Highly potent kappa opioid receptor agonists and method of use thereof

Abstract

The present disclosure is directed to kappa opioid receptor ligands and pharmaceutical compositions thereof and their utility as anti-nociceptive agents. Specifically, the disclosed kappa opioid ligands are G-protein biased kappa opioid agonists containing a bis amide core.

Description

[0001] HIGHLY POTENT KAPPA OPIOID RECEPTOR AGONISTS AND METHOD OF USE THEREOF FIELD OF THE INVENTION The present invention is directed to kappa opioid receptor ligands and pharmaceutical compositions thereof and their utility as therapeutic agents. GOVERNMENT SUPPORT This invention was made with government support under Grant No. DA031927 and Grant No. R01 DA048490 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND Opioid overdose deaths continue to be a public health issue in the United States with rates continuing to rise. Opioids, including Morphine and its analogues, have been shown to act via the μ-opioid receptor resulting in analgesia as well as physical dependence. One cause of the opioid crisis is due to the increased prescription of opioid pain-relieving drugs that target the μ-opioid receptor resulting in addiction. There are three opioid receptors, the μ-, δ-, and κ-opioid receptors, which are all G-protein coupled receptors. Of these receptors, the κ-opioid receptor (KOR) offers a unique opportunity to treat pain. It is distributed throughout the entire nervous system and is activated by opioid peptides, such as dynorphins. Like other opioid receptors, its activation promotes antinociception, and hence, is a target for development of pain therapeutics. KOR agonists have also been proven to be efficacious in the treatment of intractable, non-histamine-related itch, or pruritus. Currently, nalfurafine is the only clinically available KOR agonist, and it is used in the treatment of pruritus. In addition to providing pain relief without the threat of overdose, KOR agonists are unlikely to be addictive because they do not induce euphoria, nor do they promote increases in dopamine release, as abused drugs do. However, they are associated with dysphoria and sedation, which has limited their therapeutic investigation. Thus, despite the ongoing efforts to develop analgesic pharmaceuticals with better properties compared to standard opioids, there still remains a need to discover and develop analgesic compounds that are effective and safe. Such new treatment options may involve KOR agonists devoid of negative side effects typically associated with opioids and / or side effects associated with KORs, i.e., dysphoria and sedation. SUMMARY Provided herein are ligands which can bind to the κ-opioid receptor to ellicit beneficial therapeutic effects (i.e., an analgesic effect) while exhibiting minimal side effects typically experienced with opioids. Thus, one aspect of the current disclosure is directed to a compound of Formula (II): Formula (II) or any stereoisomer and / or pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of substituted or unsubstituted heteroaryl, substituted or unsubstituted heterobiaryl, (C1-C6) heterocycloalkyl, -CH2NH2, -CH2N(CH3)2, R2is selected from the group consisting of substituted and unsubstituted aryl, (C1-C6)cycloalkyl, substituted or unsubstituted -CH2(aryl) and substituted or unsubstituted (C1-C10)alkyl; R3is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl; X is selected from the group consisting of -CH2-, -O-, -S-, -CHF-, -CF2-, -CH(CF3)-, - CH(CHF2), -CH(CH3)-, -C(CH3)2-, -NH(CH3)-, -C=CF2,-C=CHF, R4, in each instance, is selected from the group consisting of –(C1-C6alkyl), -Br, -F, and -Cl; m and n are integers independently selected from the group consisting of 0, 1, 2, 3, 4, 5 and 6, wherein both m and n are not 0; p is an integer selected from 0, 1, 2, 3, 4, 5, and 6; and z is an integer selected from 0, 1, 2 and 3. In some embodiments, the compounds disclosed herein are G-protein biased κ-opioid receptor agonists. Another aspect of the disclosure is directed to a pharmaceutical composition comprising a compound as disclosed herein or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carrier(s). Another aspect of the disclosure is directed to the method for treating a disease or condition mediated by the kappa opioid receptor, the method comprising administering a therapeutically effective amount of a compound or a pharmaceutical composition as disclosed herein to a subject in need thereof. In some embodiments, the disease or condition to be treated is acute or chronic pain. DESCRIPTION OF THE DRAWINGS FIG. 1 shows the structures of representative KOR agonists and nontraditional KOR agonist scaffolds. FIG.2 shows the original synthetic route to probe molecule ML139 (A), and a modular synthetic route utilizing the Ugi multicomponent reaction (B). FIG.3 shows a summary of Bisamide SAR. DETAILED DESCRIPTION The presently disclosed subject matter will now be described more fully hereinafter. However, many modifications and other embodiments of the presently disclosed subject matter set forth herein will come to mind to one skilled in the art to which the presently disclosed subject matter pertains, having the benefit of the teachings presented in the foregoing descriptions. Therefore, it is to be understood that the presently disclosed subject matter is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. In other words, the subject matter described herein covers all alternatives, modifications, and equivalents. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in this field. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The kappa opioid receptor (KOR), a G protein coupled receptor (GPCR), is widely expressed in both the central and peripheral nervous systems and mediates numerous physiological effects1such as antinociception, anti-pruritus, dysphoria, diuresis and sedation.2-5Despite potential liabilities, KOR agonists remain of therapeutic interest because of their ability to produce antinociception devoid of euphoria and accordingly have little addiction potential.2-3It is now appreciated that GPCRs exert their effects via multiple intracellular pathways, most notably G protein signaling or β-arrestin recruitment pathways. The selective engagement of a particular pathway represents a valuable strategy for separating the desired and undesired effects of KOR agonists.7Previously several classes of KOR agonists have been reported that are structurally unrelated to morphine-derived agents, traditionally used KOR probes like U,69,593, or the natural product salvinorin A (Fig.1). Two of these ligand classes have been further explored, resulting in examples highly biased for G protein activation against βarrestin recruitment (triazoles and isoquinolones; Fig.1) .11Here, the systematic exploration of a third class of nontraditional KOR modulators, exemplified by probe ML139 is described. Due to the attractive properties exhibited by these bisamide compounds (i.e., ML139), the current disclosure is directed towards compounds related to ML139.12Notably, ML139 showed a binding affinity for the KOR of 0.6 nM and >900-fold selectivity over either the mu or delta opioid receptors (MOR or DOR, respectively), and no measurable affinity for 41 other CNS-relevant targets. In contrast, the physicochemical properties relevant to eventual drug development of ML139 were varied, with positive results such as blood brain barrier penetration, neutral results such as aqueous solubility, and negative results including hepatic toxicity and poor microsomal stability. However, the potential bias of these types of compounds has not been addressed yet. Accordingly, the current disclosure relates pharmaceutical compositions containing such KOR ligands and methods of preparing and using these ligands are described in more detail below. A. Definitions As used herein, the term “pharmaceutical composition” refers to the active agent in combination with a pharmaceutically acceptable carrier, e.g., a carrier commonly used in the pharmaceutical industry. The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. In some embodiments of any of the aspects, a pharmaceutically acceptable carrier can be a carrier other than water. In some embodiments of any of the aspects, a pharmaceutically acceptable carrier can be a cream, emulsion, gel, liposome, nanoparticle, and / or ointment. In some embodiments of any of the aspects, a pharmaceutically acceptable carrier can be an artificial or engineered carrier, e.g., a carrier that the active ingredient would not be found to occur in nature. As used herein, the term “alkyl group” refers to a saturated hydrocarbon radical containing 1 to 8, 1 to 6, 1 to 4, or 5 to 8 carbons. In some embodiments, the saturated radical contains more than 8 carbons. An alkyl group is structurally similar to a noncyclic alkane compound modified by the removal of one hydrogen from the noncyclic alkane and the substitution therefore of a non- hydrogen group or radical. Alkyl group radicals can be branched or unbranched. Lower alkyl group radicals have 1 to 4 carbon atoms. Higher alkyl group radicals have 5 to 8 carbon atoms. Examples of alkyl, lower alkyl, and higher alkyl group radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec butyl, t butyl, amyl, t amyl, n-pentyl, n-hexyl, i-octyl and like radicals. As used herein, the term “stereoisomer” refers to compounds which have identical chemical constitution, but differ with regards to the arrangement of the atoms or groups in space. These “stereoisomers” have a “stereogenic center” which may be a chiral center. As used herein, the term “diastereomers” refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivity. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography. As used herein, the term “enantiomers” refers to two stereoisomers of a compound which are non-superimposable mirror images of one another. Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wiley, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. The term “cycloalkyl” refers to a hydrocarbon 3-8 membered monocyclic or 7-14 membered bicyclic ring system having at least one saturated ring or having at least one non-aromatic ring, wherein the non-aromatic ring may have some degree of unsaturation. Cycloalkyl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a cycloalkyl group may be substituted by a substituent. Representative examples of cycloalkyl group include cyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like. As used herein, the term “heterocycloalkyl” refers to a nonaromatic 3-8 membered monocyclic, 7-12 membered bicyclic, or 10-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, S, B, P or Si, wherein the nonaromatic ring system is completely saturated. Heterocycloalkyl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heterocycloalkyl group may be substituted by a substituent. Representative heterocycloalkyl groups include piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,3-dioxolanyl, tetrahydrofuryl, tetrahydrothienyl, thienyl, and the like. As used herein, the term “substituted” refers to a moiety (such as an alkyl group), wherein the moiety is bonded to one or more additional organic radicals. In some embodiments, the substituted moiety comprises 1, 2, 3, 4, or 5 additional substituent groups or radicals. Suitable organic substituent radicals include, but are not limited to, hydroxyl, amino, mono-substituted amino, di-substituted amino, mercapto, alkylthiol, alkoxy, substituted alkoxy or haloalkoxy radicals, wherein the terms are defined herein. Unless otherwise indicated herein, the organic substituents can comprise from 1 to 4 or from 5 to 8 carbon atoms. When a substituted moiety is bonded thereon with more than one substituent radical, then the substituent radicals may be the same or different. As used herein, the term “unsubstituted” refers to a moiety (such as an alkyl group) that is not bonded to one or more additional organic or inorganic substituent radical as described above, meaning that such a moiety is only substituted with hydrogens. As used herein, the term “aryl” refers to a hydrocarbon monocyclic, bicyclic or tricyclic aromatic ring system. Aryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, 4, 5 or 6 atoms of each ring of an aryl group may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like. As used herein, the term “heteroaryl” or “heteroaromatic” refers to a monovalent aromatic radical of 5- or 6-membered rings and includes fused ring systems (at least one of which is aromatic) of 5-20 atoms, containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups are pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl (including, for example, 3-amino-1,2-4-triazole or 3-mercapto-1,2,4-triazole), pyrazinyl (including, for example, aminopyrazine), tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, oxazol-2(3H)-onyl, and furopyridinyl. The heteroaryl groups are thus, in some embodiments, monocyclic or bicyclic. Heteroaryl groups are optionally substituted independently with one or more substituents described herein. As used herein, the designations “C(=O),” “CO” and “C(O)” are used to indicate a carbonyl moiety. Examples of suitable carbonyl moieties include, but are not limited to, those found in ketones and aldehydes. As used herein, the term “subject” broadly refers to any animal, including but not limited to, human and non-human animals (e.g., dogs, cats, cows, horses, sheep, poultry, fish, crustaceans, etc.). As used herein, the term “patient” typically refers to a subject that is being treated for a disease or condition. As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an alkyl group” or “a phenyl” includes mixtures of two or more such alkyl groups or phenyls. 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 is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed. Further, unless specified by the term “integer,” the number specified includes fractions or numbers with decimals. For example, the range of “from about 1 to about 5” includes numbers such as 1, 1.1, 1.5, 2.0, 2.2, and so on. As used herein, the term “integer” refers to a number that is a whole number, and not a fraction. The term “administration” or “administering” includes routes of introducing the compound(s) to a subject to perform their intended function. Examples of routes of administration which can be used include injection (subcutaneous, intravenous, parenterally, intraperitoneally, intrathecal), topical, oral, inhalation, rectal and transdermal. The term “effective amount” includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result. An effective amount of compound may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. An effective amount is also one in which any toxic or detrimental effects (e.g., side effects) of the inhibitor compound are outweighed by the therapeutically beneficial effects. The terms “pharmaceutically acceptable” or “pharmacologically acceptable,” as used herein, refer to compositions that do not substantially produce adverse reactions, e.g., toxic, allergic, or immunological reactions, when administered to a subject. As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers including, but not limited to, phosphate buffered saline solution, water, emulsions (e.g., such as an oil / water or water / oil emulsions), and various types of wetting agents, any and all solvents, dispersion media, coatings, sodium lauryl sulfate, isotonic and absorption delaying agents, disintigrants (e.g., potato starch or sodium starch glycolate), and the like. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see, e.g., Martin, Remington’s Pharmaceutical Sciences, 15thEd., Mack Publ. Co., Easton, Pa. (1975), incorporated herein by reference in its entirety. As used herein, the term “pharmaceutically acceptable salt” refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention, which, upon administration to a subject, is capable of providing a compound of this invention or an active metabolite or residue thereof. As is known to those of skill in the art, “salts” of the compounds of the present invention may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic acid, and the like. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. As used herein, the term “treat”, “treating” or “treatment” of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one of the clinical symptoms thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those which may not be discernible to the patient. As used herein, a subject is “in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment. As used herein, the term “a therapeutically effective amount” of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. B. Compounds Provided herein are kappa opioid receptor ligands and methods of use thereof for the treatment of a disease or condition associated with kappa opioid receptors, such as acute and chronic pain, pruritis, addiction and mood disorders. In some embodiments, the KOR ligands are agonists. In some embodiments, the KOR ligands are G-protein biased KOR agonists. In some embodiments, the compounds disclosed herein comprise a compound of Formula (A): Formula (A) or any stereoisomer and / or pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of substituted or unsubstituted heteroaryl, substituted or unsubstituted heterobiaryl, (C1-C6) heterocycloalkyl, -CH2NH2, -CH2N(CH3)2, R2is selected from the group consisting of substituted or unsubstituted aryl, (C1-C6) cycloalkyl, substituted or unsubstituted -CH2(aryl) and substituted or unsubstituted (C1-C10) alkyl; R3is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted (C1-C6) cycloalkyl, and substituted or unsubstituted (C1-C6) heterocycloalkyl; R3aand R3bare independently selected from the group consisting of -H, substituted or unsubstituted (C1-C6) alkyl and substituted or substituted (C1-C10) cycloalkyl; X, if present, is selected from the group consisting of -CH2-, -O-, -N(CH3)-, -S-, -CF2-, - CHF-, -CH(CF3)-, -CH(CHF2)-, -CH(CH3)-, -C(CH3)2-, -C=CF2, -C=CHF z is an integer selected from 0, 1, 2 and 3. In some embodiments, X is absent. In some embodiments, z is 1. In some embodiments, R2is selected from the group consisting of substituted or unsubstituted aryl and (C1-C6) cycloalkyl. In some embodiments, R3is selected is from the group consisting of a substituted or unsubstituted aryl and a substituted or unsubstituted heteroaryl. In some embodiments, the compound disclosed herein comprises a compound of Formula (I):

