Small molecule modulators of PAR2 and uses thereof

Abstract

TIFF2025537145000106.tif48164 or a stereoisomer or salt thereof (e.g., a pharmaceutically acceptable salt thereof), wherein R 1a , R 1b , R 2 , R 3a , R 3b , R 4a , R 4b , R 5a , Z, X, and m are as defined herein. The use of the compounds as components of pharmaceutical compositions and methods for their use are also provided.

Description

[Technical Field]

[0001] The present invention is in the field of pharmaceutical pharmacology. In particular, the present invention relates to a new class of small molecules having an imidazopyrazine-dione (or related) structure that function as modulators (activators, inhibitors) of protease-activated receptor type 2 (PAR2), and their use as therapeutic agents for the treatment of conditions involving PAR2 activity (e.g., asthma, chronic pain, migraine, osteoarthritis, cancer, inflammatory disorders, and / or vascular disorders). [Background technology]

[0002] 2. Description of Related Art Chronic pain is a neurological disorder that affects the lives of millions of Americans. Chronic pain may be associated with specific diseases, including cancer, or may be idiopathic with no clear underlying cause. Current treatments for chronic pain are limited by their potential for abuse and excessive side effects. Endogenous proteases are involved in acute and chronic pain through the direct activation of PAR2. PAR2 is a G protein-coupled receptor (GPCR) known to play an important role in chemical, inflammatory, and cancer-induced pain and is involved in the transition to chronic pain states (e.g., Bao et al., Mol Pain. 2014 May 5;10:28; Tian et al., Transl Neurosci. 2015 Mar 18;6(1):111-116; Soeda et al., Mol Pain. 2021 Jan-Dec;17:17448069211002009; Tillu et al., Pain. 2015 May;156(5):859-867). PAR2, expressed in peripheral nociceptors, enhances pain transmission through the activation of transient receptor potential (TRP) channels and the production of inflammatory mediators such as neurotransmitters and prostaglandins (e.g., Zhao et al., J Biol Chem. 2014 Sep 26;289(39); Hassler et al., JCI Insight. 2020 Jun 4;5(11); Grabauskas, et al., Gastroenterology. 2020 Jun;158(8):2195-2207). Blocking peripheral PAR2 activation is a promising approach for limiting chronic non-cancer and cancer pain, and is more effective than nonsteroidal anti-inflammatory drugs (NSAIDs) without the abuse risk associated with opioids.

[0003] Asthma is a potentially debilitating disease that is on the rise in industrialized countries. Available treatments for asthma remain static, and novel approaches to treatment are needed. Cell and animal studies have revealed a prominent role for airway epithelial PAR2 in the release of harmful inflammatory cytokines and protective ecaisonoids in response to allergic asthma. These apparently opposing responses can be targeted with novel compounds that individually or collectively modulate multiple signaling pathways associated with allergen-induced PAR2 activation.

[0004] Osteoarthritis (OA) is the most common chronic pain disorder, primarily affecting people in later life. Animal models and clinical data suggest that PAR2 signaling in cells within injured joints and in nociceptors innervating joint nerves contributes to both the underlying inflammation and pain associated with OA. Proteases released by immune cells within OA joints are thought to activate PAR2 on these cells, making PAR2 antagonists a viable treatment option for OA.

[0005] Migraine pain is a major clinical problem. Nearly 15 percent of the world's population suffers from migraine during their lifetime (e.g., Vos, T., et al., Lancet, 2012, 380(9859):pp. 2163-96), with more than 36 million migraine sufferers in the United States alone. Despite this significant number of sufferers, treatments for migraine pain remain largely unchanged, often over-the-counter analgesics. Part of the problem is that the etiology of migraine is complex and poorly understood. Unlike common headaches, migraine has specific symptoms that can include prodromal, aura, and postdromal symptoms, and migraine pain lasts from 4 to 72 hours. Light and sound sensitivity, cutaneous allodynia, nausea, and other sensorimotor irregularities are also common symptoms of migraine. It is widely accepted that the trigeminal sensory system, including trigeminal ganglion (TG) nociceptors projecting to the dura mater, is responsible for migraine-related pain (e.g., Bernstein, C. and R. Burstein, Journal of Clinical Neurology, 2012, 8(2):89-99; Levy, D., Headache, 2010, 50(5):909-16). However, it is not understood how nociceptive afferents from the trigeminal nervous system are activated / sensitized during a migraine attack or where the insult that triggers a migraine attack may originate. Deep cranial tissues, such as the meninges, or perhaps the pericranium, are likely involved in nociception during a migraine attack, and both have been studied in animal models of migraine.

[0006] Previous research in the field of migraine has revealed that meningeal mast cell degranulation can release serine proteases, which can activate PARs, and this response can activate dural afferents projecting to the trigeminal nerve (e.g., Zhang, X. Can and D. Levy, Cephalalgia, 2008. 28(3): pp. 276-84). Zhang and Levy used single-unit recording electrophysiology to monitor neurons within the trigeminal ganglion of anesthetized rats and applied SLIGRL, a nonspecific peptide activator of PAR2, to the dura of these animals. SLIGRL exposure resulted in activation and sensitization of TG neurons. Direct injection of the potent and specific PAR2 agonist, 2-aminothiazole-LIGRL, or a mast cell degranulator into the dura, produced migraine-like pain, which was mediated by PAR2. - / - This study suggests an important neuro-immune relationship that may explain the diverse pathogenesis of migraine, as mast cell degranulation may be triggered by cortical spreading depression (CSD), nitric oxide (NO) donors, calcitonin gene-related peptide (CGRP), and elevated stress, all of which are associated with migraine.

[0007] Atopic dermatitis (AD) is a common inflammatory skin disease characterized by chronic, uncontrollable itching. PAR2 is activated in keratinocytes by proteases released by pathogens and endogenous proteases, such as kallikrein and tryptase, which can induce the activation of temperature-sensitive TRP channels, the release of inflammatory cytokines, and the disruption of the skin barrier, potentially resulting in itch-like behavior (e.g., Zhao et al., J Invest Dermatol. 2020 Aug;140(8):1524-1532; Buhl et al., Front Immunol. 2020 Aug 12;11:1740). Currently, topical steroids and emollient creams are the main common treatments for AD, but they fail to control itch in many patients. PAR2 inhibition is a promising potential treatment for AD in patients with inadequate control with topical agents.

[0008] There is a need for improved methods for treating conditions involving aberrant PAR2 activity, including chronic pain, asthma, osteoarthritis, and migraine. The present disclosure fulfills these needs and provides other related advantages. Summary of the Invention

[0009] Briefly, the present disclosure provides PAR2 modulator compounds, including stereoisomers or salts (e.g., pharmaceutically acceptable salts) thereof, that can be used alone or in combination with a pharmaceutically acceptable carrier. Methods for using the PAR2 modulator compounds for the treatment of various diseases or conditions, such as asthma, migraine-related pain, chronic pain, cancer, and vascular disorders, are also provided.

[0010] In one embodiment, a compound having the following structure (I):

[0011] [ka] or a stereoisomer or salt thereof, wherein R 1a , R 1b, R 2 , R 3a , R 3b , R 4a , R 4b , R 5a , Z, X, and m are as defined herein. Use of the compounds as components of pharmaceutical compositions and methods for their use are also provided. Pharmaceutical compositions comprising one or more of the foregoing compounds of structure (I) and a therapeutic agent are also provided.

[0012] In other embodiments, the disclosure provides a method for administering a therapeutic agent to a patient in need thereof, the method comprising preparing a composition comprising a compound of structure (I) and a therapeutic agent, and delivering the composition to the patient.

[0013] These and other aspects of the present disclosure will be apparent from and elucidated with reference to the following detailed description. [Brief explanation of the drawings]

[0014] [Figure 1A] 1 shows a graph of normalized cell index versus time for various concentrations of compound I-1 as an antagonist of PAR2, using the PAR2 antagonist 2-at-LIGRL-NH2 (2AT) as a reference. [Figure 1B] 1 shows a graph of normalized cell index versus time for various concentrations of compound I-1 as an antagonist of PAR2 using trypsin as a standard. [Figure 1C] 1 shows a graph of % cells in 150 nM [Ca 2+ ] versus various concentrations of compounds I-1 and 2AT as measured by digital imaging microscopy. [Figure 1D] FIG. 1 shows a graph of % increase from normalized baseline p-MAPK versus concentration of compound I-1 in an assay for β-arrestin / MAPK signaling. [Figure 2] 1 shows a graph of face withdrawal threshold versus time in a series of experiments performed with compound I-1. [Figure 3]1 is a graph of total airway resistance versus the amount of methacholine administered in a series of experiments performed with compound I-1. DETAILED DESCRIPTION OF THE INVENTION

[0015] compound In one aspect, the present disclosure provides PAR2 modulator compounds, including stereoisomers or salts thereof (e.g., pharmaceutically acceptable salts thereof), that can be used alone or in combination with a pharmaceutically acceptable carrier. Methods for using the PAR2 modulator compounds for the treatment of various diseases or conditions, such as asthma, migraine-related pain, chronic pain, cancer, and vascular disorders, are also provided.

[0016] In one embodiment, the compound has the following structure (I):

[0017] [ka] or a stereoisomer or salt thereof, wherein R 1a and R 1b are each independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, aryl, or arylalkyl; R 2 is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 heterocyclylalkyl, C3-C8 heterocyclylalkylC 1-6 alkyl, heteroaryl, heteroarylalkyl, or arylalkyl; Z is i)

[0018] [ka] is a double bond and is oxygen, or ii)

[0019] [ka] is a single bond, then hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, or arylalkyl; R 3a and R 3b are each independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, or arylalkyl; X is N or C(R 5b ) and; i)R 4a and R 4b are each independently hydrogen, C-C alkyl, C-C heteroalkyl, C-C cycloalkyl, C-C heterocyclylalkyl, arylalkyl, or heteroarylalkyl; and R 5a and R 5b are each independently hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, C3-C8 heterocyclylalkyl, arylalkyl, heteroarylalkyl, -C(=O)R 6 , -C(=O)YR 6 , -OC(=O)R 6 , -OC(=O)YR 6 , -NHC(=O)R 6 , or -NHC(=O)YR 6 However, R 5a and R 5b are each independently -NHC(=O)R 6 , or -NHC(=O)YR 6 If R 6 is not arylalkyl; or ii)R 4a forms a direct bond with X, and R 4b and R 5b together form a 5- to 9-membered fused ring; R 6 is a C3-C8 cycloalkyl, a C3-C8 heterocyclylalkyl, an arylalkyl, a heteroarylalkyl, or a fused ring; Y is O, S, or NR 7 and; R7 is hydrogen, hydroxyl, or C1-C6 alkyl; m is 1 or 2; and R 1a , R 1b , R 2 , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6 , and R 7 Each of is optionally substituted with one or more substituents.

[0020] In some embodiments, m is 1. In some other embodiments, m is 2.

[0021] In some embodiments, X is N. In certain embodiments, the compound has the following structure (Ia):

[0022] [ka] or a stereoisomer or salt thereof.

[0023] In some embodiments, X is N and Z is oxygen. In certain embodiments, the compound has the following structure (Ib):

[0024] [ka] or a stereoisomer or salt thereof.

[0025] In some other embodiments, m is 2 and X is N. In certain embodiments, the compound has the following structure (Ic):

[0026] [ka] or a stereoisomer or salt thereof.

[0027] In some embodiments, m is 2, X is N, and Z is oxygen. In certain embodiments, the compound has the following structure (Id):

[0028] [ka] or a stereoisomer or salt thereof.

