -OCH 2 Cl, -OCHCl 2 , -OCCI3, -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 , -0CH 2 CH 2 C1, -0CH 2 CHC1
• each of R 4a and R 4b is selected from hydrogen, halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, Cl- C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkoxy,
• each of R 4a and R 4b is selected from hydrogen,— F,—CI,—Br, cyano, hydroxyl, - NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CCb, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CCb, -OCH3, -OCH 2 CH 3 , -OCH 2 F, -OCHF 2 , -OCF3, -OCH 2 Cl, -OCHCl 2 , -OCCI3, -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 , -0CH 2 CH 2 C1, -0CH 2 CHC1 2 , -(
• a formula ented by a formula:
• each of R 4a and R 4b is selected from hydrogen,— F,—CI,—Br, cyano, hydroxyl, - NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CCb, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CCb, -OCH3, -OCH 2 CH 3 , -OCH 2 F, -OCHF 2 , -OCF3, -OCH 2 Cl, -OCHCl 2 , -OCCI3, -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 , -0CH 2 CH 2 C1, -0CH 2 CHC1 2 , -(
• each of R 4a and R 4b is selected from hydrogen, halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy Cl- C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkoxy,
• a compound can have a structure listed herein.
• the compounds can be selected from two or more of the structures listed herein.
• R 1 is selected hydrogen and C1-C4 alkyl. In a further aspect, R 1 is selected from hydrogen and methyl. In a still further aspect, R 1 is selected from hydrogen, ethyl, and methyl. In a yet further aspect, R 1 is methyl. In an even further aspect, R 1 is hydrogen.
• each occurrence of R 2a and R 2b is independently selected from hydrogen and C1-C3 alkyl. In a further aspect, each occurrence of R 2a and R 2b is hydrogen. In a further aspect, n is 0 and R 2a and R 2b are not present. In a still further aspect, n is 1 and each occurrence of R 2a and R 2b is hydrogen. In a yet further aspect, n is 2 and each occurrence of R 2a and R 2b is hydrogen. In an even further aspect, n is 3 and each occurrence of R 2a and R 2b is hydrogen.
• R 2a and R 2b can involve multiple occurrences of the various selected substituents, each such substituent independently selected.
• the invention relates to a structure represented by a formula:
• R 2a when present, is selected from hydrogen, methyl, and ethyl
• R 2b when present, is selected from hydrogen, methyl, and ethyl.
• Such structures are also understood to refer to a moiety having a structure alternatively represented by a formula:
• each of R 2al , R 2bl , R 2a2 , and R 2b2 is independently selected from hydrogen, methyl, and ethyl (again, irrespective of the other selections).
• each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen,— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH2CI, -CHCI2, -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH2CH2CI, -CH 2 CHC1 2 , -CH 2 CCb, -OCH3, -OCH 2 CH 3 , -OCH 2 F, -OCHF 2 , -OCF3, -OCH2CI, -OCHCl 2 , -OCCI3, -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCH2CH
• each of R 3b , R 3c , R 3d , and R 3e is hydrogen; and R 3a is selected from halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, and C1-C3 polyhaloalkoxy.
• each of R 3b , R 3c , R 3d , and R 3e is hydrogen; and R 3a is selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH2CI, -CHCI2, -CCI3,
• each of R 3b , R 3c , R 3d , and R 3e is hydrogen; and R 3a is selected from— F,—CI, -Br, methyl, ethyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 CF , -OCH , -OCF ,
• each of R 3a , R 3c , R 3d , and R 3e is hydrogen; and R 3b is selected from halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3
• each of R 3a , R 3c , R 3d , and R 3e is hydrogen; and R 3b is selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH2CI, -CHCI2, -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH2CH2CI, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH , -OCH 2 CH 3 , -OCH 2 F, -OCHF 2 , -OCF , -OCH2CI, -OCHCl 2 , -OCCI3, -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF , -OCH
• each of R 3a , R 3b , R 3d , and R 3e is hydrogen; and R 3c is selected from halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3
• each of R 3a , R 3b , R 3d , and R 3e is hydrogen; and R 3c is selected from— F,—CI,—Br, cyano, hydroxyl, -NH2, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH2CI, -CHCI2, -CCI3, -CH 2 CH 2 F,
• each of R 3a , R 3b , R 3d , and R 3e is hydrogen; and R 3c is selected from— F,—CI,—Br, methyl, ethyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 CF , -OCH , -OCF , -OCH 2 CF ,
• each of R 3a , R 3d , and R 3e is hydrogen; and each of R 3b and R 3c is selected from— F,—CI,—Br, cyano, hydroxyl, -NH2, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH2CI, -CHCI2, -CCI3, -CH2CH2F, -CH2CHF2, -CH 2 CF , -CH2CH2CI, -CH2CHCI2, -CH 2 CC1 3 , -OCH , -OCH 2 CH , -OCH2F, -OCHF2, -OCF , -OCH2CI, -OCHCI2, -OCCl 3 , -OCH 2 CH 2 F, — OCH2CHF2, -OCH 2 CF 3 , -OCH2CH2CI, -OCH2CI, -OC
• each of R 3b , R 3d , and R 3e is hydrogen; and each of R 3a and R 3c is selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CCI3,
• each of R 3a , R 3b , R 3c , R 3d , R 3e , and R 3f is independently selected from halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3
• R 3a , R 3b , R 3c , R 3d , R 3e , and R 3f are hydrogen.
• each of R 3a , R 3b , R 3c , R 3d , R 3e , and R 3f is hydrogen.
• each of R 3a , R 3b , R 3c , R 3d , R 3e , and R 3f is independently selected from hydrogen,— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH , -OCH 2 CH , -OCH 2 F,
• each of R 3b , R 3c , R 3d , R 3e , and R 3f is hydrogen; and R 3a is selected from halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, Cl- C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3
• each of R 3b , R 3c , R 3d , R 3e , and R 3f is hydrogen; and R 3a is selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CCI3, -CH 2 CH 2 F,
• each of R 3a , R 3c , R 3d , R 3e , and R 3f is hydrogen; and R 3b is selected from halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, Cl- C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3
• each of R 3a , R 3c , R 3d , R 3e , and R 3f is hydrogen; and R 3b is selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CCI3, -CH 2 CH 2 F,
• each of R 3a , R 3b , R 3d , R 3e , and R 3f is hydrogen; and R 3c is selected from halo, cyano, hydroxyl, -NH2, C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, Cl- C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3
• each of R 3a , R 3b , R 3d , R 3e , and R 3f is hydrogen; and R 3c is selected from— F,—CI,—Br, cyano, hydroxyl, -NH2, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH2CI, -CHCI2, -CCI3, -CH 2 CH 2 F,
• each of R 3a , R 3d , R 3e , and R 3f is hydrogen; and each of R 3b and R 3c is selected from— F,—CI,—Br, cyano, hydroxyl, -NH2, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH2CI, -CHCI2, -CCI3,
• each of R 3b , R 3d , R 3e , and R 3f is hydrogen; and each of R 3a and R 3c is selected from— F,—CI,—Br, cyano, hydroxyl, -NH2, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH2CI, -CHCI2, -CCI3,
• each of R 4a , R 4b , and R 4c is hydrogen.