[0002] Formula (I) or any stereoisomer and / or pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of substituted or unsubstituted heteroaryl, substituted or unsubstituted heterobiaryl, (C1-C6) heterocycloalkyl and ; R2is selected from the group consisting of substituted or unsubstituted aryl and (C1-C6) cycloalkyl; R3is selected from the group consisting of substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; and R3aand R3bare independently selected from the group consisting of -H, substituted or unsubstituted (C1-C6) alkyl and substituted or unsubstituted (C1-C10) cycloalkyl. In some embodiments, R1is selected from the group consisting of substituted or unsubstituted heteroaryl, substituted or unsubstituted heterobiaryl, and (C1-C6) heterocycloalkyl. In some embodiments, R2is (C1-C6) cycloalkyl. In some embodiments, R2is selected from the group consisting of C3-cycloalkyl, C4-cycloalkyl, C5-cycloalkyl and C6-cycloalkyl. In some embodiments, R3is a substituted or unsubstituted aryl. In some embodiments, R3is phenyl. In some embodiments, R3is phenyl substituted with one or more of the following substituents: -Cl, -Br, -F, -OCH3, -OCF3, -OH, -CHF2, -CF3, -CH3, -NH2, -NH(CH3), -NH(CH3)2. In some embodiments, R3is a substituted or unsubstituted heteroaryl. In some embodiments, R3is a substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R3is a substituted or unsubstituted 5-membered heteroaryl selected from the group consisting of pyrrole, furan, thiophene, thiazole, tetrazole, imidazole, isothiazole, triazole, oxazole, and isoxazole. In some embodiments, the 5-membered heteroaryl is not substituted (i.e., unsubstituted). In some embodiments, the 5-membered heteroaryl is substituted with one or more substituents. Exemplary substituents include, but are not limited to, Cl, -Br, -F, -OCH3, -OCF3, - OH, -CHF2, -CF3, -CH3, -NH2, -NH(CH3), and -NH(CH3)2. In some embodiments, the 5-membered heterocycle is thiophene or furan. In some embodiments, R3is 2-thiophenyl or 2-furanyl. In some embodiments, R3is 3-thiophenyl or 3-furanyl. In some embodiments, R3is a substituted or unsubstituted 6-membered heteroaryl. In some embodiment, R3is a substituted or unsubstituted 6-membered heteroaryl selected from the group consisting of pyridine, pyrimidine, and pyrazine. In some embodiments, the 6-membered heteroaryl is not substituted (i.e., unsubstituted). In some embodiments, the 6-membered heteroaryl is substituted with one or more substituents. Exemplary substituents include, but are not limited to, Cl, -Br, -F, -OCH3, -OCF3, -OH, -CHF2, -CF3, -CH3, -NH2, -NH(CH3), and -NH(CH3)2. In some embodiments, when R1is 2-pyridyl or 2-pyrazinyl, R3is an unsubstituted heteroaryl selected from 2-thiophenyl and 2-furanyl, and X is -CH2- with m+n being 3 or 4, then R2cannot be unsubstituted C5-cycloalkyl, unsubstituted C6-cycloalkyl, 2,6-dimethylphenyl, or 4-Br-phenyl. In some embodiments, the compound disclosed herein comprises a compound of Formula (Ia): or any stereoisomer and / or pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterobiaryl; R2is selected from the group consisting of substituted or unsubstituted aryl and C6- cycloalkyl; Y is -S- or -O-; and R3aand R3bare independently selected from the group consisting of -H, substituted or unsubstituted (C1-C6) alkyl and substituted or substituted (C1-C6) cycloalkyl. In some embodiments, R2is C6-cycloalkyl. In some embodiments, R2is a substituted or unsubstituted aryl. In some embodiments, R2is phenyl. In some embodiments, R2is phenyl, wherein phenyl is substituted with one or more of the following substituents: -Cl, -Br, -F, -OCH3, -OCF3, -OH, -CHF2, -CF3, -CH3, -NH2, -NH(CH3), -NH(CH3)2. In some embodiments, R2is selected from the group consisting of 4-Br-phenyl, 3-Br- phenyl, 2-Br-phenyl, 4-F-phenyl, and 2,4-dimethyl phenyl. In some embodiments, R2is 4-Br- phenyl. In some embodiments, R1is a substituted or unsubstituted heterobiaryl. Exemplary heterobiaryls include, but are not limited to, indole, benzofuran, isoquinoline, quinoline, quinazoline, and isoindole. In some embodiments, the heterobiaryl is not substituted (i.e., unsubstituted). In some embodiments, the heterobiaryl is substituted with one or more substituents. Exemplary substituents include, but are not limited to, -Cl, -Br, -F, -OCH3, -OCF3, - OH, -CHF2, -CF3, -CH3, -NH2, -NH(CH3), and -NH(CH3)2. In some embodiments, R1is a substituted or unsubstituted heteroaryl. Exemplary heteroaryls include, but are not limited to, pyridine, pyrimidine, and pyrazine. In some embodiments, the heteroaryl is not substituted (i.e., unsubstituted). In some embodiments, the heteroaryl is substituted with one or more substituents. Exemplary substituents include, but are not limited to, -Cl, -Br, -F, -OCH3, -OCF3, -OH, -CHF2, -CF3, -CH3, -NH2, -NH(CH3), and -NH(CH3)2. In some embodiments, R1is a substituted or unsubstituted pyridine. In some embodiments, R1is an unsubstituted pyridine. In some embodiments, R1is selected from the group consisting of 2-pyridyl, 3-pyridyl and 4-pyridyl. In some embodiments, R1is 2-pyridyl. In some embodiments, R2is C6-cycloalkyl and R1is a substituted pyridine (e.g., substituted with -CH3). In some embodiments, R2is C6-cycloalkyl and R1is an unsubstituted pyridine. In some embodiments, pyridine is selected from the group consisting of 2-pyridyl, 3-pyridyl and 4-pyridyl. In some embodiments, the pyridine is 2-pyridyl. In some embodiments, R2is a substituted phenyl, wherein the phenyl is substituted with one or more of -Br, -F, and -CH3, and R1is a substituted pyridine. In some embodiments, R2is phenyl substituted with one or more of -Br, -F, and -CH3, and R1is an unsubstituted pyridine selected from the group consisting of 2-pyridyl, 3-pyridyl and 4-pyridyl. In some embodiments, the pyridine is 2-pyridyl. In some embodiments, R2is a substituted phenyl selected from the group consisting of 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 4-fluorophenyl, and 2,6-dimethylphenyl, and R1is selected from the group consisting of 2-pyridyl, 3-pyridyl and 4-pyridyl. In some embodiments, R2is 4-bromophenyl and R1is 2-pyridyl. In some embodiments, Y is -O-. In some embodiments, Y is -O-, R2is C6-cycloalkyl and R1is pyridine. In some embodiments, Y is -O-, R2is C6-cycloalkyl and R1is pyridine selected from the group consisting of 2-pyridyl, 3-pyridyl and 4-pyridyl. In some embodiments, Y is -O-, R2is C6-cycloalkyl and R1is 2-pyridyl. In some embodiments, Y is -O-, R2is a phenyl substituted with one or more of -Br, -F, and -CH3, and R1is pyridine. In some embodiments, Y is -O-, R2is a phenyl substituted with one or more of -Br, -F, and -CH3, and R1is pyridine selected from the group consisting of 2-pyridyl, 3-pyridyl and 4-pyridyl. In some embodiments, Y is -O-, R2is a phenyl substituted with one or more of -Br, -F, and -CH3and R1is 2-pyridyl. In some embodiments, Y is -S-. In some embodiments, Y is -S-, R2is C6-cycloalkyl and R1is pyridine. In some embodiments, Y is -S-, R2is C6-cycloalkyl and R1is pyridine selected from the group consisting of 2-pyridyl, 3-pyridyl and 4-pyridyl. In some embodiments, Y is -S-, R2is C6-cycloalkyl and R1is 2-pyridyl. In some embodiments, Y is -S-, R2is a phenyl substituted with one or more of -Br, -F, and -CH3; and R1is pyridine. In some embodiments, Y is -S-, R2is a phenyl substituted with one or more of -Br, -F, and -CH3, and R1is pyridine selected from the group consisting of 2-pyridyl, 3-pyridyl and 4-pyridyl. In some embodiments, Y is -S-, R2is a substituted phenyl, wherein the phenyl is substituted with one or more of -Br, -F, and -CH3, and R1is 2-pyridyl. In some embodiments, R3aand R3bare independently selected from the group consisting of -H and substituted or unsubstituted (C1-C6) alkyl. In some embodiments, (C1-C6) alkyl includes, but is not limited to, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH(CH3)2, - CH2CH2CH2CH3, -CH(CH3)2CH2CH3and -CH2CH2CH2CH(CH3)2. In some embodiments, R3aand R3bare independently selected from the group consisting of -H and substituted or unsubstituted (C1-C6) alkyl, wherein substituted (C1-C6) alkyl includes at least one -F atom. In some embodiments, (C1-C6) alkyl groups such as -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH(CH3)2, -CH2CH2CH2CH3, -CH(CH3)2CH2CH3and -CH2CH2CH2CH(CH3)2are substituted with at least one -F atom. In some embodiments, R3aand R3bare independently selected from the group consisting of -H, CH3, -CH2CH3, -CH2CH(CH3)2, -CH2CH2CH2CH3. In some embodiments, R3aand R3bare independently selected from the group consisting of -H, CH3, -CH2CH3, -CH2CH(CH3)2, - and CH2CH2CH2CH3substituted with at least one -F atom. In some embodiments, R3aand R3bare the same. For example, in some embodiments, R3aand R3bare -CH3. In some embodiments, R3aand R3bare both -CH2CH3. In some embodiments, R3aand R3bare both -CH2CH(CH3)2. In some embodiments, R3aand R3bare both (C1-C6) alkyl groups substituted with at least one -F atom. In some embodiment only R3acontains at least one - F atom. In some embodiments, only R3bcontains at least one -F atom. In some embodiments, R3aand R3bare different. For example, in some embodiments, R3ais -CH3and R3bis selected from the group consisting of -CH2CH3, -CH2CH(CH3)2, - CH2CH2CH2CH3. In some embodiments, R3aor R3bis a (C1-C6) cycloalkyl selected from the group consisting of C3-cycloalkyl, C4-cycloalkyl, C5-cycloalkyl, and C6-cycloalkyl. In some embodiments, R3ais C6-cycloalkyl and R3bis -H. In some embodiments, for compounds of Formula (Ia) when R3aand R3bare both -H and Y is O, then R2cannot be C6-cycloalkyl. In some embodiments, R3ais Me and R3bis Et; Y is O or S, then R1cannot be C5-cycloalkyl or C6-cycloalkyl. In some embodiments, the compound of Formula (A), (I), or (Ia) is selected from the group of compounds consisting of 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, and 115 of Tables 1-6. Another aspect of the current disclosure is a compound of Formula (II) Formula (II) or any stereoisomer and / or pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of substituted or unsubstituted heteroaryl, substituted or unsubstituted heterobiaryl, (C1-C6) heterocycloalkyl, -CH2NH2, -CH2N(CH3)2, R2is selected from the group consisting of substituted and unsubstituted aryl, (C1-C6) cycloalkyl, substituted or unsubstituted -CH2(aryl) and substituted or unsubstituted (C1-C8) alkyl; R3is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted (C1-C6) cycloalkyl, and substituted or unsubstituted (C1-C6) heterocycloalkyl; X is selected from the group consisting of -CH2-, -N(CH3)-, -O-, -S-, -CF2, -CHF-, - CH(CF3)-, -CH(CHF2)-, -CH(CH3)-, -C(CH3)2-, -C=CF2, -C=CHF, R4, in each instance, is selected from the group consisting of –(C1-C6alkyl), -Ph, -F, Cl-, - Br and -I; m and n are integers independently selected from the group consisting of 0, 1, 2, 3, 4, 5 and 6, wherein both m and n cannot be 0; p is an integer selected from 0, 1, 2, 3, 4, 5, and 6; and z is an integer selected from 0, 1, 2 and 3. In some embodiments, z is 1. In some embodiments, m is 1, 2, or 3. In some embodiments, p is an integer selected from 0, 1, 2, 3 and 4. In some embodiments, R2is selected from the group consisting of substituted or unsubstituted aryl and (C1-C6) cycloalkyl. In some embodiments, R2is phenyl. In some embodiments, R2is (C1-C6) cycloalkyl selected from the group consisting of C3-cycloalkyl, C4- cycloalkyl, C5-cycloalkyl and C6-cycloalkyl. In some embodiments, R2is C6-cycloalkyl. In some embodiments, R2is a s phenyl substituted with at least one or more of the following substituents: -Cl, -Br, -F, -OCH3, -OCF3, -OH, -CHF2, -CF3, -CH3, -NH2, -NH(CH3), -NH(CH3)2. In some embodiments, R2is a phenyl substituted with one or more of -Cl, -Br, -F, and -CH3. In some embodiments, R3is a substituted or unsubstituted (C1-C6) cycloalkyl selected from the group consisting of C3-cycloalkyl, C4-cycloalkyl, C5-cycloalkyl, and C6-cycloalkyl. In some embodiments, R3is C6-cycloalkyl and z is 1. In some embodiments, R3is a (C1-C6) heterocycloalkyl selected from the group consisting of tetrahydrofuran, pyrrolidine, piperidine, oxetane, and azetidine. In some embodiments, R3is tetrahydrofuran. In some embodiments, R3is 2-tetrahydrofuranyl. In some embodiments R3is 2-tetrahydrofuranyl and z is 1. In some embodiments, R3is selected from the group consisting of substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. In some embodiments, R3is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted thiophene and substituted or unsubstituted furan. In some embodiments, R3is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thiophenyl, 3, thiophenyl, and phenyl, wherein R3can optionally be substituted with one or more substituents. In some embodiments, R3is 2-tetrahydrofuranyl, z is 1, R2is (C1-C6) cycloalkyl, and R1is a heteroaryl. In some embodiments, R3is 2-tetrahydrofuranyl, z is 1, R2is (C1-C6) cycloalkyl, and R1is a heteroaryl. In some embodiments, R3is 2-tetrahydrofuranyl, z is 1, R2is C6-cycloalkyl, and R1is a 6-membered heteroaryl. In some embodiments, R3is 2-tetrahydrofuranyl, z is 1, R2is C6-cycloalkyl, and R1is pyridine. In some embodiments, R3is C6-cycloalkyl, z is 1, R2is (C1-C6) cycloalkyl, and R1is a heteroaryl. In some embodiments, R3is C6-cycloalkyl, z is 1, R2is (C1-C6) cycloalkyl, and R1is a heteroaryl. In some embodiments, R3is C6-cycloalkyl, z is 1, R2is C6-cycloalkyl, and R1is a 6- membered heteroaryl. In some embodiments, R3is C6-cycloalkyl, z is 1, R2is C6-cycloalkyl, and R1is pyridine. In some embodiments, R3is 2-tetrahydrofuranyl, z is 1, R2is substituted aryl, and R1is a heteroaryl. In some embodiments, R3is 2-tetrahydrofuranyl, z is 1, R2is phenyl substituted with one or more -CH3, and R1is a heteroaryl. In some embodiments, R3is 2-tetrahydrofuranyl, z is 1, R2is 2,4-dimethylphenyl, and R1is a 6-membered heteroaryl. In some embodiments, R3is 2- tetrahydrofuranyl, z is 1, R2is 2,4-dimethylphenyl, and R1is pyridine. In some embodiments, R3is C6-cycloalkyl, z is 1, R2is substituted aryl, and R1is a heteroaryl. In some embodiments, R3is C6-cycloalkyl, z is 1, R2is phenyl substituted with one or more -CH3, and R1is a heteroaryl. In some embodiments, R3is C6-cycloalkyl, z is 1, R2is 2,4- dimethylphenyl, and R1is a 6-membered heteroaryl. In some embodiments, R3is C6-cycloalkyl, z is 1, R2is 2,4-dimethylphenyl, and R1is pyridine. In some embodiments, R3is selected from the group consisting of a substituted or unsubstituted aryl and a substituted or unsubstituted heteroaryl. In some embodiments, R3is a substituted or unsubstituted aryl. In some embodiments, R3is phenyl. In some embodiments, phenyl is not substituted. In some embodiments, R3is phenyl, wherein phenyl is substituted with one or more of the following substituents: -Cl, -Br, -F, -OCH3, -OCF3, -OH, -CHF2, -CF3, -CH3, -NH2, -NH(CH3), -NH(CH3)2. In some embodiments, R3is selected from the group consisting of 2-fluorophenyl and 2-methylphenyl. In some embodiments, R3is a substituted or unsubstituted aryl. In some embodiments, R3is phenyl. In some embodiments, R3is phenyl, wherein phenyl is substituted with one or more of the following substituents: -Cl, -Br, -F, -OCH3, -OCF3, -OH, -CHF2, -CF3, -CH3, -NH2, -NH(CH3), -NH(CH3)2. In some embodiments, R3is selected from the group consisting of 2-fluoro-phenyl, and 2 methyl-phenyl. In some embodiments, R3is a substituted or unsubstituted aryl. In some embodiments, R3is phenyl. In some embodiments, R3is phenyl, wherein phenyl is substituted with one or more of the following substituents: -Cl, -Br, -F, -OCH3, -OCF3, -OH, -CHF2, -CF3, -CH3, -NH2, -NH(CH3), -NH(CH3)2. In some embodiments, R3is selected from the group consisting of 2-fluorophenyl and 2-methylphenyl. In some embodiments, R3is selected from the group consisting of 2-fluorophenyl and 2-methylphenyl, R1is heteroaryl, and R2is C6-cycloalkyl. In some embodiments, R3is selected from the group consisting of 2-fluorophenyl and 2-methylphenyl, R1is heteroaryl, R2is C6-cycloalkyl, p is 0, and m is 2. In some embodiments, R3is selected from the group consisting of 2-fluorophenyl and 2-methylphenyl, R1is substituted pyridine or imidazole, R2is C6-cycloalkyl, p is 0, m is 2, and X is -O- or -CF2-. In some embodiments, R3is selected from the group consisting of 2-fluorophenyl and 2-methylphenyl, R1is substituted 2-pyridyl or 2-imidazinyl, R2is C6- cycloalkyl, p is 0, m and n are 2, and X is -O- or -CF2-. In some embodiments, X is selected from the group consisting of . In some embodiments, X is selected from the group consisting of -CH2-, -C(CH3)2-, z is 1, m is 1, and n is 1. In some embodiments, X is selected from the group consisting of -CH2-, -C(CH3)2-, z is 1, m is 1, n is 1, R2is (C1-C6) cycloalkyl, and R1is a heteroaryl. In some embodiments, X is selected from the group consisting of -CH2-, -C(CH3)2-, , z is 1, m is 1, n is 1, R2is C6-cycloalkyl, and R1is a 6- membered heteroaryl. In some embodiments, X is selected from the group consisting of -CH2-, - C(CH3)2-, z is 1, m is 1, n is 1, R2is C6-cycloalkyl, and R1is pyridine. In some embodiments, X is selected from the group consisting of -CH2-, -C(CH3)2-, ycloalkyl, and R1is 2-pyridyl. In some embodiments, X is selected from the group consisting of , and -N(CH are 2. In some embodiments, X is selected from the group consisting CH3), z is 1, p is 0, m and n are 2, R1is an unsubstituted heteroaryl and R3is (C1-C6) cycloalkyl. In some embodiments, X is selected from the group consisting of and -N(CH3), z is 1, p is 0, m and n are 2, R1is a 6-membered heteroaryl and R3is C6-cycloalkyl. In some embodiments, X is selected from the group consisting are 2, R1is a pyridine and R3is C6- cycloalkyl. In some embodiments, X is selected from the group consisting of , and -N(CH3), z is 1, p is 0, m and n are 2, R1is 2-pyridyl and R3is C6-cycloalkyl. In some embodiments, R2is a substituted or unsubstituted -CH2(aryl). In some embodiments, R2is a substituted -CH2(phenyl). In some embodiments, R2is an unsubstituted -CH2(phenyl). In some embodiments, R2is a substituted or unsubstituted (C1-C8) alkyl. Exemplary (C1-C8) alkyl include, but are not limited to -CH3, -CHCH3, -CH(CH3)2, -C(CH3)3, -CH2CH(CH3)2, -CH2CH(CH3)2CH3, -CH2CH(CH3)CH(CH3)CH3, -CH2CH(CH3)CH(CH3)CH2CH3, and -C(CH3)2CH2C(CH3)3. In some embodiments, R2is C(CH3)2CH2C(CH3)3. In some embodiments, when R1is 2-pyridyl or 2-pyrazinyl, R3is an unsubstituted heteroaryl selected from 2-thiophenyl and 2-furanyl, and X is -CH2- with m+n being 3 or 4, then R2cannot be unsubstituted C5-cycloalkyl, unsubstituted C6-cycloalkyl, 2,6-dimethylphenyl, or 4- Br-phenyl. In some embodiments, the compound disclosed herein comprises a compound of Formula (IIa): or any stereoisomer and / or pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of substituted or unsubstituted heteroaryl and substituted or unsubstituted heterobiaryl; R2is selected from the group consisting of substituted or unsubstituted aryl and C6- cycloalkyl; R3is selected is from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; X is selected from the group consisting of -CH2-, -O-, -S-, -CF2, -CHF-, -CH(CF3)-, - CH(CHF2)-, -CH(CH3)-, -C=CF2,-C=CHF and -C(CH3)2-; R4, in each instance, is selected from the group consisting of -F, -CH3, -Ph, and -C(CH3)3; m and n are integers independently selected from the group consisting of 1, 2 and 3; and p is an integer selected from 0, 1, 2, 3 and 4. In some embodiments, R1is selected from a substituted or unsubstituted 5-membered heteroaryl or a substituted or unsubstituted 6-membered heteroaryl. In some embodiments, R1is a 5-membered heteroaryl selected from the group consisting of furane, imidazole, pyrrole and thiopene. In some embodiments, R1is a 5-membered heteroaryl selected from the group consisting of 2-furanyl, 3-furanyl, 2-thiophenyl, 3-thiophenyl, 2-imidazoyl, 3-imidazoyl, 2-pyrolinyl and 3- pyrrolinyl. In some embodiments, R1is a 6-membered heteraryl. In some embodiments, R1is selected from the group consisting of pyridine, pyrimidine, pyridazine, pyrazole. In some embodiments, R1is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, 2 pyrimidinyl, 3-pyrimidyl, and 2-pyrazidinyl. In some embodiments, R1is a heterobiaryl selected from the group consisting of indole, benzofuran, quinoline and isoquinoline. In some embodiments R1selected from the group consisting of pyridine, thiophene, pyrrole, pyrimidine, imidazole, pyrazine, indole and quinoline. In some embodiments, R2is aryl substituted with one or more of the following substituents: -Cl, -Br, -F, -OCH3, -OCF3, -OH, -CHF2, -CF3, -CH3, -NH2, -NH(CH3), and -NH(CH3)2. In some embodiments, R2is aryl substituted with one or more of Cl, Br, F and CH3. In some embodiments, R2is selected from the group consisting of 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 4- fluorophenyl and 2,4-dimethylphenyl. In some embodiments, R3is a substituted or unsubstituted aryl. In some embodiments, R3is phenyl. In some embodiments, R3is phenyl, wherein phenyl is substituted with one or more of the following substituents: -Cl, -Br, -F, -OCH3, -OCF3, -OH, -CHF2, -CF3, -CH3, -NH2, -NH(CH3), -NH(CH3)2. In some embodiments, R3is selected from the group consisting of 2-fluorophenyl and 2-methylphenyl. In some embodiments, R3is selected from the group consisting of 2-fluorophenyl and 2-methylphenyl, R1is heteroaryl, and R2is C6-cycloalkyl. In some embodiments, R3is selected from the group consisting of 2-fluorophenyl and 2-methylphenyl, R1is heteroaryl, R2is C6-cycloalkyl, p is 0, and m is 2. In some embodiments, R3is selected from the group consisting of 2-fluorophenyl and 2-methylphenyl, R1is substituted pyridine or imidazole, R2is C6-cycloalkyl, p is 0, m is 2, and X is -O- or -CF2-. In some embodiments, R3is selected from the group consisting of 2-fluorophenyl and 2-methylphenyl, R1is substituted 2-pyridyl or 2-imidazinyl, R2is C6- cycloalkyl, p is 0, m and n are 2, and X is -O- or -CF2-. In some embodiments, R3is a substituted or unsubstituted 6-membered heteroaryl. In some embodiments, R3is a substituted or unsubstituted 6-membered heteroaryl selected from the group consisting of pyridine, pyrimidine, and pyrazine. In some embodiments, the 6-membered heteroaryl is not substituted (i.e., unsubstituted). In some embodiments, the 6-membered heteroaryl is substituted with one or more substituents. Exemplary substituents include, but are not limited to, Cl, -Br, -F, -OCH3, -OCF3, -OH, -CHF2, -CF3, -CH3, -NH2, -NH(CH3), and - NH(CH3)2. In some embodiments, R3is pyridine. In some embodiments, R3is unsubstituted pyridine selected from the group consisting of 2-pyridyl, 3-pyridyl, and 4-pyridyl. In some embodiments, R3is 3-pyridyl. In some embodiments, R3is 3-pyridyl, R1is a substituted or unsubstituted heteroaryl, p is 0 and R2is a substituted or unsubstituted aryl. In some embodiments, R3is 3-pyridyl, R1is a substituted 5-membered heteroaryl, p is 0 and R2is a substituted aryl. In some embodiments, R3is 3-pyridyl, R1is a substituted imidazole, p is 0 and R2is 4-Br-phenyl. In some embodiments, R3is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted thiophene, and substituted or unsubstituted furan. In some embodiments m+n can be 3, 4, 5, or 6. In some embodiments, m is 2, n is 1 and m+n is 3. In some embodiments, m is 2 and n is 2 and m+ n is 4. In some embodiments, m is 2, n is 3 and m+n is 5. In some embodiments, m is 3, n is 2 and m+n is 5. In some embodiments, m is 4, n is 2 and m+n is 6. In some embodiments, m is 3, n is 3 and m+n is 6. In some embodiments, m is 2, n is 4 and m+n is 6. In some embodiments, when R1is 2-pyridyl or 2-pyrazinyl; R3is an unsubstituted heteroaryl selected from 2-thiophenyl and 2-furanyl, and X is -CH2- with m+n being 3 or 4, then R2cannot be unsubstituted C5-cycloalkyl, unsubstituted C6-cycloalkyl, 2,6-dimethylphenyl, or 4- Br-phenyl. In some embodiments, the compound disclosed herein comprises a compound of Formula (III):