[0029] In some embodiments, X is C(R 5b ) and the compound has the following structure (Ij):

[0030] [ka] It has.

[0031] In some embodiments, R 4a forms a direct bond with X, and R 4b and R 5b are taken together to form a 5- to 9-membered fused ring. In some certain embodiments, the compound has one of the following structures (Ie) to (Ih):

[0032] [ka] or a stereoisomer or salt thereof, wherein R 8 is hydrogen, halo, hydroxyl, alkoxy, amino, cyano, C1-C6 alkyl, or C1-C6 heteroalkyl; and V is a carbon, nitrogen, or oxygen atom.

[0033] In some embodiments, R 1a or R 1b is hydrogen. In some particular embodiments, R 1a and R 1b Each of R is hydrogen. 1a or R 1b is C1-C6 alkyl. In some other embodiments, R 1a or R1b is C1-C6 heteroalkyl. In some other embodiments, R 1a or R 1b is C-C cycloalkyl. In some other embodiments, R 1a or R 1b is aryl. In some other embodiments, R 1a or R 1b is arylalkyl. In some other embodiments, R 1a and R 1b has one of the following structures:

[0034] [ka] In the formula, n is independently 0 to 5, n' is 1 to 4, and R 9 is hydrogen, halo, hydroxyl, alkoxy, amino, cyano, C1-C6 alkyl, or C1-C6 heteroalkyl.

[0035] In some embodiments, n is 0, 1, 2, 3, 4, or 5. In some embodiments, n is 0. In some other embodiments, n is 1. In some other embodiments, n is 2. In some other embodiments, n is 3. In some other embodiments, n is 4. In some other embodiments, n is 5.

[0036] In some embodiments, n' is 1, 2, 3, or 4. In some embodiments, n' is 1. In certain embodiments, when n' is 1, it is cyclopropane. In some other embodiments, n' is 2. In certain embodiments, when n' is 2, it is cyclobutane. In some other embodiments, n' is 3. In certain embodiments, when n' is 3, it is cyclopentane. In some other embodiments, n' is 4. In certain embodiments, when n' is 4, it is cyclohexane.

[0037] In some embodiments, R 9 is hydrogen. In some other embodiments, R 9 is halo. In some other embodiments, R 9 is hydroxyl. In some other embodiments, R 9 is alkoxy. In some other embodiments, R 9 is amino. In some other embodiments, R 9 is cyano. In some other embodiments, R 9 is C1-C6 alkyl. In some other embodiments, R 9 is C1-C6 heteroalkyl.

[0038] In some embodiments, R 2 is hydrogen. In some other embodiments, R 2 is C1-C6 alkyl. In some other embodiments, R 2 is C1-C6 heteroalkyl. In some other embodiments, R 2 is C-C heterocyclylalkyl. In some other embodiments, R 2 is a C3-C8 heterocyclylalkylC 1-6 In some other embodiments, R 2 is heteroaryl. In some other embodiments, R 2 is heteroarylalkyl. In some other embodiments, R 2 is arylalkyl. In some embodiments, R 2 has one of the following structures:

[0039] [ka] In the formula, n is independently 0 to 6, and n' is 1 to 5; G 2 is CH2, N, O, or S; W is CH or N; A is O, NH, or NHR 9 where i) if A is O, then:

[0040] [ka] is a double bond, or ii) A is NH or NHR 9 If

[0041] [ka] is a single bond; B is OR 9 , NH2, or NHR 9 and;R 9 is hydrogen, halo, hydroxyl, alkoxy, amino, cyano, C-C alkyl, or C-C heteroalkyl; and R 10 is i) absent or ii) hydrogen, alkyl, aryl, pyridyl, acylalkyl, or acylaryl.

[0042] In some particular embodiments, R 2 teeth,

[0043] [ka] is.

[0044] In some embodiments,

[0045] [ka] is a double bond, then Z is oxygen. In some particular embodiments, when Z is oxygen, the compound has one of the following structures:

[0046] [ka]

[0047] [ka]

[0048] In some other embodiments,

[0049] [ka] is a single bond, then Z is hydrogen.

[0050] [ka] is a single bond, then Z is C-C alkyl. In some embodiments,

[0051] [ka] When is a single bond, Z is C1-C6 heteroalkyl.

[0052] [ka] is a single bond, then Z is C-C cycloalkyl.

[0053] [ka] When is a single bond, Z is arylalkyl. In some embodiments,

[0054] [ka] When is a single bond, the compound has one of the following structures:

[0055] [ka]

[0056] In some embodiments, R 3a or R3b is hydrogen. In some other embodiments, R 3a or R 3b is C1-C6 alkyl. In some other embodiments, R 3a or R 3b is C1-C6 heteroalkyl. In some other embodiments, R 3a or R 3b is C-C cycloalkyl. In some other embodiments, R 3a or R 3b is arylalkyl. In some embodiments, R 3a or R 3b has one of the following structures:

[0057] [ka] In the formula, n is independently 0 to 6, and n' is 1 to 5; G 3 are each independently C(R 7 )2, O, S, or NR 7 each W is independently CH or N; and A is O, NH, or NHR 9 where i) if A is O, then:

[0058] [ka] is a double bond, or ii) A is NH or NHR 9 If

[0059] [ka] is a single bond; B is OR 9 , NH2, or NHR 9 and;R 9 is hydrogen, halo, hydroxyl, alkoxy, amino, cyano, C-C alkyl, or C-C heteroalkyl; and R 10is i) absent or ii) hydrogen, alkyl, aryl, pyridyl, acylalkyl, or acylaryl.

[0060] In some particular embodiments, R 3a or R 3b One of the groups is hydrogen, and R 3a or R 3b The other one is

[0061] [ka] In some other particular embodiments, R 3a or R 3b One of the groups is hydrogen, and R 3a or R 3b The other one is

[0062] [ka] is.

[0063] In some embodiments, R 4a or R 4b is hydrogen. In some other embodiments, R 4a or R 4b is C1-C6 alkyl. In some other embodiments, R 4a or R 4b is C1-C6 heteroalkyl. In some other embodiments, R 4a or R 4b is C-C cycloalkyl. In some other embodiments, R 4a or R 4b is C-C heterocyclylalkyl. In some other embodiments, R 4a or R 4b is arylalkyl. In some other embodiments, R 4a or R 4b is heteroarylalkyl. In some embodiments, R 4a or R 4bhas one of the following structures:

[0064] [ka] In the formula, n is independently 0 to 6, and n' is 1 to 5; G 4 are each independently C(R 7 )2, O, S, or NR 7 each W is independently CH or N; and A is O, NH, or NHR 9 where i) if A is O, then:

[0065] [ka] is a double bond, or ii) A is NH or NHR 9 If

[0066] [ka] is a single bond; B is OR 9 , NH2, or NHR 9 and;R 9 is hydrogen, halo, hydroxyl, alkoxy, amino, cyano, C-C alkyl, or C-C heteroalkyl; and R 10 is i) absent or ii) hydrogen, alkyl, aryl, pyridyl, acylalkyl, or acylaryl.

[0067] In some particular embodiments, R 4a or R 4b is hydrogen and R 4a or R 4b The other one is

[0068] [ka] is.

[0069] In some embodiments, R5a or R 5b is hydrogen. In some other embodiments, R 5a or R 5b is C1-C6 alkyl. In some other embodiments, R 5a or R 5b is C1-C6 hydroxyalkyl. In some other embodiments, R 5a or R 5b is C-C cycloalkyl. In some other embodiments, R 5a or R 5b is C-C heterocyclylalkyl. In some other embodiments, R 5a or R 5b is arylalkyl. In some other embodiments, R 5a or R 5b is heteroarylalkyl. In some embodiments, R 5a or R 5b is -C(=O)R 6 In some other embodiments, R 5a or R 5b is -C(=O)YR 6 In some other embodiments, R 5a or R 5b is -OC(=O)R 6 In some other embodiments, R 5a or R 5b is -OC(=O)YR 6 In some other embodiments, R 5a or R 5b is -NHC(=O)R 6 In some other embodiments, R 5a or R 5b is -NHC(=O)YR 6 In some embodiments, R 5a has one of the following structures:

[0070] [ka]

[0071] [ka] In the formula, n is 0 to 6, and n' is 1 to 5; G 5 are each independently C(R 7 )2, O, S, or NR 7 and each W is independently CH or N.

[0072] In some embodiments, n is 0. In some other embodiments, n is 1. In some other embodiments, n is 2. In some other embodiments, n is 3. In some other embodiments, n is 4. In some other embodiments, n is 5. In some other embodiments, n is 6.

[0073] In some embodiments, n' is 1. In some other embodiments, n' is 2. In some other embodiments, n' is 3. In some other embodiments, n' is 4. In some other embodiments, n' is 5.

[0074] In some embodiments, W is CH. In some other embodiments, W is C(R 7 )2. In some other embodiments, W is O. In some other embodiments, W is N. In some other embodiments, W is S. In some other embodiments, W is NR 7 is.

[0075] In some embodiments, R 7 is hydrogen. In some other embodiments, R 7 is hydroxyl. In some other embodiments, R 7 is C1-C6 alkyl.

[0076] In some embodiments, R 9 is hydrogen. In some other embodiments, R 9is halo. In some other embodiments, R 9 is hydroxyl. In some other embodiments, R 9 is alkoxy. In some other embodiments, R 9 is amino. In some other embodiments, R 9 is cyano. In some other embodiments, R 9 is C1-C6 alkyl. In some other embodiments, R 9 is C1-C6 heteroalkyl.

[0077] In some particular embodiments, R 5a teeth,

[0078] [ka] and R 5b is hydrogen. In certain embodiments, Z is O and R 9 is hydrogen. In some embodiments, R 5b has the following structure:

[0079] [ka]

[0080] In some embodiments, R 5a has one of the following structures:

[0081] [ka]

[0082] In some embodiments, R 6 is C-C cycloalkyl. In some other embodiments, R 6 is C-C heterocyclylalkyl. In some other embodiments, R 6 is arylalkyl. In some embodiments, R 6is heteroarylalkyl. In some embodiments, R 6 is a 5- to 9-membered fused ring.

[0083] In some embodiments, the compound is in free base form. In certain embodiments, the compound is a pharmaceutically acceptable salt. In certain embodiments, the compound is a tautomer.

[0084] In various different embodiments, the compound has one of the structures (or a stereoisomer or salt thereof) set forth in Table 1 below.

[0085] [Table 1-1] TIFF2025537145000041.tif186164

[0086] [Table 1-2] TIFF2025537145000042.tif186164

[0087] [Table 1-3] JPEG2025537145000043.jpg235158

[0088] [Table 1-4] TIFF2025537145000044.tif231164

[0089] It is understood that any embodiment of the compounds of Structures (I)-(Ih) as described above, and any particular substituents and / or variables in the compounds of Structures (I)-(Ih) as described above, can be combined individually with other embodiments of the compounds of Structures (I)-(Ih) and / or with substituents and / or variables to form embodiments of the present disclosure not specifically set forth above. Additionally, when lists of substituents and / or variables are recited in particular embodiments and / or claims for any particular R group or variable n or m, it is understood that each individual substituent and / or variable can be deleted from the particular embodiment and / or claim, and the remaining listed substituents and / or variables are considered to be within the scope of the present disclosure. It is understood that combinations of substituents and / or variables in the depicted formulae are permissible herein only if such combinations result in stable compounds.

