EP4694910A1 - Compositions and uses thereof for treating diseases or disorders associated with gas5 lncrna signaling dysfunction - Google Patents

Abstract

The present disclosure is concerned with pharmaceutical compositions that are formulated for intranasal or subcutaneous administration and that contain cyclic γ-AA compounds or pharmaceutically acceptable salts thereof. Also disclosed are methods of using cyclic γ-AA compounds to treat diseases and disorders associated with dysregulation of GAS5 IncRNA signaling such as, for example, neurodegenerative diseases (e.g., amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), AD and related dementias (AD/ADRD), Parkinson's disease (PD), Huntington's disease, frontotemporal lobar degeneration, chronic traumatic encephalopathy, Parkinsonims linked to chromosome 17, globular glial tauopathy, tauopathies, frontotemperal dementia, PSP with parkinsonism, progressive gait freezing, primary progressive apraxia of speech, motor neuron disease, ataxia, progressive supranuclear palsy (PSP), multiple system atrophy, corticobasal degeneration (CBD), argyrophilic grain disease (AGD), Pick's disease (PiD), dementia, Huntington's disease (HD), primary age-related tauopathy (PART), and aging-related tau astrogliopathy (ART AG)), diabetes (e.g., type I diabetes, type II diabetes), and obesity. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

Description

COMPOSITIONS AND USES THEREOF FOR TREATING DISEASES OR DISORDERS ASSOCIATED WITH GAS5 LNCRNA SIGNALING DYSFUNCTION CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This Application claims the benefit of U.S. Application No.63/458,872, filed on April 12, 2023, the contents of which are incorporated herein by reference in their entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH [0002] This invention was made with government support under grant numbers VA Brave GPAA-821012361, VAMR I01BX003836, VAMR I01BX005591, and VA RCS IK6BX005387, awarded by the U.S. Department of Veteran Affairs. The government has certain rights in the invention. BACKGROUND [0003] With advances in medicine and technology, humans are living longer. It is estimated that 1.4 billion people are over the age of 60 worldwide. According to the US Census, older aldults are projected to be 23.4% of the population by 2060. Healthy aging is associated with slight decreases in overall body capabilities including mild decreases in cognition. However, shifts in normal aging set the stage for neurodegeneration and cognitive disorders including dementia. Epidemiological and clinical studies have overwhelmingly confirmed that defective insulin signaling in the brain plays a central role in the early stages of eementia, a primary feature of sporadic Alzheimer’s disease (AD) and AD- Related Dementias (ADRD) pathology (Malkki, H. (2015) Nat. Rev. Neurol.11: 485; Yarchoan and Arnold (2014) Diabetes 63: 2253-2261; Westwood et al. (2014) Neurology 82: 1613-1619; Sebastiao et al. (2014) Front. Endocrinol.5: 110; Takeda et al. (2011) Mol. BioSyst.7: 1822-1827; Sato et al. (2011) Curr. Aging Sci.4: 118-127; Schrijvers et al. (2010) Neurology 75: 1982-1987; Matsuzaki et al. (2010) Neurology 75: 764-770; Correia et al. (2011) Ageing Res. Rev.10: 264-273). [0004] It is projected that by 2050, 106.23 million adults will be living with AD worldwide. In the USA, 1 in 10 adults over the age of 65 have Alzheimer’s Diseaese (AD) (Alzheimer’s Association Report 2020). Dementia and particularly Alzheimer’s disease affects almost 25% of US veterans over the age of 65 years and this number doubles in the group above 75 years. Additionally, sedentary lifestyles during post-service years dramatically increase the prevalence of type 2 diabets (T2D) and insulin resistnace which increase the risk for impaired cognitive function (affecting verbal and nonverbal memory) and dementia by 47% (Lu et al. (2009) PLoS ONE 4: e4144; Roriz-Filho et al. (2009) Biochim Biophys Acta 1792: 432-443). Of particular importance are the Vietnam War veterans exposed to Agent Orange who have a 79% increased risk of dementia with T2D as the predominant risk factor compared to other veterans (Cypel et al. (2016) J. Occup. Environ. Med./Am. Coll. Occup. Environ. Med.58: 1127-1136; Henriksen et al. (1997) Epidemiology 8: 252-258; Barrett et al. (2001) Neurotoxicology 22: 491-502; Michalek et al. (2008) J. Occup. Environ. Med./Am. Coll. Occup. Environ. Med.50: 330-340; Cypel and Kang (2010) Ann. Epidemiol.20: 339-346). The shift from normal aging to neurodegeneration is a long process with slow progression of individual symptoms sich as cognitive decline or memory losses. Efforts to treat the pathology of AD at late stages have not been effective in clinic (Vaz et al. (2022) Clin. Interv. Aging 17: 797-810; Dai et al. (2022) Curr. Drug Targets; Mehta et al. (2014) FEBS J.281: 3766-3775). Hence, there is an urgent need to target the modifiable, early risk factors during aging and thereby prevent the onset of neurodegeneration. [0005] Long noncoding RNA (lncRNA) are the largest subset of noncoding RNA found in the human genome. Recent discoveries have highlighted its multi-faceted, central role as regulators of gene expression and cellular function. It is now established that dysregulation of lncRNA expression plays an intergral role in the manifestation of human diseases (Zhu et al. (2014) FEBS J.281: 3766-3775; Zhao et al. (2014) PLoS ONE 9: 109782; Schmidt et al. (2014) J. Thoracic Oncol.9: 109782; Qin et al. (2014) Int. J. Clin. Exp. Pathol.7: 3065- 3072). The lncRNA growth-arrest specific transcript (GAS5) has been shown to regulate cell growth, proliferation and survival (Coccia et al. (1992) Mol. Cell Biochem.12: 3514-3521; Smith and Steitz (1998) Mol. Cell. Biochem.18: 6897-6989). It has previously been demonstrated that GAS5 levels are decreased consistently in humans with type 2 diabetes, an insulin resistant state (Carter et al.2015) BBA Clin.4: 102-107). This extensive prior research demonstrated that GAS5 regulates the expression of insulin receptor and insulin signaling pathways in diabetic adipocytes (Shi et al. (2019) Cell Chem. Biol.). Other studies have demonstrated the role of GAS5 in mediating an inflammatory response. [0006] As knowledge regarding the significance of GAS5 signaling in metabolic pathways, cognition, and the subsequent inflammatory responses continues to increase, the diseases or disorders for which targeting of GAS5 lncRNA may provide a therapeutic effect continues to expand. Thus, there remains a need for compositions that modulate GAS5 lncRNA signaling and methods of making and using same. SUMMARY [0007] In accordance with the purpose(s) of the invention, as embodied and broadly described herein, the invention, in one aspect, relates to pharmaceutical compositions that are formulated for intranasal or subcutaneous administration and that contain cyclic γ-AA compounds or pharmaceutically acceptable salts thereof. Also disclosed are methods of using cyclic γ-AA compounds to treat diseases and disorders associated with dysregulation of GAS5 lncRNA signaling such as, for example, neurodegenerative diseases (e.g., amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), AD and related dementias (AD/ADRD), Parkinson’s disease (PD), Huntington’s disease, frontotemporal lobar degeneration, chronic traumatic encephalopathy, Parkinsonims linked to chromosome 17, globular glial tauopathy, tauopathies, frontotemperal dementia, PSP with parkinsonism, progressive gait freezing, primary progressive apraxia of speech, motor neuron disease, ataxia, progressive supranuclear palsy (PSP), multiple system atrophy, corticobasal degeneration (CBD), argyrophilic grain disease (AGD), Pick’s disease (PiD), dementia, Huntington’s disease (HD), primary age-related tauopathy (PART), and aging-related tau astrogliopathy (ARTAG)), diabetes (e.g., type I diabetes, type II diabetes), and obesity. [0008] Thus, disclosed are pharmaceutical compositions comprising an effective amount of a compound having a structure represented by a formula: , wherein r is selected from 2 and 3; wherein R¹ is selected from C1-C4 alkyl, C1-C4 aminoalkyl, –CH₂C₆H₅, and –CH₂(unsubstituted indolyl); wherein R⁵ is selected from C2-C4 alkyl, –(C1-C4 alkyl)CO2H, –CH2C6H5, and –CH2(unsubstituted indolyl); wherein R⁶ is selected from C2-C4 alkyl, C2-C4 alkenyl, C2-C4 aminoalkyl, –(C1-C4 alkyl)CO₂H, – CH2C6H5, and –CH2(unsubstituted indolyl); wherein R⁷ is selected from –NH2, –CO2H, unsubstituted cyclopropyl, unsubstituted cyclohexyl, unsubstituted phenyl, and unsubstituted indolyl; wherein each of R⁸, R⁹, and R¹⁰ is independently selected from C1-C4 aminoalkyl, – (C1-C4 alkyl)CO2H, and –(C1-C4 alkyl)Cy¹; and wherein Cy¹ is selected from cyclopropyl, cyclohexyl, phenyl, and indolyl, and is unsubstituted, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is formulated for intranasal or subcutaneous administration. [0009] Also disclosed are methods of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: , wherein r is selected from ; 1-C4 alkyl, C1-C4 aminoalkyl, –CH₂C₆H₅, and –CH₂(unsubstituted indolyl); wherein R⁵ is selected from C2-C4 alkyl, –(C1-C4 alkyl)CO2H, –CH2C6H5, and –CH2(unsubstituted indolyl); wherein R⁶ is selected from C2-C4 alkyl, C2-C4 alkenyl, C2-C4 aminoalkyl, –(C1-C4 alkyl)CO₂H, – CH2C6H5, and –CH2(unsubstituted indolyl); wherein R⁷ is selected from –NH2, –CO2H, unsubstituted cyclopropyl, unsubstituted cyclohexyl, unsubstituted phenyl, and unsubstituted indolyl; wherein each of R⁸, R⁹, and R¹⁰ is independently selected from C1-C4 aminoalkyl, – (C1-C4 alkyl)CO₂H, and –(C1-C4 alkyl)Cy¹; and wherein Cy¹ is selected from cyclopropyl, cyclohexyl, phenyl, and indolyl, and is unsubstituted, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is a neurodegenerative disorder, diabetes, or obesity. [0010] Also disclosed are methods of treating a neurodegenerative disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: , wherein r is selected fro 1-C4 alkyl, C1-C4 aminoalkyl, –CH₂C₆H₅, and –CH₂(unsubstituted indolyl); wherein R⁵ is selected from C2-C4 alkyl, –(C1-C4 alkyl)CO2H, –CH2C6H5, and –CH2(unsubstituted indolyl); wherein R⁶ is selected from C2-C4 alkyl, C2-C4 alkenyl, C2-C4 aminoalkyl, –(C1-C4 alkyl)CO₂H, – CH2C6H5, and –CH2(unsubstituted indolyl); wherein R⁷ is selected from –NH2, –CO2H, unsubstituted cyclopropyl, unsubstituted cyclohexyl, unsubstituted phenyl, and unsubstituted indolyl; wherein each of R⁸, R⁹, and R¹⁰ is independently selected from C1-C4 aminoalkyl, – (C1-C4 alkyl)CO₂H, and –(C1-C4 alkyl)Cy¹; and wherein Cy¹ is selected from cyclopropyl, cyclohexyl, phenyl, and indolyl, and is unsubstituted, or a pharmaceutically acceptable salt thereof. [0011] Also disclosed are kits comprising a compound having a structure represented by a formula: , wherein r is selected from 2 and 3; wherein R¹ is selected from C1-C4 alkyl, C1-C4 aminoalkyl, unsubstituted phenyl, and unsubstituted indolyl; wherein R⁵ is selected from C2- C4 alkyl, –(C1-C4 alkyl)CO₂H, –CH₂C₆H₅, and –CH₂(unsubstituted indolyl); wherein R⁶ is selected from C2-C4 alkyl, C2-C4 alkenyl, C2-C4 aminoalkyl, –(C1-C4 alkyl)CO2H, – CH₂C₆H₅, and –CH₂(unsubstituted indolyl); wherein R⁷ is selected from –NH₂, –CO₂H, unsubstituted cyclopropyl, unsubstituted cyclohexyl, unsubstituted phenyl, and unsubstituted indolyl; wherein each of R⁸, R⁹, and R¹⁰ is independently selected from C1-C4 aminoalkyl, – (C1-C4 alkyl)CO₂H, and –(C1-C4 alkyl)Cy¹; and wherein Cy¹ is selected from cyclopropyl, cyclohexyl, phenyl, and indolyl, and is unsubstituted, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an agent associated with the treatment of a neurodegenerative disorder selected from amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), motor neuron disease, ataxia, progressive supranuclear palsy (PSP), multiple system atrophy, corticobasal degeneration (CBD), argyrophilic grain disease (AGD), Pick’s disease (PiD), Huntington’s disease (HD), primary age-related tauopathy (PART), and aging- related tau astrogliopathy (ARTAG); (b) instructions for administering the compound in connection with treating the neurodegenerative disorder; and (c) instructions for treating the neurodegenerative disorder. [0012] While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification. BRIEF DESCRIPTION OF THE FIGURES [0013] The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects and together with the description serve to explain the principles of the invention. [0014] FIG.1 shows representative schematics illustrating the role of long noncoding RNA GAS5. [0015] FIG.2 shows a representative schematic illustrating the multiple partners of GAS5. [0016] FIG.3A and FIG.3B show representative schematics illustrating that aberrant neuronal insulin signaling culminates in decreased cognition and neuronal dysfunction and onset Alzheimer’s disease and related dementias (ADRD). [0017] FIG. 4A-E show representative data illustrating that GAS5 is decreased in Alzheimer's disease (AD) and other neurological disorders.