[0003] Formula (III) or any stereoisomer and / or pharmaceutically acceptable salt thereof, wherein Y is O or S; X is selected from the group consisting of -CH2-, -O-, -S-, -CF2-, -CHF- -CH(CF3), - CH(CHF2)-, -CH(CH3)-, -C=CF2, -C=CHF and -C(CH3)2-; R1is selected from the group consisting of R4, in each instance, is selected from the group consisting of -F, -CH3, -Ph, and -C(CH3)3; R5a, R5b, R5c, R5d, and R5e are independently selected from the group consisting of -H, -Cl, -Br, -F and -CH3; m and n are integers independently selected from the group consisting of 1, 2, and 3; and p is an integer selected from 0, 2, and 4. In some embodiments, n is 1 and m is 2. In some embodiments, n is 2 and m is 1. In some embodiments, n is 2 and m is 2. In some embodiments, R5a, R5b, R5c, R5d, and R5e are independently selected from the group consisting of -H, -Br, -F and CH3. In some embodiments, R5a, R5b, R5d, and R5e are -H and R5c is -H, -F or -Br. In some embodiments, R5b, R5c, and R5dare -H, and R5aand R5eare -CH3. In some embodiments, one substituent selected from the group consisting of R5a, R5b, R5c, R5d, R5e is -Br, while the remaining substituents are -H. In some embodiments, R5a is -Br and R5b, R5c, R5d, and R5eare all -H. In some embodiments, R5bis -Br and R5a, R5c, R5d, and R5eare all -H. In some embodiments, R5cis -Br and R5a, R5b, R5d, and R5eare all-H. In some embodiments, R1is selected from the group consisting of . . In some embodiments, X is selected from the group consisting of -CF2, -S-, and -CH2-. In some embodiments, X is selected from the group consisting of -CF2, -S-, and -CH2and p is 0, 2, or 4. In some embodiments, X is selected from the group consisting of -CF2, -S-, and -CH2and p is 0. In some embodiments, X is selected from the group consisting of -CF2, -S-, and -CH2and p is 2. In some embodiments, X is selected from the group consisting o is 4. In some embodiments, R1is selected from the group consisting R5eare -CH3,R5b, R5c, and R5dare -H, X is -CH2-, p is 0, m is 2, n is 2, and m+n is 4. In some embodiments, R1is selected from the group consisting of , m is 2, n is 1, and m+n is 3. In some embodiments, R1is selected from the group consisting of -CF2-, -S-, or -CH2-, p is 0, m is 2, n is 2, and m+n is 4. In some embodiments, R1is selected from the group consisting of , , Y is S; R5cis -Br, -H or-F, R5b, R5c, R5d, and R5eare -H, X is -CH2-, p is 0, m is 3, n is 2, and m+n is 5. In some embodiments, R1is selected from the group consisting of , , Y is O; R5dis -Br, R5b, R5c, R5a, and R5e are -H, X is -CF2-,-CH2-, or -S-, p is 0, m is 2, n is 2, and m+n is 4. In some embodiments, n+m is 3, 4, or 5. In some embodiments, R1is selected from the group consisting R5e are -H, X is -CH2-, p is 0, m is 3, n is 2, and m+n is 5. In some embodiments, X is -CH2-, n is 1 and m is 2. In some embodiments, X is selected from the group consisting of -CH2-, -O-, -CF2-, - S-, when n and m are 2. In some embodiments, X is -CH2-, n is 3 and m is 2. In some embodiments, the compound disclosed herein comprises a compound of Formula (IV): Formula (IV) or any stereoisomer and / or pharmaceutically acceptable salt thereof, wherein Y is O or S; R1is selected from the group consisting of