• each of R 4a , R 4b , and R 40 is selected from hydrogen,— F,—CI,—Br, cyano, hydroxyl, -NH2, methyl, ethyl, propyl, isopropyl,— CH2F,— CHF2,— CF3,— CH2CI, -CHCI2, -CCI3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CI, -CH2CHCI2,
• each of R 4a , R 4b , and R 4c is selected from hydrogen,— F,—CI, -Br, methyl, ethyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 ,— CH2CF3, -OCH3, -OCF3,
• each of R 4a and R 4b is selected from hydrogen,— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CCb, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH3, -OCH 2 CH 3 , -OCH 2 F, -OCHF 2 , -OCF3, -OCH 2 Cl, -OCHCl 2 , -OCCI3, -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 , -0CH 2 CH 2 C1, -0CH 2 CHC1 2
• R 5 is selected from hydrogen and C1-C3 alkyl. In a further aspect, R 5 is selected from hydrogen, methyl, and ethyl. In a still further aspect, R 5 is selected from hydrogen and methyl. In a yet further aspect, R 5 is methyl. In an even further aspect, R 5 is hydrogen.
• each occurrence of R 9 when present, is selected from hydrogen and C1-C3 alkyl. In a further aspect, each occurrence of R 9 , when present, is hydrogen.
• each occurrence of R 9 when present, is selected from hydrogen, ethyl, and methyl. In a further aspect, each occurrence of R 9 , when present, is selected from hydrogen and methyl. In a still further aspect, each occurrence of R 9 , when present, is methyl.
• each occurrence of R 10a and R 10b when present, is independently selected from hydrogen and C1-C3 alkyl. In a further aspect, each occurrence of R 10a and R 10b , when present, is hydrogen.
• each occurrence of R 10a and R 10b when present, is independently selected from hydrogen, ethyl, and methyl. In a further aspect, each occurrence of R 10a and R 10b , when present, is independently selected from hydrogen and methyl. In a still further aspect, each occurrence of R 10a and R 10b , when present, is methyl.
• each occurrence of R 10a when present, is hydrogen; and wherein each occurrence of R 10b , when present, is selected from hydrogen and C1-C3 alkyl.
• each occurrence of R 10a when present, is hydrogen; and wherein each occurrence of R 10b , when present, is selected from hydrogen, ethyl, and methyl.
• each occurrence of R 10a when present, is hydrogen; and wherein each occurrence of R 10b , when present, is selected from hydrogen and methyl,
• Ar is aryl or heteroaryl and is unsubstituted.
• Ar is aryl substituted with 0 to 3 groups independently selected from halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, Cl- C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3
• Ar is aryl substituted with 0 to 3 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CCb, -CH 2 CH 2 F,
• Ar is aryl substituted with 0 to 3 groups independently selected from— F,—CI,—Br, methyl, ethyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 CF , -OCH , -OCF , -OCH 2 CF ,
• Ar is aryl monosubstituted with a group selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl,— CH 2 F,— CHF 2 ,— CF 3 ,— CH 2 C1, -CHC1 2 , -CCb, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 ,
• Ar is aryl substituted with 2 groups independently selected from halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3
• Ar is aryl substituted with 2 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH2, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH2CI, -CHCI2, -CCI3, -CH 2 CH 2 F,
• Ar is phenyl substituted with 0 to 3 groups independently selected from halo, cyano, hydroxyl, -NH2, C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, Cl- C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3
• Ar is phenyl substituted with 0 to 3 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH2, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH2CI, -CHCI2, -CCI3, -CH 2 CH 2 F,
• Ar is phenyl substituted with 0 to 3 groups independently selected from— F,—CI,—Br, methyl, ethyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -OCH 3 , -OCF 3 , -OCH 2 CF ,
• Ar is phenyl monosubstituted with a group selected from — F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl,— CH 2 F,— CHF 2 , -CF , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF , -CH 2 CH 2 C1,
• Ar is phenyl substituted with 2 groups independently selected from halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3
• Ar is phenyl substituted with 2 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F,
• Ar is heteroaryl substituted with 0 to 3 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CCI3,
• Ar is heteroaryl monosubstituted with a group selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl,— CH 2 F, -CHF 2 , -CF , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH , -OCH 2 CH , -OCH 2 F, -OCHF 2 , -OCF , -OCH 2 Cl, -OCHCl 2 , -OCCl 3 , -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF , -0CH 2 CH 2 C1,
• Ar is heteroaryl substituted with 2 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH3, -OCH 2 CH 3 ,
• Ar is heteroaryl substituted with 2 groups independently selected from— F,—CI,—Br, methyl, ethyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 CF , -OCH , -OCF , -OCH 2 CF ,
• Ar is selected from phenyl, pyridinyl, pyridazinyl, furanyl, thiophenyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, benzo[ ⁇ i]thiazolyl, benzo[ ⁇ i]oxazolyl, oxazolo[4,5-c]pyridinyl, quinolinyl, and lH-benzo [d] imidazolyl; and wherein Ar is substituted with 0 to 3 groups independently selected from halo, cyano, hydroxyl, -NH 2 , Cl- C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl, C
• Ar is selected from phenyl, pyridinyl, pyridazinyl, furanyl, thiophenyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, benzo[ ⁇ i]thiazolyl, benzo[ ⁇ i]oxazolyl, oxazolo[4,5-c]pyridinyl, quinolinyl, and lH-benzo[ ⁇ i]imidazolyl; and wherein Ar is substituted with 0 to 3 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF ,
• Ar is selected from phenyl, pyridinyl, pyridazinyl, furanyl, thiophenyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, benzo[if]thiazolyl, benzo[ ⁇ i]oxazolyl, oxazolo[4,5-c]pyridinyl, quinolinyl, and 1H- benzo[ ⁇ i] imidazolyl; and wherein Ar is substituted with 0 to 3 groups independently selected from -F, -CI, -Br, methyl, ethyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH2CF3, -OCH3, -OCF3, -OCH 2 CF 3 , -(C
• Ar is selected from phenyl, pyridinyl, pyridazinyl, furanyl, thiophenyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, benzo[ ⁇ i]thiazolyl, benzo[ ⁇ i]oxazolyl, oxazolo[4,5-c]pyridinyl, quinolinyl, and lH-benzo [d] imidazolyl; and wherein Ar is monosubstituted with a group selected from halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, Cl- C3 monoalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl,
• Ar is selected from phenyl, pyridinyl, pyridazinyl, furanyl, thiophenyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, benzo[ ⁇ i]thiazolyl, benzo [d] oxazolyl, oxazolo[4,5-c]pyridinyl, quinolinyl, and lH-benzo[ ⁇ i]imidazolyl; and wherein Ar is monosubstituted with a group selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF3, -CH 2 C1, -CHC1 2 , -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -
• Ar is selected from phenyl, pyridinyl, pyridazinyl, furanyl, thiophenyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, benzo[ ⁇ i]thiazolyl, benzo[ ⁇ i]oxazolyl, oxazolo[4,5-c]pyridinyl, quinolinyl, and lH-benzo [d] imidazolyl; and wherein Ar is substituted with 2 groups independently selected from halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, Cl- C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkoxy
• Ar is selected from phenyl, pyridinyl, pyridazinyl, furanyl, thiophenyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, benzo[ ⁇ i]thiazolyl, benzo[ ⁇ i]oxazolyl, oxazolo[4,5-c]pyridinyl, quinolinyl, and lH-benzo[ ⁇ i]imidazolyl; and wherein Ar is substituted with 2 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2
• Ar is selected from phenyl, pyridinyl, pyridazinyl, furanyl, thiophenyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, benzo[ ⁇ i]thiazolyl, benzo[ ⁇ i]oxazolyl, oxazolo[4,5-c]pyridinyl, quinolinyl, and 1H- benzo[ ⁇ i] imidazolyl; and wherein Ar is substituted with 2 groups independently selected from -F, -CI, -Br, methyl, ethyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 CF , -OCH , -OCF , -OCH 2 CF , -(C
• Ar is pyridinyl substituted with 0 to 3 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH , -OCH 2 CH 3 , -OCH 2 F, -OCHF 2 , -OCF , -OCH 2 Cl, -OCHCl 2 , -OCCl 3 , -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF , -0CH 2 CH 2
• Ar is pyridinyl monosubstituted with a group selected from — F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl,— CH 2 F,— CHF 2 , -CF 3 , -CH2CI, -CHCI2, -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH2CH2CI, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH3, -OCH 2 CH 3 , -OCH 2 F, -OCHF 2 , -OCF3, -OCH2CI, -OCHCI2, -OCCI3, -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCH2CH2CI, -OCHCI2, -OCCI3, -OC
• Ar is pyridinyl substituted with 2 groups independently selected from halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, Cl- C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3
• Ar is pyridinyl substituted with 2 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH2CI, -CHCI2, -CCI3, -CH 2 CH 2 F,
• Ar is pyridinyl substituted with 2 groups independently selected from— F,—CI,—Br, methyl, ethyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 CF , -OCH , -OCF , -OCH 2 CF ,
• Ar is pyridazinyl substituted with 0 to 3 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH2CI, -CHCI2, -CCI3,
• Ar is pyridazinyl monosubstituted with a group selected from— F,—CI,—Br, cyano, hydroxyl, -NH2, methyl, ethyl, propyl, isopropyl,— CH2F, -CHF2, -CF 3 , -CH2CI, -CHCI2, -CCI3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CI, -CH2CHCI2, -CH2CCI3, -OCH3, -OCH2CH3, -OCH2F, -OCHF2, -OCF3, -OCH2CI, -OCHCI2, -OCCI3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2CI,
• Ar is pyridazinyl substituted with 2 groups independently selected from halo, cyano, hydroxyl, -NH2, C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, Cl- C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3
• Ar is pyridazinyl substituted with 2 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH2, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH2CI, -CHCI2, -CCI3, -CH 2 CH 2 F, -CH2CHF2, -CH2CF3, -CH2CH2CI, -CH2CHCI2, -CH2CCI3, -OCH3, -OCH2CH3,
• Ar is pyridazinyl substituted with 2 groups independently selected from— F,—CI,—Br, methyl, ethyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -OCH , -OCF , -OCH 2 CF 3 ,
• Ar is furanyl substituted with 0 to 3 groups independently selected from halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, Cl- C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3
• Ar is furanyl substituted with 0 to 3 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F,
• Ar is furanyl substituted with 0 to 3 groups independently selected from— F,—CI,—Br, methyl, ethyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 CF 3 , -OCH , -OCF , -OCH 2 CF 3 ,
• Ar is furanyl monosubstituted with a group selected from — F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl,— CH 2 F,— CHF 2 , -CF , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH , -OCH 2 CH , -OCH 2 F, -OCHF 2 , -OCF , -OCH 2 Cl, -OCHCl 2 , -OCCl 3 , -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF , -0CH 2 CH 2 C1,
• Ar is furanyl substituted with 2 groups independently selected from halo, cyano, hydroxyl, -NH2, C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, Cl- C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3
• Ar is furanyl substituted with 2 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH2, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH2CI, -CHCI2, -CCI3, -CH 2 CH 2 F,
• Ar is thiophenyl substituted with 0 to 3 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH2, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH2CI, -CHCI2, -CCI3,
• Ar is thiophenyl monosubstituted with a group selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl,— CH 2 F, -CHF 2 , -CF3, -CH 2 C1, -CHC1 2 , -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH3, -OCH 2 CH 3 , -OCH 2 F, -OCHF 2 , -OCF3, -OCH 2 Cl, -OCHCl 2 , -OCCI3, -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 , -0CH 2 CH 2 C1,
• Ar is thiophenyl substituted with 2 groups independently selected from halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, Cl- C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3
• Ar is thiophenyl substituted with 2 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH , -OCH 2 CH , -OCH 2 F, -OCHF 2 , -OCF , -OCH 2 Cl, -OCHCl 2 , -OCCl 3 , -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF , -0CH 2 CH 2 C1, -0
• Ar is thiophenyl substituted with 2 groups independently selected from— F,—CI,—Br, methyl, ethyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 CF , -OCH , -OCF , -OCH 2 CF ,
• Ar is oxazolyl substituted with 0 to 3 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH3, -OCH 2 CH 3 ,
• Ar is oxazolyl substituted with 0 to 3 groups independently selected from— F,—CI,—Br, methyl, ethyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 CF , -OCH , -OCF , -OCH 2 CF ,
• Ar is oxazolyl monosubstituted with a group selected from — F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl,— CH 2 F,— CHF 2 , -CF , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH , -OCH 2 CH , -OCH 2 F, -OCHF 2 , -OCF , -OCH 2 Cl, -OCHCl 2 , -OCCl 3 , -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 , -0CH 2 CH 2 C
• Ar is oxazolyl substituted with 2 groups independently selected from halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, Cl- C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3
• Ar is oxazolyl substituted with 2 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CCI3, -CH 2 CH 2 F,
• Ar is oxazolyl substituted with 2 groups independently selected from— F,—CI,—Br, methyl, ethyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 CF , -OCH , -OCF , -OCH 2 CF ,