[0090] In the description, certain specific details are set forth to provide a thorough understanding of various embodiments of the present disclosure. However, those skilled in the art will understand that embodiments of the present disclosure may be practiced without these details. As used herein, the following terms have the meanings ascribed to them unless otherwise specified:

[0091] Unless the context otherwise requires, throughout this specification and claims, the term "comprise" and variations thereof, such as "comprises" and "comprising," are to be interpreted in an open-ended and inclusive sense, i.e., "including but not limited to."

[0092] Throughout this specification, references to "one embodiment" or "an embodiment" refer to a particular feature, structure, or characteristic described in connection with an embodiment included in at least one embodiment of the present disclosure. Thus, appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0093] 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 to which this disclosure pertains. As used in this specification and the claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0094] "Hydroxy" or "hydroxyl" refers to the --OH radical.

[0095] "Amino" refers to the -NH2 radical.

[0096] "Cyano" refers to the -CN radical.

[0097] "Alkyl" refers to a saturated straight or branched hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, having from 1 to 6 carbon atoms (C1-C6 alkyl), attached to the rest of the molecule by a single bond. Examples of hydrocarbon chain radicals include methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), iso-pentyl, n-hexyl, and the like. Unless specifically stated otherwise in the specification, alkyl groups are optionally substituted.

[0098] "Cycloalkyl" refers to a saturated cyclic hydrocarbon having from 3 to 8 carbon atoms (C3-C8 cycloalkyl) attached to the rest of the molecule by a single bond. Examples of saturated cyclic hydrocarbon radicals include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Unless specifically stated otherwise in the specification, cycloalkyl groups are optionally substituted.

[0099] "Halo" refers to fluoro, chloro, bromo, or iodo. Halo is in Group 17 of the periodic table.

[0100] "Alkoxy" means a group of the formula -OR a is a radical of the formula a is an alkyl radical as defined above, containing 1 to 12 carbon atoms (C1-C 12 "C-Calkoxy" refers to a radical containing 1 to 8 carbon atoms (C-Calkoxy), 1 to 8 carbon atoms (C-Calkoxy), or 1 to 6 carbon atoms (C-Calkoxy), or any value within these ranges. Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted.

[0101] "Haloalkyl" refers to an alkyl radical, as defined above, substituted with one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless stated otherwise specifically in the specification, a haloalkyl group is optionally substituted.

[0102] "Haloalkoxy" refers to a radical having the following formula: -Ohaloalkyl, where haloalkyl is as defined above. Unless stated otherwise specifically in the specification, a haloalkoxy group is optionally substituted.

[0103] "Hydroxylalkyl" or "hydroxyalkyl" refers to an alkyl radical, as defined above, substituted with one or more hydroxyl radicals. The hydroxyalkyl radical is attached to the backbone through an alkyl carbon atom. Unless specifically stated otherwise in the specification, a hydroxyalkyl group is optionally substituted.

[0104] "Aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group of 6 to 12 carbon atoms having a completely conjugated pi-electron system. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. Aryl groups can be substituted or unsubstituted. When substituted, an aryl group is substituted with one or more substituents as defined below, more preferably with 1, 2, or 3, and even more preferably with 1 or 2 substituents, which are independently selected from the group consisting of alkyl (wherein alkyl can be optionally substituted with 1 or 2 substituents), haloalkyl, halo, hydroxy, alkoxy, mercapto, alkylthio, cyano, acyl, nitro, phenoxy, heteroaryl, heteroaryloxy, haloalkyl, haloalkoxy, carboxy, alkoxycarbonyl, amino, alkylaminodialkylamino, aryl, heteroaryl, carbocycle, or heterocycle (wherein the aryl, heteroaryl, carbocycle, or heterocycle can be optionally substituted).

[0105] "Heterocyclyl," "heterocyclo," or "heterocycle" refers to a stable 3- to 18-membered non-aromatic ring radical consisting of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, a heterocyclyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heterocyclyl radical can be optionally oxidized, the nitrogen atom can be optionally quaternized, and the heterocyclyl radical can be partially saturated or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, heterocyclyl groups are optionally substituted.

[0106] "Heteroaryl" refers to a 5- to 18-membered ring, e.g., a 5- to 6-membered ring system radical containing 1 to 13 ring carbon atoms, 1 to 6 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. The heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, and isoindolinyl. Heteroaryl groups include, but are not limited to, phenyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, heteroaryl groups are optionally substituted.

[0107] "Fused ring" refers to a polycyclic ring system (i.e., three or more cyclic rings) in which any two adjacent rings share at least two adjacent atoms. Fused rings can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may contain heteroatoms. Examples include octahydrocyclopenta[c]pyrrole, hexahydrocyclopenta[c]pyrrol-1(2H)-one, 3,6-dihydrocyclopenta[c]pyrrol-1(2H)-one, 4,5-dihydropyrrolo[3,4-b]pyrrol-6(1H)-one, 4,5-dihydro-6H-furo[2,3-c]pyrrol-6-one, 3,4-dihydrocyclopenta[c]pyrrol-1(2H)-one, 5,6-dihydro These include, but are not limited to, pyrrolo[3,4-b]pyrrol-4(1H)-one, 5,6-dihydro-4H-furo[2,3-c]pyrrol-4-one, isoindolin-1-one, 3,8-dihydroindeno[1,2-c]pyrrol-1(2H)-one, 1,4-dihydropyrrolo[3,4-b]indol-3(2H)-one, 1,2-dihydro-3H-benzofuro[2,3-c]pyrrol-3-one, and the like.

[0108] A "substituent" is an atom or group of atoms that replaces (one or more) atoms and thereby becomes part of the resulting (new) molecule. For example, the one or more substituents can include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonate, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof.

[0109] As used herein, the term "substituted" refers to any of the above groups (e.g., alkyl, cycloalkyl, or heterocyclyl) in which at least one hydrogen atom has been replaced by a bond to a non-hydrogen atom, such as, but not limited to, halogen atoms such as F, Cl, Br, and I; oxo groups (=O); hydroxyl groups (-OH); alkoxy groups (-OR a , where R a is C1-C 12 alkyl or cycloalkyl); carboxyl group (-OC(=O)R a or -C(=O)OR a , where R a is H, C1-C 12 alkyl or cycloalkyl); an amine group (—NR a R b , where R a and R b are each independently H, C1-C 12 alkyl, or cycloalkyl); C1-C 12 alkyl groups; and cycloalkyl groups. In some embodiments, the substituents are C-C 12 In other embodiments, the substituent is an alkyl group. In other embodiments, the substituent is a cycloalkyl group. In other embodiments, the substituent is a halo group, such as fluoro or bromo. In other embodiments, the substituent is an oxo group. In other embodiments, the substituent is a hydroxyl group. In other embodiments, the substituent is an alkoxy group. In other embodiments, the substituent is a carboxyl group. In other embodiments, the substituent is an amine group.

[0110] "Optional" or "optionally" (e.g., optionally substituted) means that the subsequently described circumstance event may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, "optionally substituted alkyl" means that the alkyl radical may or may not be substituted, and that the description includes both substituted and unsubstituted alkyl radicals.

[0111] A "prodrug" refers to a compound that can be converted into a biologically active compound of the present disclosure under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the present disclosure. A prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the present disclosure. Prodrugs are typically rapidly transformed in vivo, for example, by hydrolysis in blood, to yield the parent compound of the present disclosure. Prodrug compounds often offer advantages such as solubility, tissue compatibility, or delayed release in mammals (see Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). Discussions of prodrugs are presented in Higuchi, T., et al., ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, Ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0112] The term "prodrug" is also meant to include any covalently bonded carriers that release an active compound of the present disclosure in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of the present disclosure can be prepared by modifying functional groups present in the compounds of the present disclosure such that the modifications are cleaved, either by routine manipulation or in vivo, to yield the parent compound of the present disclosure. Prodrugs include compounds of the present disclosure in which a hydroxy, amino, or mercapto group is bonded to any group that is cleaved to generate the free hydroxy, free amino, or free mercapto group, respectively, when a prodrug of the compound of the present disclosure is administered to a mammalian subject. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol or amide derivatives of amine functional groups in the compounds of the present disclosure.

[0113] The embodiments disclosed herein are also intended to encompass all pharmaceutically acceptable compounds of structures (I)-(Ih) that are isotopically labeled by replacing one or more atoms with an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphate, fluorine, chlorine, and iodine, such as: 2 H, 3 H, 11 C, 13 C , 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125I. These radioisotope-labeled compounds may be useful to aid in determining or measuring the efficacy of compounds, for example, by characterizing the site or mode of action, or binding affinity to a pharmacologically important site of action. Certain isotopically labeled compounds of structures (I)-(Ih), for example, compounds incorporating a radioisotope, are useful in drug and / or substrate tissue distribution studies. The radioisotope tritium, i.e., 3 H, and carbon-14, i.e., 14 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[0114] Heavier isotopes such as deuterium, i.e. 2 Substitution with H may be preferred in some cases, as it may confer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0115] 11 C. 18 F, 15 O and 13 Substitution with positron-emitting isotopes, such as N, can be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds of structures (I)-(Ih) can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the preparations and examples below, employing appropriate isotopically labeled reagents in place of previously employed non-labeled reagents.

[0116] The embodiments disclosed herein are also intended to encompass in vivo metabolic products of the compounds of the present disclosure. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily by enzymatic processes. Accordingly, the present disclosure includes compounds produced by a process comprising administering a compound of the present disclosure to a mammal for a period of time sufficient to yield its metabolic products. Such products are typically identified by administering a detectable dose of a radioisotope-labeled compound of the present disclosure to an animal, such as a rat, mouse, guinea pig, monkey, or human, allowing sufficient time for metabolism to occur, and isolating the conversion products from urine, blood, or other biological sample.

[0117] "Stable compound" and "stable structure" are intended to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0118] "Mammals" includes humans and both domestic animals, such as laboratory animals and household pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and non-domesticated animals, such as wild animals.

[0119] A "pharmaceutically acceptable carrier, diluent, or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the United States Food and Drug Administration as acceptable for human or veterinary use.

[0120] "Pharmaceutically acceptable salt" includes both acid and base addition salts.

[0121] "Pharmaceutically acceptable acid addition salts" refer to salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; and, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, gluconic acid, acetic acid, citric ... These salts refer to salts formed with organic acids such as propionic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxoglutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid (TFA), and undecylenic acid.

[0122] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acids and are not biologically or otherwise undesirable. These salts are prepared from the addition of an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0123] A "pharmaceutical composition" refers to a formulation of a compound of the present disclosure with a vehicle generally accepted in the art for the delivery of a biologically active compound to a mammal, e.g., a human, including any and all pharmaceutically acceptable carriers, diluents, or excipients thereof.

[0124] "Effective amount" or "therapeutically effective amount" refers to the amount of a compound of the present disclosure that, when administered to a mammal, preferably a human, is sufficient to treat the mammal, preferably a human. The amount of lipid nanoparticles of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the condition and its severity, the mode of administration, and the age of the mammal being treated, but can be routinely determined by one skilled in the art in light of their own knowledge and the present disclosure.

[0125] As used herein, "treating" or "treatment" encompasses the treatment of a disease or condition of interest in a mammal, preferably a human, suffering from the disease or condition of interest, and includes: (i) preventing the occurrence of a disease or condition in a mammal, particularly where such mammal is susceptible to the condition but has not yet been diagnosed with the condition; (ii) inhibiting the disease or condition, i.e., preventing its development; (iii) alleviating the disease or condition, i.e., causing the disease or condition to regress; or (iv) Relieving symptoms resulting from a disease or condition, i.e., relieving pain without addressing the underlying disease or condition. As used herein, the terms "disease" and "condition" may be used interchangeably, or may be used differently in that a particular illness or condition may not have a known causative factor (and thus its etiology has not yet been determined) and is therefore not yet recognized as a disease, but only as an undesirable condition or syndrome in which a more or less specific set of symptoms has been identified by clinicians.