[0004] ; R4, in each instance, is selected from the group consisting of -CH3, -Ph, -C(CH3)3, and -F; X is selected from the group consisting of -CH2-, -O-, -S-, -CF2-, -CHF- -CH(CF3), - CH(CHF2)-, -CH(CH3)-, -C=CF2, -C=CHF, and -C(CH3)2-; m and n are integers independently selected from the group consisting of 1, 2, and 3; and p is an integer selected from 0, 2, and 4. In some embodiments, p is 0. In some embodiments, p is 2 and R4in each instance is -CH3. In some embodiments, p is 4 and R4in each instance is CH3. In some embodiments, p is 2 and R4in each instance is -F. In some embodiments, p is 4 and R4in each instance is -F. In some embodiments, n is 1 and m is 2. In some embodiments, n is 2 and m is 1. In some embodiments, n is 2 and m is 2. In some embodiments, X is -CH2-, n is 1 and m is 2. In some embodiments, X is -CH2-, n is 2 and m is 2. In some embodiments, X is selected from the group consisting of -CF2, -S-, -CH(CF2H)-, -O- and -CH2-. In some embodiments, X is selected from the group consisting of -CF2, -S-, - CH(CF2H)-, -O- and -CH2, and p is 0, 2, or 4. In some embodiments, X is selected from the group consisting of-CF2, -S-, -CH(CF2H)-, -O- and -CH2and p is 0. In some embodiments, X is selected from the group consisting of-CF2, -S-, -CH(CF2H)-, -O- and -CH2, p is 2 and R4is -CH3. In some embodiments, X is selected from the group consisting of -CF2, -S-, -CH(CF2H)-, -O- and -CH2, p is 4 and R4is -CH3. In some embodiments, R1is selected from the group consisting of and In some embodiments, R1is selected from the group consisting of Y is O, X is -O-, -CH2-, -CF2-, -CH(CF3)-, or CH(CF2H), p is 0, m is 2, n is 2, and m+n is 4. In some embodiments, R1is selected from the group consisting of and Y is -CH2-, p is 1, R4is -CH3, -Ph, -C(CH3)3, m is 2, n is 2, and m+n is 4. In some embodiments, the compounds disclosed herein contain at least one fluoride atom. In some embodiments, when R1is 2-pyridiyl or 2-pyrazinyl; Y is -O- or -S-; then X cannot -CH2- with m+n being 3 or 4. The compounds described herein may, in some cases, exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography and / or recrystallization or by the forming diastereomers and separation thereof (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981). Stereoisomers may also be obtained by stereoselective synthesis using synthetic methods known in the art. In some embodiments, the compounds disclosed herein are enantiomers having an enantiomeric excess (% ee) of at least about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, or about 99.5%. In some embodiment, the compounds disclosed herein are in the form of the R-isomer. In some embodiments, the compounds are in the form of the S-isomer. In some embodiments, the compounds disclosed herein are diastereomers having a diastereomeric excess (% de) of at least about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, or about 99.5%. In some embodiments, the compounds disclosed herein are present as enantiomeric or diastereomeric mixtures. In some embodiments, the compounds disclosed herein can be present as tautomers and / or tautomeric mixtures. The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In some embodiments, the compounds described herein may be formed as, and / or used as, pharmaceutically acceptable salts. The type of pharmaceutical acceptable salts, include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable: inorganic acid, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid, such as, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1- carboxylic acid, glucoheptonic acid, 4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, and the like; (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion (e.g., lithium, sodium, potassium), an alkaline earth ion (e.g., magnesium, or calcium), or an aluminum ion. In some cases, compounds described herein may coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, compounds described herein may form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. In some embodiments, the compounds and salts described herein include isotopically labeled compounds. In general, isotopically labeled compounds are identical to those recited in the various formulae and structures presented herein, 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 most common in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, for example, 2H, 3H, 13C, 14C, 15N, 18O, 17O, 35S, 18F, 36Cl, respectively. Certain isotopically labeled compounds described herein, for example, those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Further, substitution with isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. In some embodiments, the compounds disclosed herein are selective KOR binding ligands. As used herein, the term “selective binding ligands” refers to compounds, which display an increased selectivity for binding a particular KOR when compared to inhibiting other opioid receptors (such as μ- and δ-opioid receptors). Initial profiling of 5 revealed less than 50% displacement of radioligand binding to as μ- and δ-opioid receptors (Psychoactive Drug Screening Program and UNC-CH). Some embodiments, the compounds disclosed herein, exhibit a selective binding activity towards the KOR that is at least about 2-fold, about 3-fold, about 4-fold, or at least about 5-fold more potent compared to its binding activity towards other opioid receptors. In addition, a biased ligand refers to compounds that display an increased potency and or efficacy for one signaling pathway over another as compared to a reference agonist (in this case U69,593). Particular examples in the report display a preference for initiating GTPyS binding upon receptor activation relative to β-arrestin recruitment. In some cases, the preference for initiating GTPɤS binding is greater than the ability to inhibit forskolin-stimulated adenylyl cyclase as measured by cAMP accumulation as well. In some embodiments, the compounds disclosed herein are, by simplistic comparison of IC50 values more potent for GTPyS activation over β- arrestin recruitment, relative to that observed for U69,593. A compound of any one of Formulae (A), (I), (Ia), (II), (IIa), (III) and (IV) may be selected from the compounds presented in the structure-activity relationship (SAR) study described in further detail below. Compounds of Formulae (A), (I), (Ia), (II), (IIa), (III) and (IV) that are not listed in the following tables are also within the scope herein. C. Structure Activity Relationship Study (SAR). One aspect of the current disclosure is directed to a SAR study by modifying various regions of the compounds as is described in more detail below. First SAR set of bisamide analogues: modification of the isocyanide and amine components. To cover a broad range of structural diversity, the Bohdan MiniBlock platform was utilized to synthesize two initial analogue sets in parallel. In order to screen a relatively large library of compounds, an assay workflow was implemented where the analogues were first screened in a GTPγS assay. If a compound possessed suitable potency in this assay (< 1 µM), only then it would be screened in a β-arrestin recruitment assay. Data from both of these assays could then be used to calculate a bias factor. The first library set kept the active motifs from initial hit optimization efforts at the secondary amide (isocyanide component) and central core (ketone component), while the other two components were systematically varied. Thus, either cyclohexyl- or 2,6- dimethylphenylisocyanide and either cyclohexanone or cyclopentanone were paired with three different carboxylic acids and four different amine components to successfully afford 47 analogues. In an effort to avoid the hepatic issues of ML139, the thiophene moiety of ML139 was replaced with a furan, tetrahydrofuran, cyclohexyl, and phenyl moiety. The furan substitution afforded a number of potent analogues (compounds 1, 12, 24, 36), while the phenyl substitution was markedly less potent (compounds 6, 18, 30, 42) and the nonaromatic building blocks did not afford any potent analogues (compounds 9, 15, 21, 27, 33, 39, 45). To explore the importance of nitrogen position on the pyridinyl moiety, picolinic acid was replaced with nicotinic or isonicotinic acid for comparison. Notably, picolinic acid afforded a number of potent analogues (compounds 1, 6, 12, 24, 30, 36) while replacement with nicotinic acid or isonicotonic acid resulted in significant potency loss (compounds 2, 3, 7, 8, 13, 14, 25, 26, 31, 32, 37, 38), suggesting a critical interaction between the pyridine nitrogen and the KOR. On the secondary amide region (from the isocyanide component) of this series, cyclohexyl moiety was favored over the 2,6-dimethylphenyl group (compound 1 vs. compound 12 and compound 24 vs. compound 36). Not to be bound theory, but one may rationalize that contributions from either the steric bulk or rotational hindrance caused by dimethyl substitution on the phenyl ring rather than the aromatic ring itself could be responsible for the decreased potency. The effect of varying secondary amide substitution is discussed in more detail below (see Table 3). Table 1. Structures and KOR potency of cyclohexyl scaffold bisamide analogues

[0005] Table 2. Structures and KOR potency of cyclopentyl scaffold bisamide analogues

[0006] Second SAR library of bisamide analogues: focused modification of isocyanide component. For this library, it was investigated the 2,6-dimethylphenyl isocyanide component results in reduced potency analogues (see Tables 1 and 2) due to restricted rotation arising from the two methyl groups. Thus, the amine and the carboxylic acid components remained furfuryl amine and picolinic acid, respectively. Cyclobutanone, cyclopentanone and cyclohexanone provided comparison across three core scaffolds while the isocyanide component was explored. The isocyanides examined ranged from unsubstituted phenyl to benzyl to a branched alkane moiety (Table 3). The additional data supports the rationale that the reduced potency of the 2,6- dimethylphenyl analogues (Table 2) is likely due to the restricted rotation of the phenyl ring since the unsubstituted phenyl ring (compounds 48-50) show potencies similar to that of 1. In addition, the small library of 4-bromophenyl analogues (compounds 110-119) also support the restricted rotation hyopthesis (Table 6) as these analogues also show potencies similar to 1. The benzyl analogues (compounds 51-53) have decreased potencies suggesting that either the methylene linker pushes the aromatic ring too deep into this area of the receptor binding pocket or, more likely, that the extra rotational freedom is not necessarily beneficial. Lastly, the bulky 2, 2, 4, 4- tetramethyl pentane moiety (compounds 54 and 55) was investigated to resemble the aliphatic bulk of the cyclohexane ring, but in an acyclic fashion. As can be seen from the low potency, this particular moiety does not replicate the potency of 1, which contains a cyclohexyl moiety for R1. These acyclic analogues also possess a significant conformational liability, and their low potency is consistent with activity dependent on hydrophobic bulk of a defined configuration. Table 3. Structures and KOR potency of analogues that explore the effect of isocyanide component modifications. Third SAR library of bisamide analogues: further modification of carboxylic acid component. In an effort to further elucidate the potency effect of modifying the picolinic moiety, a series of analogues were synthesized exploring changes to this group. In this series, the isocyanide component remained cyclohexylisocyanide, the ketone component was either cyclopentanone or cyclohexanone, and the amine component was kept furfuryl amine, while the carboxylic acid component was varied. The carboxylic acid component varied widely and included many acids that bore different dinitrogen-containing heterocycles—one nitrogen in the 2-position, and an additional nitrogen in the 4-, 5-, or 6- position (compounds 56-58 and 60-62). The results indicate that a nitrogen in the 2- position is minimally required for potency, and the addition of a second nitrogen, regardless of ring position, decreases potency. To probe the potency effect of picolinic acid substitution, an analogue series was synthesized using 4-, 5-, and 6- bromo picolinic acids and 4-trifluoromethyl picolinic acid analogues were synthesized and tested (compounds 63-66). Except for the 5-bromo substitution (compound 64), all the exploratory analogues possessed no significant KOR potency. However, compound 64 was found to be highly potent, indicating that this region has very specific steric and electronic limitations that may be worth further exploration. Interestingly, the cyclohexane-containing analogues in this series retained more potency (albeit reduced compared to 1) versus their cyclopentane counterparts (compare compounds 56 and 57 to 60 and 61), potentially due to the increased orientation range accessible to the nitrogen-containing heterocycle on a larger ring system. Additionally, despite maintaining a nitrogen in the “2- position” the indole analogues (compounds 59 and 67) lost potency, possibly suggesting that the nitrogen should act as an H-bond acceptor rather than donor. Furthermore, while compound 68 has a nitrogen in the 2-position, this analogue lost KOR potency, suggesting that an extended ring system is not tolerated in this area of the KOR binding pocket, entry 69 further corroborates this hypothesis. Compounds 70 and 71 were synthesized to determine whether additional rotational freedom could enhance the potency of the lead compound, however, the added flexibility proved to be detrimental to potency. Compound 72 was synthesized to confirm that a nitrogen is necessary for potency and indeed the loss of potency with an unsubstituted phenyl ring corroborates that a nitrogen is essential for activity. Lastly, compounds 73-77 were synthesized to determine if the pyridine heterocycle was necessary, or if a non-aromatic amine would be tolerated. As indicated by the loss of potency, not only is a nitrogen in the 2-position necessary for potency, to date it is limited to aromatic nitrogen. Table 4. Potency of KOR bisamide analogues with a modified carboxylic acid component