[0018] FIG. 5 shows a representative schematic illustrating the various stages of ADRD.

[0019] FIG. 6 shows a representative schematic illustrating a proposed strategy to treat ADRD via targeting genes for a modifiable risk factor.

[0020] FIG. 7A and FIG. 7B show representative schematics illustrating the design of small molecules to increase GAS5 levels. Briefly, GAS5 lelves are decreased in ADRD and are regulated by its rate of turnover. UPF1 binds to PTC and tags it for nonsense mediated decay. By disrupting UPF1 binding to the 3’ region of GAS5, degradation is prevented.

[0021] FIG. 8 shows representative data depicting Gas5 levels in the tissues of normal and diabetic, obese mice.

[0022] FIG. 9A and FIG. 9B shows representative data depicting in vivo assessment of subcutaneous injection of NPC86 in an insulin resistant murine model.

[0023] FIG. 10 shows representative data of glucose tolerance tests in diabetic obese mouse model treated with NPC86.

[0024] FIG. 11A-D show representative RNA-sequencing data of adipose tissue in a DIO murine model.

[0025] FIG. 12A and FIG. 12B show representative RNA-sequencing data of adipose tissue in a DIO murine model.

[0026] FIG. 13 shows representative data of GAS5 levels in the cortex following subcutaneous administration of NPC86 in a DIO murine model.

[0027] FIG. 14 shows representative data for in vivo treatment with insulin.

[0028] FIG. 15 shows representative data demonstating the efficacy of intranasal administration of NPC86 on GAS5 levels.

[0029] FIG. 16 shows representative data for GAS5 and insulin in NPC86-dosed mice.

[0030] FIG. 17A and FIG. 17B show representative data of brain tissue staining showing that NPC86 crosses the blood brain barrier.

[0031] FIG. 18 shows representative tissue data revealing no toxicity following NPC86 treatment.

[0032] FIG. 19 shows representative data comparing cortex GAS5 levels after subcutaneous versus intranasal administration of NPC86.

[0033] FIG. 20A-C show representative data of RNAseq of NPC86 in aged mice.

[0034] FIG. 21 shows a representative schematic illustrating a tauopathy model in which low GAS5 levels promote tau phosphorylation. [0035] FIG. 22A and FIG. 22B show representative data depicting GAS5 siRNA and NPC86 decreasing phosphorylation of human mutant tau in vitro.

[0036] FIG. 23A-C show representative data of GAS5 levels with LPS chronic treatment and H2O2 oxidative stress and rescue with NPC86.

[0037] FIG. 24 shows representative data relative expression of GAS5 ofNPC67 treated HT22 neuronal cells.

[0038] FIG. 25 shows reprentative data of relative expression of GAS5 and Insulin receptor in NPC86 and NPC67 treated HT22 neuronal cells.

[0039] FIG. 26 shows representative data illustrating GAS5 expression relative to U6 expression in cortex tissue of control after intranasal administration of NPC86 and NPC67. [0040] FIG. 27A and FIG. 27B show representative bar graphs depicting IL- IB and TNFa expression in brain tissue of control, NPC86, and NPC67 treated PS 19 mice.

[0041] FIG. 28 shows representative data illustrating phosphorylation levels of Tau and AKT in brain tissue of control after intranasal administration of NPC86, and NPC67 treated PS19 mice.

[0042] FIG. 29 shows a representative mass spectra of NPC67.

[0043] Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory’ only and are not restrictive of the invention.

DETAILED DESCRIPTION

[0044] The present invention can be understood more readily by reference to the following detailed description of the invention and the Examples included therein.

[0045] Before the present compounds, compositions, articles, systems, devices, and/or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary⁷. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

[0046] While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0047] Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully descnbe the state of the art to which this pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein may be different from the actual publication dates, which can require independent confirmation.

A. DEFINITIONS

[0048] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a functional group,” “an alkyl,” or “a residue” includes mixtures of two or more such functional groups, alkyls, or residues, and the like.

[0049] As used in the specification and in the claims, the term “comprising” can include the aspects “consisting of' and “consisting essentially of.”

[0050] Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as ’‘about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12. 13. and 14 are also disclosed.

[0051] As used herein, the terms “about” and “at or about” mean that the amount or value in question can be the value designated some other value approximately or about the same. It is generally understood, as used herein, that it is the nominal value indicated ±10% variation unless otherwise indicated or inferred. The term is intended to convey that similar values promote equivalent results or effects recited in the claims. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off. measurement error and the like, and other factors known to those of skill in the art. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is understood that where “about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0052] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

[0053] A weight percent (wt. %) of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.

[0054] As used herein, “IC50” is intended to refer to the concentration of a substance (e.g. , a compound or a drug) that is required for 50% inhibition of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, an IC50 can refer to the concentration of a substance that is required for 50% inhibition in vivo, as further defined elsewhere herein. In a further aspect, IC50 refers to the half-maximal (50%) inhibitory concentration (IC) of a substance.

[0055] As used herein, “EC50” is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% agonism of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, an EC50 can refer to the concentration of a substance that is required for 50% agonism in vivo, as further defined elsewhere herein. In a further aspect, EC50 refers to the concentration of agonist that provokes a response halfway between the baseline and maximum response. [0056] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0057] As used herein, the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease, disorder, or condition. The term “patient” includes human and veterinary' subjects.

