Preparation of 3,4,5-trisubstituted triazoles and methods of use thereof

Abstract

The present disclosure relates to kappa opioid receptor ligands and pharmaceutical compositions thereof, and their utility as neurological modulators (e.g., antinociceptive agents, antidepressants, anxiolytic agents, antipruritic agents). Specifically, the disclosed kappa opioid ligands are G protein-biased kappa opioid agonists containing a core and three distinct arms, as shown in formula (A) below. TIFF2026507218000102.tif2335

Description

[Technical Field]

[0001] The present invention relates to kappa opioid receptor ligands and pharmaceutical compositions thereof and their utility as neurological modulators (eg, antinociceptive agents, antidepressants, anxiolytic agents, antipruritic agents).

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to and the benefit of U.S. Provisional Patent Application No. 63 / 449,388, filed March 2, 2023, entitled PREPARATION OF 3,4,5-TRISUBSTITUTED TRIAZOLES AND METHODS OF USING THE SAME, the entire disclosure of which is incorporated herein by reference.

[0003] government support This invention was made with government support under Grant No. DA031927 awarded by the National Institutes of Health. The government has certain rights in this invention. [Background technology]

[0004] Opioid overdose deaths remain a public health problem in the United States, and rates continue to rise 1 Opioids, such as morphine and its analogs, act via the μ-opioid receptor and have been shown to produce analgesia and physical dependence. 2,3 One of the causes of the opioid crisis is the increased prescription of addictive opioid painkillers that target the mu opioid receptor.

[0005] There are three types of opioid receptors: μ, δ, and κ opioid receptors, all of which are G protein-coupled. Of these receptors, the κ opioid receptor (KOR) offers a unique opportunity for pain treatment. It is distributed throughout the nervous system and is activated by opioid peptides such as dynorphin. Like other opioid receptors, its activation promotes antinociception, making it a target for pain treatment development. KOR agonists have proven effective in treating refractory nonhistamine-related itch (pruritus). Currently, nalfurafine is the only clinically available KOR agonist used to treat pruritus. In addition to providing pain relief without the threat of overdose, KOR agonists are less likely to be addictive because they do not induce euphoria or promote increased dopamine release like drugs of abuse. However, they are associated with dysphoria and sedation, which limits therapeutic research.

[0006] Therefore, despite ongoing efforts to develop analgesics that exhibit superior properties compared to standard opioids, there remains a need to discover and develop effective and safe analgesic compounds. Such new treatment options may include KOR agonists without the typical negative side effects associated with opioids and / or the side effects associated with KOR, i.e., discomfort and sedation. Summary of the Invention

[0007] Provided herein are ligands that can bind to the kappa opioid receptor and elicit a beneficial therapeutic effect (i.e., analgesic effect) while minimizing the side effects typically experienced with opioids. Thus, one aspect of the present disclosure is a compound represented by formula (A): [ka] [In the formula, A is, [ka] is selected from the group consisting of Ar1 is [ka] is selected from the group consisting of wherein X1, X2, and X3 are each independently selected from the group consisting of -N- and -CH-; X4 is selected from the group consisting of -CH2-, -NH-, -O-, -S-, and -N(CH3)-; each R1 is independently selected from the group consisting of -Cl, -Br, -F, -CF3, -OH, -CN, -NO2, -NH2, and (C1-C6)alkyl; and n is 1, 2, or 3; Ar2 is [ka] is selected from the group consisting of wherein X5 and X8 are each independently selected from the group consisting of -CH2-, -NH-, -O-, and -S-; X6 and X7 are each independently selected from the group consisting of -N- and -CH-; and m is 1, 2, 3, 4, 5, or 6; Ar3 is [ka] wherein each R2 is independently selected from the group consisting of -Cl, -Br, -F, -CF3, -OH, -CN, -NO2, -NH2, -O(C1-C6)alkyl, and -(C1-C6)alkyl; and q is 1, 2, 3, 4, or 5; L1, L2, and L3 each independently represent a bond, -C(=O)-, -(CH2) r -, -C≡C-, -CH=CH-, -C(R 4b )(R 4a )CH2-, -CH2C(R 4b )(R 4a )-, -C(=O)CH2-, -CH2CH(R5)-, and -CH(R x )-, where r is 1, 2, 3, 4, 5, or 6; and R 4a , R 4b、 R5, and Rx are each independently selected from the group consisting of -H, -Cl, -Br, -F, -CF, -OH, -CN, -NO, -NH, and -(C-C)alkyl; or R 4a and R 4b together with the atoms between them form a C3-C7 carbocyclyl] or a pharmaceutically acceptable salt thereof.

[0008] Another aspect of the present disclosure is a compound of formula (I): [ka] [In the formula, Ar1 is [ka] is selected from the group consisting of wherein X1, X2, and X3 are each independently selected from the group consisting of -N- and -CH-; X4 is selected from the group consisting of -CH2-, -NH-, -O-, -S-, and -N(CH3)-; each R1 is independently selected from the group consisting of -Cl, -Br, -F, -CF3, -OH, -CN, -NO2, -NH2, and -(C1-C6)alkyl; and n is 1, 2, or 3; Ar2 is [ka] is selected from the group consisting of wherein X5 and X8 are each independently selected from the group consisting of -CH2-, -NH-, -O-, and -S-; X6 and X7 are each independently selected from the group consisting of -N- and -CH-; and m is 1, 2, 3, 4, 5, or 6; Ar3 is [ka] wherein R2 is independently selected from the group consisting of -Cl, -Br, -F, -CF3, -OH, -CN, -NO2, -NH2, -O(C1-C6)alkyl, and -(C1-C6)alkyl; and q is 1, 2, 3, 4, or 5; L is a bond, -(CH2) r -, -C≡C-, -CH=CH-, -C(R 4b )(R 4a )CH2-, -CH2C(R 4b )(R 4a )—, —C(═O)CH—, and —CHCH(R)—, where r is 1, 2, 3, 4, 5, or 6; R 4a , R 4b and R5 are each independently selected from the group consisting of -H, -Cl, -Br, -F, -CF3, -OH, -CN, -NO2, -NH2, and -(C1-C6)alkyl; or R 4a and R 4b together with the atoms between them form a C3-C7 carbocyclyl] or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds disclosed herein are kappa opioid receptor ligands. In some embodiments, the compounds disclosed herein are G protein-biased kappa opioid receptor agonists.

[0009] Another aspect of the present disclosure relates to pharmaceutical compositions comprising a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0010] Another aspect of the present disclosure relates to a method for treating a disease or condition mediated by a kappa opioid receptor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition provided herein, hi some embodiments, the disease or condition being treated is acute or chronic pain. [Brief explanation of the drawings]

[0011] [Figure 1] Figure 1 is a bar graph showing the number of drug-related overdose deaths across the United States by age and gender from 1999 to 2021 (https: / / nida.nih.gov / research-topics / trends-statistics / overdose-death-rates). [Figure 2] Figure 2 is a bar graph showing the proportion of adults aged 18 years and older who had chronic pain and high-impact chronic pain in the past three months in the United States in 2019, overall and by sex (https: / / www.cdc.gov / nchs / products / databriefs / db390.htm). [Figure 3] Figure 3 shows a model of functional selectivity in GPCR signaling: balanced agonists are predicted to activate multiple signaling cascades mediated by effectors that bind to the receptor, whereas biased agonists preferentially engage certain effectors over others, activating distinct signaling pathways. [Figure 4-1] Figures 4A-H show the results of testing various compounds for their ability to activate G protein pathways as measured by a GTPγ35S binding assay versus their ability to recruit β-arrestin 2 as measured by a recombinant galactosidase assay (both as described in Brust, TB, et al. Sci. Signal 2016, 9, ra117). The structures of the compounds are described in more detail below. [Figure 4-2] Figures 4A-H show the results of testing various compounds for their ability to activate G protein pathways as measured by a GTPγ35S binding assay versus their ability to recruit β-arrestin 2 as measured by a recombinant galactosidase assay (both as described in Brust, TB, et al. Sci. Signal 2016, 9, ra117). The structures of the compounds are described in more detail below. [Figure 5]Figure 5 shows the results of Compound 5 tested in a standard mouse pruritus model. Compound 5 was administered i.p. to mice at 0.3 mg / kg and 1 mg / kg. Animals were monitored for scratching behavior after administration and compared to vehicle-injected control animals. [Figure 6] Figure 6 shows the results of Compound 5, U50,488H, and Triazole 1.1 tested in a standard mouse pruritus model. Mice were administered various doses of Compound 5, U50,488H, and Triazole 1.1, and then monitored for scratching behavior over a 1-hour period. [Figure 7-1] Figures 7A-H show the results of Compound 5, U50,488H, and Triazole 1.1 tested for sedation in an open field test box mouse model. Compound 5, U50,488H, and Triazole 1.1 were administered at various doses, and the animals' behavior, such as the distance traveled in the box over a 60-minute period and the time spent in the center of the box over a 60-minute period, was observed. [Figure 7-2] Figures 7A-H show the results of Compound 5, U50,488H, and Triazole 1.1 tested for sedation in an open field test box mouse model. Compound 5, U50,488H, and Triazole 1.1 were administered at various doses, and the animals' behavior, such as the distance traveled in the box over a 60-minute period and the time spent in the center of the box over a 60-minute period, was observed. [Figure 8] 8A-8D show the results of Compound 5, U50,488H, and Triazole 1.1 tested for anxiety in mice in an elevated plus maze. Compound 5, U50,488H, and Triazole 1.1 were administered at doses of 5 mg / kg, 3 mg / kg, and 15 mg / kg, respectively, and the animals' behavior after administration was observed, including the time spent in the open arms, proximal open arms, distal open arms, and total distance traveled in the elevated plus maze. DETAILED DESCRIPTION OF THE INVENTION

[0012] The present invention is described in more detail below. However, numerous modifications and other embodiments of the invention described herein will readily suggest themselves to those skilled in the art to which the invention pertains having the benefit of the teachings presented in the foregoing description. It should therefore be understood that the present invention is not 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 invention described herein embraces all alternatives, modifications, and equivalents. In the event of a difference or conflict between one or more of the cited documents, patents, and similar materials and this application, for example, but not limited to, in terms of defined terms, term usage, described technology, or the like, this application shall control. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0013] Opioid addiction poses a significant public health crisis in the United States. Often, opioid addiction occurs when a patient is first prescribed an opioid to treat acute and chronic pain. For example, in 2019, 20.4% of adults had chronic pain in the past three months, and 7.4% of adults had chronic pain that frequently limited life or work activities (also known as high-impact chronic pain). The percentage of adults aged 18 years and older who had chronic pain and high-impact chronic pain in the past three months is shown in Figure 2.

[0014] Kappa opioid receptor (KOR) agonists are promising therapeutic agents for pain relief due to their potent analgesic activity and non-addictive side effect profile. Furthermore, KOR agonists are also effective in reducing itch. 5,6 , addiction 7 , depression 8 , and immune response 9 KOR agonists are involved in the regulation of a wide variety of physiological functions other than pain relief, such as: 1) pain relief from pain, 2) sedation, and 3) nausea and vomiting. Unfortunately, KOR agonists are also associated with discomfort and sedation, which limits therapeutic research.

[0015] However, despite these disadvantages associated with KOR, U-69,593 14 , ketazocine 15 , 6'-guanidinonaltrindole 16 A number of small molecule KOR agonists have been reported, including salvinorin A, the first small molecule KOR agonist that does not contain a basic nitrogen, and salvinorin A. These small molecule KOR agonists are shown below. [ka]

[0016] Furthermore, three crystal structures of KOR have been reported, one of which is coupled with a JDTic antagonist. 18 , one is the active conformer of the nanobody 19 Recently, the structure of KOR bound to its natural dynorphin peptide ligand was published. 20 .

[0017] Furthermore, four KOR agonist chemotypes, including a triazole chemotype, were identified by high-throughput screening. 21 In particular, Triazole 1.1 was identified as a potent G protein-biased KOR agonist. 22 In vivo experiments in mice provide evidence that triazole 1.1 possesses similar analgesic and antipruritic properties compared to the balanced KOR agonist U50,488H, while avoiding the sedative effects traditionally associated with KOR. 23 Similar results have been observed in non-human primates. 24,25 Additionally, triazole 1.1 has been shown to reduce oxycodone self-administration in male rats. 26 These studies demonstrate that G protein-biased KOR agonists can deliver desirable analgesic effects without the unwanted side effects, such as sedation and discomfort, typically associated with KOR.

[0018] Here, the effective behavior of KOR agonists is "free" from such unwanted side effects due to the simultaneous activation of G proteins and the action of β-arrestins. The concept of being able to separate these two activation pathways and / or pathways is commonly known as "functional selectivity" or "ligand bias," and compounds may exhibit activity ranging from completely "balanced" (i.e., activating each pathway with equal potency) to highly "biased" (engaging one signaling pathway preferentially over another). Suitable compounds can then function as nociceptive and / or antipruritic agents without the dysphoria, sedation, and other side effects typically associated with GPCR targets, i.e., κ-opioid receptors (Figure 3).

[0019] Over the years, various structure-activity relationship studies have been performed on triazole 1.1, focusing primarily on the three arms of the triazole. 27,28 Triazole 1.1 is potent, biased, and active in vivo, but its pharmacokinetic profile needs to be optimized. 22 .

[0020] For example, the sulfur-containing side chain on the triazole 1.1 skeleton was considered a potential site for metabolism because sulfur can be oxidized to sulfoxides or sulfones. Therefore, triazole analogs of triazole 1.1 were prepared as shown in the following scheme, in which the sulfur side chain was replaced with a carbon side chain to form a 3,4,5-trisubstituted 1,2,4 triazole. [ka] Scheme 1. Structure of triazole 1.1 and bioisosteric replacement of sulfur-containing side chains with all-carbon-containing side chains

[0021] However, metabolic studies revealed that removal of the heteroatom from the side chain did not significantly improve the microsomal stability of triazole 1.1. Furthermore, these metabolic studies indicated that the sulfur atom was not the primary site of metabolic instability. Surprisingly and unexpectedly, however, triazole analogs of triazole 1.1 exhibited KOR binding affinities comparable to those of triazole 1.1, indicating that the sulfur atom does not electronically modulate the triazole ring. Therefore, KOR ligands such as those disclosed herein are viable bioisosteric replacements for triazole 1.1.