[0126] The compounds of the present disclosure or their salts (e.g., pharmaceutically acceptable salts) may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, which may be defined in terms of absolute stereochemistry as (R)- or (S)-, or with respect to amino acids, as (D)- or (L)-. The present disclosure is intended to encompass all such possible isomers, as well as their racemic and optically pure forms. Optically active (+)- and (−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents or separated using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative), using, for example, chiral high-pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers, as well as all tautomeric forms.

[0127] "Stereoisomers" refer to compounds composed of the same atoms connected by the same bonds but with different, non-interchangeable three-dimensional structures. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers that are mirror images of one another whose molecules are non-superimposable. The present disclosure also contemplates "diastereomers," which refer to non-identical stereoisomers that are not mirror images. Diastereomers occur when two or more stereoisomers of a compound have different configurations at one or more of the equivalent stereocenters and are not mirror images of one another.

[0128] "Tautomer" refers to a proton transfer from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any of the compounds described above.

[0129] Pharmaceutical Composition Other embodiments relate to pharmaceutical compositions. The pharmaceutical composition comprises one (or more) of the aforementioned compounds and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In yet other embodiments, the pharmaceutical composition comprises a compound as disclosed herein and an additional therapeutic agent (e.g., an anti-cancer agent). Non-limiting examples of such therapeutic agents are described herein below.

[0130] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, intraocular, pulmonary, transmucosal, transdermal, intravaginal, otic, nasal, and topical administration. Additionally, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0131] In certain embodiments, compounds as described herein are administered locally rather than systemically, for example, via direct injection of the compound into an organ, often in a depot preparation or sustained-release formulation. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, compounds are delivered in targeted drug delivery systems, for example, in liposomes coated with organ-specific antibodies. In such embodiments, the liposomes are targeted and selectively taken up by the organ. In still other embodiments, compounds as described herein are provided in the form of rapid-release formulations, sustained-release formulations, or intermediate-release formulations. In still other embodiments, compounds as described herein are administered locally.

[0132] In methods of treatment according to embodiments of the present disclosure, an effective amount of at least one compound of structure (I)-(Ih) is administered to a subject suffering from or diagnosed as suffering from such a disease, disorder, or medical condition. An effective amount or dose can be ascertained by methods such as modeling, dose escalation studies, or clinical trials, taking into account, for example, the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing treatments, the subject's health status and response to the drugs, and the judgment of the treating physician.

[0133] The compounds of the present disclosure are effective over a wide dosage range. For example, in the treatment of adult humans, dosages of 10-5000 mg per day, 10 ...

[0134] In some embodiments, the compounds of the present disclosure are administered in a single dose. Typically, such administration is by injection, for example, intravenous injection, to rapidly introduce the drug. However, other routes can also be used as needed. A single dose of the compounds of the present disclosure can also be used to treat acute conditions.

[0135] In some embodiments, the compound of the present disclosure is administered in multiple doses. In some embodiments, administration is approximately once, twice, three times, four times, five times, six times, or more than six times per day. In other embodiments, administration is approximately once a month, once every two weeks, once a week, or once every other day. In another embodiment, the compound of the present disclosure and another agent (e.g., an anticancer agent) are administered together approximately once a day to approximately six times a day. In another embodiment, administration of the compound of the present disclosure and the agent continues for less than about 7 days. In yet another embodiment, administration continues for more than about 6, 10, 14, 28 days, 2 months, 6 months, or 1 year. In some cases, continuous administration is achieved and maintained for as long as necessary.

[0136] Administration of the disclosed compounds may be continued for as long as necessary. In some embodiments, the disclosed compounds are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the disclosed compounds are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the disclosed compounds are administered continuously over an extended period of time, for example, to treat chronic effects.

[0137] In some embodiments, the compounds of the present disclosure are administered in individual dosage forms. It is known in the art that due to inter-subject variability in compound pharmacokinetics, individualization of dosing regimens is necessary for optimal treatment.

[0138] In some embodiments, the compound described herein is formulated into pharmaceutical compositions.In certain embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliary agents that facilitate the processing of the compound of the present disclosure into pharmaceutically usable preparations.Suitable formulations depend on the selected route of administration. Any pharmaceutically acceptable technology, carrier, and excipient, including those described 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, Pennsylvania 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), may be used as suitable for formulating the pharmaceutical compositions described herein.

[0139] Provided herein are pharmaceutical compositions comprising one or more compounds of structures (I)-(Ih) and a pharmaceutically acceptable carrier.

[0140] Provided herein are pharmaceutical compositions comprising one or more compounds selected from the compounds of structures (I)-(Ih) and pharmaceutically acceptable diluent(s), excipient(s), and carrier(s). In certain embodiments, the described compounds are administered as pharmaceutical compositions in which one or more compounds selected from the compounds of structures (I)-(Ih) are mixed with other active ingredients, such as in combination therapy. All combinations of active agents described in the Combination Therapy section below and throughout this disclosure are encompassed herein. In certain embodiments, the pharmaceutical composition comprises one or more compounds of structures (I)-(Ih).

[0141] As used herein, a pharmaceutical composition refers to a mixture of one or more compounds selected from the compounds of structures (I)-(Ih) with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. In certain embodiments, the pharmaceutical composition facilitates administration of the compound to an organism. In some embodiments, a therapeutically effective amount of one or more compounds selected from the compounds of structures (I)-(Ih) provided herein is administered in a pharmaceutical composition to a mammal suffering from the disease, disorder, or medical condition being treated. In certain embodiments, the mammal is a human. In certain embodiments, the therapeutically effective amount will vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compounds described herein are used alone or as components of a mixture with one or more therapeutic agents.

[0142] In one embodiment, one or more compounds selected from the compounds of structures (I)-(Ih) are formulated in an aqueous solution. In certain embodiments, the aqueous solution is selected from a physiologically compatible buffer, such as, by way of example only, Hank's solution, Ringer's solution, or physiological saline. In other embodiments, one or more compounds selected from the compounds of structures (I)-(Ih) are formulated for transmucosal administration. In certain embodiments, transmucosal formulations include penetrants appropriate for the barrier to be permeated. In still other embodiments, where the compounds described herein are formulated for other parenteral injections, suitable formulations include aqueous or non-aqueous solutions. In certain embodiments, such solutions include physiologically compatible buffers and / or excipients.

[0143] In another embodiment, the compound described herein is formulated for oral administration.The compound described herein is formulated by combining active compound with, for example, pharmaceutically acceptable carrier or excipient.In various embodiments, the compound described herein is formulated in oral dosage form, and oral dosage form includes, for example, tablet, powder, pill, dragee, capsule, liquid, gel, syrup, elixir, slurry, suspension etc.

[0144] In certain embodiments, pharmaceutical preparations for oral use can be prepared by mixing one or more solid excipients with one or more of the compounds described herein, optionally grinding the resulting mixture, and then processing the resulting granule mixture to obtain tablets or dragee cores.Suitable excipients include, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others, such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.In certain embodiments, disintegrants are optionally added.Disintegrants include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or its salt, such as sodium alginate.

[0145] In one embodiment, dosage forms such as dragee cores and tablets are provided with one or more suitable coatings. In certain embodiments, a concentrated sugar solution is used to coat the dosage form. The sugar solution optionally contains additional ingredients, such as, by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. Dyes and / or pigments are also optionally added to the coating for identification purposes. Furthermore, dyes and / or pigments are optionally used to characterize different combinations of active compound doses.

[0146] In certain embodiments, a therapeutically effective amount of at least one of the compounds described herein is formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. In certain embodiments, the push-fit capsules contain the active ingredient in admixture with one or more fillers. Fillers include, by way of example only, binders such as lactose or starch, and / or lubricants such as talc or magnesium stearate, and optionally, stabilizers. In other embodiments, the soft capsules contain one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added.

[0147] In still other embodiments, the compounds described herein are formulated for parenteral injection, including formulations suitable for bolus injection or continuous infusion. In certain embodiments, the formulations for injection are provided in unit dosage form (e.g., ampoules) or in multi-dose containers. A preservative is optionally added to the injectable formulation. In still other embodiments, the pharmaceutical composition is formulated in a form suitable for parenteral injection as a sterile suspension, solution, or emulsion in an oily or aqueous vehicle. Parenteral injection formulations optionally contain formulating agents such as suspending agents, stabilizers, and / or dispersing agents. In certain embodiments, pharmaceutical formulations for parenteral administration comprise an aqueous solution of the active compound in water-soluble form. In another embodiment, a suspension of one or more compounds selected from the compounds of structures (I)-(Ih) is prepared as an appropriate oily injection suspension. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. In certain embodiments, aqueous injection suspensions contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents that increase the solubility of the compound, allowing for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.

[0148] Pharmaceutical compositions comprise at least one pharmaceutically acceptable carrier, diluent, or excipient and, as an active ingredient, one or more compounds selected from the compounds of structures (I)-(Ih) described herein. The active ingredient may be in free acid or free base form, or in a pharmaceutically acceptable salt form. Additionally, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), and active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Additionally, the compounds described herein encompass solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. Solvated forms of the compounds presented herein are also considered to be disclosed herein. Additionally, pharmaceutical compositions optionally contain other medicinal or pharmaceutical agents, carriers, adjuvants, such as preservatives, stabilizers, wetting agents, or emulsifiers, solution promoters, salts for adjusting osmotic pressure, buffers, and / or other therapeutically valuable substances.

[0149] Methods for preparing compositions containing the compounds described herein include formulating the compounds with one or more inert pharmaceutically acceptable excipients or carriers to form solid, semi-solid, or liquid forms. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which the compounds are dissolved, emulsions containing the compounds, or solutions containing liposomes, micelles, or nanoparticles containing the compounds disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. Forms of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid before use, or as emulsions. These compositions also optionally contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and the like.

[0150] In some embodiments, pharmaceutical compositions comprising one or more compounds selected from the compounds of structures (I)-(Ih) are illustratively in the form of a liquid in which the drug is present in a dissolved state, a suspended state, or both. Typically, when the composition is administered as a suspension, a first portion of the drug is present in a dissolved state and a second portion of the drug is present in a suspended state in particulate form in a liquid matrix. In some embodiments, the liquid composition comprises a gel formulation. In other embodiments, the liquid composition is aqueous.

[0151] In certain embodiments, the aqueous suspension contains one or more polymers as a suspending agent. The polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropylmethylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein include a mucoadhesive polymer selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0152] The pharmaceutical compositions also optionally include a solubilizing agent to aid in the solubility of one or more compounds selected from the compounds of structures (I)-(Ih). The term "solubilizing agent" generally includes agents that result in the formation of a micellar or true solution of the drug. Certain acceptable nonionic surfactants, e.g., polysorbate 80, are useful as solubilizing agents, as are ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.

[0153] In addition, the pharmaceutical compositions optionally contain one or more pH adjusting or buffering agents, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris-hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

[0154] The composition also optionally contains one or more salts in an amount necessary to make the composition tolerable in osmolality, including those having sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0155] Other pharmaceutical compositions optionally contain one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0156] The composition may contain one or more surfactants to enhance physical stability or for other purposes.Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers, such as octylphenol 10 and octylphenol 40.