[0058] As used herein, the term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. In various aspects, the term covers any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e.. arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease. In one aspect, the subject is a mammal such as a primate, and, in a further aspect, the subject is a human. The term “subject” also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.). [0059] As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed. [0060] As used herein, the term “diagnosed” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein. [0061] As used herein, the terms “administering” and “administration” refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition. [0062] As used herein, the terms “effective amount” and “amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition. For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the condition being treated and the severity of the condition; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount’'; that is, an amount effective for prevention of a disease or condition.

[0063] As used herein, “dosage form” means a pharmacologically active material in a medium, carrier, vehicle, or device suitable for administration to a subject. A dosage forms can comprise inventive a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, in combination with a pharmaceutically acceptable excipient, such as a preservative, buffer, saline, or phosphate buffered saline. Dosage forms can be made using conventional pharmaceutical manufacturing and compounding techniques. Dosage forms can comprise inorganic or organic buffers (e.g., sodium or potassium salts of phosphate, carbonate, acetate, or citrate) and pH adjustment agents (e.g, hydrochloric acid, sodium or potassium hydroxide, salts of citrate or acetate, amino acids and their salts) antioxidants (e.g, ascorbic acid, alpha-tocopherol), surfactants (e.g, polysorbate 20, polysorbate 80, polyoxyethylene 9-10 nonyl phenol, sodium desoxy cholate), solution and/or cryo/lyo stabilizers (e.g , sucrose, lactose, mannitol, trehalose), osmotic adjustment agents (e.g, salts or sugars), antibacterial agents (e.g, benzoic acid, phenol, gentamicin), antifoaming agents (e.g , poly dimethylsilozone), preservatives (e.g, thimerosal, 2- phenoxy ethanol, EDTA), polymeric stabilizers and viscosity-adjustment agents (e.g., polyvinylpyrrolidone, poloxamer 488, carboxymethylcellulose) and co-solvents (e.g., glycerol, polyethylene glycol, ethanol). A dosage form formulated for injectable use can have a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, suspended in sterile saline solution for injection together with a preservative.

[0064] As used herein, “kit” means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0065] As used herein. “instruction(s)” means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can comprise one or multiple documents, and are meant to include future updates.

[0066] As used herein, the terms ‘"therapeutic agent” include any synthetic or naturally occurring biologically active compound or composition of matter which, when administered to an organism (human or nonhuman animal), induces a desired pharmacologic, immunogenic, and/or physiologic effect by local and/or systemic action. The term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like. Examples of therapeutic agents are described in well-known literature references such as the Merck Index (14^th edition), the Physicians' Desk Reference (64^th edition), and The Pharmacological Basis of Therapeutics (12^th edition), and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment. For example, the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to. adjuvants; anti-infectives such as antibiotics and antiviral agents; anti-cancer and anti-neoplastic agents such as kinase inhibitors, poly ADP ribose polymerase (PARP) inhibitors and other DNA damage response modifiers, epigenetic agents such as bromodomain and extra-terminal (BET) inhibitors, histone deacetylase (HD Ac) inhibitors, iron chelotors and other ribonucleotides reductase inhibitors, proteasome inhibitors and Nedd8-activating enzyme (NAE) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, traditional cytotoxic agents such as paclitaxel, dox, irinotecan, and platinum compounds, immune checkpoint blockade agents such as cytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibody (mAB), programmed cell death protein 1 (PD-l)/programmed cell death-ligand 1 (PD-L1) mAB, cluster of differentiation 47 (CD47) mAB, toll-like receptor (TLR) agonists and other immune modifiers, cell therapeutics such as chimeric antigen receptor T-cell (CAR-T)/chimeric antigen receptor natural killer (CAR-NK) cells, and proteins such as interferons (IFNs), interleukins (ILs), and mAbs; anti-ALS agents such as entry inhibitors, fusion inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors. NCP7 inhibitors, protease inhibitors, and integrase inhibitors; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, antiepileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics. antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, beta-agonists and antiarrythmics), antihypertensives, diuretics, vasodilators; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressives; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double- and single-stranded molecules, gene constructs, expression vectors, antisense molecules and the like), small molecules (e.g, doxorubicin) and other biologically active macromolecules such as, for example, proteins and enzymes. The agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas. The term “therapeutic agent⁷’ also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro-drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment. [0067] The term “pharmaceutically acceptable’' describes a material that is not biologically or otherwise undesirable, z.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

[0068] As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (c.g.. a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary⁷ derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.

[0069] As used herein, the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.

[0070] As used herein, the term '‘substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms, such as nitrogen, can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms “substitution” or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (z.e., further substituted or unsubstituted).

[0071] In defining various terms, “A¹.” “A²,” “A³,” and “A⁴” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.

[0072] The term “aliphatic” or “aliphatic group.” as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0073] The term “alkyl” as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n -butyl, isobutyl, s- butyl, /-butyl. n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic or acyclic. The alky l group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms. The term alkyl group can also be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl. [0074] Throughout the specification “alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term “halogenated alkyl” or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl” specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine. The term “polyhaloalkyl” specifically refers to an alkyl group that is independently substituted with two or more halides, i.e. each halide substituent need not be the same halide as another halide substituent, nor do the multiple instances of a halide substituent need to be on the same carbon. The term “alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term “aminoalkyl” specifically refers to an alkyl group that is substituted with one or more amino groups. The term “hydroxyalkyl” specifically refers to an alkyl group that is substituted with one or more hydroxy groups. When “alkyl” is used in one instance and a specific term such as “hydroxyalkyl” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxyalkyl” and the like. [0075] This practice is also used for other groups described herein. That is, while a term such as “cycloalkyl” refers to both unsubstituted and substituted cycloalkyl moieties, the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.” Similarly, a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy,” a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, the practice of using a general term, such as “cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term. [0076] The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. [0077] The term “polyalkylene group” as used herein is a group having two or more CH2 groups linked to one another. The polyalkylene group can be represented by the formula — (CH2)a—, where “a” is an integer of from 2 to 500. [0078] The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an “alkoxy” group can be defined as —OA¹ where A¹ is alkyl or cycloalkyl as defined above. “Alkoxy” also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as —OA¹—OA² or — OA¹—(OA²)_a—OA³, where “a” is an integer of from 1 to 200 and A¹, A², and A³ are alkyl and/or cycloalkyl groups. [0079] The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond. Asymmetric structures such as (A¹A²)C=C(A³A⁴) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C=C. The alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein. [0080] The term “cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bound, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term “heterocycloalkenyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. The cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0081] The term “alkynyl"’ as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond. The alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0082] The term '‘cycloalkynyl” as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound. Examples of cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like. The term “heterocycloalkynyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted. The cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, ary l, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0083] The term “aromatic group” as used herein refers to a ring structure having cyclic clouds of delocalized n electrons above and below the plane of the molecule, where the a clouds contain (4n+2) a electrons. A further discussion of aromaticity' is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity ,” pages 477-497, incorporated herein by reference. The term “aromatic group” is inclusive of both aryl and heteroaryl groups.

[0084] The term “aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to. alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, — NH2, carboxylic acid, ester. ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is a specific type of aryl group and is included in the definition of “aryl.” In addition, the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carboncarbon bond. For example, bi aryl can be two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.

[0085] The term '‘aldehyde” as used herein is represented by the formula — C(O)H. Throughout this specification “C(O)” is a short hand notation for a carbonyl group, i.e., C=O. [0086] The terms “amine” or “amino” as used herein are represented by the formula — NA¹ A², where A¹ and A² can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A specific example of amino is — NH2.

[0087] The term “alkylamino” as used herein is represented by the formula — NH(-alkyl) where alkyl is a described herein. Representative examples include, but are not limited to. methylamine group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, and the like.

[0088] The term “dialkylamino” as used herein is represented by the formula — N(-alkyl)2 where alkyl is a described herein. Representative examples include, but are not limited to, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di (sec-butyl )amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group. di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N- ethyl-N-propyl amino group and the like.

[0089] The term “carboxylic acid” as used herein is represented by the formula — C(O)OH. [0090] The term “ester” as used herein is represented by the formula — OC(O)A¹ or — C(O)OA', where A¹ can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl. cycloalkynyl. aryl, or heteroaryl group as described herein. The term '‘polyester” as used herein is represented by the formula — (A¹O(O)C-A²-C(O)O)_a — or — (A¹O(O)C-A²-OC(O))_a — , where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer from 1 to 500. “Polyester” is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.

[0091] The term '‘ether” as used herein is represented by the formula A^XOA², where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein. The term “polyether” as used herein is represented by the formula — (A¹O-A²O)_a — , where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and '‘a” is an integer of from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

[0092] The terms “halo,” “halogen,"’ or “halide"’ as used herein can be used interchangeably and refer to F, Cl, Br, or I.

[0093] The terms “pseudohalide,” “pseudohalogen,” or “pseudohalo” as used herein can be used interchangeably and refer to functional groups that behave substantially similar to halides. Such functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.

[0094] The term “heteroalkyl.” as used herein refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quatemized. Heteroalkyls can be substituted as defined above for alkyl groups.