[0007] Fourth SAR library of bisamide analogues: ketone and aldehyde scope. The largest analogue set was designed to explore the central core of the scaffold by fixing the carboxylic acid component to picolinic acid, the amine component to furfurylamine and isocyanide component to cyclohexylisocyanide while systematically exploring the carbonyl component. Overall, 28 ketone analogues were successfully synthesized (Table 5). Exploring carbonyl variation revealed several general SAR trends (Table 5). For example, the ring size of the ketone was well-tolerated from five- to eight-membered rings, suggesting that the hydrocarbon cycle serves as scaffolding to orient the other moieties (e.g., furan and pyridine) that can act as hydrogen bond donors or acceptors. In addition, a four-membered ring produced analogues with severely reduced potency while six- and seven-membered rings appeared to be the optimal ring size for potency. Interestingly, potency was boosted, when methyl substitution was introduced at 2- or 4-position of cyclohexanone moiety in a cis configuration to the cyclohexylamide moiety (compounds 84 and 88 compared to compound 1). The 3-position appears to be less tolerant of substitution as the 3,3-dimethyl analogue (compound 86) lost all potency and the 3,3,5,5-tetramethyl analogue (compound 87) lost almost all potency. The substituent’s configuration appears to be more important than the size of the group for substituted cyclohexane analogues, as evidenced by the significant potency difference for the two instances where both the cis and trans isomers could be tested (compounds 88 vs.89, 91 vs.92, and 93 vs. 94). Compared to the all carbon exemplar 1, selective oxygen incorporation was found to be beneficial (tetrahydropyran and 1,4-dioxaspiro[4.5]decane analogues, compounds 98 and 99) and even β-arrestin biased in the case of compound 99. Conversely, nitrogen incorporation appears to be detrimental (piperidine analogues, compounds 100 and 101) to potency. Using non-cyclic ketones yielded compounds 102-104. As can be seen, the dimethyl (compound 102) and diethyl (compound 103) analogues retained potency compared to compound 1, while the diisobutyl analogue (compound 104) lost all potency, indicating that a cyclic ketone is preferred to maintain some conformational rigidity. Additionally, the analogue derived from aldehyde component (R1= hydrogen) possessed dramatically reduced potency (compound 105). Reduced potency for the aldehyde-derived analogue appears to be a general trend (we have previously shown that analogues where R1and R2were both hydrogen that lost all measurable potency). Table 5. Potency of KOR bisamide analogues that explore central scaffold diversity with cyclic ketones Fifth SAR library of bisamide analogues: symmetrical versus unsymmetrical ketones. When unsymmetrical carbonyl components (e.g., 2-butanone) were employed as building blocks, the reaction products contain a stereogenic center. The potency effect of configuration at the stereogenic center was determined through the synthesis of three 4-bromophenyl analogue sets. The enantiomers were separated using preparative, chiral HPLC purification, the absolute configuration established by X-ray crystallographic analysis and the discrete enantiomer analogues screened for KOR potency (Table 6). Employing 2-butanone as the carbonyl component afforded methyl and ethyl substituted enantiomers, both of which possessed approximately 25 nM potency (compounds 110 and 111). The ketones 2-hexanone and 4-methyl-2-pentanone afforded analogues with increased steric bulk on one of the R groups (i.e., R = n-butyl, compounds 112 and 113; or iso-butyl, compounds 114 and 115), resulting in decreased potency for both enantiomers compared to compounds 110 and 111. Notably, the drop was more pronounced for the S- enantiomer, indicating that the R-enantiomer possessed the stereochemistry leading to the more potent compounds. Overall, we established that the R-configuration was more potent in all cases and, not surprisingly, that the effect of configuration increased with greater steric bulk difference between the groups. However, as noted above increased steric bulk resulted in decreased potency overall. It is also interesting to note, that as the steric bulk increases, (and thus the potency decreases), the bias for Gprotein over β-Arrestin increases, suggesting that it is possible to tease out some potent analogues with bias for Gprotein if asymmetrical ketones are used. Table 6. Structures and KOR potency of three pairs of enantiopure bisamide analogues compared to three structurally related symmetrical analogues. The various SAR studies shown above mapped important structural features for activity and identified additional areas worth further exploration (Fig. 3). For example, two important requirements were an aromatic moiety, preferably a furan or thiophene, on the tertiary amide nitrogen, and a 2-pyridinyl on the tertiary amide carbonyl. Other regions of the molecule were more tolerant to subtle changes, though excessive steric bulk or conformational flexibility were found to decrease activity. Through the preparation of a focused set of enantiopure analogues, we identified a stereochemical preference for the R-enantiomeric series. Lastly, the compounds shown below investigate other functionalities in the compounds disclosed herein, e.g, the inclusion of fluoride atoms or additional combinations of R1, R2and R3moieties. In many cases, these modifications led to unexpectedly potent agonists in the GTP assay (including many that have EC50 values of <20 nM, Table 7). Some molecules, particularly those with GTP EC50 values of ca.1 nM or lower, also have high bias factors that are comparable to or even exceed the highest values known for KOR binders (e.g., compounds 145–150 and 152–156). Table 7. Highly Potent Bisamides

[0008] D. Method of Preparing The current disclosure is also directed to any methods for preparing the compounds disclosed herein. A skilled artisan would be aware that such preparative methods can vary. The compounds disclosed herein may be synthesized by synthetic routes that include processes analogous to those well known in the chemical arts, particularly in light of the description contained herein. Starting materials are generally available from commercial sources or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents / or Organic Synthesis, v.1-23, Wiley, N.Y. (1967-2006 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database)). The compounds disclosed herein were prepared using the Ugi reaction. In general, the Ugi reaction is a multi-component reaction involving a ketone or aldehyde, an amine, an isocyanide and a carboxylic acid to form a bis-amide, as is shown below: Exemplary methods are described in detail further below, i.e., the preparation of compounds of Formula (A). Such methods comprise: contacting an acid with a ketone an amine an isocyanate to render a compound of Formula (A), Initial efforts used a six-step linear sequence that required the isolation of zwitterionic intermediates and, in some cases, amide coupling reactions at very hindered centers (Fig.2A). For analog expansion, one switched to a Ugi multicomponent reaction that permitted the construction of analogs in a single chemical step. The Ugi reaction is well established for the synthesis of compound libraries and was likely used to construct the original library from which ML 139 was derived.9, 6The Ugi sequence was carried out on in Bohdan MiniBlocks, which were shaken. The reactions were run at ambient temperature overnight in methanol with agitation from a shaker station. A catch-and-release strategy using either Dowex or Amberlyst acidic resin to purify the crude reactions was also explored, however, to identify a satisfactory solvent combination that could be universally applicable to the wide polarity range of the Ugi reaction products could not be determined. In the end, simply quenching the reaction with trifluoroacetic acid and solvent evaporation provided a crude reaction product of suitable purity for mass-directed HPLC purification. This straightforward protocol was applied toward the synthesis of the initial bisamide compound sets. The syntheses of subsequent, focused analogues did not utilize the parallel synthesis protocol, and were run at ambient temperature overnight on a stir plate while monitoring by TLC for sufficient product formation. Upon consumption of starting material, the crude reaction mixture was adsorbed on Celite and chromatographed to afford the final product. If additional purification was necessary, reverse-phase chromatography was utilized. For complete synthetic details on individual analogues, see the Experimental Section and the Supporting Information. In summary, agonists of the kappa opioid receptor (KOR) are of interest as antinociceptive and anti-itch agents, with particular value attached to pharmacologically novel chemotypes. Previous studies identified ML139 as a structurally distinct KOR agonist that notably lacks the basic nitrogen common among many KOR ligands. The current disclosure reports above a more comprehensive structure-activity relationship (SAR) study of more than 100 ML139 analogues prepared by a one-pot, Ugi multicomponent reaction route. This work shows that the thiophene group in ML139 can be replaced by an unsubstituted phenyl moiety with minimal loss in potency, while only modest substitutions are permitted at the 2-pyridyl group. Modifications to the secondary amide or the central aliphatic core produced more modest effects on potency, though, here too, trends were established. In one series, chiral, racemic analogues were resolved, revealing a correlation between absolute configuration and potency. Overall, these efforts both afforded higher-potency ML139 analogues with less metabolic liability. E. Pharmaceutical Compositions In certain embodiments, compounds or salts of Formulae (A), (I), (II), (III) and / or (IV) disclosed herein, are combined with one or more additional agents to form pharmaceutical compositions. In some embodiments, compounds of Formulae (A), (I), (II), (III) and / or (IV) are already in the form of a salt. Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Additional details about suitable excipients for pharmaceutical compositions described herein may be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference for such disclosure. A pharmaceutical composition, as used herein, refers to a mixture of a compound or salt of Formulae (A), (I), (II), (III) and / or (IV) with any suitable substituents and functional groups disclosed herein, with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. In practicing the methods of treatment or use provided herein, therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated. In some embodiments, the mammal is a human. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. The compounds or salts of Formula (I) with any suitable substituents and functional groups disclosed herein, can be used singly or in combination with one or more therapeutic agents as components of mixtures (as in combination therapy).

[0009] The pharmaceutical formulations described herein can be administered to a subject by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes. Moreover, the pharmaceutical compositions described herein, which include a compound of Formula (A), (I), (II), (III) and / or (IV) with any suitable substituents and functional groups disclosed herein, can be formulated into any suitable dosage form, including but not limited to, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, aerosols, fast-melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, and capsules.

[0010] One may administer the compounds and / or compositions in a local rather than systemic manner, for example, via injection of the compound directly into an organ or tissue, often in a depot preparation or sustained release formulation. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with organ-specific antibody. The liposomes will be targeted to and taken up selectively by the organ. In addition, the drug may be provided in the form of a rapid release formulation, in the form of an extended-release formulation or in the form of an intermediate release formulation.

[0011] Pharmaceutical compositions including a compound described herein may be manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

[0012] The pharmaceutical compositions will include at least one compound of Formula (I) disclosed herein, as an active ingredient in free-acid or free-base form, or in a pharmaceutically acceptable salt form.

[0013] In some embodiments, compositions provided herein may also include one or more preservatives to inhibit microbial activity. Suitable preservatives include quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

[0014] In some embodiments, the pharmaceutical solid dosage forms described herein can include a compound of Formulae (A), (I), (II), (III) and / or (IV) and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof. In still other aspects, using standard coating procedures, such as those described in Remington’s Pharmaceutical Sciences, 20th Edition (2000), a film coating is provided around the formulation of the compound described herein. In one embodiment, some or all of the particles of the compound described herein are coated. In another embodiment, some or all of the particles of the compound described herein are microencapsulated. In still another embodiment, the particles of the compound described herein are not microencapsulated and are uncoated.

[0015] Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol and the like.

[0016] Suitable filling agents for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, hydroxypropylmethycellulose (HPMC), hydroxypropylmethycellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol and the like. Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, and Solka- Floc®, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross-linked polymer such as crospovidone, a cross-linked polyvinylpyrrolidone, alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a clay such as Veegum® HV (magnesium aluminum silicate), a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, a natural sponge, a surfactant, a resin such as a cation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination starch and the like. Suitable binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose (e.g., Hypromellose USP Pharmacoat-603), hydroxypropylmethylcellulose acetate stearate (Aqoate HS LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), lactose, a natural or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks, starch, polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone® XL-10 and Povidone® K-12), larch arabinogalactan, Veegum®, polyethylene glycol, waxes, sodium alginate and the like. Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumerate, alkali-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol such as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, and the like. Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol and sorbitol), cyclodextrins and the like. Suitable wetting agents for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10®), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS and the like. Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic® (BASF) and the like. Suitable suspending agents for use in the solid dosage forms described here include, but are not limited to, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 5400 to about 7000, vinyl pyrrolidone / vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone and the like.

[0017] Suitable antioxidants for use in the solid dosage forms described herein include, for example, e.g., butylated hydroxytoluene (BHT), sodium ascorbate and tocopherol.

[0018] There is considerable overlap between additives used in the solid dosage forms described herein. Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in solid dosage forms of the pharmaceutical compositions described herein.

[0019] Liquid formulation dosage forms for oral administration can be aqueous suspensions selected from the group including, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels and syrups. See, e.g., Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002).

[0020] The pharmaceutical compositions described herein may include sweetening agents such as, but not limited to, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate (MagnaSweet®), maltitol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidin DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin, sucralose, sorbitol, Swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any combination of these flavoring ingredients, e.g., anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof.