• Ar is thiazolyl substituted with 0 to 3 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH , -OCH 2 CH 3 , -OCH 2 F, -OCHF 2 , -OCF , -OCH 2 Cl, -OCHCl 2 , -OCCl 3 , -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF , -0CH 2 CH 2 C
• Ar is thiazolyl substituted with 0 to 3 groups independently selected from— F,—CI,—Br, methyl, ethyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 CF , -OCH , -OCF , -OCH 2 CF ,
• Ar is thiazolyl monosubstituted with a group selected from — F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl,— CH 2 F,— CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH , -OCH 2 CH 3 , -OCH 2 F, -OCHF 2 , -OCF , -OCH 2 Cl, -OCHCl 2 , -OCCl 3 , -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF , -0CH 2 CH 2
• Ar is thiazolyl substituted with 2 groups independently selected from halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, Cl- C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3
• Ar is thiazolyl substituted with 2 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F,
• Ar is thiazolyl substituted with 2 groups independently selected from— F,—CI,—Br, methyl, ethyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 CF , -OCH , -OCF , -OCH 2 CF ,
• Ar is imidazolyl substituted with 0 to 3 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 C1, -CHC1 2 , -CC1 3 ,
• Ar is imidazolyl monosubstituted with a group selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl,— CH 2 F, -CHF 2 , -CF , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH , -OCH 2 CH , -OCH 2 F, -OCHF 2 , -OCF , -OCH 2 Cl, -OCHCl 2 , -OCCl 3 , -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF , -0CH 2 CH 2 C1,
• Ar is imidazolyl substituted with 2 groups independently selected from halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, Cl- C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3
• Ar is imidazolyl substituted with 2 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH , -OCH 2 CH , -OCH 2 F, -OCHF 2 , -OCF , -OCH 2 Cl, -OCHCl 2 , -OCCl 3 , -OCH 2 CH 2 F, -OCCl 3 , -OCH 2 CH 2 F, -OCCl 3 , -OCH 2 CH 2 F, -OCH
• Ar is imidazolyl substituted with 2 groups independently selected from— F,—CI,—Br, methyl, ethyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 CF 3 , -OCH , -OCF , -OCH 2 CF 3 ,
• Ar is pyrrolyl substituted with 0 to 3 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH3, -OCH 2 CH 3 , -OCH 2 F, -OCHF 2 , -OCF3, -OCH 2 Cl, -OCHCl 2 , -OCCI3, -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 , -0CH 2 CH 2 C1, -0CH
• Ar is pyrrolyl substituted with 0 to 3 groups independently selected from— F,—CI,—Br, methyl, ethyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF , -OCH 3 , -OCF 3 , -OCH 2 CF ,
• Ar is pyrrolyl monosubstituted with a group selected from — F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl,— CH 2 F,— CHF 2 , -CF , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH , -OCH 2 CH , -OCH 2 F, -OCHF 2 , -OCF , -OCH 2 Cl, -OCHCl 2 , -OCCl 3 , -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF , -0CH 2 CH 2 C1,
• Ar is pyrrolyl substituted with 2 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CCI3, -CH 2 CH 2 F,
• Ar is pyrrolyl substituted with 2 groups independently selected from— F,—CI,—Br, methyl, ethyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 CF , -OCH , -OCF , -OCH 2 CF ,
• Ar is benzo[ ⁇ i]thiazolyl substituted with 0 to 3 groups
• Ar is benzo[ ]thiazolyl substituted with 0 to 3 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, - NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH ,
• Ar is benzo[ ⁇ i]thiazolyl monosubstituted with a group selected from halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, Cl- C3 alkoxy, C1-C3 monohaloalkoxy C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3
• Ar is benzo[if]thiazolyl monosubstituted with a group selected from— F,—CI,—Br, methyl, ethyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 CF , -OCH , -OCF , -OCH 2 CF ,
• Ar is benzo[ ]thiazolyl substituted with 2 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH , -OCH 2 CH 3 , -OCH 2 F, -OCHF 2 , -OCF , -OCH 2 Cl, -OCHCl 2 , -OCCl 3 , -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF , -0CH 2 CH 2
• Ar is benzo[ ⁇ i]oxazolyl substituted with 0 to 3 groups
• Ar is benzo[ ]oxazolyl substituted with 0 to 3 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, - NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH , -OCH 2 CH , -OCH 2 F, -OCHF 2 , -OCF , -OCH 2 Cl, -OCHCl 2 , -OCCl 3 , -OCH 2 CH 2 F, -OCH2CHF2, -OCH2CF3, -OCH2CH2
• Ar is benzo[ ⁇ i]oxazolyl monosubstituted with a group selected from halo, cyano, hydroxyl, -NH2, C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, Cl- C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3
• Ar is benzo[ ]oxazolyl monosubstituted with a group selected from— F,—CI,—Br, cyano, hydroxyl, -NH2, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH2CI, -CHCI2, -CCI3, -CH 2 CH 2 F, -CH2CHF2, -CH 2 CF , -CH2CH2CI, -CH2CHCI2, -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH , -OCH2F, -OCHF2, -OCF , -OCH2CI, -OCHCI2, -OCCl 3 , -OCH2CH2F, -OCHCI2, -OCCl 3 , -OCH2CH2F, -OCHCI2, -OCCl 3 , -OCH2CH2
• Ar is benzo[if]oxazolyl monosubstituted with a group selected from— F,—CI,—Br, methyl, ethyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 CF , -OCH , -OCF , -OCH 2 CF ,
• Ar is benzo[ ]oxazolyl substituted with 2 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH2, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH2CI, -CHCI2, -CCI3,
• Ar is oxazolo[4,5- cjpyridinyl substituted with 0 to 3 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH , -OCH 2 CH , -OCH 2 F, -OCHF 2 , -OCF , -OCH 2 Cl, -OCHCl 2 , -OCCl 3 , -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 , -OCH 2
• Ar is oxazolo[4,5-c]pyridinyl monosubstituted with a group selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH , -OCH 2 CH , -OCH 2 F, -OCHF 2 , -OCF , -OCH 2 Cl, -OCHCl 2 , -OCCl 3 , -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF
• Ar is oxazolo[4,5- cjpyridinyl substituted with 2 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CCb, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH , -OCH 2 F, -OCHF 2 , -OCF , -OCH 2 Cl, -OCHCl 2 , -OCCl 3 , -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF , -OCH 2 CH
• Ar is quinolinyl substituted with 0 to 3 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 C1, -CHC1 2 , -CC1 3 ,
• Ar is quinolinyl monosubstituted with a group selected from— F,—CI,—Br, cyano, hydroxyl, -NH2, methyl, ethyl, propyl, isopropyl,— CH2F, -CHF2, -CF3, -CH2CI, -CHCI2, -CCI3, -CH2CH2F, -CH2CHF2, -CH2CF3,— CH2CH2CI, -CH2CHCI2, -CH2CCI3, -OCH3, -OCH2CH3, -OCH2F, -OCHF2, -OCF3, -OCH2CI, -OCHCI2, -OCCI3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2CI,
• Ar is quinolinyl substituted with 2 groups independently selected from halo, cyano, hydroxyl, -NH2, C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, Cl- C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3