[0095] The term “heteroaryl,” as used herein refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. The heteroaryl group can be substituted or unsubstituted. The heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. Heteroary l groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, fury l, imidazolyl, pyrimidinyl. tetrazolyl, thienyl, pyridinyl. pyrrolyl, A-methy 1 pyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further not limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzof^oxazolyl. benzo|<7|thiazolvl. quinolinyl, quinazolinyl, indazolyl. imidazo[l,2-b]pyridazinyl, imidazo[l,2-a]pyrazinyl. benzo[c][l,2,5]thiadiazolyl, benzo[c][1.2.5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.

[0096] The terms ‘“heterocycle” or “heterocyclyl,” as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Thus, the term is inclusive of, but not limited to, “heterocycloalkyl”. “heteroaryl”. “bicyclic heterocycle” and “polycyclic heterocycle.” Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3- oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1,2, 5 -thiadiazole, and 1,3,4-thiadiazole, triazole, including, 1.2.3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including 1,2,4-triazine and 1,3,5-triazine, tetrazine, including 1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. The term heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2- C4 heterocyclyl. C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl. For example, a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl. oxiranyl. thiiranyl. and the like. Alternatively, for example, a C5 heterocyclyl comprises a group which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like. It is understood that a heterocyclyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocyclyl ring.

[0097] The term “bicyclic heterocycle” or “bicyclic heterocyclyl,” as used herein refers to a ring system in which at least one of the ring members is other than carbon. Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring. Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6- membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[l,5-a]pyridinyl. benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-l,4-benzodioxinyl, 3,4-dihydro-2H- chromenyl, lH-pyrazolo[4,3-c]pyridin-3-yl; lH-pyrrolo[3,2-b]pyridin-3-yl; and 1H- pyrazolo[3,2-b]pyridin-3-yl.

[0098] The term '‘heterocycloalkyl” as used herein refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems. The heterocycloalkyd ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted. Representative heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

[0099] The term '‘hydroxyl” or “hydroxyl” as used herein is represented by the formula — OH.

[00100] The term “ketone” as used herein is represented by the formula A¹C(O)A², where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[00101] The term '‘azide” or “azido” as used herein is represented by the formula — N₃.

[00102] The term “nitro” as used herein is represented by the formula — NO2.

[00103] The term “nitrile” or “cyano” as used herein is represented by the formula — CN.

[00104] The term “silyl” as used herein is represented by the formula — SiA^A³, where A¹, A², and A³ can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl. cycloalkynyl, aryl, or heteroaryl group as described herein. [00105] The term “sulfo-oxo” as used herein is represented by the formulas — S(O)A', — S(O)2A¹, — OS(O)2A¹, or — OS(O)2OA¹, where A¹ can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, ary l, or heteroaryl group as described herein. Throughout this specification “S(O)” is a short hand notation for S=O. The term "sulfonyl” is used herein to refer to the sulfo-oxo group represented by the formula — S(O)2A\ where A¹ can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfone” as used herein is represented by the formula A¹S(O)2A², where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfoxide” as used herein is represented by the formula A’S(O)A², where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. [00106] The term '‘thiol’’ as used herein is represented by the formula — SH.

[00107] “R¹,” “R²,” “R³,” “Rⁿ,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above. For example, if R¹ is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group. For example, with the phrase “an alkyl group comprising an amino group,’’ the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group. [00108] As described herein, compounds of the invention may contain “optionally substituted” moi eties. In general, the term “substituted.” whether preceded by the term “optionally” or not, means that one or more hydrogen of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. In is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

[00109] The term '‘stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein.

[00110] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH₂)o 4R⁰; -(CH₂)o 4OR⁰; - 0(CH₂)o-4R°. -0-(CH₂)O ₄C(O)OR°; -(CH₂)O ₄CH(OR^O)₂; -(CH₂)O ₄SR°; -(CH₂)O ₄Ph, which may be substituted with R°; -(CH₂)o-40(CH₂)o-iPh which may be substituted with R°; - CH=CHPh, which may be substituted with R°; -(CH₂)o-40(CH₂)o-i-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R ^)2; –(CH2)0–4N(R ^)C(O)R ^; – N(R ^)C(S)R ^; –(CH2)0–4N(R ^)C(O)NR ^2; -N(R ^)C(S)NR ^2; –(CH2)0–4N(R ^)C(O)OR ^; – N(R ^)N(R ^)C(O)R ^; -N(R ^)N(R ^)C(O)NR ^₂; -N(R ^)N(R ^)C(O)OR ^; –(CH₂)_0–4C(O)R ^; – C(S)R ^; –(CH₂)_0–4C(O)OR ^; –(CH₂)_0–4C(O)SR ^; -(CH₂)_0–4C(O)OSiR ^₃; –(CH₂)_0–4OC(O)R ^; –OC(O)(CH2)0–4SR–, SC(S)SR°; –(CH2)0–4SC(O)R ^; –(CH2)0–4C(O)NR ^2; –C(S)NR ^2; – C(S)SR°; -(CH2)0–4OC(O)NR ^2; -C(O)N(OR ^)R ^; –C(O)C(O)R ^; –C(O)CH2C(O)R ^; – C(NOR ^)R ^; -(CH₂)_0–4SSR ^; –(CH₂)_0–4S(O)₂R ^; –(CH₂)_0–4S(O)₂OR ^; –(CH₂)_0–4OS(O)₂R ^; – S(O)₂NR ^₂; -(CH₂)_0–4S(O)R ^; -N(R ^)S(O)₂NR ^₂; –N(R ^)S(O)₂R ^; –N(OR ^)R ^; – C(NH)NR ^2; –P(O)2R ^; -P(O)R ^2; -OP(O)R ^2; –OP(O)(OR ^)2; SiR ^3; –(C1–4 straight or branched alkylene)O–N(R ^)2; or –(C1–4 straight or branched alkylene)C(O)O–N(R ^)2, wherein each R ^ may be substituted as defined below and is independently hydrogen, C_{1– 6} aliphatic, –CH₂Ph, –O(CH₂)_0–1Ph, -CH₂-(5-6 membered heteroaryl ring), or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ^, taken together with their intervening atom(s), form a 3–12– membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below. [00111] Suitable monovalent substituents on R ^ (or the ring formed by taking two independent occurrences of R ^ together with their intervening atoms), are independently halogen, –(CH2)0–2R ^{^}, –(haloR ^{^}), –(CH2)0–2OH, –(CH2)0–2OR ^{^}, –(CH2)0–2CH(OR ^{^})2; -O(haloR ^{^}), –CN, –N3, –(CH2)0–2C(O)R ^{^}, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR ^{^}, –(CH2)0– 2SR ^{^}, –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR ^{^}, –(CH2)0–2NR ^{^}2, –NO2, –SiR ^{^}3, –OSiR ^{^}3, -C(O)SR ^{^}, –(C1–4 straight or branched alkylene)C(O)OR ^{^}, or –SSR ^{^} wherein each R ^{^} is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R ^ include =O and =S. [00112] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR^*2, =NNHC(O)R^*, =NNHC(O)OR^*, =NNHS(O)₂R^*, =NR^*, =NOR^*, –O(C(R^* ₂))_2–3O–, or –S(C(R^* ₂))_2–3S–, wherein each independent occurrence of R^* is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)2 3O-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[00113] Suitable substituents on the aliphatic group of R* include halogen, -R*, -(haloR*), -OH, -OR*. -O(haloR’), -CN, -C(O)OH, -C(O)OR*, -NH₂, -NHR*, -NR*₂, or - NO₂, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Cu aliphatic, -CH₂Ph, -0(CH₂)o iPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[00114] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -Rt -NRf₂. -C(O)Rt -C(O)ORt, -C(O)C(O)Rt, -C(O)CH₂C(O)Rt, - S(O)₂R^t, -S(O)₂NRt₂, -C(S)NR^t2, -C(NH)NR^t ₂, or -N(R^t)S(O)₂R^t; wherein each R^: is independently hydrogen, C 1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R\ taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[00115] Suitable substituents on the aliphatic group of R are independently halogen, - R*, -(haloR*), -OH, -OR’, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH₂, -NHR*, -NR*₂, or -NO₂, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH₂Ph, -0(CH₂)o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[00116] The term “leaving group” refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons. Examples of suitable leaving groups include halides and sulfonate esters, including, but not limited to, triflate, mesylate, tosylate, and brosylate. [00117] The terms “hydrolysable group” and “hydrolysable moiety” refer to a functional group capable of undergoing hydrolysis, e.g., under basic or acidic conditions. Examples of hydrolysable residues include, without limitation, acid halides, activated carboxylic acids, and various protecting groups known in the art (see, for example, “Protective Groups in Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999).

[00118] The term “organic residue” defines a carbon-containing residue, i.e. , a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove. Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc. Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In a further aspect, an organic residue can comprise 2 to 18 carbon atoms, 2 to 15. carbon atoms, 2 to 12 carbon atoms. 2 to 8 carbon atoms. 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

[00119] A very close synonym of the term “residue” is the term “radical,” which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared. For example, a 2,4-thiazolidinedione radical in a particular compound has the structure: regardless of whether thiazolidinedione is used to prepare the compound. In some embodiments the radical (for example an alky l) can be further modified (i.e., substituted alkyl) by having bonded thereto one or more “substituent radicals.” The number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein.

[00120] “Organic radicals,” as the term is defined and used herein, contain one or more carbon atoms. An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical. One example, of an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2- naphthyl radical. In some embodiments, an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, disubstituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein. A few non-limiting examples of organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.