[0021] Potential excipients for intranasal formulations include formulations solutions in saline, employing benzyl alcohol or other suitable preservatives, fluorocarbons, and / or other solubilizing or dispersing agents. See, for example, Ansel, H. C. et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth Ed. (1995). Preferably, these compositions and formulations are prepared with suitable nontoxic pharmaceutically acceptable ingredients. The choice of suitable carriers is highly dependent upon the exact nature of the nasal dosage form desired, e.g., solutions, suspensions, ointments, or gels. Nasal dosage forms generally contain large amounts of water in addition to the active ingredient. Minor amounts of other ingredients such as pH adjusters, emulsifiers or dispersing agents, preservatives, surfactants, gelling agents, or buffering and other stabilizing and solubilizing agents may also be present. Preferably, the nasal dosage form should be isotonic with nasal secretions. For administration by inhalation, the compounds described herein may be in a form as an aerosol, a mist or a powder. Pharmaceutical compositions described herein are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound described herein and a suitable powder base such as lactose or starch. Buccal formulations that include compounds described herein may be administered using a variety of formulations which include, but are not limited to, U.S. Pat. Nos.4,229,447; 4,596,795; 4,755,386; and 5,739,136. In addition, the buccal dosage forms described herein can further include a bioerodible (hydrolysable) polymeric carrier that also serves to adhere the dosage form to the buccal mucosa. The buccal dosage form is fabricated so as to erode gradually over a predetermined time period, wherein the delivery of the compound is provided essentially throughout. Buccal drug delivery avoids the disadvantages encountered with oral drug administration, e.g., slow absorption, degradation of the active agent by fluids present in the gastrointestinal tract and / or first-pass inactivation in the liver. With regard to the bioerodible (hydrolysable) polymeric carrier, virtually any such carrier can be used, so long as the desired drug release profile is not compromised, and the carrier is compatible with the compounds described herein, and any other components that may be present in the buccal dosage unit. Generally, the polymeric carrier comprises hydrophilic (water-soluble and water-swellable) polymers that adhere to the wet surface of the buccal mucosa. Examples of polymeric carriers useful herein include acrylic acid polymers and co, e.g., those known as “carbomers” (Carbopol®, which may be obtained from B.F. Goodrich, is one such polymer). Other components that may also be incorporated into the buccal dosage forms described herein include, but are not limited to, disintegrants, diluents, binders, lubricants, flavoring, colorants, preservatives and the like. For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, or gels formulated in a conventional manner. Transdermal formulations described herein may incorporate certain pharmaceutically acceptable excipients which are conventional in the art. In some embodiments, formulations suitable for transdermal administration of compounds described herein may employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and / or dispersed in a polymer or an adhesive. Formulations suitable for intramuscular, subcutaneous, or intravenous injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles including water, ethanol, polyols (propylene glycol, polyethylene-glycol, glycerol, cremophor and the like), 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 a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Formulations suitable for subcutaneous injection may also contain additives such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the growth of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may 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 use of agents delaying absorption, such as aluminum monostearate and gelatin. For intravenous injections, compounds described herein may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank’s solution, Ringer’s solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally recognized in the field. For other parenteral injections, appropriate formulations may include aqueous or nonaqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are generally recognized in the field.

[0022] Parenteral injections may involve bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi -dose containers, with an added preservative. The pharmaceutical composition described herein may be in a form suitable for parenteral injection as sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0023] In certain embodiments, delivery systems for pharmaceutical compounds may be employed, such as, for example, liposomes and emulsions. In certain embodiments, compositions provided herein also include an mucoadhesive polymer, selected from among, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly (methylmethacryl ate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate and dextran.

[0024] In some embodiments, the compounds described herein may be administered topically and are formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments. Such pharmaceutical compounds can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives. The compounds described herein may also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.

[0025] In some embodiments, the compounds of Formulae (A), (I), (II), (III) and / or (IV) disclosed herein are combined with other therapeutic agents, such as other cardiovascular agents, anti-nausea agents (or anti-emetics), anti-pruritic agents, pain relievers (including chronic and acute pain relievers and hyperalgesia), anti-inflammatory agents, neuroprotective agents, neuroleptic agents, anesthetic agents, hypertensive agents (including agents for hypoxic pulmonary hypertension), multiple sclerosis agents, muscle relaxants, and combinations thereof.

[0026] In another embodiment, the compounds of Formulae (A), (I), (II), (III) and / or (IV) disclosed herein are combined with another therapeutic agent, which are described in more detail further below.

[0027] Generally, an agent, such as a compound of Formula (A), (I), (II), (III) and / or (IV) disclosed herein, is administered in an amount effective for treating the disease or disorder (i.e., a therapeutically effective amount). Thus, a therapeutically effective amount can be an amount that is capable of at least partially treating, preventing or reversing a disease or disorder. The dose required to obtain an effective amount may vary depending on the agent, formulation, disease or disorder, and individual to whom the agent is administered.

[0028] Determination of effective amounts may also involve in vitro assays in which varying doses of agent are administered to cells in culture and the concentration of agent effective for ameliorating some or all symptoms is determined in order to calculate the concentration required in vivo. Effective amounts may also be based in in vivo animal studies.

[0029] An agent, such as a compound of Formulae (A), (I), (II), (III) and / or (IV), can be administered prior to, concurrently with, and subsequent to the appearance of symptoms of a disease or disorder. In some embodiments, an agent is administered to a subject with a family history of the disease or disorder or who has a phenotype that may indicate a predisposition to a disease or disorder or who has a genotype which predisposes the subject to the disease or disorder. In some embodiments, the compositions described herein are provided as pharmaceutical and / or therapeutic compositions. The pharmaceutical and / or therapeutic compositions of the present disclosure can be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration can be topical (including ophthalmic and to mucous membranes including vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer, as well as: intratracheal, intranasal, epidermal and transdermal), oral or parenteral. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Compositions and formulations for topical administration can include: transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional carriers; aqueous, powder, or oily bases; thickeners; and the like can be necessary or desirable. Compositions and formulations for oral administration include: powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets or tablets. Thickeners, flavoring agents, diluents, emulsifiers, dispersing aids or binders can be desirable. Compositions and formulations for parenteral, intrathecal or intraventricular administration can include sterile aqueous solutions that can also contain buffers, diluents and other suitable additives such as, but not limited to, penetration enhancers, carrier compounds and other pharmaceutically acceptable carriers or excipients. Pharmaceutical and / or therapeutic compositions of the present disclosure include, but are not limited to, solutions, emulsions, and liposome containing formulations. These compositions can be generated from a variety of components that include, but are not limited to, preformed liquids, self-emulsifying solids and self-emulsifying semisolids.

[0030] The pharmaceutical and / or therapeutic formulations, which can conveniently be presented in unit dosage form, can be prepared according to conventional techniques well known in the pharmaceutical / nutraceutical industries. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s). In general the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. The compositions of the present disclosure can be formulated into any of many possible dosage forms such as, but not limited to, tablets, capsules, liquid syrups, soft gels, suppositories, and enemas. The compositions of the present disclosure can also be formulated as suspensions in aqueous, non-aqueous, oil-based, or mixed media. Suspensions can further contain substances that increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and / or dextran. The suspension can also contain stabilizers. In one embodiment of the present disclosure, the pharmaceutical compositions can be formulated and used as foams. Pharmaceutical foams include formulations such as, but not limited to, emulsions, microemulsions, creams, jellies and liposomes. While basically similar in nature these formulations vary in the components and the consistency of the final product. The pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compound. The unit dosage may be in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition. By way of example only, formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative. Dosing and administration regimes are tailored by the clinician, or others skilled in the pharmacological arts, based upon well-known pharmacological and therapeutic considerations including, but not limited to, the desired level of therapeutic effect and the practical level of therapeutic effect obtainable. Generally, it is advisable to follow well-known pharmacological principles for administrating chemotherapeutic agents (e.g., it is generally advisable to not change dosages by more than 50% at time and no more than every 3-4 agent half-lives). For compositions that have relatively little or no dose-related toxicity considerations, and where maximum efficacy is desired, doses in excess of the average required dose are not uncommon. This approach to dosing is commonly referred to as the “maximal dose” strategy. In certain embodiments, the compounds are administered to a subject at a dose of about 0.01 mg / kg to about 200 mg / kg, more preferably at about 0.1 mg / kg to about 100 mg / kg, even more preferably at about 0.5 mg / kg to about 50 mg / kg. When the compounds described herein are co-administered with another agent (e.g., as sensitizing agents), the effective amount may be less than when the agent is used alone. Dosing may be once per day or multiple times per day for one or more consecutive days. F. Methods of use

[0031] The disclosure provides compounds and methods for treating a subject suffering from a disease and / or condition that has been identified as being associated with the kappa opioid receptor. In some embodiments, the disclosure provides a method of treating such a disease and / or condition comprising administering a therapeutically effective amount of a compound or salt described herein, for example, a compound or salt of Formulae (A), (I), (II), (III) and / or (IV) disclosed herein, to a subject in need thereof. In some embodiments, the compound or salt being administered is a kappa opioid agonist as disclosed herein. In some embodiments, the compound or salt being administered is a g-protein biased kappa opioid agonist as disclosed herein, for example, a compound or salt of Formulae (A), (I), (II), (III) and / or (IV).

[0032] In some embodiments, such diseases and / or conditions can be treated by activating or inactivating signaling of the kappa opioid receptor [please confirm]. In some embodiments, such diseases and / or disorders can be treated by agonizing or inactivating signaling of the kappa opioid receptor.

[0033] The kappa opioid receptor-associated disease or conditions treatable with the compounds disclosed herein can be any kappa opioid receptor-associated condition. Such diseases and conditions to be treated include, but are not limited to, acute and chronic pain, inflammation, cardiovascular disease (e.g., congestive heart failure, stroke, hypertension), liver cirrhosis, edema, ileus, tussis, eye diseases (i.e., glaucoma, ocular inflammation), itching, addiction, anxiety, depression, myocardial infarction, pruritus, nausea, neuro-inflammation, hypoxic pulmonary hypertension, multiple sclerosis, osteoarthritis, rheumatoid arthritis, inflammatory bowel disease, substance abuse disorder, and eczema.

[0034] For instance, the kappa opioid receptor-associated pain can be neuropathic pain, somatic pain, visceral pain or cutaneous pain. Some diseases or conditions are associated with more than one form of pain, e.g., postoperative pain can have any or all of neuropathic, somatic, visceral, and cutaneous pain components, depending upon the type and extent of surgical procedure employed.

[0035] The kappa opioid receptor-associated inflammation can be any inflammatory disease or condition including, but not limited to sinusitis, rheumatoid arthritis tenosynovitis, bursitis, tendonitis, lateral epicondylitis, adhesive capsulitis, osteomyelitis, osteoarthritic inflammation, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), ocular inflammation, otitic inflammation or autoimmune inflammation.

[0036] The kappa opioid receptor-associated pruritus can be any pruritic disease or condition such as, for instance, ocular pruritus, e.g., associated with conjunctivitis, otitic pruritus, pruritus associated with end-stage renal disease, where many patients are receiving kidney dialysis, and other forms of cholestasis, including primary biliary cirrhosis, intrahepatic cholestasis of pregnancy, chronic cholestatic liver disease, uremia, malignant cholestasis, jaundice, as well as dermatological conditions such as eczema (dermatitis), including atopic or contact dermatitis, psoriasis, polycythemia vera, lichen planus, lichen simplex chronicus, pediculosis (lice), thyrotoxicosis, tinea pedis, urticaria, scabies, vaginitis, anal pruritis associated with hemorrhoids and, as well as insect bite pruritis and drug-induced pruritis, such as mu opioid-induced pruritis.

[0037] The kappa opioid receptor-associated edema can be any edematous disease or condition such as, for instance, edema due to congestive heart disease or to a syndrome of inappropriate antidiuretic hormone (ADH) secretion.

[0038] Kappa opioid receptor-associated ileus can be any ileus disease or condition including, but not limited to, post-operative ileus and opioid-induced bowel dysfunction.

[0039] Kappa opioid receptor-associated neuropathic pain can be any neuropathic pain, such as, for instance, trigeminal neuralgia, diabetic pain, viral pain such as herpes zoster-associated pain, chemotherapy-induced pain, nerve-encroaching metastatic cancer pain, neuropathic pain associated with traumatic injury and surgical procedures, as well as variants of headache pain that are thought to have a neuropathic component, e.g., migraine.

[0040] Kappa opioid-associated pain also includes ocular pain, such as that following photo- refractive keratectomy (PRK), ocular laceration, orbital floor fracture, chemical bums, comeal abrasion or irritation, or pain associated with conjunctivitis, comeal ulcers, scleritis, episcleritis, sclerokeratitis, herpes zoster ophthalmicus, interstitisal keratitis, acute iritis, keratoconjunctivitis sicca, orbital cellulites, orbital pseudotumor, pemphigus, trachoma or uveitis.

[0041] Kappa opioid-associated pain also includes throat pain, particularly associated with inflammatory conditions, such as allergic rhinitis, acute bronchitis, the common cold, contact ulcers, herpes simplex viral lesions, infectious mononucleosis, influenza, laryngeal cancer, acute laryngitis, acute necrotizing ulcerative gingivitis, peritonsillar abscess, pharyngeal bums, pharyngitis, reflux laryngopharyngitis, acute sinusitis, and tonsillitis.

[0042] Kappa opioid receptor-associated pain can be arthritic pain, kidney-stone, urinary tract stone, gallstone, and bile duct stone pain, dysmenorrhea, uterine cramping, endometriosis, mastitis, dyspepsia, post-surgical pain (such as, for instance, from appendectomy, open colorectal surgery, hernia repair, prostatectomy, colonic resection, gastrectomy, splenectomy, colectomy, colostomy, pelvic laparoscopy, tubal ligation, hysterectomy, vasectomy or cholecystectomy), post medical procedure pain (such as, for instance, after colonoscopy, cystoscopy, hysteroscopy or cervical or endometrial biopsy), otitic pain, breakthrough cancer pain, and pain associated with a GI disorder such as IBD or IBS or other inflammatory conditions, particularly of the viscera (e.g., gastroesophageal reflux disease, pancreatitis, acute pyelonephritis, ulcerative colitis, acute pyelonephritis, cholecystitis, cirrhosis, hepatic abscess, hepatitis, duodenal or gastric ulcer, esophagitis, gastritis, gastroenteritis, colitis, diverticulitis, intestinal obstruction, ovarian cyst, pelvic inflammatory disease, perforated ulcer, peritonitis, prostatitis, interstitial cystitis), or exposure to toxic agents, such as insect toxins, or inflammation due to the effects of drugs such as salicylates orNSAIDs.

[0043] Kappa opioid receptor-associated pain also includes hyperalgesia, which is believed to be caused by changes in the milieu of the peripheral sensory terminal occur secondary to local tissue damage. Tissue damage (e.g., abrasions, burns) and inflammation can produce significant increases in the excitability of polymodal nociceptors (C fibers) and high threshold mechanoreceptors (Handwerker et al. (1991) Proceeding of the Vlth World Congress on Pain, Bond et al., eds., Elsevier Science Publishers BV, pp. 59-70; Schaible et al. (1993) Pain 55:5-54). This increased excitability and the exaggerated responses of sensory afferents is believed to underlie hyperalgesia, where the pain response is the result of an exaggerated response to a stimulus. The importance of the hyperalgesic state in the post-injury pain state has been repeatedly demonstrated and appears to account for a major proportion of the post-injury / inflammatory pain state. See for example, Woold et al. (1993) Anesthesia and Analgesia 77:362-79; Dubner et al. (1994) In, Textbook of Pain, Melzack et al., eds., Churchill-Livingstone, London, pp. 225-242.