• Ar is quinolinyl substituted with 2 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH2, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH2CI, -CHCI2, -CCI3, -CH 2 CH 2 F,— CH2CHF2, -CH2CF3, -CH2CH2CI, -CH2CHCI2, -CH2CCI3, -OCH3, -OCH2CH3, -OCH2F, -OCH2F,
• Ar is lH-benzo[ ]imidazolyl substituted with 0 to 3 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, - NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CCb, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH3, -OCH 2 CH 3 , -OCH 2 F, -OCHF 2 , -OCF3, -OCH 2 Cl, -OCHCl 2 , -OCCI3, -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 , -0
• Ar is lH-benzo[ ]imidazolyl monosubstituted with a group selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH , -OCH 2 CH 3 , -OCH 2 F, -OCHF 2 , -OCF , -OCH 2 Cl, -OCHCl 2 , -OCCl
• Ar is lH-benzo[ ⁇ i]imidazolyl monosubstituted with a group selected from— F,—CI,—Br, methyl, ethyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 CF , -OCH , -OCF , -OCH 2 CF ,
• Ar is lH-benzo[ ]imidazolyl substituted with 2 groups independently selected from— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 C1, -CHC1 2 , -CC1 3 ,
• Ar is a moiety having a structure represented by a formula:
• Ar is a moiety having a structure represented by a formula:
• each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen,— F,—CI, —Br, cyano, hydroxyl, -NH2, methyl, ethyl, propyl, isopropyl,— CH2F,— CHF2,— CF 3 , -CH2CI, -CHCI2, -CCI3, -CH2CH2F, -CH2CHF2, -CH 2 CF , -CH2CH2CI, -CH2CHCI2, -CH 2 CC1 3 , -OCH , -OCH 2 CH 3 , -OCH2F, -OCHF2, -OCF , -OCH2CI, -OCHCI2, -OCCl 3 , -OCH2CH2F, -OCH2CHF2, -OCH 2CF , -OCH2CH2CI, -OCH2CHCI2, -OCHCI
• Ar is a moiety having a structure represented by a formula:
• Ar is a moiety having a structure represented by a formula:
• Ar is a moiety having a structure represented by a formula:
• each of R 3a , R 3b , and R 3c when present, is independently selected from— F,—CI, —Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl,— CH 2 F,— CHF 2 ,— CF3,
• Ar is a moiety having a structure represented by a formula: wherein each of R 3a , R 3b , and R 3c , when present, is independently selected from— F,—CI, -Br, methyl, ethyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -OCH 3 , -OCF 3 ,
• Ar is a moiety having a structure represented by a formula:
• Ar is a moiety having a structure represented by a formula:
• each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen,— F,—CI, —Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl,— CH 2 F,— CHF 2 ,— CF 3 ,
• Ar is a moiety having a structure represented by a formula:
• each of R 3a , R 3b , and R 3c when present, is independently selected from— F,—CI, —Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl,— CH 2 F,— CHF 2 ,— CF3, -CH 2 C1, -CHC1 2 , -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH3, -OCH 2 CH 3 , -OCH 2 F, -OCHF 2 , -OCF3, -OCH 2 Cl, -OCHCl 2 , -OCCI3, -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 , -0CH 2 CH 2 C1, -0CH 2 CH 2 C
• each of R 3a , R 3b , and R 3c when present, is independently selected from— F,—CI, -Br, methyl, ethyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 CF , -OCH , -OCF ,
• Ar is a moiety having a structure represented by a formula:
• Ar is a moiety having a structure represented by a formula:
• Ar is a moiety having a structure represented by a formula:
• Ar is a moiety having a structure represented by a formula:
• each of R 4a , R 4b , and R 4c when present, is independently selected from hydrogen, halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3
• Ar is a moiety having a structure represented by a formula:
• each of R 4a , R 4b , and R 4c when present, is independently selected from hydrogen, — F,—CI,—Br, cyano, hydroxyl, -NH2, methyl, ethyl, propyl, isopropyl,— CH2F,— CHF2, -CF3, -CH2CI, -CHCI2, -CCI3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CI, -CH2CHCI2, -CH2CCI3, -OCH3, -OCH2CH3, -OCH2F, -OCHF2, -OCF3, -OCH2CI, -OCHCI2, -OCCI3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2CI,
• Ar is a moiety having a structure represented by a formula:
• Ar is a moiety having a structure represented by a formula:
• each of R 4a , R 4b , and R 4c when present, is independently selected from hydrogen, halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3
• Ar is a moiety having a structure represented by a formula:
• each of R 4a , R 4b , and R 4c when present, is independently selected from hydrogen, — F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl,— CH 2 F,— CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1,
• Ar is a moiety having a structure represented by a formula:
• Ar is a moiety having a structure represented by a formula:
• Ar is a moiety having a structure represented by a formula:
• each of R 4a and R 4b when present, is independently from hydrogen,— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl,— CH 2 F,— CHF 2 ,— CF3,— CH 2 C1, -CHC1 2 , -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 ,
• Ar is a moiety having a structure represented by a formula:
• Ar is a moiety having a structure represented by a formula:
• Ar is a moiety having a structure represented by a formula:
• each of R 4a and R 4b when present, is independently from hydrogen,— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl,— CH 2 F,— CHF 2 ,— CF3,— CH 2 C1, -CHC1 2 , -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 ,
• Ar is a moiety having a structure represented by a formula:
• Ar is a moiety having a structure represented by a formula:
• Ar is a moiety having a structure represented by a formula:
• each of R 4a and R 4b when present, is independently from hydrogen,— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl,— CH 2 F,— CHF 2 ,— CF3,— CH 2 C1, -CHC1 2 , -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 ,
• Ar is a moiety having a structure represented by a formula:
• Ar is a moiety having a structure represented by a formula:
• Ar is a moiety having a structure represented by a formula:
• each of R 4a and R 4b when present, is independently from hydrogen,— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl,— CH 2 F,— CHF 2 ,— CF3,— CH 2 C1, -CHCI2, -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH2CH2CI, -CH 2 CHC1 2 ,
• Ar is a moiety having a structure represented by a formula:
• Ar is a moiety having a structure represented by a formula:
• Ar is a moiety having a structure represented by a formula:
• each of R 4a and R 4b when present, is independently from hydrogen,— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl,— CH 2 F,— CHF 2 ,— CF3,— CH 2 C1, -CHCI2, -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH2CH2CI, -CH 2 CHC1 2 ,
• Ar is a moiety having a structure represented by a formula:
• Ar is a moiety having a structure represented by a formula:
• each of R 4a , R 4b , and R 4c when present, is independently selected from hydrogen, halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3
• R 5 when present, is selected from hydrogen and C1-C3 alkyl.