[00121] Compounds described herein can contain one or more double bonds and, thus, potentially give rise to cis/trans (E/Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the invention includes all such possible isomers, as well as mixtures of such isomers.

[00122] Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers. Unless stated to the contrary, the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art. the products of such procedures can be a mixture of stereoisomers. [00123] Many organic compounds exist in optically active forms having the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory⁷. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane). The Cahn-Ingold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.

[00124] When the disclosed compounds contain one chiral center, the compounds exist in two enantiomeric forms. Unless specifically stated to the contrary, a disclosed compound includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as a racemic mixture. The enantiomers can be resolved by methods known to those skilled in the art. such as formation of diastereoisomeric salts which may be separated, for example, by crystallization (see, CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation by David Kozma (CRC Press, 2001)); formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography⁷ in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step can liberate the desired enantiomeric form. Alternatively, specific enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.

[00125] Designation of a specific absolute configuration at a chiral carbon in a disclosed compound is understood to mean that the designated enantiomeric form of the compounds can be provided in enantiomeric excess (e.e.). Enantiomeric excess, as used herein, is the presence of a particular enantiomer at greater than 50%, for example, greater than 60%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 98%, or greater than 99%. In one aspect, the designated enantiomer is substantially free from the other enantiomer. For example, the “R” forms of the compounds can be substantially free from the “S” forms of the compounds and are, thus, in enantiomeric excess of the “S” forms. Conversely, “S” forms of the compounds can be substantially free of “R” forms of the compounds and are, thus, in enantiomeric excess of the “R” forms.

[00126] When a disclosed compound has two or more chiral carbons, it can have more than two optical isomers and can exist in diastereoisomeric forms. For example, when there are two chiral carbons, the compound can have up to four optical isomers and two pairs of enantiomers ((S,S)/(R,R) and (R,S)/(S,R)). The pairs of enantiomers (e.g., (S,S)/(R,R)) are mirror image stereoisomers of one another. The stereoisomers that are not mirror-images (e.g., (S,S) and (R,S)) are diastereomers. The diastereoisomeric pairs can be separated by methods known to those skilled in the art. for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above. Unless otherwise specifically excluded, a disclosed compound includes each diastereoisomer of such compounds and mixtures thereof.

[00127] The compounds according to this disclosure may form prodrugs at hydroxyl or amino functionalities using alkoxy, amino acids, etc., groups as the prodrug forming moieties. For instance, the hydroxymethyl position may form mono-, di-, or triphosphates and again these phosphates can form prodrugs. Preparations of such prodrug derivatives are discussed in various literature sources (examples are: Alexander et al., J. Med. Chem. 1988. 31, 318; Aligas-Martin et al., PCT WO 2000/041531, p. 30). The nitrogen function converted in preparing these derivatives is one (or more) of the nitrogen atoms of a compound of the disclosure.

[00128] “Derivatives” of the compounds disclosed herein are pharmaceutically acceptable salts, prodrugs, deuterated forms, radio-actively labeled forms, isomers, solvates and combinations thereof. The “combinations” mentioned in this context refer to derivatives falling within at least two of the groups: pharmaceutically acceptable salts, prodrugs, deuterated forms, radio-actively labeled forms, isomers, and solvates. Examples of radio- actively labeled forms include compounds labeled with tritium, phosphorous-32. iodine-129, carbon-11, fluorine- 18, and the like. [00129] Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance. The disclosed compounds can be isotopically- labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number ty pically found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ²H. ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷0, ³⁵ S, ¹⁸ F and ³⁶ Cl, respectively. Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as ³ H and ¹⁴ C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³ H, and carbon-14, i.e., ¹⁴ C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.

[00130] The compounds described in the invention can be present as a solvate. In some cases, the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate. The compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the invention to form solvates and hydrates. Unless stated to the contrary, the invention includes all such possible solvates.

[00131] The term “co-crystaF’ means a physical association of two or more molecules which owe their stability through non-covalent interaction. One or more components of this molecular complex provide a stable framework in the crystalline lattice. In certain instances, the guest molecules are incorporated in the cry stalline lattice as anhydrates or solvates, see e.g. “Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?” Almarasson, □.. et. al., The Royal Society of Chemistry⁷, 1889-1896, 2004. Examples of co-crystals include p- toluenesulfonic acid and benzenesulfonic acid.

[00132] It is also appreciated that certain compounds described herein can be present as an equilibrium of tautomers. For example, ketones with an a-hydrogen can exist in an equilibrium of the keto form and the enol form.

[00133] Likewise, amides wi th an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. As another example, pyrazoles can exist in two tautomeric forms, A¹ -unsubstituted. 3-A³ and A¹ -unsubstituted. 5-A³ as shown below.

Unless stated to the contrary, the invention includes all such possible tautomers.

[00134] It is known that chemical substances form solids, which are present in different states of order which are termed polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. The compounds according to the invention can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the invention includes all such possible polymorphic forms.

[00135] In some aspects, a structure of a compound can be represented by a formula: which is understood to be equivalent to a formula: wherein n is typically an integer. That is, R" is understood to represent five independent substituents, R”^(a), R^n(b), R^n(c), R^n(d), R^n(e). By "‘independent substituents." it is meant that each R substituent can be independently defined. For example, if in one instance R”^(a)is halogen, then R”^(b) is not necessarily halogen in that instance.

[00136] Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Strem Chemicals (Newbury port, MA), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry⁷ of Carbon Compounds, Volumes 1-5 and supplemental volumes (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[00137] Unless otherw ise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically^ stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[00138] Disclosed are the components to be used to prepare the compositions of the invention as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the invention. [00139] It is understood that the compounds and compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result. B. P^{HARMACEUTICAL} C^OMPOSITIONS [00140] In one aspect, disclosed are pharmaceutical compositions comprising an effective amount of a compound having a structure represented by a formula: , wherein r is selected from 2 and 3; wherein R¹ is selected from C1-C4 alkyl, C1-C4 aminoalkyl, –CH₂C₆H₅, and –CH₂(unsubstituted indolyl); wherein R⁵ is selected from C2-C4 alkyl, –(C1-C4 alkyl)CO2H, –CH2C6H5, and –CH2(unsubstituted indolyl); wherein R⁶ is selected from C2-C4 alkyl, C2-C4 alkenyl, C2-C4 aminoalkyl, –(C1-C4 alkyl)CO₂H, – CH2C6H5, and –CH2(unsubstituted indolyl); wherein R⁷ is selected from –NH2, –CO2H, unsubstituted cyclopropyl, unsubstituted cyclohexyl, unsubstituted phenyl, and unsubstituted indolyl; wherein each of R⁸, R⁹, and R¹⁰ is independently selected from C1-C4 aminoalkyl, – (C1-C4 alkyl)CO₂H, and –(C1-C4 alkyl)Cy¹; and wherein Cy¹ is selected from cyclopropyl, cyclohexyl, phenyl, and indolyl, and is unsubstituted, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is formulated for intranasal or subcutaneous administration. [00141] In various aspects, the pharmaceutical composition is sterile or sterilizable. The therapeutic compositions featured in the invention can contain carriers or excipients, many of which are known to skilled artisans. Excipients that can be used include buffers (for example, citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid, phospholipids, polypeptides (for example, serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, water, and glycerol. [00142] In various aspects, the disclosed pharmaceutical compositions comprise the disclosed compounds (including pharmaceutically acceptable salt(s) thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, optionally, other therapeutic ingredients or adjuvants. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy. [00143] In various aspects, the pharmaceutical compositions of this invention can include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of the compounds of the invention. The compounds of the invention, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds. [00144] The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. [00145] Pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms. [00146] Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability⁷. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[00147] In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound of the invention, and/or pharmaceutically acceptable salts thereof, can also be prepared in powder or liquid concentrate form.

[00148] In a further aspect, an effective amount is a therapeutically effective amount. In a still further aspect, an effective amount is a prophylactically effective amount.

[00149] In a further aspect, the pharmaceutical composition is administered to a mammal. In a still further aspect, the mammal is a human. In an even further aspect, the human is a patient.

[00150] In a further aspect, the pharmaceutical composition is used to useful for treating diseases and disorders associated with dysregulation of GAS5 IncRNA signaling such as, for example, neurodegenerative diseases (e g., amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), AD and related dementias (AD/ADRD), Parkinson's disease (PD). Huntington’s disease, frontotemporal lobar degeneration, chronic traumatic encephalopathy, Parkinsonims linked to chromosome 17. globular glial tauopathy. tauopathies, frontotemperal dementia, PSP with parkinsonism, progressive gait freezing, primary progressive apraxia of speech, motor neuron disease, ataxia, progressive supranuclear palsy (PSP), multiple system atrophy, corticobasal degeneration (CBD), argyrophilic grain disease (AGD). Pick’s disease (PiD). dementia, Huntington’s disease (HD), primary age-related tauopathy (PART), and aging-related tau astrogliopathy (ARTAG)), diabetes (e.g., type I diabetes, type II diabetes), and obesity. [00151] It is understood that the disclosed compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using. 1. STRUCTURE [00152] In one aspect, the compound has a structure represented by a formula: , wherein r is selected fro 1-C4 alkyl, C1-C4 aminoalkyl, –CH₂C₆H₅, and –CH₂(unsubstituted indolyl); wherein R⁵ is selected from C2-C4 alkyl, –(C1-C4 alkyl)CO2H, –CH2C6H5, and –CH2(unsubstituted indolyl); wherein R⁶ is selected from C2-C4 alkyl, C2-C4 alkenyl, C2-C4 aminoalkyl, –(C1-C4 alkyl)CO₂H, – CH2C6H5, and –CH2(unsubstituted indolyl); wherein R⁷ is selected from –NH2, –CO2H, unsubstituted cyclopropyl, unsubstituted cyclohexyl, unsubstituted phenyl, and unsubstituted indolyl; wherein each of R⁸, R⁹, and R¹⁰ is independently selected from C1-C4 aminoalkyl, – (C1-C4 alkyl)CO₂H, and –(C1-C4 alkyl)Cy¹; and wherein Cy¹ is selected from cyclopropyl, cyclohexyl, phenyl, and indolyl, and is unsubstituted, or a pharmaceutically acceptable salt thereof. [00153] In various aspects, the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

[00154] In various aspects, the compound has a structure represented by a formula: or a pharmaceutically acceptable salt thereof.