[0022] Pharmaceutical compositions containing KOR ligands and methods of use thereof are described in more detail below.

[0023] A.Definition Definitions of specific functional groups and chemical terms are explained in more detail below. Chemical elements are defined in the Handbook of Chemistry and Physics, 75 th The general principles of organic chemistry and specific functional groups and reactivities are described in detail in "Organic Chemistry," by Thomas Sorrell, "Organic Chemistry," University Science Books, Sausalito, 1999; and "Advanced Organic Chemistry," by Michael B. Smith, March 1999. th Edition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rdEdition, Cambridge University Press, Cambridge, 1987.

[0024] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various stereoisomers, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers, such as a racemic mixture or a mixture enriched in one or more stereoisomers. Isomers can be separated from mixtures by methods known to those skilled in the art, such as chiral high-performance liquid chromatography (HPLC), formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present disclosure further encompasses compounds as individual isomers substantially free of other isomers or as mixtures of various isomers.

[0025] Unless otherwise stated, the formulas and structures depicted herein include compounds that do not contain isotopically enriched atoms, as well as compounds that contain isotopically enriched atoms, e.g., replacement of hydrogen by deuterium or tritium, 18 By F 19 Substitution of F, or 13 C or 14Compounds having this structure, except for the replacement of a carbon by a C-enriched carbon, are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in bioassays.

[0026] When a range of values ​​("range") is listed, each value and subrange within that range is encompassed therein. Unless otherwise specified, a range includes both endpoints of the range. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 It includes alkyl.

[0027] As used herein, the term "alkyl group" or "alkyl" refers to a saturated hydrocarbon radical containing 1 to 8, 1 to 6, 1 to 4, or 5 to 8 carbon atoms. In some embodiments, saturated radicals contain more than 8 carbon atoms. Alkyl groups are structurally similar to acyclic alkane compounds modified by removing a hydrogen from the acyclic alkane and replacing it with a non-hydrogen group or radical. Alkyl radicals can be branched or unbranched. Lower alkyl radicals have 1 to 4 carbon atoms. Higher alkyl radicals have 5 to 8 carbon atoms. Examples of alkyl, lower alkyl, and higher alkyl 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 similar radicals.

[0028] The term "alkyl" refers to the radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1-20 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C 1-12 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1-10 In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2-6 alkyl). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl), and hexyl (C6) (e.g., n-hexyl). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), n-dodecyl (C9), n-octyl (C10), n-isopropyl (C11), n-isopropyl (C12), n-isopropyl (C13), n-isopropyl (C14), n-isopropyl (C15), n-isopropyl (C16), n-isopropyl (C17), n-isopropyl (C18), n-isopropyl (C19), n-isopropyl (C20), n-isopropyl (C21), n-isopropyl (C22), n-isopropyl (C23), n-isopropyl (C24), n-isopropyl (C25), n-isopropyl (C26), n-isopropyl (C27), n-isopropyl (C28), n-isopropyl (C29 ... 12), and the like. Unless otherwise specified, each alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents (e.g., halogen, such as F). In some embodiments, an alkyl group is an unsubstituted C 1-12 unsubstituted C alkyl (e.g., —CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu), etc. 1-6 In some embodiments, the alkyl group is a substituted C 1-12 alkyl (e.g., -CHF, -CHF, -CF, -CHCHF, -CHCHF, -CHCF, or substituted C such as benzyl (Bn) 1-6 alkyl).

[0029] The term "carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having 3 to 14 ring carbon atoms and 0 heteroatoms in a non-aromatic ring system ("C 3-14 In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms ("C 3-14 In some embodiments, the carbocyclyl group has 3 to 13 ring carbon atoms ("C 3-13 In some embodiments, the carbocyclyl group has 3 to 12 ring carbon atoms ("C 3-12 In some embodiments, the carbocyclyl group has 3 to 11 ring carbon atoms ("C 3-11 In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, the carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8In some embodiments, the carbocyclyl group has 3 to 7 ring carbon atoms ("C 3-7 In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, the carbocyclyl group has 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, the carbocyclyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, the carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 Carbocyclyl). Representative C 3-6 Carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Representative C 3-8 The carbocyclyl group includes the C 3-6 Included are carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Representative C 3-10 The carbocyclyl group includes the C 3-8 Carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like. Representative C 3-8 The carbocyclyl group includes the C 3-10 Carbocyclyl group and cycloundecyl (C 11 ), spiro[5.5]undecanyl (C11 ), cyclododecyl (C 12 ), cyclododecenyl (C 12 ), cyclotridecane (C 13 ), cyclotetradecane (C 14 ), and the like. As the above examples illustrate, in certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., containing fused, bridged, or spiro ring systems such as a bicyclic ring system ("bicyclic carbocyclyl") or a tricyclic ring system ("tricyclic carbocyclyl")), and in some embodiments, is saturated or contains one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups (wherein the point of attachment is on the carbocyclyl ring), in which case the number of carbons continues to refer to the number of carbons in the carbocyclyl ring system. Unless otherwise specified, each carbocyclyl group is independently unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, the carbocyclyl group is an unsubstituted C 3-14 In one embodiment, the carbocyclyl group is a substituted C 3-14 It is a carbocyclyl.

[0030] In some embodiments, "carbocyclyl" refers to a monocyclic saturated carbocyclyl group having 3 to 14 ring carbon atoms ("C 3-14 In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C 4-6In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 Cycloalkyl). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of cycloalkyl groups include the C 5-6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of cycloalkyl groups include the C 3-6 Cycloalkyl groups include cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In some embodiments, cycloalkyl groups include unsubstituted C 3-14 In some embodiments, the cycloalkyl group is a substituted C 3-14 In certain embodiments, a carbocyclyl contains, 0, 1, or 2 C=C double bonds in the carbocyclic ring system, valence permitting.

[0031] Unless otherwise expressly specified, a group may be optionally substituted. The term "optionally substituted" refers to substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups may be optionally substituted. "Optionally substituted" refers to a group that is substituted or unsubstituted (e.g., a "substituted" or "unsubstituted" alkyl, a "substituted" or "unsubstituted" alkenyl, a "substituted" or "unsubstituted" alkynyl, a "substituted" or "unsubstituted" heteroalkyl, a "substituted" or "unsubstituted" heteroalkenyl, a "substituted" or "unsubstituted" heteroalkynyl, a "substituted" or "unsubstituted" carbocyclyl, a "substituted" or "unsubstituted" heterocyclyl, a "substituted" or "unsubstituted" aryl, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted" means that at least one hydrogen atom on a group is replaced with an acceptable substituent, e.g., a substituent that, upon substitution, results in a stable compound (e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group; when more than one position is substituted in a given structure, the substituents are either the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, including any of the substituents described herein, that result in the formation of stable compounds. The present disclosure contemplates any and all such combinations in order to arrive at stable compounds. For purposes of this disclosure, heteroatoms, such as nitrogen, may have hydrogen substituents and / or any suitable substituents described herein that satisfy the valences of the heteroatom and result in the formation of a stable moiety. The present disclosure is not limited in any way by the representative substituents described herein.

[0032] As used herein, the symbols "C(=O)", "CO", and "C(O)" are used to refer to a carbonyl moiety. Examples of suitable carbonyl moieties include, but are not limited to, those found in ketones and aldehydes.

[0033] A "subject" to which administration is contemplated refers to a human (i.e., male or female of any age, e.g., a pediatric subject (e.g., an infant, child, or adolescent) or an adult subject (e.g., a young adult, middle-aged adult, or geriatric adult)) or a non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus or rhesus monkey), a commercially relevant mammal (e.g., a cow, pig, horse, sheep, goat, cat, or dog), or a bird (e.g., a commercially relevant bird such as a chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal can be male or female at any stage of development. The non-human animal can be a transgenic or genetically modified animal. The term "patient" refers to a human subject in need of treatment for a disease.

[0034] As used herein, the terms "co-administration" and "co-administering" refer to the administration of at least two agents (e.g., a KOR agonist as disclosed herein and one or more additional therapeutic agents) or therapies to a subject. In some embodiments, co-administration of two or more agents or therapies is simultaneous. In other embodiments, a first agent / therapy is administered before a second agent / therapy. Those skilled in the art will appreciate that the formulations and / or routes of administration of the various agents or therapies used may vary. Appropriate dosages for co-administration can be readily determined by those skilled in the art. In some embodiments, when agents or therapies are co-administered, each agent or therapy is administered at a lower dosage than would be appropriate if administered alone. Thus, co-administration is particularly desirable in embodiments where co-administration of agents or therapies reduces the required dosage of a potentially harmful (e.g., toxic) agent and / or when co-administration of two or more agents results in sensitization of the subject to the beneficial effects of one agent via co-administration of another agent.

[0035] As used herein, the term "pharmaceutical composition" refers to a combination of an active agent with an inert or active carrier that makes the composition particularly suitable for diagnostic or therapeutic use in vitro, in vivo, or ex vivo.

[0036] As used herein, the term "pharmaceutically acceptable" or "pharmacologically acceptable" refers to a composition that does not substantially cause an adverse reaction, e.g., a toxic, allergic, or immunological reaction, when administered to a subject.

[0037] As used herein, the term "pharmaceutically acceptable carrier" refers to any of the standard pharmaceutical carriers, including, but not limited to, phosphate buffered saline, water, emulsions (e.g., oil / water or water / oil emulsions), and various types of wetting agents, any solvents, dispersion media, coatings, sodium lauryl sulfate, isotonicity and absorption delaying agents, disintegrants (e.g., potato starch or sodium starch glycolate), and the like. The composition may also contain stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, for example, Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, Pa. (1975) (incorporated herein by reference in its entirety).

[0038] The term "pharmaceutically acceptable salt" refers to a salt that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable risk-benefit ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (incorporated herein by reference). Pharmaceutically acceptable salts of the compounds of the present disclosure include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, etc.) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, etc.), or formed using other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobacillus acid salts, and benzoates. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-methyl-N ... + (C 1-4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations, formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, as appropriate.

[0039] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset, or inhibiting the progression of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of a disease have appeared or been observed. In other embodiments, treatment may be administered when there are no signs or symptoms of a disease. For example, treatment may be administered to a susceptible subject before the onset of symptoms (e.g., taking into account symptom history and / or exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. As used herein, a subject is "in need of" treatment if the subject would benefit from such treatment biologically, medically, or in terms of quality of life.

[0040] An "effective amount" of a compound described herein refers to an amount sufficient to elicit a desired biological response. An effective amount of a compound described herein may vary depending on factors such as the desired biological endpoint, side effects, severity of the disease or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the method, route, and desired or required frequency of administration, the species, age, and health or general condition of the subject, etc. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactic treatment. In some embodiments, the effective amount is the amount of a compound described herein in a single administration. In some embodiments, the effective amount is the combined amount of a compound described herein in multiple administrations. In some embodiments, the desired dosage is delivered three times a day, twice a day, once a day, every other day, every third day, once a week, once every two weeks, once every three weeks, or once every four weeks. In certain embodiments, the desired dose is delivered using multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more administrations).

[0041] In certain embodiments, an effective amount of the compound for one or more daily administrations to a 70 kg adult contains from about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg of the compound per unit dosage form.

[0042] In certain embodiments, the compounds of the present disclosure are administered orally or parenterally, one or more times per day, at a dosage level sufficient to achieve the desired therapeutic effect, to deliver about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, preferably about 0.1 mg / kg to about 40 mg / kg, preferably about 0.5 mg / kg to about 30 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, more preferably about 1 mg / kg to about 25 mg / kg of subject body weight per day.

[0043] It is understood that the dosage ranges described herein provide guidance for administering the provided pharmaceutical compositions to adults. For example, the amount to be administered to a child or adolescent can be determined by a physician or person skilled in the art and may be lower than or the same as the amount administered to an adult.

[0044] A "therapeutically effective amount" of a compound described herein is an amount sufficient to provide a therapeutic effect in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other treatments, that provides a therapeutic effect in the treatment of a condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, reduces or avoids symptoms, signs, or causes of a condition, and / or enhances the therapeutic effect of another therapeutic agent.

[0045] The terms "condition," "disease," and "disorder" are used interchangeably.

[0046] B. Compound Provided herein are kappa opioid receptor ligands and methods of using them to treat diseases or conditions associated with the kappa opioid receptor, such as acute and chronic pain, pruritus, addiction, and mood disorders. In some embodiments, the KOR ligand is an agonist. In some embodiments, the KOR ligand is a G protein-biased KOR agonist.

[0047] In one embodiment, the compound of formula (A): [ka] [In the formula, A is, [ka] is selected from the group consisting of Ar1 is [ka] is selected from the group consisting of wherein X1, X2, and X3 are each independently selected from the group consisting of -N- and -CH-; X4 is selected from the group consisting of -CH2-, -NH-, -O-, -S-, and -N(CH3)-; each R1 is independently selected from the group consisting of -Cl, -Br, -F, -CF3, -OH, -CN, -NO2, -NH2, and (C1-C6)alkyl; and n is 1, 2, or 3; Ar2 is [ka] is selected from the group consisting of wherein X5 and X8 are each independently selected from the group consisting of -CH2-, -NH-, -O-, and -S-; X6 and X7 are each independently selected from the group consisting of -N- and -CH-; and m is 1, 2, 3, 4, 5, or 6; Ar3 is [ka] wherein each R2 is independently selected from the group consisting of -Cl, -Br, -F, -CF3, -OH, -CN, -NO2, -NH2, -O(C1-C6)alkyl, and -(C1-C6)alkyl; and q is 1, 2, 3, 4, or 5; L1, L2, and L3 each independently represent a bond, -C(=O)-, -(CH2) r-, -C≡C-, -CH=CH-, -C(R 4b )(R 4a )CH2-, -CH2C(R 4b )(R 4a )-, -C(=O)CH2-, -CH2CH(R5)-, and -CH(R x )-, where r is 1, 2, 3, 4, 5, or 6; and R 4a , R 4b、 R5, and R x are each independently selected from the group consisting of -H, -Cl, -Br, -F, -CF, -OH, -CN, -NO, -NH, and -(C-C)alkyl; or R 4a and R 4b together with the atoms between them form a C3-C7 carbocyclyl] or a pharmaceutically acceptable salt thereof.