[0157] The compositions may also include one or more antioxidants where required to enhance chemical stability. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[0158] In certain embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multi-dose reclosable containers are used, in which case the compositions typically contain a preservative.

[0159] In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are used. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also used. In another embodiment, the compounds described herein are delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. A variety of sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the compound for several weeks up to 100 days. Depending on the chemical nature and biological stability of the therapeutic reagent, additional strategies for protein stabilization are employed.

[0160] In certain embodiments, the formulations described herein include one or more antioxidants, metal chelators, thiol-containing compounds, and / or other general stabilizers. Examples of such stabilizers include, but are not limited to, (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003 to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc, or (n) combinations thereof.

[0161] In some embodiments, the concentration of one or more compounds selected from the compounds of structures (I)-(Ih) provided in the pharmaceutical compositions of the present disclosure is 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 16. %,15.75%,15.50%,15.25%,15%,14.75%,14.50%,14.25%,14%,13.75%,13.50%,13.25%,13%,12.75%,12.50%,12.25%,12%,11.75%,11.50%,11.25%,11%,10.75%,10.50%,10.25%,10%,9.75%,9.50%,9.25%,9%,8.75%,8.50%,8.25%,8 %,7.75%,7.50%,7.25%,7%,6.75%,6.50%,6.25%,6%,5.75%,5.50%,5.25%,5%,4.75%,4.50%,4.25%,4%,3.75%,3.50%,3.25%,3%,2.75%,2.50%,2.25%,2%,1.75%,1.50%,125%,1%,0.5%,0.4%,0.3%,0.2%,0.1%,0.09%,0.08%,0.07%,0 Greater than 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w / w, w / v, or v / v.

[0162] In some embodiments, the concentration of one or more compounds selected from the compounds of structures (I)-(Ih) provided in the pharmaceutical compositions of the present disclosure is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about The range is 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, or about 1% to about 10% w / w, w / v, or v / v.

[0163] In some embodiments, the amount of one or more compounds selected from the compounds of structures (I)-(Ih) provided in the pharmaceutical compositions of the present disclosure is 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.45 g, 0.55 g, 0.55 g, 0.45 g, 0.55 g, 0.55 g, 0.55 g, 0.45 g, 0.45 g, 0.55 g, 0.55 g, 0.55 g, 0.55 g, 0.55 g, 0.55 g, 0.55 g, 0.55 g, 0.55 g, 0.4 ... g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.

[0164] In some embodiments, the amount of one or more compounds selected from the compounds of structures (I)-(Ih) provided in the pharmaceutical compositions of the present disclosure ranges from 0.0001 to 10 g, 0.0005 to 9 g, 0.001 to 8 g, 0.005 to 7 g, 0.01 to 6 g, 0.05 to 5 g, 0.1 to 4 g, 0.5 to 4 g, or 1 to 3 g.

[0165] Packaging materials used to package the pharmaceutical compositions described herein include those taught in U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the selected formulation and intended mode of administration and treatment. For example, a container(s) contains one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (e.g., the container is an intravenous solution bag or vial with a stopper pierceable by a hypodermic injection needle). Such kits optionally contain the compound along with an identifying description or label or instructions for its use in the methods described herein.

[0166] For example, a kit typically includes one or more additional containers, each containing one or more of various materials (e.g., reagents, optionally in concentrated form, and / or devices) desirable from a commercial and user standpoint for use of the compounds described herein. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; labels on the carrier, package, container, vial, and / or tube that describe the contents and / or instructions for use, and package inserts indicating instructions for use. A set of instructions is also typically included. The label is optionally on or associated with the container. For example, a label is on the container when letters, numbers, or other characters forming the label are attached, molded, or engraved on the container itself, and is associated with the container when the label is present, for example, as a package insert, in a receptacle or carrier that holds the container. In addition, the label is used to indicate that the contents should be used for a particular therapeutic application. In addition, the label indicates instructions for use of the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical compositions are provided in a pack or dispenser device containing one or more unit dosage forms containing a compound provided herein. The pack comprises, for example, metal or plastic foil, such as a blister pack. Alternatively, the pack or dispenser device is accompanied by instructions for administration. Alternatively, the pack or dispenser is accompanied by a notice associated with the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the approval by the government agency of the drug form for administration to humans or livestock. Such notice may be, for example, a label approved by the US Food and Drug Administration for prescription drugs or an approved product insert. In some embodiments, a composition containing a compound provided herein formulated in a compatible pharmaceutical carrier is prepared, placed in an appropriate container, and labeled for the treatment of an indicated condition.

[0167] As mentioned above, the compounds and compositions of the present disclosure will find utility in a wide range of diseases and conditions mediated by protein kinases, including, by way of example, lung cancer, NSCLC (non-small cell lung cancer), oat cell carcinoma, bone cancer, pancreatic cancer, skin cancer, dermatofibrosarcoma protuberans, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, colorectal cancer, anal cancer, gastric cancer, colon cancer, breast cancer, gynecological tumors (e.g., uterine sarcoma, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, or vulvar cancer), Hodgkin's disease, hepatocellular carcinoma, esophageal cancer, small intestine cancer, endocrine system cancers (e.g., thyroid cancer, pancreatic cancer, parathyroid cancer, or adrenal cancer), soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer (especially hormone-refractory), chronic or acute leukemia, childhood solid tumors, hyperacidosis, and the like. These may include, but are not limited to, cancers such as cytosis, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer (e.g., renal cell carcinoma, renal pelvis cancer), childhood malignancies, neoplasms of the central nervous system (e.g., primary CNS lymphoma, spinal axis tumor, medulloblastoma, brainstem glioma, or pituitary adenoma), Barrett's esophagus (premalignant syndrome), neoplastic skin diseases, psoriasis, mycosis fungoides, and benign prostatic hyperplasia; diabetes-related diseases such as diabetic retinopathy, retinal ischemia, and retinal neovascularization, liver cirrhosis, angiogenesis; cardiovascular diseases such as atherosclerosis; immune diseases such as autoimmune diseases; and renal diseases.

[0168] In some embodiments, the pharmaceutical composition comprises a compound as described above and a pharmaceutically acceptable carrier, including any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier, that has been approved, for example, by the United States Food and Drug Administration as acceptable for human or veterinary use.

[0169] In some embodiments, there is provided a method of treating a disease or disorder, the method comprising administering an effective amount of a compound or pharmaceutical composition described herein to a subject in need thereof. In some embodiments, the subject is experiencing aberrant PAR2 activity. In some embodiments, the subject is at risk of experiencing aberrant PAR2 activity. In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human. In some embodiments, the subject suffers from or is at risk of developing an inflammatory condition involving aberrant PAR2 activity. In some embodiments, the disease or disorder is asthma, migraine-related pain, chronic pain, cancer, and vascular disorders.

[0170] In some embodiments, the method further comprises administering to the subject one or more anti-inflammatory agents, hi some embodiments, the anti-inflammatory agent is a nonsteroidal anti-inflammatory drug.

[0171] In some embodiments, the kit comprises the pharmaceutical composition, a container, pack, or dispenser, and instructions for administration.

[0172] Preparation of compounds Methods for preparing the above-mentioned compounds and compositions are described herein below and / or known in the art. Those skilled in the art will understand that in the processes described herein, functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, amino, mercapto, and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, trityl, t-butyl, and the like. Suitable protecting groups for amino, amidino, and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl, and the like. Suitable protecting groups for mercapto include -C(O)-R" (where R" is alkyl, aryl, or arylalkyl), p-methoxybenzyl, trityl, and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl, or arylalkyl esters. Protecting groups can be added or removed according to standard techniques well known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T W and P G M Hutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As will be appreciated by those skilled in the art, the protecting group may also be a polymer resin such as a Wang resin, a Rink resin, or a 2-chlorotrityl-chloride resin.

[0173] Those skilled in the art will also appreciate that, although such protected derivatives of the compounds of the present disclosure may not have pharmacological activity, they may be administered to a mammal and then metabolized in the body to form pharmacologically active compounds of the present disclosure. Such derivatives may therefore be described as "prodrugs." All prodrugs of the compounds of the present disclosure are included within the scope of the present disclosure.

[0174] Furthermore, all compounds of the present disclosure that exist in free base or acid form can be converted into their pharmaceutically acceptable salts by treatment with an appropriate inorganic or organic base or acid by methods well known to those skilled in the art. Salts of the compounds of the present disclosure can be converted into their free base or acid form by standard techniques.

[0175] The following reaction scheme illustrates the synthesis of compounds of the present disclosure, i.e., compounds of structure (I):

[0176] [ka] or a salt (e.g., a pharmaceutically acceptable salt) or stereoisomer thereof, wherein R 1a , R 1b , R 2 , R 3a , R 3b , R 4a , R 4b , R 5a , Z, X, and m are as defined herein. It is understood that one of ordinary skill in the art may be able to prepare these compounds by similar methods or in combination with other methods known to those of ordinary skill in the art. It is also understood that one of ordinary skill in the art may be able to prepare other compounds of structure (I) not specifically exemplified below in a similar manner to that described below by using appropriate starting components and modifying the synthetic parameters as necessary. Generally, the starting components can be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, or synthesized according to sources known to those of ordinary skill in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)), or prepared as described in this disclosure.

[0177] Embodiment The present disclosure further provides the following embodiments. Embodiment 1. The following structure (I):

[0178] [ka] or a stereoisomer or salt thereof, wherein R 1a and R 1b are each independently hydrogen, C-C alkyl, C-C heteroalkyl, C-C cycloalkyl, aryl, or arylalkyl; R 2 is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 heterocyclylalkyl, C3-C8 heterocyclylalkylC 1-6 alkyl, heteroaryl, heteroarylalkyl, or arylalkyl; Z is i)

[0179] [ka] is a double bond and is oxygen, or ii)

[0180] [ka] is a single bond, hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, or arylalkyl; R 3a and R 3b are each independently hydrogen, C-C alkyl, C-C heteroalkyl, C-C cycloalkyl, or arylalkyl; X is N or C(R 5b ) and;i)R 4a and R 4b are each independently hydrogen, C-C alkyl, C-C heteroalkyl, C-C cycloalkyl, C-C heterocyclylalkyl, arylalkyl, or heteroarylalkyl; and R 5a and R 5bare each independently hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, C3-C8 heterocyclylalkyl, arylalkyl, heteroarylalkyl, -C(=O)R 6 , -C(=O)YR 6 , -OC(=O)R 6 , -OC(=O)YR 6 , -NHC(=O)R 6 , or -NHC(=O)YR 6 However, R 5a and R 5b are each independently -NHC(=O)R 6 , or -NHC(=O)YR 6 If R 6 is not arylalkyl; or ii) R 4a forms a direct bond with X, and R 4b and R 5b together form a 5- to 9-membered fused ring; R 6 is C3-C8 cycloalkyl, C3-C8 heterocyclylalkyl, arylalkyl, heteroarylalkyl, or a 5- to 9-membered fused ring; Y is O, S, or NR 7 and;R 7 is hydrogen, hydroxyl, or C1-C6 alkyl; m is 1 or 2; and R 1a , R 1b , R 2 , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6 , and R 7 wherein each of is optionally substituted with one or more substituents.

[0181] Embodiment 2. The compound of embodiment 1, wherein m is 1.

[0182] Embodiment 3. The compound of embodiment 1 or embodiment 2, wherein X is N.

[0183] Embodiment 4. The following structure (Ia):

[0184] [ka] or a stereoisomer or salt thereof.

[0185] Embodiment 5. The compound of any one of embodiments 1-4, wherein Z is oxygen.