• Ar is a moiety having a structure represented by a formula:
• each of R 4a , R 4b , and R 4c when present, is independently from hydrogen,— F,—CI, —Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl,— CH 2 F,— CHF 2 ,— CF3, -CH2CI, -CHCI2, -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH2CH2CI, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH3, -OCH 2 CH 3 , -OCH 2 F, -OCHF 2 , -OCF3, -OCH2CI, -OCHCl 2 , -OCCI3, -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCH2CH2CI, -0CH 2 CHC
• Ar is a moiety having a structure represented by a formula:
• Ar is a moiety having a structure represented by a formula:
• each of R 4a , R 4b , and R 4c when present, is independently selected from hydrogen, halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3
• Ar is a moiety having a structure represented by a formula:
• each of R 4a , R 4b , and R 4c when present, is independently from hydrogen,— F,—CI, —Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl,— CH 2 F,— CHF 2 ,— CF3, -CH2CI, -CHCI2, -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH2CH2CI, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH3, -OCH 2 CH 3 , -OCH 2 F, -OCHF 2 , -OCF3, -OCH 2 Cl, -OCHCl 2 , -OCCI3, -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCH2CH2CI, -0CH 2 CHC
• Ar is a moiety having a structure represented by a formula:
• each of R 4a , R 4b , and R 4c when present, is independently from hydrogen,— F,—CI,
• Ar is a moiety having a structure represented by a formula:
• each of R 3a , R 3b , R 3c , and R 3d when present, is independently selected from hydrogen, halo, cyano, hydroxyl, -NH2, C1-C3 alkyl, C1-C3 monoalkyl, C1-C3
• R 3a , R 3b , R 3c , and R 3d is hydrogen.
• Ar is a moiety having a structure represented by a formula:
• each of R 3a , R 3b , R 3c , and R 3d when present, is independently selected from hydrogen,— F,—CI,—Br, cyano, hydroxyl, -NH2, methyl, ethyl, propyl, isopropyl,— CH2F, -CHF2, -CF3, -CH2CI, -CHCI2, -CCI3, -CH2CH2F, -CH2CHF2, -CH2CF3,— CH2CH2CI, -CH2CHCI2, -CH2CCI3, -OCH3, -OCH2CH3, -OCH2F, -OCHF2, -OCF3, -OCH2CI, -OCHCI2, -OCCI3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2CI,
• R 3a , R 3b , R 3c , and R 3d are hydrogen.
• Ar is a moiety having a structure represented by a formula:
• each of R 3a , R 3b , R 3c , and R 3d when present, is independently selected from hydrogen, halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3
• R 3a , R 3b , R 3c , and R 3d are hydrogen.
• Ar is a moiety having a structure represented by a formula:
• each of R 3a , R 3b , R 3c , and R 3d when present, is independently selected from hydrogen,— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl,— CH 2 F, -CHF 2 , -CF3, -CH 2 C1, -CHC1 2 , -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH , -OCH 2 F, -OCHF 2 , -OCF , -OCH 2 Cl, -OCHCl 2 , -OCCl 3 , -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCH 2
• Ar is a moiety having a structure represented by a formula:
• Ar is a moiety having a structure represented by a formula:
• each of R 3a , R 3b , R 3c , and R 3d when present, is independently selected from hydrogen, halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3
• Ar is a moiety having a structure represented by a formula:
• each of R 3a , R 3b , R 3c , and R 3d when present, is independently selected from hydrogen,— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl,— CH 2 F, -CHF 2 , -CF 3 , -CH2CI, -CHCI2, -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH2CH2CI, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH3, -OCH 2 CH 3 , -OCH 2 F, -OCHF 2 , -OCF3, -OCH2CI, -OCHCl 2 , -OCCI3, -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCH2CH2CI, -
• R 4a when present, is selected from hydrogen,— F, —CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl,— CH 2 F,— CHF 2 ,— CF 3 , -CH2CI, -CHCI2, -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF , -CH2CH2CI, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH , -OCH 2 CH , -OCH 2 F, -OCHF 2 ,
• Ar is a moiety having a structure represented by a formula:
• Ar is a moiety having a structure represented by a formula:
• each of R 3a , R 3b , R 3c , R 3d , R 3e , and R 3f when present, is independently selected from hydrogen, halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3
• R 3a , R 3b , R 3c , R 3d , R 3e , and R 3f are hydrogen.
• Ar is a moiety having a structure represented by a formula:
• each of R 3a , R 3b , R 3c , R 3d , R 3e , and R 3f when present, is independently selected from hydrogen,— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl,— CH 2 F, -CHF 2 , -CF 3 , -CH2CI, -CHCI2, -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH3, -OCH 2 CH 3 , -OCH 2 F, -OCHF 2 , -OCF3, -OCH2CI, -OCHCl 2 , -OCCI3, -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3
• Ar is a moiety having a structure represented by a formula:
• Ar is a moiety having a structure represented by a formula: wherein each of R 3a , R 3b , R 3c , and R 3d , when present, is independently selected from hydrogen, halo, cyano, hydroxyl, -NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3
• R 5 when present, is selected from hydrogen and C1-C3 alkyl; and wherein at least one R 3a , R 3b , R 3c , and R 5 is hydrogen.
• Ar is a moiety having a structure represented by a formula:
• each of R 3a , R 3b , R 3c , and R 3d when present, is independently selected from hydrogen,— F,—CI,—Br, cyano, hydroxyl, -NH 2 , methyl, ethyl, propyl, isopropyl,— CH 2 F, -CHF 2 , -CF3, -CH2CI, -CHCI2, -CCI3, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH2CH2CI, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH3, -OCH 2 CH 3 , -OCH 2 F, -OCHF 2 , -OCF3, -OCH2CI, -OCHCl 2 , -OCCI3, -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCH2CH2CI, -OCHC
• R 5 when present, is selected from hydrogen and methyl; and wherein at least one R 3a , R 3b , R 3c , and R 5 is hydrogen.
• Ar is a moiety having a structure represented by a formula:
• a compound is selected from:
• a compound is selected from:
• a compound is selected from:
• a compound is selected from:
• a compound is selected from: or a subgroup thereof.
• a compound is selected from
• one or more compounds can optionally be omitted from the disclosed invention.
• pharmaceutically acceptable derivatives of the disclosed compounds of Formula I can be used also in connection with the disclosed methods, compositions, kits, and uses.
• the pharmaceutical acceptable derivatives of the compounds can include any suitable derivative, such as pharmaceutically acceptable salts as discussed below, isomers, radiolabeled analogs, tautomers, and the like.
• Spectinomycin is an aminocyclitol antibiotic that specifically inhibits bacterial protein synthesis by binding to 30S ribosome at a unique site that is highly conserved across bacterial pathogens (Carter et al. Nature 2000, 407(6802), 340-348; Borovinskaya et al. ACS Chem. Biol. 2007, 2 (8), 545-552; Wirmer et al. Methods in enzymology 2006, 415, 180-202). Although spectinomycin is potent in cell free assays its clinical use is restricted to second line treatment for Neisseria gonorrhoeae infections (McCormack et al.