[0048] In some embodiments, the compound of formula (I) has the formula (A-1): [ka] wherein L2 is a bond, -(CH2) r - or -CH(R x )-, where r is 1 or 2, and R x is selected from the group consisting of -H and -(C1-C6)alkyl. or a pharmaceutically acceptable salt thereof.

[0049] In one embodiment, a compound of formula (I): [ka] [In the formula, Ar1 is [ka] is selected from the group consisting of wherein X1, X2, and X3 are each independently selected from the group consisting of -N- and -CH-; X4 is selected from the group consisting of -CH2-, -NH-, -O-, -S-, and -N(CH3)-; each R1 is independently selected from -Cl, -Br, -F, -CF3, -OH, -CN, -NO2, -NH2, and -(C1-C6)alkyl; and n is 1, 2, or 3; Ar2 is [ka] is selected from the group consisting of wherein X5 and X8 are each independently selected from the group consisting of -CH2-, -NH-, -O-, and -S-; X6 and X7 are each independently selected from the group consisting of -N- and -CH-; and m is 1, 2, 3, 4, 5, or 6; Ar3 is [ka] wherein each R2 is independently selected from -Cl, -Br, -F, -CF3, -OH, -CN, -NO2, -NH2, -O(C1-C6)alkyl, and -(C1-C6)alkyl; and q is 1, 2, 3, 4, or 5; L is a bond, -(CH2) r -, -C≡C-, -CH=CH-, -C(R 4b )(R 4a )CH2-, -CH2C(R 4b )(R 4a )—, —C(═O)CH—, and —CHCH(R)—, where r is 1, 2, 3, 4, 5, or 6; R 4a , R 4b and R5 are each independently selected from -H, -Cl, -Br, -F, -CF3, -OH, -CN, -NO2, -NH2, and -(C1-C6)alkyl; or R 4a and R 4b together with the atoms between them form a C3-C7 carbocyclyl] Provided herein are compounds having the structure: or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds disclosed herein are kappa opioid receptor ligands. In some embodiments, the compounds disclosed herein are G protein-biased kappa opioid receptor agonists.

[0050] In some embodiments, L is a bond.

[0051] In some embodiments, L is —(CH) r -, where r is 1, 2, or 3. In some embodiments, L is -(CH) r - and r is 2.

[0052] In some embodiments, L is -C≡C-.

[0053] In some embodiments, L is an olefin such as -CH=CH-. In some embodiments, the olefin is a trans olefin. In some embodiments, the olefin is a cis olefin. In some embodiments, L is -CH=CH-.

[0054] In some embodiments, L is —C(R 4b )(R 4a )CH2-, -CH2C(R 4b )(R 4a )—, —C(═O)CH—, and —CHCH(R)—, where R 4a , R 4b and R5 are each independently selected from -H, -F, and -OH; or R 4a and R 4b together with the atoms therebetween form a C3-C7 carbocyclyl. In some embodiments, L is -C(R 4b )(R 4a )CH2-, -CH2C(R 4b )(R 4a)—, —C(═O)CH—, and —CHCH(R)—, where R 4a , R 4b and R5 are each independently selected from -H, -F, and -OH.

[0055] In some embodiments, Ar1 is [ka] In some embodiments, X2 is -CH-. In some embodiments, X2 is -CH- and X1 is -N. In some embodiments, X1 and X2 are each -CH-. In some embodiments, each R1 is -CH3 and n is 1.

[0056] In some embodiments, Ar1 is [ka] wherein X3 is -N- or -CH-. In some embodiments, X3 is -N-. In some embodiments, X3 is -CH-.

[0057] In some embodiments, Ar1 is [ka] wherein X4 is selected from -CH2-, -NH-, -O-, -S-, and -N(CH3)-. In some embodiments, X4 is -CH2-. In some embodiments, X4 is -NH-. In some embodiments, X4 is -O-. In some embodiments, X4 is -S-. In some embodiments, X4 is -N(CH3)-.

[0058] In some embodiments, Ar1 is [ka] is selected from the group consisting of:

[0059] In some embodiments, Ar1 is [ka] In some embodiments, Ar1 is [ka] In some embodiments, Ar1 is [ka] is.

[0060] In some embodiments, the compound of formula (I) has formula (II): [ka] or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, Ar3 is [ka] In some embodiments, each R2 is independently selected from -Cl, -Br, -CF3, and -(C1-C6)alkyl. In some embodiments, each R2 is independently selected from -Cl and -Br. In some embodiments, each R2 is independently selected from -CF3 and -(C1-C6)alkyl. In some embodiments, q is 1 or 2. In some embodiments, Ar3 is [ka] In some embodiments, Ar3 is selected from the group consisting of [ka] In some embodiments, Ar3 is [ka] In some embodiments, Ar3 is [ka] In some embodiments, Ar3 is [ka] In some embodiments, Ar3 is [ka] is.

[0062] In some embodiments, the compound of formula (II) has formula (III): [ka] or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, Ar2 is [ka] and X5 is selected from -NH-, -O-, and -S-.

[0064] In some embodiments, Ar2 is [ka] wherein X5 is selected from -NH-, -O-, and -S-, and X6 is -CH-.

[0065] In some embodiments, Ar2 is [ka] wherein X5 is selected from -NH-, -O-, and -S-, and X6 is -N-. In one embodiment, Ar2 is [ka] In some embodiments, Ar2 is [ka] In some embodiments, Ar2 is selected from the group consisting of [ka] In some embodiments, Ar2 is [ka] In some embodiments, Ar2 is [ka] is.

[0066] In some embodiments, Ar2 is [ka] wherein X7 is -N- or -CH-. In some embodiments, Ar2 is [ka] where m is 1, 2, or 3.

[0067] In some embodiments, the compound of Formula (A) or Formula (I) is: [ka] or a pharmaceutically acceptable salt thereof.

[0068] In one embodiment, the compound of formula (A) is: [ka] or a pharmaceutically acceptable salt thereof.

[0069] The compounds described herein may exist as diastereomers, enantiomers, or other stereoisomers. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms, as well as the appropriate mixtures thereof. Separation of stereoisomers may be carried out by chromatography and / or recrystallization, or by diastereomeric formation and separation (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 with 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 embodiments, the compounds disclosed herein are diastereomers with 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 exist as enantiomeric or diastereomeric mixtures.

[0070] The methods and compositions described herein include the use of amorphous and crystalline forms (also known as crystalline polymorphs).The compounds described herein can be in the form of pharmaceutically acceptable salts.The active metabolites of these compounds with the same activity are also included in the scope of this disclosure.

[0071] In some embodiments, the compounds described herein may be formed and / or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to, the following: (1) Acid Addition Salts. The free base form of the compound may be dissolved in a pharmaceutically acceptable inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, and the like) or organic acid (e.g., 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]octa-2 (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as 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, the compounds described herein may be coordinated with organic bases, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, and tris(hydroxymethyl)methylamine. In other cases, the 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 containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0072] In some embodiments, the compounds and salts described herein comprise isotope-labeled compounds.Generally, isotope-labeled compounds are identical to the compounds described in various formulas and structures presented herein, except that one or more atoms are replaced by atoms with atomic mass or mass number that is different from the atomic mass or mass number that is most commonly found in nature.The examples of isotopes that can be incorporated into the compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 Certain isotopically labeled compounds described herein, such as 3 H and 14 Compounds incorporating radioactive isotopes such as C are useful for drug and / or substrate tissue distribution studies. Additionally, deuterium, i.e., 2 Substitution with isotopes such as H may afford therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0073] In some embodiments, the compounds disclosed herein are selective KOR-binding ligands. As used herein, the term "selective binding ligand" refers to a compound that exhibits increased selectivity for binding to a specific KOR compared to inhibition of other opioid receptors (such as μ and δ opioid receptors). Initial profiling of 5 showed less than 50% displacement of the radioligand binding to μ and δ opioid receptors (Psychoactive Drug Screening Program and UNC-CH). In some embodiments, the compounds disclosed herein exhibit selective binding activity to KOR that is at least about 2-fold, about 3-fold, about 4-fold, or at least about 5-fold stronger than its binding activity to other opioid receptors.

[0074] Furthermore, biased ligands exhibit increased potency and / or efficacy for some signaling pathways over others compared to a reference agonist (here, U69,593). Certain examples in this report preferentially induce GTPyS binding over β-arrestin recruitment upon receptor activation. In some cases, the preference for eliciting GTPyS binding is also superior to the ability to inhibit forskolin-stimulated adenylate cyclase, as measured by cAMP accumulation. In some embodiments, a simple comparison of IC50 values ​​indicates that the compounds disclosed herein are more potent at activating GTPyS than at recruiting β-arrestin compared to that observed with U69,593.

[0075] In some embodiments, the compound of Formula (A), (I), (II), or (III) is a compound provided herein or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (A) is a compound provided herein or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is a compound provided herein or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (II) is a compound provided herein or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (III) is a compound provided herein or a pharmaceutically acceptable salt thereof.

[0076] In some embodiments, the compounds of Formula (A), (I), (II), and (III) are compounds provided in the tables described herein or pharmaceutically acceptable salts thereof. In some embodiments, the compounds of Formula (A) are compounds provided in the tables described herein (e.g., Tables 1-8) or pharmaceutically acceptable salts thereof. In some embodiments, the compounds of Formula (I) are compounds provided in the tables described herein (e.g., Tables 1-7) or pharmaceutically acceptable salts thereof. In some embodiments, the compounds of Formula (II) are compounds provided in the tables described herein (e.g., Tables 1-7) or pharmaceutically acceptable salts thereof. In some embodiments, the compounds of Formula (III) are compounds provided in the tables described herein (e.g., Tables 1-7) or pharmaceutically acceptable salts thereof. The compounds represented by any one of Formulas (I), (II), and (III) may be selected from the compounds listed in the tables below. Compounds of Formula (A), (I), (II), and (III) not listed in the tables below are also within the scope of the present disclosure.

[0077] Table 1 below shows compounds with various linkers. [Table 1] Pharmacological parameters were determined by the GTPγS binding assay and β-arrestin 2 enzyme fragment complementation assay described in Zhou et al., 2013 (22). EC 50 and Emax were calculated from three-parameter nonlinear regression analysis of concentration-response analysis and curve fitting using Graphpad Prism (9.0) software. Data are presented with reference to U69,593, which was assayed with each compound tested and used to define the maximum response (100% Emax). Bias analysis was performed using global parameter fitting of averaged data by operational model curve fitting analysis using Graphpad Prism (9.0) software. Bias factors were calculated as 10^ΔΔ(logτ / K) using U69,593 as the reference agonist, as described by Zhou et al. (22). A ) Gタンパク質-Barr2 Bias analysis is performed for compounds from a single experiment or for the EC 50 This was not applicable when EC was greater than 150 nM. 50 indicates that the EC50 was estimated. Bias factors were calculated only when n was 3 or greater and the EC50 for GTP was less than 150 nM. The analysis was based on a global parameter fit of replicate experiments. Values ​​may change as individual replicates are fitted to the analysis separately. nc means the nonlinear regression did not converge. * indicates maximal stimulation observed at 10 μM for compounds that did not reach a plateau. ND means not determined. Microsomal stability values ​​were determined in mouse liver microsome preparations as previously described (Zhou et al., 2013, (22)).

[0078] Compound 2 exhibits good activity in G protein activation. Interestingly, the C-S bond length is longer than the C-C bond, resulting in a two-carbon linker shorter than the sulfur-containing side chain of triazole 1.1. Compound 2 exhibits similar microsomal stability to triazole 1.1, with a stability of 0.9 and 1.1 min, respectively.

[0079] Next, Table 2 shows compounds with various Ar2 substituents. [Table 2] Pharmacological parameters were determined by the GTPγS binding assay and β-arrestin 2 enzyme fragment complementation assay described in Zhou et al., 2013 (22). EC 50 and Emax were calculated from three-parameter nonlinear regression analysis of concentration-response analysis and curve fitting using Graphpad Prism (9.0) software. Data are presented with reference to U69,593, which was assayed with each compound tested and used to define the maximum response (100% Emax). Bias analysis was performed using global parameter fitting of averaged data by operational model curve fitting analysis using Graphpad Prism (9.0) software. Bias factors were calculated as 10^ΔΔ(logτ / K) using U69,593 as the reference agonist, as described by Zhou et al. (22). A ) Gタンパク質-Barr2 Bias analysis is performed for compounds from a single experiment or for the EC 50 This was not applicable when EC was greater than 150 nM. 50indicates that the EC50 was estimated. Bias factors were calculated only when n was 3 or greater and the EC50 for GTP was less than 150 nM. The analysis was based on a global parameter fit of replicate experiments. Values ​​may change as individual replicates are fitted to the analysis separately. nc means the nonlinear regression did not converge. * indicates maximal stimulation observed at 10 μM for compounds that did not reach a plateau. ND means not determined. Microsomal stability values ​​were determined in mouse liver microsome preparations as previously described (Zhou et al., 2013, (22)).