[0186] Embodiment 6. The following structure (Ib):

[0187] [ka] or a stereoisomer or salt thereof.

[0188] Embodiment 7. The compound of embodiment 1, wherein m is 2.

[0189] Embodiment 8. The compound of embodiment 7, wherein X is N.

[0190] Embodiment 9. The following structure (Ic):

[0191] [ka] or a stereoisomer or salt thereof.

[0192] Embodiment 10. The compound of embodiment 9, wherein Z is oxygen.

[0193] Embodiment 11. The following structure (Id):

[0194] [ka] or a stereoisomer or salt thereof.

[0195] Embodiment 12. The compound has one of the following structures (Ia)-(Id):

[0196] [ka] or a stereoisomer or salt thereof.

[0197] Embodiment 13. X is C(R 5b 13. The compound of any one of embodiments 1-12, wherein

[0198] Embodiment 14.R 4a forms a direct bond with X, and R 4b and R 5b and R are taken together to form a 5- to 9-membered fused ring.

[0199] Embodiment 15. The compound has one of the following structures (Ie)-(Ih):

[0200] [ka] or a stereoisomer or salt thereof, wherein R 8 The compound of embodiment 14, wherein R is hydrogen, halo, hydroxyl, alkoxy, amino, cyano, C1-C6 alkyl, or C1-C6 heteroalkyl; and V is a carbon, nitrogen, or oxygen atom.

[0201] Embodiment 16.R 1a or R 1b 16. The compound of any one of embodiments 1-15, wherein at least one of is hydrogen.

[0202] Embodiment 17.R 1a and R 1b 16. The compound of any one of embodiments 1-15, wherein each of is hydrogen.

[0203] Embodiment 18.R 1a and R1b has one of the following structures:

[0204] [ka] wherein each n is independently 0 to 6, n' is 1 to 5; and R9 is hydrogen, halo, hydroxyl, alkoxy, amino, cyano, C1-C6 alkyl, or C1-C6 heteroalkyl.

[0205] Embodiment 19.R 2 has one of the following structures:

[0206] [ka] In the formula, n is independently 0 to 6, and n' is 1 to 5; G 2 is CH2, NH, O, or S; W is CH or N; A is O, NH, or NHR 9 where i) if A is O, then:

[0207] [ka] is a double bond, or ii) A is NH or NHR 9 If

[0208] [ka] is a single bond; B is OR 9 , NH2, or NHR 9 and;R 9 is hydrogen, halo, hydroxyl, alkoxy, amino, cyano, C-C alkyl, or C-C heteroalkyl; and R 10 The compound of any one of embodiments 1-18, wherein is i) absent or ii) hydrogen, alkyl, aryl, pyridyl, acylalkyl, or acylaryl.

[0209] Embodiment 20.R 2 teeth,

[0210] [ka] 20. The compound of any one of embodiments 1-19, wherein:

[0211] Embodiment 21.R 3a or R 3b has one of the following structures:

[0212] [ka] wherein each n is independently 0 to 6, and n' is 1 to 5; each G3 is independently C(R7)2, O, S, or NR7; each W is independently CH or N; and A is O, NH, or NHR9, where i) when A is O,

[0213] [ka] is a double bond, or ii) A is NH or NHR9,

[0214] [ka] A compound according to any one of embodiments 1 to 20, wherein R is a single bond; B is OR9, NH2, or NHR9; R9 is hydrogen, halo, hydroxyl, alkoxy, amino, cyano, C1-C6 alkyl, or C1-C6 heteroalkyl; and R10 is i) absent or ii) hydrogen, alkyl, aryl, pyridyl, acylalkyl, or acylaryl.

[0215] Embodiment 22.R 3a or R 3b One of the groups is hydrogen, and R 3a or R 3bThe other one is

[0216] [ka] 22. The compound of any one of embodiments 1-21, wherein:

[0217] Embodiment 23.R 3a or R 3b One of the groups is hydrogen, and R 3a or R 3b The other one is

[0218] [ka] 23. The compound of any one of embodiments 1-22, wherein:

[0219] Embodiment 24.R 4a or R 4b has one of the following structures:

[0220] [ka] wherein each n is independently 0 to 6, and n' is 1 to 5; each G4 is independently C(R7)2, O, S, or NR7; each W is independently CH or N; and A is O, NH, or NHR9, where i) when A is O,

[0221] [ka] is a double bond, or ii) A is NH or NHR9,

[0222] [ka] A compound according to any one of embodiments 1 to 23, wherein R is a single bond; B is OR9, NH2, or NHR9; R9 is hydrogen, halo, hydroxyl, alkoxy, amino, cyano, C1-C6 alkyl, or C1-C6 heteroalkyl; and R10 is i) absent or ii) hydrogen, alkyl, aryl, pyridyl, acylalkyl, or acylaryl.

[0223] Embodiment 25.R 4a or R 4b One of the groups is hydrogen, and R 4a or R 4b The other one is

[0224] [ka] 25. The compound of any one of embodiments 1-24, wherein:

[0225] Embodiment 26.R 5a has one of the following structures:

[0226] [ka]

[0227] [ka] wherein n is 0 to 6, n' is 1 to 5; each G5 is independently C(R7)2, O, S, or NR7; and each W is independently CH or N.

[0228] Embodiment 27.R 5a teeth,

[0229] [ka] and R 5b The compound of any one of embodiments 1-26, wherein is hydrogen.

[0230] Embodiment 28. W is O and R 9 is hydrogen.

[0231] Embodiment 29.R 5a is one of the following structures:

[0232] [ka] 26. The compound of any one of embodiments 1-25, having the formula:

[0233] Embodiment 30. The compound has one of the following structures:

[0234] [ka]

[0235] [ka] or a stereoisomer or salt thereof.

[0236] Embodiment 31. The compound of any one of embodiments 1 to 30, wherein the compound is a pharmaceutically acceptable salt.

[0237] Embodiment 32. A pharmaceutical composition comprising a compound or salt according to any one of embodiments 1 to 31 and a pharmaceutically acceptable carrier.

[0238] Embodiment 33. A method for treating a disease or disorder, comprising administering to a subject in need thereof an effective amount of a compound described in any one of embodiments 1 to 30, or a pharmaceutical composition described in embodiment 32.

[0239] Embodiment 34. A composition according to any one of embodiments 1 to 30 or a pharmaceutical composition according to embodiment 32 for use in a method for treating a disease or disorder.

[0240] Embodiment 35. A composition according to any one of embodiments 1 to 30 or a pharmaceutical composition according to embodiment 32 for use in the preparation of a medicament for the treatment of a disease or disorder.

[0241] Embodiment 36 The method of embodiment 33, or the composition of embodiment 34 or 35, wherein the subject is experiencing aberrant PAR2 activity associated with a disease or disorder.

[0242] Embodiment 37. The method of embodiment 33, or the composition of embodiment 34 or 35, wherein the subject is at risk of experiencing aberrant PAR2 activity associated with a disease or disorder.

[0243] Embodiment 38. The method of embodiment 33, or the composition of embodiment 34 or 35, wherein the disease or disorder is in a mammal.

[0244] Embodiment 39. The method or composition of embodiment 38, wherein the mammal is a human.

[0245] Embodiment 40. The method or composition of embodiment 39, wherein the mammal suffers from or is at risk of developing an inflammatory condition involving aberrant PAR2 activity.

[0246] Embodiment 42. The method or composition of embodiment 40, wherein the inflammatory condition is one or more conditions selected from the group consisting of asthma, migraine-associated pain, chronic pain, cancer, and vascular disorders.

[0247] Embodiment 43. The method or composition of embodiment 40, further comprising administering to the subject one or more anti-inflammatory agents, or the composition of claim 32, further comprising one or more anti-inflammatory agents.

[0248] Embodiment 44. The method or composition of embodiment 43, wherein the anti-inflammatory agent is a nonsteroidal anti-inflammatory drug.

[0249] Embodiment 45. A kit comprising the pharmaceutical composition of embodiment 32, a container, pack, or dispenser, and instructions for administration.

[0250] Embodiment 46. The kit of embodiment 45, wherein the instructions for administration include the method or use of any one of embodiments 33 to 44. [Example]

[0251] The following examples are offered by way of illustration and not by way of limitation.

[0252] Compound I-1 as used in these examples is 4-(((2R,5S)-1-(furan-2-carbonyl)-2,5-diisobutyl-3,6-dioxohexahydroimidazolo[1,2-a]pyrazin-7(1H)-yl)methyl)piperidin-1-ium chloride.

[0253] Example 1: Preparation of Compound I-1 Abbreviations: The following abbreviations are used throughout this Example 1:

[0254] °C (degrees Celsius); 1H NMR (proton nuclear magnetic resonance); DCM (dichloromethane); DMSO (dimethyl sulfoxide); eq (equivalent); EtOAc (ethyl acetate); g (gram); h (hour); MeOH (methanol); mg (milligram); min (minute); mL (milliliter); mmol (millimol); TFA (trifluoroacetic acid); THF (tetrahydrofuran); TLC (thin layer chromatography); Boc (t-butyloxycarbonyl); DIC (N,N'-diisopropylcarbodiimide); DIEA (diisopropylethylamine); DMF (N,N'-dimethylformamide); EDT (1,2-ethylenedithiol); ESI-MS (electrospray spectroscopy). spray ionization-mass spectrometry); EtO (diethyl ether); Fmoc ((9H-fluoren-9-ylmethoxy)carbonyl); HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate); HOBt (N-hydroxybenzotriazole); HPLC (high performance liquid chromatography); OBt (O-benzotriazolyl); Pd(TPP) (palladium(0) tetrakistriphenylphosine); SPE (solid phase extraction); SPPS (solid phase peptide synthesis); TCFH (tetramethylchloroformamidium hexafluorophosphate); and TMS (tetramethylsilane).

[0255] Chemical Materials: The following reagents and materials are used throughout this Example 1.

[0256] N αFmoc-protected amino acids and activators (HBTU, TCFH, DIC, and HOBt) were purchased from P3BioSystems (Louisville, KY) or Novabiochem (San Diego, CA). Bromoacetal and 2-chloro-chlorotrityl resins were obtained from Rapp Polymere (Tübingen, Germany). HPLC-grade solvents, reagents, and acetonitrile were obtained from VWR (West Chester, PA) or Sigma-Aldrich (St. Louis, MO) and used without further purification unless otherwise noted. Chemicals and reagents were obtained from Sigma-Aldrich or TCI (Portland, OR). Solid-phase synthesis was performed with fritted syringes using a Domino manual synthesizer from Torviq (Tucson, AZ).

[0257] General synthesis: 1H NMR spectra were recorded on a Bruker-DRX-300 MHz instrument and chemical shifts are reported relative to an internal tetramethylsilane standard (TMS, 0.0 ppm) and residual dimethyl sulfoxide (DMSO; 2.50 ppm). 13 C NMR spectra were referenced to CDCl (77.0 ppm) and DMSO (39.51 ppm). Low-resolution mass spectra were obtained on a Bruker Amazon SL Ion Trap Mass Spectrometer (Madison, WI) equipped with an ESI source. High-resolution mass spectra (HRMS) were recorded on a Bruker SolariX Fourier-transform Ion Cyclotron Resonance Mass Spectrometer equipped with an ESI source, 9.4 T magnet.