[00155] In various aspects, the compound has a structure represented by a formula: or a pharmaceutically acceptable salt thereof.

[00156] In various aspects, the compound has a structure represented by a formula:

wherein each of m, n, and q is independently selected from 1, 2, 3, and 4; wherein r is selected from 2 and 3; wherein R¹ is selected from C3-C4 alkyl, C3-C4 aminoalkyl, and unsubstituted benzyl; wherein each of R², R³, and R⁴ is independently selected from -NH2, unsubstituted cyclopropyl, unsubstituted cyclohexyl, and unsubstituted phenyl; wherein R⁵ is selected from C3-C4 alkyl, -(C2-C3 alkyl)CO2H, and unsubstituted benzyl; wherein R⁶ is selected from C3-C4 aminoalkyl, -(C2-C3 alkyl)CO2H, and unsubstituted benzyl; and wherein R⁷ is selected from -NH2 and unsubstituted phenyl, or a pharmaceutically acceptable salt thereof, provided that when R¹ is C3-C4 alkyl, R² and R³ are unsubstituted phenyl, R⁴ is unsubstituted cyclopropyl, and R⁵ is unsubstituted benzyl, then either (i) R⁷ is unsubstituted phenyl or (ii) R⁶ is C3-C4 aminoalkyl or -(C2-C3 alkyl)CO2H.

[00157] In various aspects, the compound has a structure represented by a formula: or a pharmaceutically acceptable salt thereof.

[00158] In various aspects, the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

[00159] In various aspects, the compound has a structure represented by a formula: or a pharmaceutically acceptable salt thereof.

[00160] In various aspects, the compound has a structure represented by a formula: or a pharmaceutically acceptable salt thereof.

[00161] In various aspects, the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

[00162] In various aspects, the compound has a structure represented by a formula: or a pharmaceutically acceptable salt thereof.

[00163] In various aspects, the compound has a structure represented by a formula: or a pharmaceutically acceptable salt thereof.

[00164] In various aspects, the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

[00165] In various aspects, the compound is selected from:

or a pharmaceutically acceptable salt thereof.

[00166] In various aspects, the compound is: or a pharmaceutically acceptable salt thereof.

[00167] In various aspects, the compound is selected from:

or a pharmaceutically acceptable salt thereof.

[00168] In various aspects, the compound is: or a pharmaceutically acceptable salt thereof.

[00169] In one aspect, each of m. n, and q is independently selected from 1, 2. 3, and 4.