[0080] Table 2 shows compounds with aromatic substitution at the 4-position of triazole 1.1, which are structurally distinct from previous SAR studies. 21,27,28 First, the furan moiety was substituted with other five-membered aromatic heterocycles. Both thiophene and thiazole substitutions resulted in compounds exhibiting comparable potency (compounds 5 and 7). Next, the size of the aromatic ring was explored by increasing to benzyl substitution, which resulted in a slight decrease in potency (compound 8). However, removing the -CH2 bond resulted in [ka] The potency was completely lost, indicating that the methylene linker is beneficial for positioning the aromatic ring. Pyridine rings are also tolerated (compounds 10, 11, and 12). Finally, considering the frequency of cyclopropane substituents in KOR agonists, 31 Compound 13 did not show any increase in potency.

[0081] Next, Table 3 shows compounds with various Ar1 substituents. [Table 3] Pharmacological parameters were determined by the GTPγS binding assay and β-arrestin 2 enzyme fragment complementation assay described in Zhou et al., 2013 (22). EC 50and Emax were calculated from three-parameter nonlinear regression analysis of concentration-response analysis and curve fitting using Graphpad Prism (9.0) software. Data are presented with reference to U69,593, which was assayed with each compound tested and used to define the maximum response (100% Emax). Bias analysis was performed using global parameter fitting of averaged data by operational model curve fitting analysis using Graphpad Prism (9.0) software. Bias factors were calculated as 10^ΔΔ(logτ / K) using U69,593 as the reference agonist, as described by Zhou et al. (22). A ) Gタンパク質-Barr2 Bias analysis is performed for compounds from a single experiment or for the EC 50 This was not applicable when EC was greater than 150 nM. 50 indicates that the EC50 was estimated. Bias factors were calculated only when n was 3 or greater and the EC50 for GTP was less than 150 nM. For some compounds, the analysis was based on a global parameter fit of replicates. Values ​​may change as individual replicates are fitted to the analysis separately. nc means the nonlinear regression did not converge. * means the maximal stimulation observed at 10 μM for compounds that did not reach a plateau. ND means not determined. Microsomal stability values ​​were determined in mouse liver microsome preparations as previously described (Zhou et al., 2013, (22)).

[0082] Table 3 lists compounds where the 5-position of the triazole skeleton was explored. Here, compounds 15, 20, and 24 showed good activity. Extension of the linker attached to the naphthyl substitution is poorly tolerated, likely due to the lack of nitrogen at the 2-position (e.g., in 2-pyridyl heteroaryls). Finally, 5-membered rings with nitrogen at the 2-position are also tolerated.

[0083] Next, Table 4 shows compounds with various Ar3 substituents. [Table 4] [Table 5] Pharmacological parameters were determined by the GTPγS binding assay and β-arrestin 2 enzyme fragment complementation assay described in Zhou et al., 2013 (22). EC 50 and Emax were calculated from three-parameter nonlinear regression analysis of concentration-response analysis and curve fitting using Graphpad Prism (9.0) software. Data are presented with reference to U69,593, which was assayed with each compound tested and used to define the maximum response (100% Emax). Bias analysis was performed using global parameter fitting of averaged data by operational model curve fitting analysis using Graphpad Prism (9.0) software. Bias factors were calculated as 10^ΔΔ(logτ / K) using U69,593 as the reference agonist, as described by Zhou et al. (22). A ) Gタンパク質-Barr2 Bias analysis is performed for compounds from a single experiment or for the EC 50 This was not applicable when EC was greater than 150 nM. 50indicates that the EC50 was estimated. Bias factors were calculated only when n was 3 or greater and the EC50 for GTP was less than 150 nM. The analysis was based on a global parameter fit of replicate experiments. Values ​​may change as individual replicates are fitted to the analysis separately. nc means the nonlinear regression did not converge. * indicates maximal stimulation observed at 10 μM for compounds that did not reach a plateau. ND means not determined. Microsomal stability values ​​were determined in mouse liver microsome preparations as previously described (Zhou et al., 2013, (22)).

[0084] Table 4 shows compounds with various aromatic rings as substitutions for Ar3.

[0085] First, it is noteworthy that when Ar3 is a substituted aromatic ring, superior activity is observed compared to compounds with an unsubstituted aromatic ring at Ar3. Electron-donating groups are tolerated as substituents on the aromatic ring, but electron-withdrawing groups appear to be preferred. For monosubstituted aromatic rings, substitution at the 4-position appears to be preferred. 3,4-disubstituted aromatic rings show increased potency compared to monosubstituted aromatic rings.

[0086] Next, Table 5 shows compounds with various linkers (L). [Table 6] [Table 7] Pharmacological parameters were determined by the GTPγS binding assay and β-arrestin 2 enzyme fragment complementation assay described in Zhou et al., 2013 (22). EC 50and Emax were calculated from three-parameter nonlinear regression analysis of concentration-response analysis and curve fitting using Graphpad Prism (9.0) software. Data are presented with reference to U69,593, which was assayed with each compound tested and used to define the maximum response (100% Emax). Bias analysis was performed using global parameter fitting of averaged data by operational model curve fitting analysis using Graphpad Prism (9.0) software. Bias factors were calculated as 10^ΔΔ(logτ / K) using U69,593 as the reference agonist, as described by Zhou et al. (22). A ) Gタンパク質-Barr2 Bias analysis is performed for compounds from a single experiment or for the EC 50 This was not applicable when EC was greater than 150 nM. 50 indicates that the EC50 was estimated. Bias factors were calculated only when n was 3 or greater and the EC50 for GTP was less than 150 nM. The analysis was based on a global parameter fit of replicate experiments. Values ​​may change as individual replicates are fitted to the analysis separately. nc means the nonlinear regression did not converge. * indicates maximal stimulation observed at 10 μM for compounds that did not reach a plateau. ND means not determined. Microsomal stability values ​​were determined in mouse liver microsome preparations as previously described (Zhou et al., 2013, (22)).

[0087] Various compounds with modified linkers (L) were prepared and screened. First, compounds with restricted rotation around the linker L, such as 39, lost activity. Next, several compounds with varying degrees of unsaturation in the linker were prepared. In all cases, loss of potency was observed (compounds 40, 41, and 42). Next, compounds containing alpha alcohols, alpha ketones, and beta alcohols were completely inactive (compounds 43, 44, and 47). Finally, since fluorine is well known to slow metabolism, 32 Compounds with fluorinated linkers (compounds 46 and 48) were also prepared to determine whether improved metabolic stability was observed.

[0088] Next, Table 6 shows compounds with various trans alkene linkers (L). [Table 8] Pharmacological parameters were determined by the GTPγS binding assay and β-arrestin 2 enzyme fragment complementation assay described in Zhou et al., 2013 (22). EC 50 and Emax were calculated from three-parameter nonlinear regression analysis of concentration-response analysis and curve fitting using Graphpad Prism (9.0) software. Data are presented with reference to U69,593, which was assayed with each compound tested and used to define the maximum response (100% Emax). Bias analysis was performed using global parameter fitting of averaged data by operational model curve fitting analysis using Graphpad Prism (9.0) software. Bias factors were calculated as 10^ΔΔ(logτ / K) using U69,593 as the reference agonist, as described by Zhou et al. (22). A ) Gタンパク質-Barr2 Bias analysis is performed for compounds from a single experiment or for the EC 50This was not applicable when EC was greater than 150 nM. 50 indicates that the EC50 was estimated. Bias factors were calculated only when n was 3 or greater and the EC50 for GTP was less than 150 nM. The analysis was based on a global parameter fit of replicate experiments. Values ​​may change as individual replicates are fitted to the analysis separately. nc means the nonlinear regression did not converge. * indicates maximal stimulation observed at 10 μM for compounds that did not reach a plateau. ND means not determined. Microsomal stability values ​​were determined in mouse liver microsome preparations as previously described (Zhou et al., 2013, (22)). [Table 9] Pharmacological parameters were determined by the GTPγS binding assay and β-arrestin 2 enzyme fragment complementation assay described in Zhou et al., 2013 (22). EC 50 and Emax were calculated from three-parameter nonlinear regression analysis of concentration-response analysis and curve fitting using Graphpad Prism (9.0) software. Data are presented with reference to U69,593, which was assayed with each compound tested and used to define the maximum response (100% Emax). Bias analysis was performed using global parameter fitting of averaged data by operational model curve fitting analysis using Graphpad Prism (9.0) software. Bias factors were calculated as 10^ΔΔ(logτ / K) using U69,593 as the reference agonist, as described by Zhou et al. (22). A ) Gタンパク質-Barr2 Bias analysis is performed for compounds from a single experiment or for the EC 50 This was not applicable when EC was greater than 150 nM. 50indicates that the EC50 was estimated. Bias factors were calculated only when n was 3 or greater and the EC50 for GTP was less than 150 nM. The analysis was based on a global parameter fit of replicate experiments. Values ​​may change as individual replicates are fitted to the analysis separately. nc means the nonlinear regression did not converge. * indicates maximal stimulation observed at 10 μM for compounds that did not reach a plateau. ND means not determined. Microsomal stability values ​​were determined in mouse liver microsome preparations as previously described (Zhou et al., 2013, (22)).

[0089] Given the increased metabolic stability of trans-olefins, including compound 42, further compounds with this type of linker were investigated. In each case, a loss of potency was observed for these compounds. However, increased metabolic stability was observed for the compounds tested. For example, despite a loss of potency, compound 54 appears to be a weak partial agonist, exhibiting an Emax of approximately 26%. Partial agonists of KOR are of interest due to their potential to treat opioid use disorder. 33,34 .

[0090] Table 7 then shows some additional compounds that were prepared. [Table 10] Pharmacological parameters were determined by the GTPγS binding assay and β-arrestin 2 enzyme fragment complementation assay described in Zhou et al., 2013 (22). EC 50and Emax were calculated from three-parameter nonlinear regression analysis of concentration-response analysis and curve fitting using Graphpad Prism (9.0) software. Data are presented with reference to U69,593, which was assayed with each compound tested and used to define the maximum response (100% Emax). Bias analysis was performed using global parameter fitting of averaged data by operational model curve fitting analysis using Graphpad Prism (9.0) software. Bias factors were calculated as 10^ΔΔ(logτ / K) using U69,593 as the reference agonist, as described by Zhou et al. (22). A ) Gタンパク質-Barr2 Bias analysis is performed for compounds from a single experiment or for the EC 50 This was not applicable when EC was greater than 150 nM. 50 indicates that the EC50 was estimated. Bias factors were calculated only when n was 3 or greater and the EC50 for GTP was less than 150 nM. The analysis was based on a global parameter fit of replicate experiments. Values ​​may change as individual replicates are fitted to the analysis separately. nc means the nonlinear regression did not converge. * indicates maximal stimulation observed at 10 μM for compounds that did not reach a plateau. ND means not determined. Microsomal stability values ​​were determined in mouse liver microsome preparations as previously described (Zhou et al., 2013, (22)).

[0091] Next, Table 8 shows compounds lacking the triazole core. [Table 11] Pharmacological parameters were determined by the GTPγS binding assay and β-arrestin 2 enzyme fragment complementation assay described in Zhou et al., 2013 (22). EC 50and Emax were calculated from three-parameter nonlinear regression analysis of concentration-response analysis and curve fitting using Graphpad Prism (9.0) software. Data are presented with reference to U69,593, which was assayed with each compound tested and used to define the maximum response (100% Emax). Bias analysis was performed using global parameter fitting of averaged data by operational model curve fitting analysis using Graphpad Prism (9.0) software. Bias factors were calculated as 10^ΔΔ(logτ / K) using U69,593 as the reference agonist, as described by Zhou et al. (22). A ) Gタンパク質-Barr2 Bias analysis is performed for compounds from a single experiment or for the EC 50 This was not applicable when EC was greater than 150 nM. 50 indicates that the EC50 was estimated. Bias factors were calculated only when n was 3 or greater and the EC50 for GTP was less than 150 nM. The analysis was based on a global parameter fit of replicate experiments. Values ​​may change as individual replicates are fitted to the analysis separately. nc means the nonlinear regression did not converge. * indicates maximal stimulation observed at 10 μM for compounds that did not reach a plateau. ND means not determined. Microsomal stability values ​​were determined in mouse liver microsome preparations as previously described (Zhou et al., 2013, (22)).

[0092] Table 7 demonstrates the importance of the role of the triazole core on KOR activity. Various compounds lacking the triazole backbone were prepared. These backbone-less compounds retained agonist activity but were significantly less potent than the triazole compounds disclosed herein, indicating that the triazole core plays an important role in the activity of the disclosed triazole compounds. One hypothesis for this finding is that the triazole core orients the three substituents Ar1, Ar2, and Ar3 in the binding pocket, maximizing binding interactions with KOR.

[0093] Table 9 shows additional compounds. [Table 12] Pharmacological parameters were determined by the GTPγS binding assay and β-arrestin 2 enzyme fragment complementation assay described in Zhou et al., 2013 (22). EC 50 and Emax were calculated from three-parameter nonlinear regression analysis of concentration-response analysis and curve fitting using Graphpad Prism (9.0) software. Data are presented with reference to U69,593, which was assayed with each compound tested and used to define the maximum response (100% Emax). Bias analysis was performed using global parameter fitting of averaged data by operational model curve fitting analysis using Graphpad Prism (9.0) software. Bias factors were calculated as 10^ΔΔ(logτ / K) using U69,593 as the reference agonist, as described by Zhou et al. (22). A ) Gタンパク質-Barr2 Bias analysis is performed for compounds from a single experiment or for the EC 50 This was not applicable when EC was greater than 150 nM. 50indicates that the EC50 was estimated. Bias factors were calculated only when n was 3 or greater and the EC50 for GTP was less than 150 nM. The analysis was based on a global parameter fit of replicate experiments. Values ​​may change as individual replicates are fitted to the analysis separately. nc means the nonlinear regression did not converge. * indicates maximal stimulation observed at 10 μM for compounds that did not reach a plateau. ND means not determined. Microsomal stability values ​​were determined in mouse liver microsome preparations as previously described (Zhou et al., 2013, (22)).