[0258] Quality Control and Purification: The purity of the product was confirmed by analytical reverse-phase HPLC using an Agilent 1260 Infinity II Separation Model (Santa Clara, CA) equipped with a dual wavelength detector (220 and 280 nm) on a reverse-phase column (Agilent Boroshell C18, 3.0 × 100 mm, 2.7 μm). The crude compound was eluted with a linear gradient of aqueous CH3CN / 0.1% CF3CO2H at a flow rate of 0.3 mL / min. Purification of the compound was performed on an Agilent 1260 Infinity II Prep Model HPLC using a reverse-phase column (YMC ODS C18, 10 μm, 20 × 250 mm). The compound was eluted with a linear gradient of CH3CN / 0.1% CF3CO2H at a flow rate of 3.0 to 10.0 mL / min. The separation was monitored at a suitable wavelength ranging from 220 to 280 nm. Flash chromatography was performed on a borosilicate glass column (2.6 × 250 mm, Sigma-Aldrich) packed with 60 Å silica gel (Sigma-Aldrich). Compounds were eluted with a step gradient flow of hexane / EtOAc / MeOH mixtures.

[0259] [ka] Solid-phase synthesis of compound I-1 (a) 0.5 M solution of Boc-protected diamine in DMSO, overnight at 60°C. (b) (i) Fmoc-Leu coupling, TCFH / collidine, (II) 10% piperidine in DMF, 20 min, (iii) Fmoc-Leu, DIC / HOBt, 3 h. (c) (i) 60% formic acid, 4 h, (ii) column purification. (d) Attachment to 2-chloro-chlorotrityl resin, 2.5 equivalents in DCM, DIEA. (e) 10% piperidine in DMF, 20 min. (f) 0.5 M furoic acid, DCM, TCFH, DIEA, overnight. (g) (i) 94% TFA, 3% water in DCM, 1 h, (ii) HPLC purification.

[0260] Intermediate I: Bromoacetal resin (0.2 g, 0.25 mmol) was swollen by the addition of DCM for 2 hours. The swollen resin was removed via solid phase treatment. The resin was washed successively with DMF (3 × 2 min), DCM (3 × 2 min), and DMSO (5 × 2 min). Amine displacement of the bromine was carried out overnight at 60 °C using a 0.5 M solution of 1-N-Boc-4-(aminomethyl)piperidine (0.214 g, 1 mmol, 4 equiv.) in DMSO. The reaction mixture was removed by filtration, and the resin was washed successively with DMSO (5 × 2 min) and DCM (3 × 2 min). Prior to Fmoc-Leu coupling, the resin was neutralized with 10% diisopropylethylamine (DIEA) in DCM (2 × 3 min), followed by successive washing with DCM (3 × 2 min) and DMF (5 × 2 min).

[0261] Intermediate II: The above intermediate resin I (0.2 g, 0.25 mmol) was coupled with Fmoc-Leu. The coupling was carried out by adding Fmoc-Leu (0.353 g, 1 mmol, 4 eq.) and coupling reagents [TCFH (0.28 g, 1 mmol, 4 eq.) and DIEA (0.35 mL, 2 mmol, 8 eq.)] in DMF (2 mL) to the resin and stirring the mixture overnight. A second TCFH coupling was carried out in a THF / DMF mixture for 2 h. The reaction mixture was removed by filtration, and the resin was washed with DMF (5 × 2 min) and DCM (3 × 2 min). α The -Fmoc protecting group was removed using 1:10 piperidine in DMF (1 x 2 min and 1 x 20 min). The resin was washed successively with DMF (5 x 2 min), DCM (3 x 2 min), a 0.05 mM solution of bromophenol blue in 0.2 M HOBt in DMF, and then DMF (3 x 2 min). N was purified using preactivated 0.3 M HOBt ester in a DMF-DCM mixture. α -Fmoc-Leu was coupled (3 equivalents of N α-Fmoc-Leu, 3 equivalents of HOBt, and 3 equivalents of DIC). The resin slurry was stirred for 2 hours or until the bromophenol test was negative (yellow). The resin was washed with DMF (3 x 2 min). The second coupling was performed by HBTU / 2,4,6-lutidine treatment (3 equivalents of N in DMF). α The reaction mixture was filtered off and the resin was washed with DMF (5 x 2 min), DCM (3 x 2 min), and then MeOH (3 x 2 min). The reactor was placed in a vacuum oven and the solvent was removed.

[0262] Intermediate III: The above intermediate resin II (0.2 g, 0.25 mmol) was treated with 60% formic acid (2 mL) for 4 hours. The resin was filtered and washed with formic acid (2 x 2 min). The acid filtrate and washes were collected, diluted with DI water, and lyophilized. The crude intermediate III was purified using column chromatography to give pure III (74 mg, 53%, (M+H) + 559.3, HPLC > 95%).

[0263] Intermediate IV: The above dried Intermediate III (74 mg, 132 μmol) was added to dry 2-chloro-chlorotrityl resin (250 mg, 430 μmol, 2.5 equiv.). Dry DCM (2.0 mL) and DIEA (171 μL, 1.0 mmol) were injected onto the resin, and the mixture was stirred at room temperature overnight. The reaction was quenched by the addition of MeOH (0.2 mL, 30 min). The reaction mixture was removed by filtration, and the resin was washed with DMF (3 × 2 min), DCM (5 × 2 min), and then DMF (2 × 2 min).

[0264] Final product compound I-1: The intermediate resin IV described above was deprotected with piperidine. αThe -Fmoc protecting group was removed using 1:10 piperidine in DMF (1 × 2 min and 1 × 20 min). The resin was washed with DMF (5 × 2 min) and then DCM (5 × 2 min). 2-Furoic acid was coupled by adding 2-furoic acid (1 mmol, 4 eq) and coupling reagents [TCFH (0.28 g, 1 mmol, 4 eq) and DIEA (0.35 mL, 2 mmol, 8 eq)] in DMF (2 mL) to the resin and stirring the mixture overnight. The reaction mixture was removed by filtration, the resin was washed with DMF (5 × 2 min), and 2-furoic acid was recoupled using 5 eq in a THF / DMF mixture. The reaction mixture was removed by filtration, and the resin was washed successively with DMF (5 × 2 min) and DCM (3 × 2 min). The reaction mixture was filtered off, and the resin was washed successively with DMF (5 × 2 min) and DCM (7 × 2 min), followed by strong acid cleavage. A cleavage cocktail (2.0 mL) consisting of CF3CO2H (97%) and HO (3%) was injected onto the resin, and the mixture was stirred at room temperature for 1 h. The solution was filtered, the resin was washed with CF3CO2H (2 × 3 min), the liquid phase was collected and concentrated under a stream of nitrogen, and the product was precipitated using cold Et2O / hexane. The crude product was washed three times with cold Et2O / hexane, lyophilized, purified by HPLC, and characterized as described above. The desired product was 25 mg of compound I-1 (19% yield) as a white lyophilizate.

[0265] Analytical data for compound I-1: (M+H)+ 515.30, HPLC>95%). 1 H NMR:0.86(d,6H),0.90(d,6H),1.30(m,4H),1.60(m,1H),1.74(t,2H),1.97(m.1H),2.0(d,2H),2.02(m.1H),2.81(m,4H),3. 3(t,2H),3.50(t,2H),3.70(m,2H),4.5(t,1H),5.0(t,1H),6.10(t,1H),6.7(t,1H),7.30(d,1H),7.92(d,1H),8.25(d,1H). 13C NMR:26.8(CH3),27.5(CH3),28.3(CH),29.5(CH),30.7(CH2),32.0((CH),32.5(CH),48.2((CH2),49.5(CH2),52.3(CH2),52.8(CH 2),54.1(CH2),58.5(CH),114.1(CH),117.3(ArCH),150.5(ArCH),151.5(ArCH),164.1(CO),170.07(CO),172.3(CO),177.6(CO).

[0266] Example 2: In vitro efficacy of compound I-1 Compound I-1 (denoted as "C I-1" in Figures 1A-1D) was evaluated for its ability to antagonize protease-activated receptor-2 (PAR2) in several cellular assays using human bronchial epithelial cells (16HBE14o cells, see Figures 1A-1D) that naturally express PAR2.

[0267] The first assay to detect physiological responses in vitro used xCELLigence Real-Time Cellular Analysis (RTCA). RTCA assays can identify full, partial, and / or limited agonist potency, as well as biased signaling and antagonism. Boitano S, Flynn AN, Schulz SM, Hoffman J, Price TJ, and Vagner J. “Potent Agonists of the Protease Activated Receptor 2(PAR2)”, J Med Chem(2011), 54, 1308-13; Boitano S, Hoffman J, Tillu DV, Asiedu MN, Zhang Z, Sherwood CL, Wang Y, Dong X,Price TJ,and Vagner J. “Development and Evaluation of Small Peptidomimetic Ligands to Protease-Activated Receptor-2(PAR2)through the Use of Lipid Tethering”,PLoS One,(2014),9,e99140;Flynn AN,Hoffman J,Tillu DV,Sherwood CL,Zhang Z,Patek R,Asiedu MN,Vagner J,Price TJ,and Boitano S. “Development of highly potent protease-activated receptor 2 agonists via synthetic lipid tethering”Faseb J,(2013),27,1498-1510;Flynn AN,Tillu DV,Asiedu MN,Hoffman J,Vagner J,Price TJ,and Boitano S."The protease-activated receptor-2-specific agonists 2-aminothiazol-4-yl-LIGRL-NH2 and 6-aminonicotinyl-LIGRL-NH2 stimulate multiple signaling pathways to induce physiological responses in vitro and in vivo", J Biol Chem, (2011), 286:19076-88; and see Rivas CM, Schiff HV, Moutul A, Khanna R, Kiela PR, Dussor G, Price TJ, Vagner J, DeFea KA, and Boitano S. "Alternaria alternata-induced airway epithelial signaling and inflammatory responses via protease-activated receptor-2 expression", Biochemical and Biophysical Research Communications, (2022).

[0268] After overnight growth, various concentrations of compound I-1 were added to individual wells (in quadruplicates) at final concentrations of 300 nM, 1 μM, 3 μM, and 10 μM. After a 5-minute preincubation, 300 nM of the highly potent and specific PAR2 antagonist 2-2-at-LIGRL-NH2 (2AT, see Flynn AN, Tillu DV, Asiedu MN, Hoffman J, Vagner J, Price TJ, and Boitano S. "The protease-activated receptor-2-specific agonists 2-aminothiazol-4-yl-LIGRL-NH2 and 6-aminonicotinyl-LIGRL-NH2 stimulate multiple signaling pathways to induce physiological responses in vitro and in vivo," J Biol Chem, (2011), 286:19076-88) or 30 nM trypsin was added to the wells. See Figures 1A and 1B. The increase and recovery of cell index shown in response to control 300 nM (Figure 1A) or 30 nM (Figure 1B) 2AT is typical of EC 50 High concentrations of compound I-1 reduced the response, consistent with partial antagonism.

[0269] Two major signaling outcomes of PAR2 activation are Gq / Ca 2+ and the initiation of β-arrestin / MAPK signaling. To determine whether the observed physiological antagonism in vitro is a partial or intracellular signaling-dependent antagonism, we used digital imaging microscopy to examine the Gq / Ca 2+ Intracellular Ca as a measure of signal transduction 2+ Changes in [Ca 2+ ] i , see Figure 3), and also used an in cell Western approach to measure phosphorylation of extracellular regulated kinase 1 / 2 (pERK1 / 2 ICW, see Figure 1D) as an assay of β-arrestin / MAPK signaling. 2+Although no antagonistic effects were observed in the signaling pathway, significant antagonism of the β-arrestin / MAPK signaling pathway was observed. We conclude that compound I-1 is a β-arrestin / MAPK-biased PAR2 antagonist.