In a further aspect, each of m, n, and q is independently selected from 1, 2, and 3. In a still further aspect, each of m, n, and q is independently selected from 1 and 2. In a yet further aspect, each of m, n, and q is independently selected from 1 and 3. In an even further aspect, each of m, n, and q is independently selected from 1 and 4. In a still even further aspect, each of m, n, and q is independently selected from 2 and 3. In yet an even further aspects, each of m, n, and q is independently selected from 2 and 4. In a further aspect, each of m, n, and q is independently selected from 3 and 4. [00170] In various aspects, m is selected from 1, 2, and 3. In a futher aspect, m is selected from 1 and 3. In a still further aspect, m is selected from 2 and 3. In yet a futher aspect, m is selected from 1 and 2. In an even further aspect, m is 1. In an even still further aspect, m is 2. In yet an even further aspect, m is 3. [00171] In various aspects, n is selected from 1 and 4. In a futher aspect, n is selected from 1, 2, and 3. In a still further aspect, n is selected from 1 and 2. In yet a futher aspect, n is selected from 1 and 3. In an even further aspect, n is selected from 1 and 4. In an even still further aspect, n n is selected from 2 and 3. In yet an even further aspect, n is selected from 2 and 4. In a futher aspect, n is selected from 3 and 4. In a still further aspect, n is 1. In yet a futher aspect, n is 2. In an even further aspect, n is 3. In an even still further aspect, n is 4. [00172] In various aspects, q is selected from 1, 2, and 3. In a futher aspect, q is selected from 1 and 3. In a still further aspect, q is selected from 2 and 3. In yet a futher aspect, q is selected from 1 and 2. In an even further aspect, m is 1. In an even still further aspect, q is 2. In yet an even further aspect, q is 3. [00173] In one aspect, r is selected from 2 and 3. In a further aspect, r is 2. In a still further aspect r is 3. [00174] In one aspect, s is selected from 1, 2, and 3. In a futher aspect, s is selected from 1 and 3. In a still further aspect, s is selected from 2 and 3. In yet a futher aspect, s is selected from 1 and 2. In an even further aspect, s is 1. In an even still further aspect, s is 2. In yet an even further aspect, s is 3. a. R¹ G^ROUPS [00175] In one aspect, R¹ is selected from C1-C4 alkyl, C1-C4 aminoalkyl, – CH₂C₆H₅, and –CH₂(unsubstituted indolyl). In a further aspect, R¹ is selected from C3-C4 alkyl, C3-C4 aminoalkyl, –CH₂C₆H₅, and –CH₂(unsubstituted indolyl). [00176] In various aspects, R¹ is selected from C3-C4 alkyl, C3-C4 aminoalkyl, and unsubstituted benzyl. In a further aspect, R¹ is selected from n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-propylamine, n-butylamine, and unsubstituted benzyl. In a still further aspect, R¹ is selected from n-butyl, iso-butyl, sec-butyl, tert-butyl, n-butylamine, and unsubstituted benzyl. [00177] In various aspects, R¹ is selected from C1-C4 alkyl and C1-C4 aminoalkyl. In a further aspect, R¹ is selected from C3-C4 alkyl and C3-C4 aminoalkyl. In a still further aspect, R¹ is selected from n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n- propylamine, and n-butylamine. In yet a further aspect, R¹ is selected from n- n-butyl, iso- butyl, sec-butyl, tert-butyl, and n-butylamine. [00178] In various aspects, R¹ is selected from C4 alkyl and C3-C4 aminoalkyl. In a further aspect, R¹ is selected from isobutyl and n-butylamine. [00179] In various aspects, R¹ is selected from C1-C4 aminoalkyl and –CH₂C₆H₅. In a further aspect, R¹ is selected from C3-C4 aminoalkyl and –CH2C6H5. In a still further aspect, R¹ is selected from n-propylamine, n-butylamine, and –CH₂C₆H₅. In yet a further aspect, R¹ is selected from n-butylamine and –CH2C6H5. [00180] In various aspects, R¹ is selected from C1-C4 alkyl and –CH₂C₆H₅. In a further aspect, R¹ is selected from C3-C4 alkyl and –CH2C6H5. In a still further aspect, R¹ is selected from n-propyl, iso-propyl, n-butyl, 2-methyl propyl, 3-methyl propyl, 1,1-dimethyl ethyl, and –CH2C6H5. In yet a further aspect, R¹ is selected from n-butyl, 2-methyl propyl, 3- methyl propyl, 1,1-dimethyl ethyl, and –CH₂C₆H₅. [00181] In various aspects, R¹ is C3-C4 alkyl. In a further aspect, R¹ is selected from propyl, iso-propyl, butyl, iso-butyl, sec-butyl, and tert-butyl. In a still further aspect, R¹ is selected from propyl and iso-propyl. In yet a further aspect, R¹ is selected from butyl, iso- butyl, sec-butyl, and tert-butyl. In an even still further aspect, R¹ is isobutyl. [00182] In various aspects, R¹ is C3-C4 aminoalkyl. In a further aspect, R¹ is selected from n-propyl amine, and n-butylamine. In a further aspect, R¹ is n-propyl amine. In a still further aspect, R¹ is n-butylamine. [00183] In various aspects, R¹ is selected from –CH₂C₆H₅ and –CH₂(unsubstituted indolyl). In a further aspect, R¹ is –CH2C6H5. In a still further aspect, R¹ is – CH₂(unsubstituted indolyl). b. R², R³, ^AND R⁴ G^ROUPS [00184] In one aspect, each of R², R³, and R⁴ is independently selected from –NH₂, unsubstituted cyclopropyl, unsubstituted cyclohexyl, and unsubstituted phenyl. In a further aspect, each of R², R³, and R⁴ is independently selected from –NH₂, unsubstituted cyclopropyl, and unsubstituted cyclohexyl. In a still further aspect, each of R², R³, and R⁴ is independently selected from –NH2, unsubstituted cyclopropyl, and unsubstituted phenyl. In yet a further aspect, each of R², R³, and R⁴ is independently selected from –NH₂, unsubstituted cyclohexyl, and unsubstituted phenyl. In an even further aspect, each of R², R³, and R⁴ is independently selected from unsubstituted cyclopropyl, unsubstituted cyclohexyl, and unsubstituted phenyl. In an even still further aspect, each of R², R³, and R⁴ is independently selected from –NH₂ and unsubstituted phenyl. In yet an even further aspect, each of R², R³, and R⁴ is independently selected from –NH2 and unsubstituted cyclohexyl. In a further aspect, each of R², R³, and R⁴ is independently selected from –NH₂ and unsubstituted cyclopropyl. [00185] In various aspects, R² is selected from –NH₂, unsubstituted cyclopropyl, unsubstituted cyclohexyl, and unsubstituted phenyl. In a further aspect, R² is selected from – NH₂, unsubstituted cyclopropyl, and unsubstituted cyclohexyl. In a still further aspect, R² is selected from –NH2, unsubstituted cyclopropyl, and unsubstituted phenyl. In yet a further aspect, R² is selected from –NH₂, unsubstituted cyclohexyl, and unsubstituted phenyl. In an even further aspect, R² is selected from unsubstituted cyclopropyl, unsubstituted cyclohexyl, and unsubstituted phenyl. In an even still further aspect, R² is selected from –NH₂ and unsubstituted phenyl. In yet an even further aspect, R² is selected from –NH2 and unsubstituted cyclohexyl. In a further aspect, R² is selected from –NH₂ and unsubstituted cyclopropyl. In a still further aspect, R² is –NH2. In yet a further aspect, R² is unsubstituted cyclopropyl. In an even further aspect, R² is unsubstituted cyclohexyl. In an even still further aspect, R² is unsubstituted phenyl. [00186] In various aspects, R³ is selected from –NH₂, unsubstituted cyclopropyl, unsubstituted cyclohexyl, and unsubstituted phenyl. In a further aspect, R³ is selected from – NH₂, unsubstituted cyclopropyl, and unsubstituted cyclohexyl. In a still further aspect, R³ is selected from –NH2, unsubstituted cyclopropyl, and unsubstituted phenyl. In yet a further aspect, R³ is selected from –NH₂, unsubstituted cyclohexyl, and unsubstituted phenyl. In an even further aspect, R³ is selected from unsubstituted cyclopropyl, unsubstituted cyclohexyl, and unsubstituted phenyl. In an even still further aspect, R³ is selected from –NH₂ and unsubstituted phenyl. In yet an even further aspect, R³ is selected from –NH2 and unsubstituted cyclohexyl. In a further aspect, R³ is selected from –NH₂ and unsubstituted cyclopropyl. In a still further aspect, R³ is –NH2. In yet a further aspect, R³ is unsubstituted cyclopropyl. In an even further aspect, R³ is unsubstituted cyclohexyl. In an even still further aspect, R³ is unsubstituted phenyl. [00187] In various aspects, R⁴ is selected from –NH2, unsubstituted cyclopropyl, unsubstituted cyclohexyl, and unsubstituted phenyl. In a further aspect, R⁴ is selected from – NH2, unsubstituted cyclopropyl, and unsubstituted cyclohexyl. In a still further aspect, R⁴ is selected from –NH₂, unsubstituted cyclopropyl, and unsubstituted phenyl. In yet a further aspect, R⁴ is selected from –NH2, unsubstituted cyclohexyl, and unsubstituted phenyl. In an even further aspect, R⁴ is selected from unsubstituted cyclopropyl, unsubstituted cyclohexyl, and unsubstituted phenyl. In an even still further aspect, R⁴ is selected from –NH2 and unsubstituted phenyl. In yet an even further aspect, R⁴ is selected from –NH₂ and unsubstituted cyclohexyl. In a further aspect, R⁴ is selected from –NH2 and unsubstituted cyclopropyl. In a still further aspect, R⁴ is –NH₂. In yet a further aspect, R⁴ is unsubstituted cyclopropyl. In an even further aspect, R⁴ is unsubstituted cyclohexyl. In an even still further aspect, R⁴ is unsubstituted phenyl. c. R⁵ G^ROUPS [00188] In one aspect, R⁵ is selected from C2-C4 alkyl, –(C1-C4 alkyl)CO₂H, – CH2C6H5, and –CH2(unsubstituted indolyl). In a further aspect, R⁵ is selected from C2-C3 alkyl, –(C2-C3 alkyl)CO₂H, –CH₂C₆H₅, and –CH₂(unsubstituted indolyl). [00189] In various aspects, R⁵ is selected from C3-C4 alkyl, –(C2-C3 alkyl)CO2H, and unsubstituted benzyl. In a further aspect, R⁵ is selected from n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, –CH2CH2CO2H, –CH2CH2CH2CO2H, and unsubstituted benzyl. [00190] In various aspect, R⁵ is selected from C2-C4 alkyl and –(C1-C4 alkyl)CO₂H. In a further aspect, R⁵ is selected from C3-C4 alkyl and –(C2-C3 alkyl)CO2H. In a still further aspect, R⁵ is selected from propyl, iso-propyl, butyl, iso-butyl, tert-butyl, – CH2CH2CO2H, and –CH2CH2CH2CO2H. [00191] In various aspects, R⁵ is selected from C2-C4 alkyl and –CH₂C₆H₅. In a further aspect, R⁵ is selected from C3-C4 alkyl and –CH2C6H5. In a still further aspect, R⁵ is selected from propyl, iso-propyl, butyl, iso-butyl, tert-butyl, and –CH₂C₆H₅. [00192] In various aspects, R⁵ is selected from –(C1-C4 alkyl)CO₂H and –CH₂C₆H₅. In a further aspect, R⁵ is selected from –(C2-C3 alkyl)CO₂H and –CH₂C₆H₅. In a further aspect, R⁵ is selected from –CH₂CH₂CO₂H and –CH₂C₆H₅. [00193] In various aspects, R⁵ is C2-C4 alkyl. In a further aspect, R⁵ is selected from C3-C4 alkyl. In a still further aspect, R⁵ is selected from propyl, iso-propyl, butyl, iso-butyl, and tert-butyl. In yet a further aspect, R⁵ is selected from propyl and iso-propyl. In an even further aspect, R⁵ is selected from butyl, iso-butyl, sec-butyl, and tert-butyl. In a still further aspect, R⁵ is iso-butyl. [00194] In various aspects, R⁵ is –(C1-C4 alkyl)CO2H. In a further aspect, R⁵ is –(C2- C3 alkyl)CO₂H. In a still further aspect, R⁵ is –CH₂CH₂CO₂H. In yet a further aspect, R⁵ is –CH2CH2CH2CO2H. [00195] In various aspects, R⁵ is selected from –CH₂C₆H₅ and –CH₂(unsubstituted indolyl). In a further aspect, R⁵ is –CH2C6H5. In a still further aspect, R⁵ is – CH₂(unsubstituted indolyl). d. R⁶ G^ROUPS [00196] In one aspect, R⁶ is selected from C2-C4 alkyl, C2-C4 alkenyl, C2-C4 aminoalkyl, –(C1-C4 alkyl)CO2H, –CH2C6H5, and –CH2(unsubstituted indolyl). In a further aspect, R⁶ is selected from n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, isopropenyl, 1-butene, cis-2-butene, trans-2-butene, isobutylene, n-propylamine, n- butylamine, –(C2-C3 alkyl)CO₂H, –CH₂C₆H₅, and –CH₂(unsubstituted indolyl). In a still further aspect, R⁶ is selected from n-butyl, isobutyl, sec-butyl, tert-butyl, 1-butene, cis-2- butene, trans-2-butene, isobutylene, n-propylamine, n-butylamine, –CH₂CH₂CH₂CO₂H, – CH2C6H5, and –CH2(unsubstituted indolyl). [00197] In various aspects, R⁶ is selected from C3-C4 alkyl, –(C2-C3 alkyl)CO₂H, and unsubstituted benzyl. In a further aspect, R⁶ is selected from propyl, iso-propyl, butyl, iso- butyl, sec-butyl, tert-butyl, –CH₂CH₂CO₂H, –CH₂CH₂CH₂CO₂H, and unsubstituted benzyl. [00198] In various aspects, R⁶ is selected from C2-C4 alkyl and C2-C4 alkenyl. In a further aspect, R⁶ is selected from n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, isopropenyl, 1-butene, cis-2-butene, trans-2-butene, and isobutylene. In a still further aspect, R⁶ is selected from n-butyl, isobutyl, sec-butyl, tert-butyl, 1-butene, cis-2-butene, trans-2- butene, and isobutylene. [00199] In various aspect, R⁶ is selected from C2-C4 alkyl and –(C1-C4 alkyl)CO₂H. In a further aspect, R⁶ is selected from C3-C4 alkyl and –(C2-C3 alkyl)CO₂H. In a still further aspect, R⁶ is selected from propyl, iso-propyl, butyl, iso-butyl, tert-butyl, – CH₂CH₂CO₂H, and –CH₂ CH₂CH₂CO₂H. In yet a further aspect, R⁶ is selected from butyl, iso-butyl, tert-butyl, and –CH₂CH₂CH₂CO₂H. [00200] In various aspects, R⁶ is selected from C2-C4 alkyl and –CH₂C₆H₅. In a further aspect, R⁶ is selected from C3-C4 alkyl and –CH₂C₆H₅. In a still further aspect, R⁶ is selected from propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, and –CH₂C₆H₅. [00201] In various aspects, R⁶ is selected from –(C1-C4 alkyl)CO2H and –CH2C6H5. In a further aspect, R⁶ is selected from –(C2-C3 alkyl)CO₂H and –CH₂C₆H₅. In a still further aspect, R⁶ is selected from –CH2CH2CO2H, –CH2 CH2CH2CO2H, and –CH2C6H5. [00202] In various aspects, R⁶ is selected from C2-C4 aminoalkyl and –(C1-C4 alkyl)CO2H. In a further aspect, R⁶ is selected from n-propylamine, n-butylamine, and –(C2- C3 alkyl)CO₂H. In a still further aspect, R⁶ is selected from n-propylamine, n-butylamine, and –CH2CH2CH2CO2H. [00203] In various aspects, R⁶ is C2-C4 alkyl. In a further aspect, R⁶ is C3-C4 alkyl. In a still further aspect, R⁶ is selected from propyl, iso-propyl, butyl, iso-butyl, sec-butyl, and tert-butyl. In yet a further aspect, R⁶ is selected from propyl and iso-propyl. In an even further aspect, R⁶ is selected butyl, iso-butyl, sec-butyl, and tert-butyl. In a still further aspect, R⁶ is iso-butyl. [00204] In various aspects, R⁶ is selected from –(C1-C4 alkyl)CO2H and –CH2C6H5. In a further aspect, R⁶ is selected from –(C2-C3 alkyl)CO₂H and –CH₂C₆H₅. In a still further aspect, R⁶ is selected from –CH2CH2CO2H and –CH2C6H5. [00205] In various aspects, R⁶ is –(C2-C3 alkyl)CO₂H. In a further aspect, R⁶ is –(C2- C3 alkyl)CO2H. In a still further aspect, R⁶ is selected from –CH2CH2CO2H, and –CH2 CH₂CH₂CO₂H. In yet a further aspect, R⁶ is –CH₂CH₂CO₂H. In an even further aspect, R⁶ is –CH2 CH2CH2CO2H. [00206] In various aspects, R⁶ is selected from –CH₂C₆H₅ and –CH₂(unsubstituted indolyl). In a further aspect, R⁶ is –CH2C6H5. In a still further aspect, R⁶ is selected from – CH₂(unsubstituted indolyl). e. R⁷ G^ROUPS [00207] In one aspect, R⁷ is selected from –NH₂, –CO₂H, unsubstituted cyclopropyl, unsubstituted cyclohexyl, unsubstituted phenyl, and unsubstituted indolyl. In a further aspect, R⁷ is selected from –NH₂, –CO₂H, unsubstituted phenyl, and unsubstituted indolyl. In a still further aspect, R⁷ is selected from –NH₂, –CO₂H, and unsubstituted phenyl. [00208] In various aspects, R⁷ is selected from –NH₂ and –CO₂H. In a further aspect, R⁷ is –NH₂. In a still further aspect, R⁷ is –CO₂H. [00209] In various aspects, R⁷ is selected from unsubstituted cyclopropyl and unsubstituted cyclohexyl. In a further aspect, R⁷ is unsubstituted cyclopropyl. In a still further aspect, R⁷ is unsubstituted cyclohexyl. [00210] In various aspects, R⁷ is selected from unsubstituted cyclopropyl and unsubstituted phenyl. [00211] In various aspects, R⁷ is selected from unsubstituted phenyl and unsubstituted indolyl. In a further aspect, R⁷ is unsubstituted phenyl. In a still further aspect, R⁷ is unsubstituted indolyl. [00212] In various aspects, R⁷ is selected is selected from –NH₂ and unsubstituted phenyl. f. R⁸, R⁹, AND R¹⁰ GROUPS [00213] In one aspect, each of R⁸, R⁹, and R¹⁰ is independently selected from C1-C4 aminoalkyl, –(C1-C4 alkyl)CO₂H, and –(C1-C4 alkyl)Cy¹. In a further aspect, each of R⁸, R⁹, and R¹⁰ is independently selected from C2-C4 aminoalkyl, –(C2-C4 alkyl)CO2H, and – (C2-C4 alkyl)Cy¹. In a still futher aspect, each of R⁸, R⁹, and R¹⁰ is independently selected from C3-C4 aminoalkyl, –(C3-C4 alkyl)CO2H, and –(C3-C4 alkyl)Cy¹. [00214] In various aspects, R⁸ is selected from C1-C4 alkylamino and –(C1-C4 alkyl)Cy¹. In a further aspect, R⁸ is selected from C2-C4 alkylamino and –(C2-C4 alkyl)Cy¹. In a still further aspect, R⁸ is selected from C3-C4 alkylamino and –CH₂Cy¹. In yet a further aspect, R⁸ is selected from n-butylamine and –CH2(unsubstituted cyclopropyl). [00215] In various aspects, R⁹ is C1-C4 alkylamino. In a further aspect, R⁹ is C2-C4 alkylamino. In a still further aspect, R⁹ is C3-C4 alkylamino. In yet a further aspect, R⁹ is n- butylamine. [00216] In various aspects, R¹⁰ is –(C1-C4 alkyl)Cy¹. In a further aspect, R¹⁰ is –(C2- C4 alkyl)Cy¹. In a still further aspect, R¹⁰ is –(C3-C4 alkyl)Cy¹. In yet a further aspect, R¹⁰ is –CH2Cy¹. In an even further aspect, R¹⁰ is –CH2(unsubstituted phenyl). g. CY¹ GROUPS [00217] In one aspect, Cy¹ is selected from cyclopropyl, cyclohexyl, phenyl, and indolyl, and is unsubstituted. [00218] In various aspects, Cy¹ is selected from cyclopropyl and cyclohexyl, and is unsubstituted. In a further aspect, Cy¹ is unsubstituted cyclopropyl. In a still further aspect, Cy¹ is unsubstituted cyclohexyl. [00219] In various aspects, Cy¹ is selected from phenyl and indolyl, and is unsubstituted. In a further aspect, Cy¹ is unsubstituted phenyl. In a still further aspect, Cy¹ is unsubstiuted indolyl. 2. EXAMPLE COMPOUNDS