[0044] In another embodiment the kappa opioid receptor-associated condition is pain, inflammation (such as rheumatoid arthritic inflammation, osteoarthritic inflammation, IBD inflammation, IBS inflammation, ocular inflammation, otitic inflammation or autoimmune inflammation), pruritus (such as atopic dermatitis, kidney-dialysis-associated pruritus, ocular pruritus, otitic pruritus, insect bite pruritus, or opioid-induced pruritus), edema, ileus, tussis or glaucoma. In one aspect, the pain is a neuropathic pain (such as trigeminal neuralgia, migraine, diabetic pain, viral pain, chemotherapy-induced pain or metastatic cancer pain), a somatic pain, a visceral pain or a cutaneous pain. In another aspect the pain is arthritic pain, kidney-stone pain, uterine cramping, dysmenorrhea, endometriosis, dyspepsia, post-surgical pain, post medical procedure pain, ocular pain, otitic pain, breakthrough cancer pain or pain associated with a GI disorder, such as IBD or IBS. In another aspect the pain is pain associated with surgery, wherein the surgery is pelvic laparoscopy, tubal ligation, hysterectomy and cholecystecomy. Alternatively, the pain can be pain associated with a medical procedure, such as for instance, colonoscopy, cystoscopy, hysteroscopy or endometrial biopsy. In a specific aspect, the atopic dermatitis can be psoriasis, eczema or contact dermatitis. In another specific aspect, the ileus is post-operative ileus or opioid-induced bowel dysfunction.

[0045] The disclosure also provides a method of treating or preventing a neuro-degenerative disease or condition in a subject, wherein the method includes administering to the subject a composition that includes an effective amount of a composition as disclosed herein. The neurodegenerative disease or condition can be any neurodegenerative disease or condition, such as for instance, ischemia, anoxia, stroke, brain injury, spinal cord injury or reperfusion injury. Alternatively, the neurodegenerative disease or condition can be a neurodegenerative disease of the eye. Particular neurodegenerative diseases of the eye treatable or preventable by the method of the invention include glaucoma, macular degeneration, retinal ischemic disease and diabetic neuropathy.

[0046] In some embodiments, the disclosure provides methods of prevention or treatment of certain neuronal diseases and conditions, such as diseases and conditions having a neurodegenerative component. Compounds as disclosed herein can be administered in an amount effective to protect neuronal cells against the effects of pathology or injury that would lead to neurodegeneration and / or neuronal cell death of the untreated cells. For example, several diseases or conditions of the eye that have a neurodegenerative component can be prevented or treated by administration of an effective amount of compounds as disclosed herein. Such diseases and conditions of the eye include glaucoma, macular degeneration, retinal ischemic disease and diabetic neuropathy. Progression of these diseases and conditions is believed to involve neurodegeneration or neuronal cell death, for example by programmed cell death (apoptosis) in which the neuronal cells are committed to a pathway that without intervention would lead to cell death. It has been found that development or progression of these diseases and conditions can be prevented, or at least slowed, by treatment with kappa opioid receptor agonists. This improved outcome is believed to be due to neuroprotection by the kappa opioid receptor agonists. See for instance, Kaushik et al. “Neuroprotection in Glaucoma” (2003) J. Postgraduate Medicine vol. 49 (1): pp. 90-95.

[0047] Moreover, the compounds as disclosed herein can be administered by methods disclosed herein for the treatment or prevention of any hyperalgesic condition associated with bums, abrasions, bruises, abrasions (such as corneal abrasions), contusions, frostbite, rashes, acne, insect bites / stings, skin ulcers (for instance, diabetic ulcers or a decubitus ulcers), mucositis, inflammation, gingivitis, bronchitis, laryngitis, sore throat, shingles, fungal irritation (such as athlete’s foot or jock itch), fever blisters, boils, Plantar’s warts or vaginal lesions (such as vaginal lesions associated with mycosis or sexually transmitted diseases).

[0048] Hyperalgesic conditions associated with post-surgery recovery can also be addressed by administration of the composition disclosed herein. The hyperalgesic conditions associated with post-surgery recovery can be any hyperalgesic conditions associated with post-surgery recovery, such as for instance, radial keratectomy, tooth extraction, lumpectomy, episiotomy, laparoscopy and arthroscopy.

[0049] Hyperalgesic conditions associated with inflammation are also addressable by administration of the compounds disclosed herein. Periodontal inflammation, orthodontic inflammation, inflammatory conjunctivitis, hemorrhoids and venereal inflammations can be treated or prevented by topical or local administration of the compounds disclosed herein.

[0050] In some embodiments, the methods described above further comprise co-administration of a second therapeutic agent. Such a therapeutic agent can be administered at the same time as the compound disclosed herein or can be administered before or after administration of the compound disclosed herein. A skilled artisan would be aware that the mode and timing of administration and the dose being administered can vary depending on the therapeutic agent being administered. Examples of therapeutic agents being co-administered include, but are not limited to, other opioids, cannabinoids, antidepressants, anticonvulsants, neuroleptics, antihistamines, acetaminophen, corticosteroids, ion channel blocking agents, non-steroidal anti-inflammatory drugs (NSAIDs), and diuretics.

[0051] Suitable opioids, include, without limitation, alfentanil, alphaprodine, anileridine, bremazocine, buprenorphine, butorphanol, codeine, conorphone, dextromoramide, dextropropoxyphene, dezocine, diamorphine, dihydrocodeine, dihydromorphine, diphenoxylate, dipipanone, doxpicomine, ethoheptazine, ethylketazocine, ethylmorphine, etorphine, fentanyl, hydrocodone, hydromorphone, ketobemidone, levomethadyl, levorphanol, lofentanil, loperamide, meperidine (pethidine), meptazinol, methadone, morphine, morphine-6-glucuronide, nalbuphine, nalorphine, nicomorphine, oxycodone, oxymorphone, pentazocine, phenazocine, phenoperidine, piritramide, propiram, propoxyphene, remifentanil, sufentanil, tilidate, tonazocine, and tramadol.

[0052] Additional opioids include opioids with substantial agonist activity at the mu opioid receptor, such as morphine, fentanyl, hydromorphone, or oxycodone, together with the compounds disclosed herein, for the purpose of a mu opioid dose-sparing effect, where the dose of the mu opioid is reduced to minimize common mu opioid side effects, particularly in opioid-naive patients. Such side effects include constipation, nausea, vomiting, sedation, respiratory depression, pruritus (itching), mental confusion, disorientation and cognitive impairment, urinary retention, biliary spasm, delirium, myoclonic jerks, and seizures. The selection of the reduced mu opioid dose requires expert clinical judgment, and depends on the characteristics of the various mu opioids, as well as patient characteristics such as pain intensity, patient age, coexisting disease, current drug regimen and potential drug interactions, prior treatment outcomes, and patient preference (McCaffery, M. and Pasero, C., Pain Clinical Manual, Second Edition, Mosby, 1999).

[0053] Cannabinoids suitable for administration with or incorporation into the pharmaceutical compositions of the invention, include any natural cannabinoid, such as for instance, tetrahydrocannabinol (THC), or a THC derivative, or a synthetic cannabinoid, such as, for instance, levonantradol, marinol, nabilone, rimonabant or sativex.

[0054] Suitable antidepressants that can be co-administered with or incorporated into the pharmaceutical compositions of the invention, include for example, tricyclic antidepressants such as imipramine, desipramine, trimipramine, protriptyline, nortriptyline, amitriptyline, doxepin, and clomipramine; atypical antidepressants such as amoxapine, maprotiline, trazodone, bupropion, and venlafaxine; serotonin-specific reuptake inhibitors such as fluoxetine, sertraline, paroxetine, citalopram and fluvoxamine; norepinephrine-specific reuptake inhibitors such as reboxetine; or dual-action antidepressants such as nefazodone and mirtazapine.

[0055] Suitable neuroleptics that can be co-administered with or incorporated into the pharmaceutical compositions of the invention, include any neuroleptic, for example, a compound with D2 dopamine receptor antagonist activity such as domperidone, metoclopramide, levosulpiride, sulpiride, thiethylperazine, ziprasidone, zotepine, clozapine, chlorpromazine, acetophenazine, carphenazine, chlorprothixene, fluphenazine, loxapine, mesoridazine, molindone, prochlorperazine, pimozide, pi peracetazine, perchlorperazine, thioridazine, thiothixene, trifluoperazine, triflupromazine, pipamperone, amperozide, quietiapine, melperone, remoxipride, haloperidol, rispiridone, olanzepine, sertindole, ziprasidone, amisulpride, prochlorperazine, and thiothixene.

[0056] Anticonvulsants such as phenobarbital, phenytoin, primidone, carbamazepine, ethosuximide, lamotrigine, valproic acid, vigabatrin, felbamate, gabapentin, levetiracetam, oxcarbazepine, remacemide, tiagabine, and topiramate can also usefully be incorporated into the pharmaceutical compositions of the invention.

[0057] Muscle relaxants such as methocarbamol, orphenadrine, carisoprodol, meprobamate, chlorphenesin carbamate, diazepam, chlordiazepoxide and chlorzoxazone; anti-migraine agents such as sumitriptan, analeptics such as caffeine, methylphenidate, amphetamine and modafinil; antihistamines such as chlorpheniramine, cyproheptadine, promethazine and pyrilamine, as well as corticosteroids such as methylprednisolone, betamethasone, hydrocortisone, prednisolone, cortisone, dexamethasone, prednisone, alclometasone, clobetasol, clocortolone, desonide, desoximetasone, diflorasone, fluocinolone, fluocinonide, flurandrenolide, fluticasone, flouromethalone, halcinonide, halobetasol, loteprednol, mometasone, prednicarbate, and triamcinolone can also be incorporated into the pharmaceutical compositions of the invention.