• spectinamides More recently, a highly specific set of 3 '-dihydro-3 '-deoxy-(R)-acylamino spectinomycins, or alternatively referred to as spectinamides (see Figure 1, panel (C)) demonstrated excellent efficacy in acute and chronic models of tuberculosis infection (see US 2011/ 0118272). This class of compounds, which has a tight structure activity relationship as demonstrated by the synthesis over 140 analogs, is highly selective for M. tuberculosis.
• the disclosed compounds of the present invention i.e., aryl substituted 3 '-aminomethyl-3 '-hydroxy spectinomycins, were found to provide broad spectrum anti- bacterial activity against a variety of gram negative and gram positive pathogens, including drug resistant pathogens and biodefense pathogens, a result in strong contrast to the results obtained with the spectinamides previously described in US 2011/ 0118272.
• the crystal structure of SPC bound to the bacterial ribosome from E. coli is available and was used for the structure-based design of the disclosed compounds of the present invention.
• the binding site of SPC is situated near the RNA helix34 and a small loop from RspE protein.
• SPC forms an intricate hydrogen bonding network with ribosome that contributes significantly to its excellent ribosomal inhibition.
• a homology model of both M. tuberculosis and S. pneumoniae ribosomes was built for a 15A sphere centered at the SPC binding site which is highly conserved among these species with only a single RNA residue variance (A1081G) observed. More structural differences were observed for the RspE protein loop (see Figure 2 and the amino acid variances noted therein).
• Protein variations at this site are particularly important for the disclosed compounds of the present invention as the RspE loop makes close contacts with the 3 ' side chain (e.g. the methylene linker of compound 2). Docking and short molecular dynamics simulations were performed on E coli, M.
• tuberculosis and S. pneumoniae ribosomes to investigate the binding of the disclosed compounds of the present invention.
• Compound 2 will be used as an example. Docking study shows this representative compound retains the active conformation of SPC and the modified ⁇ side chain fits well into an extended binding pocket sandwiched by both nucleic acids and protein. In addition a well-defined binding mode was seen between different species suggesting excellent ribosome inhibition against all three ribosomes.
• the disclosed compounds according to Formula I may have a known mechanism of antimicrobial action and/or may bind to and/or inhibit one or more bacterial target molecules or macromolecular complexes containing a bacterial target molecule.
• Mechanisms of action may include inhibiting or interfering with a biological or biochemical pathway of the bacterium.
• Exemplary pathways include, but are not limited to, protein synthesis, cell wall synthesis, DNA replication, transcription, and cell division. It will be appreciated that biological and biochemical pathways are not mutually exclusive and that some biological or biochemical pathways may be considered to be subsets or sub-pathways of other biological or biochemical pathways.
• Mechanisms of action include, but are not limited to, inhibiting protein synthesis (e.g., by binding ribosomal RNA or proteins, blocking tRNA binding to the ribosome-mRNA complex, inhibiting peptidyl transferase), inhibiting or interfering with synthesis of a cell wall component (e.g., inhibition of peptidoglycan synthesis, disruption of peptidoglycan cross-linkage, disruption of movement of
• peptidoglycan precursors disruption of mycolic acid or arabinoglycan synthesis
• cell membrane disruption inhibiting or interfering with nucleic acid synthesis of processing, acting as "antimetabolites” and either inhibiting an essential bacterial enzyme or competing with a substrate of an essential bacterial enzyme, inhibiting or interfering with cell division.
• Molecules, or macromolecular complexes containing them, that may be targets for antibiotics include, but are not limited to, peptidoglycans, penicillin binding proteins, lipopolysaccharides, ribosomes or ribosomal subunits or RNA or protein components thereof (23S rRNA, 16S rRNA, proteins of the 30S or 50S subunit), DNA-dependent DNA polymerase, DNA-dependent RNA polymerase, microbial type I topoisomerase, microbial type II topoisomerase (e.g., topoisomerase IV or gyrase), enzymes involved in cell division such as FtsZ, etc.
• peptidoglycans penicillin binding proteins, lipopolysaccharides, ribosomes or ribosomal subunits or RNA or protein components thereof (23S rRNA, 16S rRNA, proteins of the 30S or 50S subunit)
• DNA-dependent DNA polymerase DNA-dependent RNA poly
• the disclosed compounds of the present invention inhibit bacterial protein synthesis.
• the bacterial species may be of any one or more types, e.g., gram-negative bacteria, gram-positive bacteria, atypical bacteria, and/or acid fast bacteria.
• Suitable organisms can include, but are not limited to members of the following genera: Actinomyces, Staphylococcus, Streptococcus, Enterococcus, Erysipelothrix, Neisseria, Branhamella, Listeria, Bacillus, Corynbacterium, Erysipelothrix, Gardnerella, Mycobacterium, Nocardia, Enterobacteriaceae, Escherichia, Salmonella, Shigella, Yersinia, Enterobacter, Klebsiella, Citrobacter, Serratia, Providencia, Proteus, Morganella, Edwardsiella, Erwinia, Vibrio, Aeromonas, Helicobacter, Campylobacter, Eikenella, Pasteurella
• Burkholderia Stenotrophomonas, Acinetobacter, Ralstonia, Alcaligenes, Moraxella, Mycoplasma, Legionella, Francisella, Brucella, Haemophilus, Bordetella, Clostridium, Bacteroides, Porphyromonas, Prevotella, Fusobacterium, Borrelia, Chlamydia, Rickettsia, Ehrlichia, Bartonella, Trichomonas, and Treponema.
• the bacteria are species that are causative agents of disease in humans and/or animals. Examples include, but are not limited to, Acinetobacter baumannii, Aeromonas hydrophila, Bacillus anthracis, Bacillus anthracis sterne, Bacillus subtilis, Burkholderia cepacia, Escherichia coli, Enterobacter cloacae, Enterococcus faecalis, Francisella tularensis, Campylobacter jejuni, Haemophilus influenzae, Klebsiella pneumoniae, Klebsiella oxytoca, Legionella pneumophila, Pasteurella multocida, Proteus mirabilis, Proteus vulgaris, Mycobacterium tuberculosis, Morganella morganii, Helicobacter pylori, Neisseria meningitides, Neisseria gonorrhoeae, Chlamydia trachomatis, Pseu
• Strenotrophomonas maltophilia Streptococcus agalactiae, and Yersinia pestis.
• the disclosed compounds of the present invention inhibit bacterial protein synthesis.
• the inhibition of bacterial protein synthesis can be demonstrated by methodology known in the art.
• inhibition of bacterial protein synthesis can be determined by measurement of cell proliferation in response to antagonist.
• the cell proliferation was analyzed as a concentration-dependent decrease in the IC50 antagonist response (i.e. the ribosomal response at a concentration of antagonist that yields 50% of the maximal response).