[0094] C. Preparation method The present disclosure also relates to any method for preparing the compounds disclosed herein.Those skilled in the art will recognize that such preparation methods can be various.The compounds disclosed herein can be synthesized by synthetic routes including processes well known in the chemical arts, particularly in light of the present disclosure, and processes similar to those for heterocycles such as triazoles, as described in Comprehensive Heterocyclic Chemistry II, Editors Katritzky and Rees, Elsevier, 1997, e.g., Volume 3; Liebigs Annalen der Chemie, (9):1910-16, (1985); Helvetica Chimica Acta, 41:1052-60, (1958); Arzneimittel-Forschung, 40(12):1328-31, (1990) (each of which is expressly incorporated by reference). The starting materials are generally available from commercial sources or readily prepared using methods well known to those of skill 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, NY (1967-2006 ed.), or Beilstein's Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available in the Beilstein online database)).

[0095] An exemplary method, i.e., when L is -(CH2) r The preparation of compounds of formula (I) wherein - is described in further detail below. Such a method can be carried out by preparing intermediate A [ka] to intermediate B [ka] and L becomes -(CH2)r A compound of formula (I) [ka] This includes obtaining

[0096] Intermediate A can be synthesized from precursors A.1 and A.2, and intermediate B can be synthesized from precursor B.1 according to the general scheme shown below. [ka]

[0097] The compounds shown in Tables 1-4 were prepared according to the above general reaction scheme 2. Shown below is a more detailed reaction scheme for preparing compound No. 5 (listed in Table 2). [ka] Scheme 3. Reagents and conditions: (a) acid (1 equiv), DMAP (0.1 equiv), CDI (1.5 equiv), THF (0.2 M), 30 min, then amine (1.1 equiv), 3.5 h, rt, 62% yield; (b) Lawesson's reagent (1.2 equiv), toluene (0.1 M), 4 h, 120 °C, 45% yield; (c) H2SO4 (0.1 equiv), MeOH (2 M), reflux, 2 h, then H2NNH2, reflux, 3 h, 63% yield; (d) thioamide (1.0 equiv), hydrazide (1.2 equiv), AgOBz (2.0 equiv), HOAc (3.0 equiv), DCM (0.2 M), 15 h, 34% yield

[0098] Building blocks (i.e., precursors and / or intermediates) of the compounds disclosed herein that are not commercially available starting materials were synthesized via the Heck reaction, Knoevenagel condensation, or Grignard reaction. The preparation of representative building blocks is shown in the following schemes, where the building block of compound 5 was prepared via the Heck reaction (Scheme 4a) or the Grignard reaction (Scheme 4b), while the building block of compound 34 was prepared using the Knoevenagel condensation (Scheme 4c). [ka] Scheme 4. (a) aryl bromide (1.0 equiv.), acrylic acid (1.5 equiv.), CsCO3 (1.2 equiv.), tri-o-tolylphosphane (0.1 equiv.), Pd(OAc)2 (0.05 equiv.), DMA (0.4 M), 17 h, 120 °C, 95%; (b) Pd / C (0.1 equiv.), THF (0.2 M), 17 h, rt, 55%; (c) aryl aldehyde (1.0 equiv.), malonic acid (1.0 equiv.), β-alanine (d) Pd / C (0.1 equiv), H2, THF (0.2 M), 17.5 h, rt, 97%; (e) Mg (1.0 equiv), THF (3.8 M), then aryl bromide (1.0 equiv) in THF (0.9 M), rt, 17.5 h, 8%; (f) Pd / C (0.1 equiv), H2, AcOH (0.3 M), 70 °C, 1 h, 34%

[0099] The compounds in Tables 5 and 6 containing various linkers were prepared by different methods, for example, compound 41 in Table 5 was prepared according to the reaction scheme shown below. [ka] Scheme 5.Reagents and conditions: (a) picolinic acid hydrazide (1.0 equiv.), 2-(isothiocyanatomethyl)furan (1.0 equiv.), ACN (0.2 M), 18 h, rt, 58% yield; (b) 4 M NaOH, 2 h, rt, 85% yield; (c) HOAc (0.7 M), 30% HO (2.2 equiv.), DCM (0.5 M), 5 h, 0 °C to rt, 52% yield; (d) paraformaldehyde (5 equiv.), p-xylene (0.2 M), 4 h, reflux, 27% yield; (e) MnO (10.5 equiv.), THF (0.2 M), 4 h, rt, 57% yield; (f) Ohira-Bestmann reagent (1.3 (equivalent), K2CO3 (2 equiv), MeOH (0.2 M), 17.5 h, rt, 53% yield; (g) aryl iodide (1 equiv), intermediate from step (f) (2 equiv), CuI (0.12 equiv), PdCl2(PPh3)2 (0.06 equiv), TEA (0.2 M), 75 °C, 19 h, 38% yield; (h) Lindlar's catalyst (0.1 equiv), THF (0.2 M), rt, 3 h, 34% yield

[0100] Compound 41 was synthesized by functionalizing a 3,4-disubstituted triazole as previously described. 21,37 After functionalization with an aldehyde, Ohira-Bestmann alkylation followed by Sonogashira coupling afforded compound 40. Subsequent reduction of the alkyne functionality of compound 40 using Lindlar's catalyst afforded the cis-alkene analog (compound 41). This reaction sequence can be applied to all compounds in Table 5 containing a cis-alkene in the linker (L), as will be apparent to those skilled in the art.

[0101] The synthesis of compounds containing alpha-oxygenated or alpha-fluorinated containing linkers in Table 5 were prepared as shown in the reaction scheme below. [ka] Scheme 6.Reagents and conditions: (a) arylmagnesium chloride (1.0 equiv), THF (0.2 M), 1 h, rt, 68% yield; (b) MnO (10.5 equiv), THC (0.2 M), 25 h, rt, 16% yield; (c) XX (1.0 equiv), DAST (1.96 equiv), DCM (0.055 M), 16 h, -78 °C to rt, 57% yield; (d) DAST (eq), (M), h, %, % yield

[0102] Specifically, the linker was synthesized by adding a Grignard reagent to a functionalized aldehyde starting material. The resulting alcohol was then oxidized to a ketone to give compound 44, or monofluorinated with DAST to give compound 45. Alternatively, compound 44 could be treated with DAST to give the difluorinated compound 46.

[0103] The synthesis of the scaffoldless analogs in Table 7 lacking the triazole were generally prepared via a series of amide coupling reactions. For example, the synthesis of compound 55 is shown in the scheme below. [ka] Scheme 7. Reagents and conditions: (a) 4-methyl-3-(trifluoromethyl)benzoic acid (1.0 equiv), DMAP (0.1 equiv), CDI (1.5 equiv), THF (0.2 M), rt, 30 min, then furan-2-ylmethanamine (1.1 equiv), 3.5 h, rt, 92% yield; (b) NiCl(dme) (0.1 equiv), phenylsilane (2.0 equiv), toluene (1.0 M), 46 h, 115 °C, 42% yield; (c) 2-picolinic acid (1.0 equiv), DMAP (0.1 equiv), CDI (1.5 equiv), THF (0.2 M), 30 min, rt, then intermediate from step (b) (1.0 equiv), 3.5 h, rt, 41% yield.

[0104] D. Pharmaceutical Compositions Another aspect of the present disclosure relates to pharmaceutical compositions comprising a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0105] In certain embodiments, the compounds or salts of Formula (A), (I), (II), and / or (III) disclosed herein are combined with one or more additional agents to form a pharmaceutical composition. In some embodiments, the compounds of Formula (A), (I), (II), and / or (III) are already in the form of a salt. Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers, such as excipients and auxiliaries, that facilitate processing of the active compound into a pharmaceutically acceptable formulation. The appropriate formulation depends on the selected route of administration. Further details about excipients suitable for the pharmaceutical compositions described herein can 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, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

[0106] As used herein, a pharmaceutical composition refers to a mixture of a compound or salt of Formula (A), (I), (II), and / or (III), having any suitable substituents and functional groups disclosed herein, with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. Pharmaceutical compositions facilitate the administration of a compound to an organism. In practicing the methods of treatment or use provided herein, a therapeutically effective amount of a compound described herein is administered as a pharmaceutical composition to a mammal having the disease, disorder, or condition to be treated. In some embodiments, the mammal is a human. The 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. Compounds or salts of Formula (A), (I), (II), and / or (III), having any suitable substituents and functional groups disclosed herein, can be used alone or in combination with one or more therapeutic agents as components of a mixture (as a combination therapy).

[0107] The pharmaceutical formulations described herein can be administered to a subject by a variety of routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration. Furthermore, the pharmaceutical compositions described herein, including compounds of Formula (A), (I), (II), and / or (III) having any suitable substituents and functional groups disclosed herein, can be formulated into any suitable dosage form, including, but not limited to, oral aqueous dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, aerosols, fast-dissolve formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, and capsules.

[0108] The compounds and / or compositions may be administered locally rather than systemically, for example, by direct injection of the compound into an organ or tissue, often in a depot or sustained-release formulation. Such long-acting formulations may be administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Furthermore, the drug may be administered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. The liposome will target the organ and be selectively taken up by the organ. Furthermore, the drug may be provided in the form of a fast-release formulation, a sustained-release formulation, or an intermediate-release formulation.

[0109] Pharmaceutical compositions containing the compounds described herein may be manufactured in a conventional manner, by way of example only, using conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or compressing processes.

[0110] The pharmaceutical compositions will contain at least one compound of formula (I) disclosed herein as the active ingredient, in free acid or free base form or in the form of a pharmaceutically acceptable salt.

[0111] In some embodiments, the 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.

[0112] In some embodiments, the pharmaceutical solid dosage forms described herein may comprise a compound of Formula (A), (I), (II), and / or (III) and one or more pharmaceutically acceptable excipients, such as a compatible carrier, binder, filler, suspending agent, flavoring agent, sweetener, disintegrant, dispersing agent, surfactant, lubricant, coloring agent, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, antifoaming agent, antioxidant, preservative, or one or more combinations thereof. In yet other embodiments, the pharmaceutical solid dosage forms described herein may comprise a compound of Formula (A), (I), (II), and / or (III) and one or more pharmaceutically acceptable excipients, such as a compatible carrier, binder, filler, suspending agent, flavoring agent, sweetener, disintegrant, dispersing agent, surfactant, lubricant, coloring agent, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, antifoaming agent, antioxidant, preservative, or one or more combinations thereof. th Using standard coating methods, such as those described in 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 yet another embodiment, the particles of the compound described herein are not microencapsulated or coated.

[0113] Carriers suitable 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, glycerin, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol, and the like.

[0114] Fillers suitable 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, dextrate, dextran, starch, pregelatinized starch, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[0115] Disintegrants suitable for use in the solid dosage forms described herein include natural starches such as corn starch or potato starch, pregelatinized starches such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, wood, methyl crystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming cross-linked celluloses such as Tia® and Solka-Floc®, methylcellulose, croscarmellose, or cross-linked sodium carboxymethylcellulose (Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linked croscarmellose, cross-linked starches such as sodium starch glycolate, cross-linked polymers such as crospovidone, cross-linked polyvinylpyrrolidone, alginates such as alginic acid or salts of alginic acid such as sodium alginate, clays such as Veegum® HV (aluminum magnesium silicate), gums such as agar, guar, locust bean, karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, natural sponge, surfactants, resins such as cation exchange resins, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination with starch, and the like.

[0116] Suitable binders for the solid dosage forms described herein include carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropyl methylcellulose (e.g., Hypromellose USP Pharmacoat-603), hydroxypropyl methylcellulose acetate stearate (Aqoate HS), and the like. LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®), microcrystalline dextrose, amylose, aluminum magnesium silicate, polysaccharide acids, bentonite, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, sugars such as sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), lactose, acacia, tragacanth, ghatti gum, mucilage of psyllium husk (isapol husk), starch, polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone®), XL-10, and Povidone® K-12), larch arabinogalactan, natural or synthetic gums such as Veegum®, polyethylene glycol, waxes, sodium alginate, and the like.

[0117] Lubricants or glidants suitable for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali metal and alkaline earth metal salts such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearate, magnesium stearate, zinc stearate, wax, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, Carbowax™, polyethylene glycol or methoxypolyethylene glycol such as PEG4000, PEG5000, PEG6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, and the like.

[0118] Diluents suitable for use in the solid dosage forms described herein include, but are not limited to, sugars (such as lactose, sucrose, and dextrose), polysaccharides (such as dextrates and maltodextrins), polyols (such as mannitol, xylitol, and sorbitol), cyclodextrins, and the like.

[0119] Wetting agents suitable 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, docusate sodium, triacetin, vitamin E TPGS, and the like.

[0120] Surfactants suitable 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.

[0121] Suspending agents suitable for use in the solid dosage forms described herein include 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, vinylpyrrolidone / vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, polysorbate 80, methylcellulose ... Examples of suitable cellulose esters include, but are not limited to, sodium alginate, polysorbate 80, hydroxyethylcellulose, sodium alginate, gums such as tragacanth gum and acacia gum, guar gum, xanthans such as xanthan gum, sugars, celluloses such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, polysorbate 80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, and the like.

[0122] Suitable antioxidants for use in the solid dosage forms described herein include, for example, butylhydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[0123] There is considerable overlap among the excipients used in the solid dosage forms described herein, and therefore the excipients listed above should be construed as merely limiting examples of the types of excipients that may be included in the solid dosage forms of the pharmaceutical compositions described herein.

[0124] The liquid pharmaceutical dosage form for oral administration may be an aqueous suspension selected from the group including, but not limited to, pharmaceutically acceptable oral aqueous dispersions, emulsions, solutions, elixirs, gels, and syrups. See, for example, Singh et al., Encyclopedia of Pharmaceutical Technology, 2000. nd Ed., pp. 754-757 (2002).

[0125] The pharmaceutical compositions described herein may contain any of a wide variety of flavors, including, but not limited to, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, bavarois, berry, blackcurrant, 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, cyclamic acid, dextrose, Roasted rice, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, licorice syrup, grapes, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrrhizinate (MagnaSweet®), maltitol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidin DC, neotame, orange, pear, peach, Sweeteners may be included such as 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 frutti, 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.