[0058] Ion channel blocking agents such as, for instance, the sodium ion channel blocker, carbamazepine, as commonly used in the treatment of tinnitus, arrhythmia, ischemic stroke and epilepsy can be co-administered with or incorporated into the pharmaceutical compositions of the invention. Alternatively, or in addition, calcium ion channel blockers, such as ziconotide, can also be used, as can antagonists of the ion channel associated with the NMDA receptor, such as ketamine. There is evidence that at least some of these ion channel blockers can potentiate the analgesic effects of the kappa agonist and thereby reduce the dose required for affective pain relief. See for instance, Wang et al., 2000, Pain 84: 271-81. Suitable NSAIDs, or other non-opioid compounds with anti-inflammatory and / or analgesic activity, that can be co-administered with or incorporated into the pharmaceutical compositions of the invention include, but are not limited to one or more of the following: aminoarylcarboxylic acid derivatives such as etofenamate, meclofenamic acid, mefanamic acid, niflumic acid; arylacetic acid derivatives such as acemetacin, amfenac, cinmetacin, clopirac, diclofenac, fenclofenac, fenclorac, fenclozic acid, fentiazac, glucametacin, isoxepac, lonazolac, metiazinic acid, naproxin, oxametacine, proglumetacin, sulindac, tiaramide and tolmetin; arylbutyric acid derivatives such as butibufen and fenbufen; arylcarboxylic acids such as clidanac, ketorolac and tinoridine. Arylpropionic acid derivatives such as bucloxic acid, carprofen, fenoprofen, flunoxaprofen, ibuprofen, ibuproxam, oxaprozin, phenylalkanoic acid derivatives such as flurbiprofen, piketoprofen, pirprofen, pranoprofen, protizinic acid and tiaprofenic acid; pyranocarboxylic acids such as etodolac; pyrazoles such as mepirizole; pyrazolones such as clofezone, feprazone, mofebutazone, oxyphinbutazone, phenylbutazone, phenyl pyrazolidininones, suxibuzone and thiazolinobutazone; salicylic acid derivatives such as aspirin, bromosaligenin, diflusinal, fendosal, glycol salicylate, mesalamine, 1-naphthyl salicylate, magnesium salicylate, olsalazine and salicylamide, salsalate, and sulfasalazine; thiazinecarboxamides such as droxicam, isoxicam and piroxicam others such as ε- acetamidocaproic acid, acetaminophen, s-adenosylmethionine, 3-amino-4-hydroxybutyric acid, amixetrine, bendazac, bucolome, carbazones, cromolyn, difenpiramide, ditazol, hydroxychloroquine, indomethacin, ketoprofen and its active metabolite 6-methoxy-2- naphthylacetic acid; guaiazulene, heterocylic aminoalkyl esters of mycophenolic acid and derivatives, nabumetone, nimesulide, orgotein, oxaceprol, oxazole derivatives, paranyline, pifoxime, 2-substituted-4, 6-di-tertiary-butyl-s-hydroxy-1,3-pyrimidines, proquazone and tenidap, and cox-2 (cyclooxygenase II) inhibitors, such as celecoxib or rofecoxib. Suitable diuretics that can be co-administered with or incorporated into the pharmaceutical preparations of the invention, include, for example, inhibitors of carbonic anhydrase, such as acetazolamide, dichlorphenamide, and methazolamide; osmotic diuretics, such as glycerin, isosorbide, mannitol, and urea; inhibitors of Na+—K+-2Cl− symport (loop diuretics or high- ceiling diuretics), such as furosemide, bumetanide, ethacrynic acid, torsemide, axosemide, piretanide, and tripamide; inhibitors of Na+—Cl− symport (thiazide and thiazidelike diuretics), such as bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethazide, methyclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone, and quinethazone; and, in addition, inhibitors of renal epithelial Na+ channels, such as amiloride and triamterene, and antagonists of mineralocorticoid receptors (aldosterone antagonists), such as spironolactone, canrenone, potassium canrenoate, and eplerenone, which, together, are also classified as K+-sparing diuretics In some embodiments, any of the above therapeutic agents can also be formulated with the composition disclosed herein to obtain pharmaceutical compositions as described above. In accordance with the purpose(s) of the currently disclosed subject matter, as embodied and broadly described herein, in one aspect relates to a method of preventing or treating a disease or condition mediated by the kappa opioid receptor, the method comprising administering a therapeutically effective amount of a compound of Formula A to a subject in need thereof, wherein the compound of Formula (A) is: or any stereoisomer and / or pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of substituted or unsubstituted heteroaryl, substituted or unsubstituted heterobiaryl, (C1-C6) heterocycloalkyl, -CH2NH2, -CH2N(CH3)2, R2is selected from the group consisting of substituted or unsubstituted aryl, (C1-C6) cycloalkyl, substituted or unsubstituted -CH2(aryl) and substituted or unsubstituted (C1-C10) alkyl; R3is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted (C1-C6) cycloalkyl, and substituted or unsubstituted (C1-C6) heterocycloalkyl; R3aand R3bare independently selected from the group consisting of -H, substituted or unsubstituted (C1-C6) alkyl and substituted or substituted (C1-C10) cycloalkyl; X, if present, is selected from the group consisting of -CH2-, -O-, -N(CH3)-, -S-, -CF2-, - CHF-, -CH(CF3)-, -CH(CHF2)-, -CH(CH3)-, -C(CH3)2-, -C=CF2, -C=CHF, z is an integer selected from 0, 1, 2 and 3. EXAMPLES Example 1: Assays used for Structure-Activity Relationship Studies in Tables 1-6. Compounds in Tables 1-6 were examined for G-protein activation using the GTPγS biochemical assay.29In additions, compounds in Tables 1-7 were examined for β-arrestin recruitment using the PathHunter®DiscoverX β-arrestin recruitment assay.30Bias was determined by fitting to the operational model as previously described (Zhou et al., 2013, 22). Microsomal stability was determined using mouse hepatic microsomes and LC / MS detections over time (Zhou et al., 2013, 22). Example 2: Preparation of Bisamides The compounds disclosed herein were prepared using a combinatorial library approach of the Ugi reaction. A general procedure is described below. General Procedure for the Ugi Multicomponent Reaction in Bisamide Library Synthesis. On a 24-position Bohdan MiniBlock, reaction tubes were installed. Each reaction tube was charged with a suspension of carboxylic acid (0.4 mmol), amine (0.4 mmol), and ketone / aldehyde (0.4 mmol) in methanol (0.5 mL), was added isocyanide (0.4 mmol) at room temperature. The Bohdan MiniBlock was agitated for 24 h on the shaker station. To each reaction tube, was added TFA (0.14 mL) prior to 30 min of shaking at room temperature. Each reaction mixture was transferred to a CCT tube then concentrated under N2. The crude sample was purified via MS-directed HPLC to afford the title compound. Modified general procedure. To an argon filled scintillation vial was added anhydrous MeOH (2.0 mL, 0.25 M), ketone (1 equiv, 0.50 mmol) and amine (1 equiv, 0.50 mmol) via syringe. The mixture was stirred at room temp for at least 15 minutes after which acid (1 equiv, 0.50 mmol) was added. The reaction vessel was again evacuated and purged with argon and isonitrile (1 equiv, 0.50 mmol) was syringed into solution and stirred for 2 days. Flash column chromatography afforded the desired compound. REFERENCES 1. Anupama Koneru, S. S., Shaik Rizwan, Endogenous Opioids: Their Physiological Role and Receptors. Global Journal of Pharmacology 2009, 3 (3), 149-153. 2. Vanderah, T. W., Delta and Kappa Opioid Receptors as Suitable Drug Targets for Pain. The Clinical Journal of Pain 2010, 26, 10-15. 3. Yu-hua Wang, J.-f. S., Yi-min Tao, Zhi-qiang Chi, Jing-gen Liu, The role of κ-opioid receptor activation in mediating antinociception and addiction. Acta Pharmacologica Sinica 2010, 31 (9), 1065-1070. 4. Hiroshi Nagase, H. F., Opioids in Preclinical and Clinical Trials. Top Curr Chem 2010, 299, 29-62. 5. Bryan L. Roth, K. B., Richard Westkaemper, Daniel Paul Ernsberger, and Richard B. Rothman, Salvinorin A: A potent naturally occuring nonnitrogenous k opioid selective agonist. PNAS 2002,99 (18), 11934-11939. 6. Domling, A.; Wang, W.; Wang, K., Chemistry and biology of multicomponent reactions. Chem. Rev.2012, 112 (6), 3083-135. 7. Brust, T. F.; Morgenweck, J.; Kim, S. A.; Rose, J. H.; Locke, J. L.; Schmid, C. L.; Zhou, L.; Stahl, E. L.; Cameron, M. D.; Scarry, S. M.; Aube, J.; Jones, S. R.; Martin, T. J.; Bohn, L. M. Biased agonists of the kappa opioid receptor suppress pain and itch without causing sedation or dysphoria. Sci. Signal 2016, 9 (456), ra117. 8. Manglik, A.; Lin, H.; Aryal, D. K.; McCorvy, J. D.; Dengler, D.; Corder, G.; Levit, A.; Kling, R. C.; Bernat, V.; Hübner, H.; Huang, X.-P.; Sassano, M.F.; Giguère, P.M.; Löber, S.; Duan, D.; Scherrer, G.; Kobilka, B. K.; Gmelner, P.; Roth, B.L.; Shoichet, B. K. Structure–based discovery of opioid analgesics with reduced side effects. Nature, 2016, 537(7619), 185–190. 9. Varadi, A.; Palmer, T. C.; Haselton, N.; Afonin, D.; Subrath, J. J.; Le Rouzic, V.; Hunkele, A.; Pasternak, G. W.; Marrone, G. F.; Borics, A.; Majumdar, S., Synthesis of Carfentanil Amide Opioids Using the Ugi Multicomponent Reaction. ACS. Chem. Neurosci.2015, 6 (9), 1570-1577. 10. Tang, Y.; Yang, J.; Lunzer, M. M.; Powers, M. D.; Portoghese, P. S., A kappa Opioid Pharmacophore Becomes a Spinally Selective kappa-delta Agonist When Modified with a Basic Extender Arm. ACS Med Chem Lett 2011,2 (1), 7-10. 11. Zhou, L.; Lovell, K. M.; Frankowski, K. J.; Slauson, S. R.; Phillips, A. M.; Streicher, J. M.; Stahl, E.; Schmide, C. L.; Hodder, P.; Madoux, F.; Cameron, M. D.; Prisinzano, T. E.; Aube, J.; Bohn, L. M. Development of functionally selective, small molecule agonists at kappa opioid receptors. J. Biol. Chem., 2013, 288, 36703-16. 12. Frankowski, K. J.; Hedrick, M. P.; Gosalia, P.; Li, K.; Shi, S.; Whipple, D.; Ghosh, P.; Prisinzano, T. E.; Schoenen, F. J.; Su, Y.; Vasile, S.; Sergieno, E.; Gray, W.; Hariharan, S.; Milan, L.; Heynen-Genel, S.; Mangravita-Novo, A.; Vicchiarelli, M.; Smith, L. H.; Streicher, J. M.; Caron, M. G.; Barak, L. S.; Bohn, L. M.; Chung, T. D. Y.; Aubé, J. Discovery of small molecule kappa opioid receptor agonist and antagonist chemotypes through a HTS and hit refinement strategy. ACS Chem. Neurosci.2012, 3, 221-236.

Claims

THAT WHICH IS CLAIMED IS:

1. A compound of Formula (I):Formula (II) or any stereoisomer and / or pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of substituted or unsubstituted heteroaryl, substituted or unsubstituted heterobiaryl, (C1-C6) heterocycloalkyl, -CH2NH2, -CH2N(CH3)2,R2is selected from the group consisting of substituted and unsubstituted aryl, (C1- C6)cycloalkyl, substituted or unsubstituted -CH2(aryl) and substituted or unsubstituted (C1- C10)alkyl; R3is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted (C1-C6) cycloalkyl, and substituted or unsubstituted (C1-C6) heterocycloalkyl; X is selected from the group consisting of -CH2-, -O-, -S-, -CF2, -CH(CF3), - CH(CHF2), -CH(CH3), -C(CH3)2, -N(CH3)-, -CHF, -C=CF2, -C=CHF,m and n are integers independently selected from the group consisting of 0, 1, 2, 3, 4, 5 and 6, wherein both m and n cannot be 0;p is an integer selected from 0, 1, 2, 3, 4, 5, and 6; z is an integer selected from 0, 1, 2 and 3; and R4, in each instance, is selected from the group consisting of –(C1-C6alkyl), Br, Cl, and F.

2. The compound of claim 1, wherein m and n are an integer independently selected from the group consisting of 1, 2 and 3.

3. The compound of claim 1, wherein z is 1.

4. The compound of claim 1, wherein R2is selected from the group consisting of substituted or unsubstituted aryl and (C1-C6) cycloalkyl.

5. The compound of claim 1, wherein R3is selected is from the group consisting of a substituted or unsubstituted aryl and a substituted or unsubstituted heteroaryl.

6. The compound of claim 1, wherein p is an integer selected from 0, 1, 2, 3 and 4.

7. The compound of claim 1, wherein the compound is a compound of Formula (IIa):or any stereoisomer and / or pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of substituted or unsubstituted heteroaryl and substituted or unsubstituted heterobiaryl; R2is selected from the group consisting of substituted or unsubstituted aryl and C6- cycloalkyl;R3is selected is from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R4, in each instance, is selected from the group consisting of –CH3, -Ph, -C(CH3)3, and -F; m and n are integers independently selected from the group consisting of 1, 2 and 3; p is an integer selected from 0, 1, 2, 3 and 4; and X is selected from the group consisting of -CH2-, -O-, -S-, -CF2, -CHF-, -CH(CF3), -CH(CHF2), -CH(CH3), -C=CF2, -C=CHF, and -C(CH3)2.

8. The compound of claim 7, wherein R1is selected from the group consisting of pyridine, thiophene, pyrrole, pyrimidine, imidazole, pyrazine, indole and quinoline.

9. The compound of claim 7, wherein R1is a substituted or unsubstituted 5-membered heteroaryl or a substituted or unsubstituted 6-membered heteroaryl.

10. The compound of claim 7, wherein R2is a substituted aryl having one or more substituents selected from the group consisting of Cl, Br, F and CH3.

11. The compound of claim 7, wherein m+n is 3, 4, 5, or 6.

12. The compound of claim 7, wherein R3is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thiophenyl and substituted or unsubstituted furanyl.

13. The compound of claim 7, wherein the compound is a compound of Formula (III):or any stereoisomer and / or pharmaceutically acceptable salt thereof, wherein Y is O or S; R1is selected from the group consisting of; R4, in each instance, is selected from the group consisting of –CH3, and -F; R5a, R5b, R5c, R5d, and R5eare independently selected from the group consisting of -H, -Cl, -Br, -F and- CH3; m and n are integers independently selected from the group consisting of 1, 2, and 3; p is an integer selected from 0, 2, and 4; and X is selected from the group consisting of -CH2-, -O-, -S-, -CF2, -CHF-, -CH(CF3), -CH(CHF2), -C=CF2, -C=CHF, -CH(CH3), -C(CH3)2.

14. The compound of claim 13, wherein R5a, R5b, R5c, R5d, and R5eare independently selected from the group consisting of -H, -Br, -F and CH3.

15. The compound of claim 13, wherein R5a, R5b, R5d, and R5eare -H and R5cis -H, -F or -Br.

16. The compound of claim 13, wherein R5b, R5c, and R5dare -H; and R5aand R5eare - CH3.

17. The compound of claim 13, wherein one substituent selected from the group consisting of R5a, R5b, R5c, R5d, R5eis -Br, while the remaining substituents are -H.

18. The compound of any one of claims 13-17, wherein R1is selected from the groupconsisting of19. The compound of claim 13, wherein X is selected from the group consisting of - CF2, -S-, and -CH2-.

20. The compound of claim 13, wherein n+m is 3, 4, or 5.

21. The compound of claim 13, wherein X is -CH2-, n is 1 and m is 2.

22. The compound of claim 13, wherein X is selected from the group consisting of - CH2-, -O-, -CF2-, -S-, when n and m are 2.

23. The compound of claim 13, wherein X is -CH2-, n is 3 and m is 2.

24. The compound of claim 13, wherein the compound is a compound of Formula (IV):or any stereoisomer and / or pharmaceutically acceptable salt thereof, wherein Y is O or S; R1is selected from the group consisting ofR4, in each instance, is selected from the group consisting of –CH3, -Ph, -C(CH3)3, and -F; m and n are integers independently selected from the group consisting of 1, 2, and 3; p is an integer selected from 0, 2, and 4; and X is selected from the group consisting of X is selected from the group consisting of -CH2-, -O-, -S-, -CF2, -CHF, -CH(CF3), -C=CF2, -C=CHF, -CH(CHF2), -CH(CH3), and - C(CH3)2.

25. The compound of claim 24, wherein R1is selected from the group consisting of26. The compound of claim 24, wherein X is selected from the group consisting of - CH(CF3), -CF2-, , -O-, -S-, -CH2-, -CH(CHF2)-, and -CH(CH3).

27. The compound of claim 24, wherein X is -CH2-, n is 1 and m is 2 28. The compound of claim 24, wherein X is -CH2-, n is 2 and m is 2.

29. The compound of claim 1, wherein the compound contains at least one fluorine atom.

30. The compound of claim 1, wherein the compound is present in an enantiomeric excess of at least 95% ee.

31. The compound of claim 1, wherein the compound is in the form of an R- stereoisomer.

32. A pharmaceutical composition comprising a compound according to claim 1 or a stereoisomer and / or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carrier(s).

33. A method for treating a disease or condition mediated by the kappa opioid receptor, the method comprising administering a therapeutically effective amount of a compound of any one of the preceding claims or a pharmaceutical composition of claim 32 to a subject in need thereof.

34. The method of claim 33, wherein the disease or condition to be treated is selected from the group consisting of pain, itching, addiction, anxiety, depression, myocardial infarction, pruritus, inflammation, edema, nausea, neuro-inflammation, stroke, hypoxic pulmonary hypertension, ocular inflammation, glaucoma, multiple sclerosis, osteoarthritis, rheumatoid arthritis, inflammatory bowel disease and eczema.

35. The method of claim 33, wherein the subject may experience less dysphoria, sedation or diuresis.

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