• the disclosed compounds of the present invention exhibit inhibition of bacterial protein synthesis.
• a compound can exhibit inhibition of bacterial protein synthesis with an IC50 of less than about 10 ⁇ g/mL, less than about 5 ⁇ g/mL, less than about 1 ⁇ g/mL, less than about 0.5 ⁇ g/mL, or less than about 0.25 ⁇ g/mL.
• the invention relates to methods of making compounds according to Formula I that are useful as antibacterial agents, which can be useful in the treatment of bacterial infections.
• the invention relates to the disclosed synthetic manipulations.
• the disclosed compounds of the present invention comprise the products of the synthetic methods described herein.
• the disclosed compounds of the present invention comprise a compound produced by a synthetic method described herein.
• the invention comprises a pharmaceutical composition comprising the product of the disclosed methods and a pharmaceutically acceptable carrier.
• the invention comprises a method for manufacturing a medicament comprising combining at least one product of the disclosed methods with a pharmaceutically acceptable carrier or diluent.
• the invention comprises a pharmaceutical composition comprising a therapeutically effective amount of the product of the disclosed methods and a
• the compounds of this invention can be prepared by employing reactions as shown in the disclosed schemes, in addition to other standard manipulations that are known in the literature, exemplified in the experimental sections or clear to one skilled in the art. For clarity, examples having a fewer substituent can be shown where multiple substituents are allowed under the definitions disclosed herein. Thus, the following examples are provided so that the invention might be more fully understood, are illustrative only, and should not be construed as limiting.
• each disclosed method can further comprise additional steps, manipulations, and/or components. It is also contemplated that any one or more step, manipulation, and/or component can be optionally omitted from the invention. It is understood that a disclosed method can be used to provide the disclosed compounds of the present invention. It is also understood that the products of the disclosed methods can be employed in the disclosed compositions, kits, and uses.
• the 3 Tiydroxy-3 '-methylamino derivative i.e. compound 1.4 in reaction Scheme IB above, and related compounds, can be prepared beginning with spectinomycin, 1.1.
• the 1- and 3- aminomethyl groups are protected.
• the specific reaction shown above yields the CBz protected, 1.2, following reaction with benzyl chloroformate, with the reaction carried out in the presence of a suitable base, e.g., Na 2 HC03, in a suitable solvent, e.g., water, and the reaction carried out a suitable temperature, e.g. about 20-30 °C, for a suitable period of time, e.g., 10-18 hr, to complete the reaction.
• a suitable base e.g., Na 2 HC03
• a suitable solvent e.g., water
• a suitable temperature e.g. about 20-30 °C
• the cyanohydrin, 1.3 is prepared by reaction of 1.2 with a suitable cyano nucleophile, e.g. KCN, in the presence of a suitable acid, e.g., acetic acid, in a suitable solvent system, e.g. methanol/water, at a suitable temperature, e.g., about 20-30 °C, for a suitable period of time sufficient to complete the reaction, e.g., 15-60 minutes.
• a suitable cyano nucleophile e.g. KCN
• a suitable acid e.g., acetic acid
• a suitable solvent system e.g. methanol/water
• the reaction can be carried out in the presence of a suitable hydrogen source, e.g., hydrogen gas, a suitable reducing agent, e.g., Raney Ni, and a suitable acid, e.g., acetic acid, at a suitable temperature, e.g., about 20-30 °C, for a suitable period of time sufficient to complete the reaction, e.g., about 4-12 hr.
• a suitable hydrogen source e.g., hydrogen gas
• a suitable reducing agent e.g., Raney Ni
• a suitable acid e.g., acetic acid
• the cyanohydrin, 1.5 is prepared by reaction of 1.2 with suitable cyano nucleophile, e.g., acetone cyanohydrin, in the presence of a suitable base, e.g., K2CO3, in a suitable solvent system, e.g., methanol, at a suitable temperature, e.g., about 20-30 °C, for a suitable period of time sufficient to complete the reaction, e.g., 4-5 hrs.
• a suitable cyano nucleophile e.g., acetone cyanohydrin
• suitable solvent system e.g., methanol
• the reaction can be carried out in the presence of a suitable hydrogen source, e.g., hydrogen gas, a suitable reducing agent, e.g., Raney Ni, and a suitable acid, e.g., acetic acid, at a suitable temperature, e.g., about 20-30 °C, for a suitable period of time sufficient to complete the reaction, e.g., about 4-12 hr.
• a suitable hydrogen source e.g., hydrogen gas
• a suitable reducing agent e.g., Raney Ni
• a suitable acid e.g., acetic acid
• aryl substituted aminomethyl spectinomycin analogues of the present invention can be prepared generically by the synthesis scheme as shown below. All positions are defined herein.
• compounds of type 2.2 can be prepared according to reaction Scheme 2B above.
• compounds of type 2.2 can be prepared by reductive amination of an appropriate amine, e.g., dibenzyl ((2/?,4/?,4a5',65',75',8/?,95')-4- (aminomethyl)-4,4a,7,9-tetrahydroxy-2-methyldecahydro-2H-benzo[b]pyrano[2,3- e][l ,4]dioxine-6,8-diyl)bis(methylcarbamate) (1.4) as shown above, which can be prepared by methods similar to those discussed for Route 1 above.
• dibenzyl ((2/?,4/?,4a5',65',75',8/?,95')-4- (aminomethyl)-4,4a,7,9-tetrahydroxy-2-methyldecahydro-2H-benzo[b]pyrano[2,3- e][l ,
• the reaction can be carried out using an appropriate solvent system, e.g., acetic acid and methanol, in the presence of a suitable borane reagent, e.g., 2-picoline borane as shown above, and a suitable aldehyde, e.g., 4-fluorbenzaldehyde (compound 2.1), as shown above.
• a suitable borane reagent e.g., 2-picoline borane as shown above
• a suitable aldehyde e.g., 4-fluorbenzaldehyde (compound 2.1)
• Suitable aldehydes that can be used in the reaction are commercially available or can be prepared by methods known to one skilled in the art.
• a compound of type 2.3 can be prepared by deprotection of a compound of type 2.3 via a hydrogenation reaction.
• such a hydrogenation reaction can be accomplished using a suitable hydrogen source, e.g., hydrogen gas, with a suitable catalyst, e.g., 10% Pd/C, in a suitable protic solvent, e.g., methanol, in the presence of an acid, e.g., 1.25 M HC1, at a suitable temperature, e.g., about 20-30 °C, for a suitable period of time, e.g., about 15 to about 120 min.
• a suitable hydrogen source e.g., hydrogen gas
• a suitable catalyst e.g., 10% Pd/C
• a suitable protic solvent e.g., methanol
• an acid e.g., 1.25 M HC1
• a suitable temperature e.g., about 20-30 °C
• a suitable period of time e.g., about 15 to about 120 min.

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