[0126] Potential excipients for intranasal formulations include saline solutions using benzyl alcohol or other suitable preservatives, fluorocarbons, and / or other solubilizing or dispersing agents. See, for example, Ansel, HC et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth Ed. (1995). Preferably, these compositions and formulations are prepared with suitable non-toxic pharmaceutically acceptable ingredients. The selection of suitable carriers largely depends on the exact nature of the desired intranasal dosage form, e.g., solution, suspension, ointment, or gel. Intranasal dosage forms generally contain a large amount of water in addition to the active ingredient. Small amounts of other ingredients, such as pH adjusters, emulsifiers or dispersing agents, preservatives, surfactants, gelling agents, or buffers, and other stabilizers and solubilizers, may also be present. Preferably, the intranasal dosage form should be isotonic with nasal secretions.

[0127] For administration by inhalation, the compounds described herein may be in the form of aerosol, mist, or powder.The pharmaceutical compositions described herein are conveniently delivered in the form of aerosol spray formulations from pressurized packs or nebulizers, using suitable propellants such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases.In the case of pressurized aerosols, dosage units can be determined by providing a valve to deliver a metered amount.Capsules and cartridges, such as (for example only) gelatin, for use in inhalers or insufflators, can be formulated to contain a powder mixture of the compounds described herein and suitable powder bases such as lactose or starch.

[0128] Buccal formulations containing the compounds described herein may be administered using various formulations, such as, but not limited to, those described in U.S. Patent Nos. 4,229,447; 4,596,795; 4,755,386; and 5,739,136. Furthermore, the buccal dosage forms described herein may further comprise a biodegradable (hydrolyzable) polymeric carrier, which also helps to adhere the dosage form to the buccal mucosa. The buccal dosage form is manufactured to slowly disintegrate over a predetermined period of time, during which time compound delivery is provided almost throughout. Buccal drug delivery avoids the disadvantages faced by oral drug administration, such as slow absorption, degradation of the active agent by fluids in the digestive tract, and / or first-pass inactivation in the liver. For biodegradable (hydrolyzable) polymeric carriers, virtually any such carrier can be used, as long as the desired drug release profile is not compromised and the carrier is compatible with the compounds described herein and any other ingredients that may be present in the buccal dosage unit. Generally, polymeric carriers comprise 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 copolymers, such as those known as "carbomers" (Carbopol® available from BF Goodrich is one such polymer). Other ingredients that can also be incorporated into the oral dosage forms described herein include, but are not limited to, disintegrants, diluents, binders, lubricants, flavoring agents, coloring agents, preservatives, and the like. For oral or sublingual administration, the composition can take the form of tablets, lozenges, or gels that are formulated in a conventional manner.

[0129] The transdermal formulations described herein can comprise conventional pharmaceutically acceptable excipients in the art.In some embodiments, the formulation suitable for transdermal administration of the compounds described herein may utilize transdermal delivery devices and transdermal delivery patches, and can be lipophilic emulsion or aqueous buffer solution, and can be dissolved and / or dispersed in polymer or adhesive.

[0130] Formulations suitable for intramuscular, subcutaneous, or intravenous injection may include physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include 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 maintaining 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 preservatives, wetting agents, emulsifying agents, and dispensing agents. Prevention of microbial growth 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 stearate and gelatin.

[0131] For intravenous injection, the 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 art. For other parenteral injections, suitable formulations may include aqueous or non-aqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are generally recognized in the art.

[0132] Parenteral injections may involve bolus injection or continuous infusion. Injectable formulations may be provided in single-dose form (e.g., ampoules) or in multidose containers with added preservatives. The pharmaceutical compositions 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 compound in water-soluble form. Additionally, suspensions of the active compound 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 that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound, allowing for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

[0133] In certain embodiments, delivery systems for pharmaceutical compounds, such as, for example, liposomes and emulsions, may be utilized. In certain embodiments, the compositions provided herein also include a mucoadhesive polymer selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylic acid), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0134] In some embodiments, the compounds described herein may be administered topically and are formulated into a variety of topical compositions such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments. Such pharmaceutical compounds may include solubilizers, stabilizers, tonicity-increasing agents, buffers, and preservatives.

[0135] The compounds described herein may also be formulated into 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 and synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In suppository forms of the composition, a low melting wax, such as, but not limited to, a mixture of fatty acid glycerides, optionally combined with cocoa butter, is first melted.

[0136] In some embodiments, the compounds of Formula (I), (II), and / or (III) disclosed herein are combined with other therapeutic agents, such as other cardiovascular agents, antiemetics (or anti-emetics), antipruritics, analgesics (such as chronic and acute pain relievers and hyperalgesics), anti-inflammatory agents, neuroprotectants, neuroleptics, anesthetics, vasopressors (such as agents for hypoxic pulmonary hypertension), multiple sclerosis agents, muscle relaxants, and combinations thereof.

[0137] In another embodiment, the compounds of Formula (A), (I), (II), and / or (III) disclosed herein are combined with another therapeutic agent, as described in more detail below.

[0138] Generally, agents such as compounds of Formula (A), (I), (II), and / or (III) disclosed herein are administered in an amount effective to treat a disease or disorder (i.e., a therapeutically effective amount). Thus, a therapeutically effective amount can be an amount that can at least partially treat, prevent, or reverse a disease or disorder. The dosage required to achieve an effective amount may vary depending on the agent, formulation, disease or disorder, and the individual to whom the agent is administered.

[0139] Determination of an effective amount may involve in vitro assays in which various doses of the drug are administered to cultured cells to determine the concentration of the drug effective to ameliorate some or all symptoms in order to calculate the concentration needed in vivo. Effective amounts may also be based on in vivo animal studies.

[0140] Agents such as compounds of Formula (A), (I), (II), or (III) can be administered prior to, concurrently with, and after the manifestation of a disease or disorder. In some embodiments, the agent is administered to a subject who has a family history of the disease or disorder, or who has a phenotype that may indicate a predisposition to the disease or disorder, or who has a genotype that predisposes the subject to the disease or disorder.

[0141] 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 variety of ways, depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (including ophthalmic and mucosal administration, such as vaginal and rectal delivery), pulmonary (e.g., administration by inhalation or insufflation of powders or aerosols, such as with a nebulizer, as well as intratracheal, intranasal, epithelial, and transdermal), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion, or intracranial administration, 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 may 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 may be desirable. Compositions and formulations for parenteral, intrathecal, or intraventricular administration may include sterile aqueous solutions, which may 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 liposomes containing formulations. These compositions may be created from a variety of components, including, but not limited to, preformed liquids, self-emulsifying solids, and self-emulsifying semisolids.

[0142] Pharmaceutical and / or therapeutic formulations, which may be conveniently provided in single-dose form, may be prepared according to conventional techniques well known in the pharmaceutical / nutraceutical industry. Such techniques include combining the active ingredient with pharmaceutical carriers or excipients. Generally, formulations are prepared by uniformly and intimately combining the active ingredient with liquid carriers, finely divided solid carriers, or both, and then, if necessary, shaping the product. The compositions of the present disclosure may be formulated into any of a number of possible dosage forms, including, but not limited to, tablets, capsules, liquid syrups, soft gels, suppositories, and enemas. The compositions of the present disclosure may also be formulated as suspensions in aqueous, non-aqueous, oily, or mixed media. Suspensions may further contain substances that increase the viscosity of the suspension, such as, for example, sodium carboxymethylcellulose, sorbitol, and / or dextran. Suspensions may also contain stabilizers. In one embodiment of the present disclosure, the pharmaceutical composition may be formulated and used as a foam. Pharmaceutical foams include, but are not limited to, formulations such as emulsions, microemulsions, creams, jellies, and liposomes, which are essentially similar in nature but differ in the ingredients and consistency of the final product.

[0143] The pharmaceutical compositions described herein can be in single-dose form suitable for single administration of precise dosages. In single-dose form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. The unit doses can be in the form of packages containing discrete amounts 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, multi-dose reclosable containers can be used, which usually contain preservatives in the composition. By way of example only, formulations for parenteral injection can be provided in single-dose forms, such as, but not limited to, ampoules, or in multi-dose containers, with added preservatives.

[0144] Dosages and administration regimens are developed by clinicians or other pharmacologists based on well-known pharmacological and therapeutic considerations, including, but not limited to, the desired level of therapeutic effect and the actual level of therapeutic effect available. Generally, it is desirable to follow well-known pharmacological principles for the administration of chemotherapeutic agents (e.g., it is generally desirable not to change the dosage by more than 50% at intervals of 3-4 half-lives or less). For compositions where maximum efficacy is desired and where dose-dependent toxicity is relatively little or not a consideration, doses exceeding the average required dose are not uncommon. This approach to dosing is commonly referred to as a "maximal dose" strategy. In certain embodiments, the compound is administered to a subject at a dose of about 0.01 mg / kg to about 200 mg / kg, more preferably about 0.1 mg / kg to about 100 mg / kg, and even more preferably about 0.5 mg / kg to about 50 mg / kg. When the compounds described herein are co-administered with another agent (e.g., a sensitizer), the effective amount may be less than when that agent is used alone. Dosing can be once daily or multiple times daily for one or more consecutive days.

[0145] E.How to use The present disclosure provides compounds and methods for treating subjects suffering from diseases and / or conditions identified as being associated with the kappa opioid receptor. In one aspect, the present disclosure provides a method for treating a disease or condition mediated by the kappa opioid receptor, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound provided herein or a pharmaceutical composition described herein. In some embodiments, the disease or condition to be treated is selected from the group consisting of pain, itch, addiction, depression, myocardial infarction, pruritus, inflammation, edema, nausea, neuroinflammation, stroke, hypoxic pulmonary hypertension, ocular inflammation, glaucoma, multiple sclerosis, osteoarthritis, rheumatoid arthritis, inflammatory bowel disease, and eczema. In some embodiments, the subject does not experience any discomfort or sedation.

[0146] In some embodiments, the present disclosure provides methods of treating such diseases and / or conditions, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound or salt described herein, e.g., a compound or salt of Formula (A), (I), (II), and / or (III) disclosed herein. In some embodiments, the administered compound or salt is a kappa opioid agonist as disclosed herein. In some embodiments, the administered compound or salt is a g protein-biased kappa opioid agonist as disclosed herein, e.g., a compound or salt of Formula (A), (I), (II), and / or (III).

[0147] In some embodiments, such diseases and / or conditions can be treated by activating or inactivating kappa opioid receptor signaling. In some embodiments, such diseases and / or disorders can be treated by stimulating or inactivating kappa opioid receptor signaling.

[0148] The kappa opioid receptor-associated disease or condition 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), cirrhosis, edema, ileus, cough, eye disease (i.e., glaucoma, ocular inflammation), itch, addiction, depression, myocardial infarction, pruritus, nausea, neuroinflammation, hypoxic pulmonary hypertension, multiple sclerosis, osteoarthritis, rheumatoid arthritis, inflammatory bowel disease, substance abuse disorders, and eczema.

[0149] For example, kappa opioid receptor-associated pain can be neuropathic, somatic, visceral, or cutaneous. Some diseases or conditions involve more than one type of pain; for example, postoperative pain can have any or all of the components of neuropathic, somatic, visceral, and cutaneous pain, depending on the type and extent of the surgical procedure used.

[0150] The kappa opioid receptor-associated inflammation can be any inflammatory disease or condition, such as, but not limited to, sinusitis, rheumatoid arthritis, tenosynovitis, bursitis, tendonitis, lateral epicondylitis, adhesive capsulitis, osteomyelitis, osteoarthritis, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), eye inflammation, otitis, or autoimmune inflammation.

[0151] Kappa opioid receptor-associated pruritus can be any pruritic disease or condition, such as ocular pruritus, e.g., associated with conjunctivitis, ear pruritus, pruritus associated with end-stage renal disease, in which many patients undergo renal dialysis, and other types of cholestasis, such as primary biliary cirrhosis, intrahepatic cholestasis of pregnancy, chronic cholestatic liver disease, uremia, malignant cholestasis, jaundice, as well as skin diseases such as eczema (dermatitis), such as atopic or contact dermatitis, psoriasis, polycythemia vera, lichen planus, lichen simplex chronicus, pediculosis (lice), thyrotoxicosis, tinea pedis, urticaria, scabies, vaginitis, ani pruritus associated with hemorrhoids, and drug-induced pruritus, such as insect bite pruritus and mu opioid-induced pruritus.

[0152] The kappa opioid receptor-associated edema can be any edematous disease or condition, such as, for example, edema due to congestive heart disease or the syndrome of inappropriate antidiuretic hormone (ADH) secretion.

[0153] 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.

[0154] Kappa opioid receptor-associated neuropathic pain can be any neuropathic pain, such as trigeminal neuralgia, diabetic pain, viral pain such as shingles-associated pain, chemotherapy-induced pain, nerve-invasion metastatic cancer pain, neuropathic pain associated with trauma and surgery, and variants of headache thought to have a neuropathic component (e.g., migraine).

[0155] Kappa opioid-associated pain also includes eye pain such as that after photorefractive keratectomy (PRK), ocular lacerations, orbital floor fractures, chemical burns, corneal abrasions or irritation, or pain associated with conjunctivitis, corneal ulcers, scleritis, episcleritis, sclerokeratitis, herpes zoster ophthalmicus, interstitial keratitis, acute iritis, keratoconjunctivitis sicca, orbital cellulitis, orbital pseudotumor, pemphigus, trachoma, or uveitis.

[0156] Kappa opioid-associated pain also includes sore throat associated with inflammatory diseases such as allergic rhinitis, acute bronchitis, the common cold, contact ulcers, herpes simplex virus lesions, infectious mononucleosis, influenza, laryngeal cancer, acute laryngitis, acute necrotizing ulcerative gingivitis, peritonsillar abscess, pharyngeal burn, pharyngitis, reflux pharyngitis, acute sinusitis, and tonsillitis, among others.