[0270] Example 3: In vivo efficacy of compound I-1 Compound I-1 was evaluated for its plasma stability and oral bioavailability. Mice were fasted overnight and then dosed and given water ad libitum throughout the study. Three animals were administered 10 mg / kg (10 mL / kg) orally via gavage needle, 2 mg / kg (2 mL / kg) intravenously via tail vein injection, and 10 mg / kg (10 mL / kg) intraperitoneally via injection into the right lower quadrant of the abdomen. Blood samples (25–30 μL per sample) were collected via the saphenous or submandibular vein at 5, 15, and 30 minutes and 1, 2, 4, 6, 8, and 24 hours after administration, and drug concentrations were determined by LC-MS / MS. Plasma concentrations were then graphed versus time, and pharmacokinetic parameters (terminal half-life, t 1 / 2 ;Initial plasma concentration, C o Area under the curve (AUC); Steady-state volume of distribution; V ss : Total plasma clearance CL p ;Mean residence time, MRT;Maximum plasma concentration C max ;C max The time it takes to reach max ; and bioavailability, F) were determined using non-compartmental analysis.

[0271] Table 1 below summarizes the pharmacokinetic data for compound I-1.

[0272] [Table 2] TIFF2025537145000076.tif98167

[0273] Example 4: In vivo efficacy of compound I-1 in preventing stress-induced migraine Migraine is characterized by increased sensitivity of pain-sensing neurons in the dura mater to innocuous stimuli, such as the nitric oxide donor, sodium nitroprusside (SNP). Compound I-1 was evaluated in vivo using a mouse migraine model to assess its potential for treating stress-induced migraine-like pain. Figure 2 summarizes the results of this in vivo study.

[0274] Mice were subjected to restraint stress for 3 days (□ and ◇ data points in Figure 2) or left unrestrained (○ and △ data points in Figure 2). Significant facial withdrawal responses were observed up to 3 days after stress. After 14 days of recovery, administration of SNP induced a significant facial withdrawal response, whereas administration of compound I-1 abolished this response. This demonstrates that compound I-1 prevents the development of dural sensitization associated with chronic migraine pain and is a promising therapeutic agent for migraine.

[0275] Example 5: In vivo efficacy of compound I-1 in reducing allergen-induced asthma Alternaria alternata is a fungal allergen that activates PAR2 in the airways, promoting inflammation and bronchoconstriction. Compound I-1 was evaluated in vivo to assess whether it could be used to treat airway hyperresponsiveness induced by Alternaria alternata. Figure 3 summarizes the results of this in vivo study.

[0276] Alternaria alternata or saline (Δ data points in Figure 3 ) was administered intranasally to a mouse asthma model three times over an 8-day period in the presence (□ data points in Figure 3 ) or absence (○ data points in Figure 3 ) of compound I-1. Total airway resistance in response to increasing doses of methacholine was monitored using the FLEXIVENT® (Scireq, Quebec, Canada) system. The results in Figure 3 suggest that compound I-1 is a promising therapeutic agent for reducing allergen-induced asthma attacks.

[0277] Aspects of the embodiments may be modified, as necessary, to adopt concepts from various patents, applications, and publications to provide still further embodiments. These and other changes can be made to the embodiments in light of the above detailed description. In general, in the following claims, the terms used should not be construed to limit the scope of the claims to the specific embodiments disclosed in the specification and claims, but rather to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the scope of the claims is not limited by the present disclosure.

Claims

1. The following structure (I): 【Chemistry 1】 or a stereoisomer or salt thereof, wherein R １ａ and R １ｂ are each independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, C ３ -C ８ is cycloalkyl, aryl, or arylalkyl; R ２ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, C ３ -C ８ Heterocyclylalkyl, C ３ -C ８ Heterocyclylalkyl C １－６ alkyl, heteroaryl, heteroarylalkyl, or arylalkyl; Z is i) 【Chemistry 2】 is a double bond and is oxygen; or ii) 【Transformation 3】 is a single bond, hydrogen, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, C ３ -C ８ cycloalkyl, or arylalkyl; R ３ａ and R ３ｂ are each independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, C ３ -C ８ cycloalkyl, or arylalkyl; X is N or C(R ５ｂ ) and i) R ４ａ and R ４ｂ are each independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, C ３ -C ８ Cycloalkyl, C ３ -C ８ heterocyclylalkyl, arylalkyl, or heteroarylalkyl; and R ５ａ and R ５ｂ are each independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Hydroxyalkyl, C ３ -C ８ Cycloalkyl, C ３ -C ８ Heterocyclylalkyl, arylalkyl, heteroarylalkyl, —C(═O)R ６ , —C(═O)YR ６ , —OC(═O)R ６ , -OC(=O)YR ６ , -NHC(=O)R ６ or —NHC(═O)YR ６ However, R ５ａ and R ５ｂ are each independently —NHC(═O)R ６ or —NHC(═O)YR ６ If R ６ is not arylalkyl; or ii) R ４ａ forms a direct bond with X, and R ４ｂ and R ５ｂ taken together form a 5- to 9-membered fused ring; R ６ is C ３ -C ８ Cycloalkyl, C ３ -C ８ heterocyclylalkyl, arylalkyl, heteroarylalkyl, or a 5- to 9-membered fused ring; Y is O, S, or NR ７ and R ７ is hydrogen, hydroxyl, or C １ -C ６ is alkyl; m is 1 or 2; and R １ａ , R １ｂ , R ２ , R ３ａ , R ３ｂ , R ４ａ , R ４ｂ , R ５ａ , R ５ｂ , R ６ , and R ７ wherein each of is optionally substituted with one or more substituents.

2. 2. The compound of claim 1, wherein m is 1.

3. The compound according to claims 1 to 2, wherein X is N.

4. The following structure (Ia): 【Chemistry 4】 4. The compound of claim 3, wherein:

5. The compound according to any one of claims 1 to 4, wherein Z is oxygen.

6. The following structure (Ib): 【Transformation 5】 6. The compound of claim 5, wherein:

7. 2. The compound of claim 1, wherein m is 2.

8. 8. The compound of claim 7, wherein X is N.

9. The following structure (Ic): 【Transformation 6】 9. The compound of claim 8, wherein:

10. 10. The compound of claim 9, wherein Z is oxygen.

11. The following structure (Id): 【Transformation 7】 11. The compound of claim 10, wherein:

12. The compound has one of the following structures (Ia) to (Id): 【Transformation 8】 2. The compound of claim 1, wherein:

13. X is C(R ５ｂ 13. The compound according to any one of claims 1 to 12, wherein

14. R ４ａ forms a direct bond with X, and R ４ｂ and R ５ｂ The compound according to any one of claims 1 to 13, wherein:

15. The compound has one of the following structures (Ie) to (Ih): 【Chemistry 9】 or a stereoisomer or salt thereof, wherein R ８ is hydrogen, halo, hydroxyl, alkoxy, amino, cyano, C １ -C ６ Alkyl, or C １ -C ６ is heteroalkyl; and 15. The compound of claim 14, wherein V is a carbon, nitrogen, or oxygen atom.

16. R １ａ or R １ｂ The compound according to any one of claims 1 to 15, wherein at least one of is hydrogen.

17. R １ａ and R １ｂ The compound of any one of claims 1 to 15, wherein each of is hydrogen.

18. R １ａ and R １ｂ has one of the following structures: 【Chemistry 10】 During the ceremony, n' is independently 0 to 6 and n' is 1 to 5; and The compound of any one of claims 1 to 15, wherein R9 is hydrogen, halo, hydroxyl, alkoxy, amino, cyano, C1-C6 alkyl, or C1-C6 heteroalkyl.

19. R ２ has one of the following structures: 【Chemistry 11】 During the ceremony, n' is independently 0 to 6 and n' is 1 to 5; G ２ is CH ２ , NH, O, or S; W is CH or N; A is O, NH, or NHR ９ where i) if A is O, then: 【Chemistry 12】 is a double bond, or ii) A is NH or NHR ９ If 【Chemistry 13】 is a single bond; B is OR ９ , N.H. ２ , or NHR ９ and R ９ is hydrogen, halo, hydroxyl, alkoxy, amino, cyano, C １ -C ６ Alkyl, or C １ -C ６ is heteroalkyl; and R １０ The compound of any one of claims 1 to 18, wherein is i) absent or ii) hydrogen, alkyl, aryl, pyridyl, acylalkyl, or acylaryl.

20. R ２ teeth, 【Chemistry 14】 The compound according to any one of claims 1 to 19,

21. R ３ａ or R ３ｂ has one of the following structures: 【Chemistry 15】 During the ceremony, n' is independently 0 to 6 and n' is 1 to 5; Each G3 is independently C(R7)2, O, S, or NR7; Each W is independently CH or N; A is O, NH, or NHR9, where i) when A is O, 【Chemistry 16】 is a double bond, or ii) when A is NH or NHR9, 【Chemistry 17】 is a single bond; B is OR9, NH2, or NHR9; R9 is hydrogen, halo, hydroxyl, alkoxy, amino, cyano, C1-C6 alkyl, or C1-C6 heteroalkyl; and The compound of any one of claims 1 to 20, wherein R10 is i) absent or ii) hydrogen, alkyl, aryl, pyridyl, acylalkyl, or acylaryl.

22. R ３ａ or R ３ｂ is hydrogen, and R ３ａ or R ３ｂ The other one is, [Chemistry 18] The compound according to any one of claims 1 to 21,

23. R ３ａ or R ３ｂ is hydrogen, and R ３ａ or R ３ｂ The other one is, 【Chemistry 19】 The compound according to any one of claims 1 to 22,

24. R ４ａ or R ４ｂ has one of the following structures: 【Chemistry 20】 During the ceremony, n' is independently 0 to 6 and n' is 1 to 5; Each G4 is independently C(R7)2, O, S, or NR7; Each W is independently CH or N; A is O, NH, or NHR9, where i) when A is O, 【Chemistry 21】 is a double bond, or ii) when A is NH or NHR9, 【Chemistry 22】 is a single bond; B is OR9, NH2, or NHR9; R9 is hydrogen, halo, hydroxyl, alkoxy, amino, cyano, C1-C6 alkyl, or C1-C6 heteroalkyl; and The compound of any one of claims 1 to 23, wherein R10 is i) absent or ii) hydrogen, alkyl, aryl, pyridyl, acylalkyl, or acylaryl.

25. R ４ａ or R ４ｂ is hydrogen, and R ４ａ or R ４ｂ The other one is, 【Chemistry 23】 The compound according to any one of claims 1 to 24,

26. R ５ａ has one of the following structures: 【Chemistry 24-1】 【Chemistry 24-2】 During the ceremony, n is 0 to 6 and n' is 1 to 5; Each G5 is independently C(R7)2, O, S, or NR7; and 26. The compound of any one of claims 1 to 25, wherein each W is independently CH or N.

27. R ５ａ teeth, 【Chemistry 25】 and R ５ｂ The compound according to any one of claims 1 to 26, wherein is hydrogen.

28. W is O and R ９ 28. The compound of claim 27, wherein is hydrogen.

29. R ５ａ is one of the following structures: 【Chemistry 26】 The compound according to any one of claims 1 to 25, having the formula:

30. The compound has one of the following structures: 【Chemistry 27-1】 【Chemistry 27-2】 2. The compound of claim 1, wherein:

31. The compound of any one of claims 1 to 30, wherein the compound is a pharmaceutically acceptable salt.

32. A pharmaceutical composition comprising a compound or salt according to any one of claims 1 to 31 and a pharmaceutically acceptable carrier.

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