[0157] Kappa opioid receptor-associated pain includes arthralgia, pain from kidney stones, urinary stones, gallstones, and bile duct stones, dysmenorrhea, uterine cramps, endometriosis, mastitis, dyspepsia, postoperative pain (e.g., from appendectomy, open colorectal surgery, hernia repair, prostatectomy, colectomy, gastrectomy, splenectomy, colectomy, colostomy, pelvic laparoscopy, tubal ligation, hysterectomy, vasectomy, or cholecystectomy), post-medical procedure pain (e.g., after colonoscopy, cystoscopy, hysteroscopy, or cervical or endometrial biopsy), earache, breakthrough cancer pain, and The pain may be associated with inflammation due to GI disorders such as IBD or IBS, or other inflammatory diseases, particularly inflammatory diseases of the internal organs (e.g., gastroesophageal reflux disease, pancreatitis, acute pyelonephritis, ulcerative colitis, acute pyelonephritis, cholecystitis, cirrhosis, liver 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 toxins such as insect venom, or the effects of drugs such as salicylates or NSAIDs.

[0158] Kappa opioid receptor-associated pain also includes hyperalgesia, which is thought to be caused by changes in the environment of peripheral sensory terminals secondary to local tissue injury. Tissue injury (e.g., abrasion, burn) and inflammation can result in a significant increase in the excitability of polymodal nociceptors (C fibers) and high-threshold mechanoreceptors (Handwerker et al. (1991) Proceedings of the VIth 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 hyperresponsiveness of sensory afferents is thought to underlie hyperalgesia, where pain responses are the result of an exaggerated response to stimuli. The importance of hyperalgesia in postinjury pain states has been repeatedly demonstrated and is believed to account for the majority of postinjury / inflammatory pain states. See, e.g., 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.

[0159] In another embodiment, the kappa opioid receptor-related pathology is pain, inflammation (such as rheumatoid arthritis, osteoarthritis, IBD inflammation, IBS inflammation, ocular inflammation, otitis, or autoimmune inflammation), pruritus (such as atopic dermatitis, renal dialysis-related pruritus, ocular pruritus, ocular pruritus, insect bite pruritus, or opioid-induced pruritus), edema, ileus, cough, or glaucoma. In one embodiment, the pain is neuropathic pain (such as trigeminal neuralgia, migraine, diabetic pain, viral pain, chemotherapy-induced pain, or metastatic cancer pain), somatic pain, visceral pain, or cutaneous pain. In another embodiment, the pain is arthralgia, kidney stone pain, uterine cramps, dysmenorrhea, endometriosis, dyspepsia, postoperative pain, post-medical procedure pain, ocular pain, ocular pain, breakthrough cancer pain, or pain associated with GI disorders such as IBD or IBS. In another embodiment, the pain is associated with surgery, where the surgery is pelvic laparoscopy, tubal ligation, hysterectomy, and cholecystectomy. Alternatively, the pain may be associated with medical procedures such as colonoscopy, cystoscopy, hysteroscopy, or endometrial biopsy. In a specific embodiment, the atopic dermatitis may be psoriasis, eczema, or contact dermatitis. In another specific embodiment, the ileus is postoperative ileus or opioid-induced bowel dysfunction.

[0160] The present disclosure also provides a method for treating or preventing a neurodegenerative disease or condition in a subject, comprising administering to the subject an effective amount of a composition comprising the composition disclosed herein. The neurodegenerative disease or condition can be any neurodegenerative disease or condition, such as ischemia, anoxia, stroke, brain injury, spinal cord injury, or reperfusion injury. Alternatively, the neurodegenerative disease or condition can be an ocular neurodegenerative disease. Specific ocular neurodegenerative diseases that can be treated or prevented by the method of the present invention include glaucoma, macular degeneration, retinal ischemic disease, and diabetic neuropathy.

[0161] In some embodiments, the compounds disclosed herein are neurological modulators (eg, antinociceptive agents, antidepressants, anxiolytic agents, antipruritic agents).

[0162] In some embodiments, the present disclosure provides methods for preventing or treating certain neurological diseases and conditions, such as those with a neurodegenerative component. Compounds as disclosed herein can be administered in an amount effective to protect neurons from the effects of pathology or injury that would otherwise result in neurodegeneration and / or neuronal cell death in untreated cells. For example, some ocular diseases or conditions with a neurodegenerative component can be prevented or treated by administering an effective amount of a compound as disclosed herein. Such ocular diseases and conditions include glaucoma, macular degeneration, retinal ischemic disease, and diabetic neuropathy. The progression of these diseases and conditions is believed to involve neurodegeneration or neuronal cell death, for example, through programmed cell death (apoptosis), in which neurons are involved in a pathway that leads to cell death without intervention. It has been found that the onset or progression of these diseases and conditions can be prevented or at least slowed by treatment with a kappa opioid receptor agonist. This improved outcome is believed to be due to neuroprotection provided by the kappa opioid receptor agonist. See, for example, Kaushik et al. "Neuroprotection in Glaucoma" (2003) J. Postgraduate Medicine vol. 49 (1): pp. 90-95.

[0163] Additionally, compounds as disclosed herein may be administered by the methods disclosed herein for the treatment or prevention of any hyperalgesic condition associated with burns, abrasions, bruises, abrasions (such as corneal abrasions), contusions, frostbite, rashes, acne, insect bites, skin ulcers (e.g., diabetic ulcers or pressure ulcers), mucositis, inflammation, gingivitis, bronchitis, laryngitis, pharyngitis, shingles, fungal irritations (tinea pedis or tinea cruris), herpes simplex, boils, plantar warts, or vaginal lesions (such as those associated with mycoses or sexually transmitted diseases).

[0164] Hyperalgesic conditions associated with post-operative recovery may also be addressed by administering the compositions disclosed herein, such as any hyperalgesic condition associated with post-operative recovery, including, for example, radial keratectomy, tooth extraction, lumpectomy, episiotomy, laparoscopy, and arthroscopy.

[0165] Hyperalgesic conditions associated with inflammation can also be addressed by administration of the compounds disclosed herein. Periodontitis, orthodontic inflammation, inflammatory conjunctivitis, hemorrhoids, and inflammation due to sexually transmitted diseases can be treated or prevented by topical or local administration of the compounds disclosed herein.

[0166] In some embodiments, the method further comprises co-administration of a second therapeutic agent. Such therapeutic agent can be administered simultaneously with the compound disclosed herein, or can be administered before or after the compound disclosed herein.Those skilled in the art will know that the administration method, administration timing and administered dose can vary depending on the therapeutic agent administered.

[0167] Examples of co-administered therapeutic agents include, but are not limited to, other opioids, cannabinoids, antidepressants, anticonvulsants, neuroleptics, antihistamines, acetaminophen, corticosteroids, ion channel blockers, nonsteroidal anti-inflammatory drugs (NSAIDs), and diuretics.

[0168] Suitable opioids include, but are not limited to, alfentanil, alphaprodine, anileridine, bremazocine, buprenorphine, butorphanol, codeine, conorphone, dextromoramide, dextropropoxyphene, dezocine, diamorphine, dihydrocodeine, dihydromorphine, diphenoxylate, dipipanone, doxycycline, ethoheptazine, ethylketazocine, ethylmorphine, etorphine, fentanyl, hydrocodone, hydrochloride, thiazolinone ... These include morphone, 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, tonazosin, and tramadol.

[0169] Additional opioids, including opioids with substantial agonist activity at the μ-opioid receptor, such as morphine, fentanyl, hydromorphone, or oxycodone, are used in combination with the compounds disclosed herein for μ-opioid dose-sparing effects (wherein the μ-opioid dose is minimized to minimize common μ-opioid side effects, particularly in opioid-naive patients). Such side effects include constipation, nausea, vomiting, sedation, respiratory depression, pruritus (itching), confusion, disorientation and cognitive impairment, urinary retention, biliary spasm, delirium, myoclonic seizures, and seizures. The selection of a reduced μ-opioid dose requires expert clinical judgment and depends on the characteristics of various μ-opioids, as well as patient demographics such as pain intensity, patient age, comorbidities, current dosing regimen and potential drug interactions, results from previous treatments, and patient preference (McCaffery, M. and Pasero, C., Pain Clinical Manual, Second Edition, Mosby, 1999).

[0170] Cannabinoids suitable for administration with or incorporation into the pharmaceutical compositions of the present invention include any naturally occurring cannabinoid, such as, for example, tetrahydrocannabinol (THC), or a THC derivative, or a synthetic cannabinoid, such as, for example, levonantradol, marinol, nabilone, rimonabant, or sativex.

[0171] Suitable antidepressants that may be co-administered with or incorporated into the pharmaceutical compositions of the present 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 venlafexine; selective serotonin reuptake inhibitors such as fluoxetine, sertraline, paroxetine, citalopram, and fluvoxamine; selective norepinephrine reuptake inhibitors such as reboxetine; or dual action antidepressants such as nefazodone and mirtazapine.

[0172] Suitable neuroleptic agents that may be co-administered with or incorporated into the pharmaceutical compositions of the present invention include any neuroleptic agent, such as domperidone, metoclopramide, levosulpiride, sulpiride, thiethylperazine, ziprasidone, zotepine, clozapine, chlorpromazine, acetophenazine, carphenazine, chlorprothixene, fluphenazine, loxapine, mesoridazine, molindone, prochlorperazine, pimozide, piperacetazine, perchlorperazine, Compounds with D2 dopamine receptor antagonist activity include amine amine, thioridazine, thiothixene, trifluoperazine, triflupromazine, pipamperone, amperozide, quietiapine, melperone, remoxipride, haloperidol, rispiridone, olanzapine, sertindole, ziprasidone, amisulpride, prochlorperazine, and thiothixene.

[0173] Anticonvulsants such as phenobarbital, phenytoin, primidone, carbamazepine, ethosuximide, lamotrigine, valproic acid, vigabatrin, felbamate, gabapentin, levetiracetam, oxcarbazepine, remacemide, tiagabine, and topiramate may also be usefully incorporated into the pharmaceutical compositions of the present invention.

[0174] Muscle relaxants such as methocarbamol, orphenadrine, carisoprodol, meprobamate, chlorphenesin carbamate, diazepam, chlordiazepoxide, and chlorzoxazone; antimigraine medications such as sumatriptan; stimulants such as caffeine, methylphenidate, amphetamines, and modafinil; antihistamines such as chlorpheniramine, cyproheptadine, promethazine, and pyrilamine; and antihistamines such as methylprednisolone, betamethasone, hydrocortisone, prednisolone. Corticosteroids such as fluoxetine, cortisone, dexamethasone, prednisone, alclometasone, clobetasol, clocortolone, desonide, desoximetasone, diflorasone, fluocinolone, fluocinonide, flurandrenolide, fluticasone, fluorometholone, halcinonide, halobetasol, loteprednol, mometasone, prednicarbate, and triamcinolone may also be incorporated into the pharmaceutical compositions of the present invention.

[0175] For example, ion channel blockers such as carbamazepine, a sodium ion channel blocker commonly used in the treatment of tinnitus, arrhythmia, ischemic stroke and epilepsy, can be co-administered with or incorporated into the pharmaceutical composition of the present invention.Alternatively, or in addition, calcium ion channel blockers such as ziconotide can also be used as antagonists of ion channels related to NMDA receptors, such as ketamine.It has been proven that at least some of these ion channel blockers can enhance the analgesic effect of kappa agonists, thereby reducing the dose required for affective pain relief.For example, see Wang et al., 2000, Pain 84: 271-81.

[0176] Suitable NSAIDs or other non-opioid compounds with anti-inflammatory and / or analgesic activity that may be co-administered with or incorporated into the pharmaceutical compositions of the present 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, etc.; arylacetic acid derivatives such as acemetacin, amfenac, cinmetacin, clopirac, diclofenac, fenclofenac, fenclorac, fenclozic acid, fentiazac, glucametacin, isoxepac, lonazolac, metiazinic acid, naproxen, oxametacine, proglumetacin, sulindac, tiaramide, and tolmetin; arylbutyric acid derivatives such as butibufen and fenbufen; arylcarboxylic acids such as clidanac, ketorolac, and tinoridine; bucloxic acid arylpropionic acid derivatives such as carprofen, fenoprofen, flunoxaprofen, ibuprofen, ibuproxam, and oxaprozin; phenylalkanoic acid derivatives such as flurbiprofen, piketoprofen, pirprofen, pranoprofen, protizinic acid, and tiaprofenic acid; pyranocarboxylic acids such as etodolac; pyrazoles such as mepirizole; clofezone, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone, and phenylpyrazolidinone pyrazolones such as pyrazolidininone, suxibuzone, and thiazolinobutazone; salicylic acid derivatives such as aspirin, bromosaligenin, diflunisal, fendosal, glycol salicylate, mesalamine, 1-naphthyl salicylate, magnesium salicylate, olsalazine, and salicylamide, salsalate, and sulfasalazine; thiazinecarboxamides such as droxicam, isoxicam, and piroxicam;Other drugs such as ε-acetamidocaproic acid, acetaminophen, s-adenosylmethionine, 3-amino-4-hydroxybutyric acid, amixetrine, bendazac, bucolome, carbazone, cromolyn, difenpyramide, dithiazol, hydroxychloroquine, indomethacin, ketoprofen, and its active metabolite 6-methoxy-2-naphthylacetic acid; guaiazulene, heterocyclic aminoalkyl esters of mycophenolic acid and derivatives, nabumetone, nimesulide, orgotein, oxaceprol, oxazole derivatives, paranyline, pifoxime, 2-substituted-4,6-di-tert-butyl-s-hydroxy-1,3-pyrimidines, proquasone, and tenidap; and COX-2 (cyclooxygenase II) inhibitors such as celecoxib or rofecoxib.

[0177] Suitable diuretics that may be co-administered with or incorporated into the pharmaceutical preparations of the invention include, for example, inhibitors of carbonic anhydrase, such as acetazolamide, diclofenamide, and methazolamide; osmotic diuretics, such as glycerin, isosorbide, mannitol, and urea; Na+-K+-2Cl- cotransport inhibitors (loop diuretics or high-potency diuretics), such as furosemide, bumetanide, ethacrynic acid, torsemide, azosemide, piretanide, and tripamide; These include Na+-Cl- cotransport inhibitors (thiazide and thiazide-like diuretics) such as flumethiazide, methyclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone, and quinethazone; and inhibitors of renal epithelial Na+ channels such as amiloride and triamterene, and mineralocorticoid receptor antagonists (aldosterone antagonists) such as spironolactone, canrenone, potassium canrenoate, and eplerenone (which are also collectively classified as K+-sparing diuretics).

[0178] In some embodiments, any of the above therapeutic agents may also be formulated with the compositions disclosed herein to obtain a pharmaceutical composition as described above.

[0179] In accordance with the purposes of the present invention, as embodied and broadly described herein, one embodiment is a method for preventing or treating a kappa opioid receptor-mediated disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (A), wherein the compound of Formula (A) is: [ka] [In the formula, A is, [ka] is selected from the group consisting of Ar1 is [ka] is selected from the group consisting of wherein X1, X2, and X3 are each independently selected from the group consisting of -N- and -CH-; X4 is selected from the group consisting of -CH2-, -NH-, -O-, -S-, and -N(CH3)-; each R1 is independently selected from the group consisting of -Cl, -Br, -F, -CF3, -OH, -CN, -NO2, -NH2, and (C1-C6)alkyl; and n is 1, 2, or 3; Ar2 is [ka] is selected from the group consisting of wherein X5 and X8 are each independently selected from the group consisting of -CH2-, -NH-, -O-, and -S-; X6 and X7 are each independently selected from the group consisting of -N- and -CH-; and m is 1, 2, 3, 4, 5, or 6; Ar3 is [ka] wherein each R2 is independently selected from the group consisting of -Cl, -Br, -F, -CF3, -OH, -CN, -NO2, -NH2, -O(C1-C6)alkyl, and -(C1-C6)alkyl; and q is 1, 2, 3, 4, or 5; L1, L2, and L3 each independently represent a bond, -C(=O)-, -(CH2) r -, -C≡C-, -CH=CH-, -C(R 4b )(R 4a )CH2-, -CH2C(R 4b )(R 4a )-, -C(=O)CH2-, -CH2CH(R5)-, and -CH(R x )-, where r is 1, 2, 3, 4, 5, or 6; and R 4a , R 4b、 R5, and R x are each independently selected from the group consisting of -H, -Cl, -Br, -F, -CF, -OH, -CN, -NO, -NH, and -(C-C)alkyl; or R 4a and R 4b together with the atoms between them form a C3-C7 carbocyclyl] or a pharmaceutically acceptable salt thereof.

[0180] In accordance with the purposes of the present invention, as embodied and broadly described herein, one embodiment is a method for preventing or treating a kappa opioid receptor-mediated disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), wherein the compound of formula (I) is [ka] [In the formula, Ar1 is [ka] is selected from the group consisting of wherein X1, X2, and X3 are each independently selected from the group consisting of -N- and -CH-; X4 is selected from the group consisting of -CH2-, -NH-, -O-, -S-, and -N(CH3)-; each R1 is independently selected from the group consisting of -Cl, -Br, -F, -CF3, -OH, -CN, -NO2, -NH2, and -(C1-C6)alkyl; and n is 1, 2, or 3; Ar2 is [ka] is selected from the group consisting of wherein X5 and X8 are each independently selected from the group consisting of -CH2-, -NH-, -O-, and -S-; X6 and X7 are each independently selected from the group consisting of -N- and -CH-; and m is 1, 2, 3, 4, 5, or 6; Ar3 is [ka] wherein R2 is independently selected from the group consisting of -Cl, -Br, -F, -CF3, -OH, -CN, -NO2, -NH2, -O(C1-C6)alkyl, and -(C1-C6)alkyl; and q is 1, 2, 3, 4, or 5; L is a bond, -(CH2) r -, -C≡C-, -CH=CH-, -C(R 4b )(R 4a )CH2-, -CH2C(R 4b )(R 4a )—, —C(═O)CH—, and —CHCH(R)—, where r is 1, 2, 3, 4, 5, or 6; R 4a , R 4b and R5 are independently selected from the group consisting of -H, -Cl, -Br, -F, -CF3, -OH, -CN, -NO2, -NH2, and -(C1-C6)alkyl; or R 4a and R 4b together with the atoms between them form a C3-C7 carbocyclyl] or a pharmaceutically acceptable salt thereof. [Example]

[0181] Example 1 Assays used in structure-activity relationship studies in Tables 1-8 GTPγS biochemical assay 29 The compounds listed in Tables 1-8 were tested for G protein activation using the PathHunter® DiscoverX β-arrestin recruitment assay. 30 The compounds listed in Tables 1-7 were tested for β-arrestin recruitment using the β-arrestin assay. Bias was determined by fitting to an operational model as previously described (Zhou et al., 2013, 22). Microsomal stability was determined using mouse liver microsomes and long-term LC / MS detection (Zhou et al., 2013, 22).

[0182] Example 2: Compounds tested in standard mouse models of pruritus Compound 5, U50,488H, and triazole 1.1 were tested for their antipruritic activity in a standard mouse model of pruritus (adult male C57BL6 / J mice from Jackson Labs were used in all assays). Compound injections were administered 15 minutes before the injection of the pruritic drug chloroquine phosphate. Scratching counts were recorded by two investigators blinded to treatment. Data shown in Figures 6, 7A, and 7B demonstrate that 5 reduces scratching behavior after injection of chloroquine phosphate (40 mg / kg, sc, nuchal). Furthermore, 5 exhibits essentially equipotent antipruritic activity to the conventional agonist U50,488H and the KOR agonist triazole 1.1, as described in Brust et al., 2016 (23).

[0183] Example 3: Compounds tested in a standard mouse model (open field test box model) for sedation Compound 5, U50,488H, and Triazole 1.1 were tested for their ability to induce sedation in an open field test activity monitor, a standard mouse model for determining sedation. Adult male C57BL6 / J mice were administered the drugs and immediately placed in a box where movement is assessed by monitoring beam occlusion in real time. Data shown in Figure 8 demonstrate that, unlike U50,488H, Triazole 1.1 does not induce sedation. Compound 5 also does not induce sedation. The bottom four panels show that U50,488H increases the time spent in the center of the open field box, whereas Triazole 1.1 had no effect on time spent in the center. However, animals treated with 5 also increased their time in the center. An increase in time spent in the center without sedation is a highly desirable property of KOR agonists. This was previously described by Brust et al., 2016 (23).

[0184] Example 4: Compounds tested in a standard mouse model of anxiety (elevated plus maze mouse model) Compound 5, U50,488H, and triazole 1.1 were tested for their ability to exhibit anxiolytic effects in the elevated plus maze mouse model, a standard mouse model of anxiety. Adult male C57BL6 mice were injected 30 minutes before the start of testing, followed by automated video analysis of the time spent in the open (2) versus closed (2) arms. Drug administration was randomized to ensure vehicle was present in each cohort over the 4-day test, and testers were blinded to drug administration. Data shown in Figure 5 indicate that, at the doses tested, none of the agonists produced sedation during the 30-minute test (5 minutes) after drug treatment. However, only 5 increased the time spent in the distal open arms in this test. These data suggest that 5 has anxiolytic effects. **Ordinary one-way ANOVA; p<0.01

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Claims

1. Formula (A): 【Chemistry 1】 [In the formula, A is, 【Chemistry 2】 is selected from the group consisting of Ar １ teeth, 【Transformation 3】 is selected from the group consisting of Here, X １ , X ２ , and X ３ are each independently selected from the group consisting of —N— and —CH—; ４ is -CH ２ -, -NH-, -O-, -S-, and -N(CH ３ )-, and R １ are each independently —Cl, —Br, —F, or —CF ３ , -OH, -CN, -NO ２ , -NH ２ , and (C １ -C ６ ) alkyl, where n is 1, 2, or 3; Ar ２ teeth, 【Chemistry 4】 is selected from the group consisting of Here, X ５ and X ８ are each independently —CH ２ is selected from the group consisting of —, —NH—, —O—, and —S—; ６ and X ７ are each independently selected from the group consisting of —N— and —CH—; and m is 1, 2, 3, 4, 5, or 6; Ar ３ teeth, 【Transformation 5】 wherein R ２ are each independently —Cl, —Br, —F, or —CF ３ , -OH, -CN, -NO ２ , -NH ２ , -O(C １ -C ６ ) alkyl, and —(C １ -C ６ ) alkyl, and q is 1, 2, 3, 4, or 5; L １ , L ２ , and L ３ are each independently a bond, —C(═O)—, or —(CH ２ ) ｒ -, -C≡C-, -CH=CH-, -C(R ４ｂ ) (R ４ａ ) CH ２ -, -CH ２ C (R ４ｂ ) (R ４ａ )-, -C(=O)CH ２ -, -CH ２ CH (R ５ )-, and -CH(R ｘ )-, where r is 1, 2, 3, 4, 5, or 6; R ４ａ , R ４ｂ、 R ５ , and R ｘ are each independently —H, —Cl, —Br, —F, or —CF ３ , -OH, -CN, -NO ２ , -NH ２ , and -(C １ -C ６ ) alkyl; or R ４ａ and R ４ｂ C together with the atoms between them ３ -C ７ forming a carbocyclyl] or a pharmaceutically acceptable salt thereof.

2. Formula (A-1): 【Transformation 6】 [In the formula, L ２ is a bond, -(CH ２ ) ｒ -, or -CH(R ｘ )-, where r is 1 or 2, and R ｘ is -H and -(C １ -C ６ ) alkyl] 2. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt thereof.

3. Formula (I): 【Transformation 7】 [In the formula, Ar １ teeth, 【Transformation 8】 is selected from the group consisting of Here, X １ , X ２ , and X ３ are each independently selected from the group consisting of —N— and —CH—; ４ is -CH ２ -, -NH-, -O-, -S-, and -N(CH ３ )-, and R １ are -Cl, -Br, -F, and -CF, respectively. ３ , -OH, -CN, -NO ２ , -NH ２ , and -(C １ -C ６ ) alkyl, and n is 1, 2, or 3; Ar ２ teeth, 【Chemistry 9】 is selected from the group consisting of Here, X ５ and X ８ are each independently —CH ２ is selected from the group consisting of —, —NH—, —O—, and —S—; ６ and X ７ are each independently selected from the group consisting of —N— and —CH—; and m is 1, 2, 3, 4, 5, or 6; Ar ３ teeth, 【Chemistry 10】 wherein R ２ are -Cl, -Br, -F, and -CF, respectively. ３ , -OH, -CN, -NO ２ , -NH ２ , -O(C １ -C ６ ) alkyl, and —(C １ -C ６ ) alkyl, and q is 1, 2, 3, 4, or 5; L is a bond, -(CH ２ ) ｒ -, -C≡C-, -CH=CH-, -CR ４ｂ (R ４ａ ) CH ２ , —C(═O)CH ２ - and -CH ２ CH (R ５ )-, where r is 1, 2, 3, 4, 5, or 6; R ４ａ , R ４ｂ , and R ５ are independently —H, —Cl, —Br, —F, or —CF ３ , -OH, -CN, -NO ２ , -NH ２ , and -(C １ -C ６ ) alkyl; or R ４ａ and R ４ｂ C together with the atoms between them ３ -C ７ forming a carbocyclyl] or a pharmaceutically acceptable salt thereof.

4. L is -(CH ２ ) ｒ - and r is 2.

5. Ar １ but 【Chemistry 11】 The compound according to any one of claims 1 to 4,

6. X ２ The compound of claim 5, wherein is -CH-.

7. R １ are -CH ３ and n is 1.

8. Ar １ but 【Chemistry 12】 5. The compound of claim 4 selected from the group consisting of:

9. Formula (II): 【Chemistry 13】 The compound according to any one of claims 1 to 8, having the structure: or a pharmaceutically acceptable salt thereof.

10. Ar ３ but 【Chemistry 14】 10. The compound of claim 9, wherein:

11. R ２ are each independently —Cl, —Br, or —CF ３ , and -(C １ -C ６ 11. The compound of claim 10, wherein the alkyl is selected from the group consisting of:

12. 12. The compound of claim 11, wherein q is 1 or 2.

13. Ar ３ but 【Chemistry 15】 13. The compound of claim 12 selected from the group consisting of:

14. Formula (III): 【Chemistry 16】 The compound according to any one of claims 1 to 13, having the structure: or a pharmaceutically acceptable salt thereof.

15. Ar ２ but 【Chemistry 17】 and X ５ is selected from the group consisting of —NH—, —O—, and —S—; X ６ The compound of claim 14, wherein is -CH- or -N-.

16. Ar ２ but [Chemistry 18] 15. The compound of claim 14, wherein:

17. Ar ２ but 【Chemistry 19】 4. The compound of claim 1 or 3, selected from the group consisting of: 【Request Item 18】 【Chemistry 20】 4. The compound of claim 3 having the structure: or a pharmaceutically acceptable salt thereof.

19. 2. The compound of claim 1, which is a compound described in any one of Tables 1 to 8.

20. 4. The compound of claim 3, which is a compound described in any one of Tables 1 to 7.

21. 21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

22. 22. A method for treating a disease or condition mediated by the kappa opioid receptor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 20 or a pharmaceutical composition of claim 21.

23. 23. The method of claim 22, wherein the disease or condition being treated is selected from the group consisting of pain, itch, addiction, depression, myocardial infarction, pruritus, inflammation, edema, nausea, neuroinflammation, stroke, hypoxic pulmonary hypertension, ocular inflammation, glaucoma, multiple sclerosis, osteoarthritis, rheumatoid arthritis, inflammatory bowel disease, and eczema.

24. 24. The method of claim 22 or 23, wherein the subject does not experience discomfort or sedation.

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