[00220] In one aspect a compound can be present as:

or a pharmaceutically acceptable salt thereof.

[00221] In one aspect a compound can be present as: or a pharmaceutically acceptable salt thereof.

[00222] In one aspect, a compound can be present as:

or a pharmaceutically acceptable salt thereof.

[00223] In one aspect, a compound can be present as: or a pharmaceutically acceptable salt thereof.

[00224] It is contemplated that one or more compounds can optionally be omitted from the disclosed invention.

[00225] It is understood that the disclosed compounds can be used in connection with the disclosed methods, compositions, kits, and uses.

[00226] It is understood that pharmaceutical acceptable derivatives of the disclosed compounds can be used also in connection with the disclosed methods, compositions, kits, and uses. The pharmaceutical acceptable derivatives of the compounds can include any suitable derivative, such as pharmaceutically acceptable salts as discussed below, isomers, radiolabeled analogs, tautomers, and the like. C. METHODS OF MAKING A COMPOUND

[00227] The compounds of this invention can be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature, exemplified in the experimental sections or clear to one skilled in the art. For clarity, examples having a single substituent are shown where multiple substituents are allowed under the definitions disclosed herein.

[00228] Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the following Reaction Schemes, as described and exemplified below. In certain specific examples, the disclosed compounds can be prepared by Route I. as described and exemplified below. The following examples are provided so that the invention might be more fully understood, are illustrative only, and should not be construed as limiting.

1. ROUTE I

[00229] In one aspect, the disclosed cyclic y-AA compounds can be prepared as shown below.

SCHEME 1A.

Solid

Support Solid Support 1 3

1 -IR Solid Support

[00230] Compounds are represented in generic form, wherein PG¹ and PG² are amine protecting groups (e.g, carbobenzyloxy, /i-melhoxybenzyl carbonyl, /-butyloxycarbonyl. 9- fluorenylmethyloxy carbonyl, allyloxy carbonyl), provided that they are orthogonally deprotected from each other and the resin, and with other substituents as noted in compound descriptions elsewhere herein. A specific non-limiting example of the synthesis shown in Scheme 1A is provided below.

[00231] In one aspect, compounds of type 1.40, and similar compounds, can be prepared according to reaction Scheme IB above. Thus, compounds of type 1.23 can be prepared by coupling an appropriate solid phase resin, e.g., 1.22 rink amide resin as shown above, and an appropriate orthoganolly bis protected di-amino acid, e.g., 1.22 as shown above, followed by a mono-deprotection. Appropriate resins and appropriate orthoganolly bis protected di-amino acids are commercially available or prepared by methods known to one of skill in the art. The coupling reaction is carried out in the presence of appropriate coupling reagents, e.g., diisopropylcarbodiimide (DIC) and 1 -hydroxybenzotriazole (HOBt), in an appropriate solvent, e.g., dimethyl formimide (DMF), at an appropriate temperature, e. g-, rt, for an appropriate amount of time, e.g., 6 h. The alloc-amine is subsequently deprotected with an appropriate catalyst, e.g., tetrakis(triphenylphosphine)palladium(0), in the presense of an appropriate scavenger, e.g., dimethylamine borane complex (Me2NH»BHs). Compounds of type 1.25 can be prepared by coupling an appropriate amine, e.g., 1.23 as shown above, and an appropriate carboxylic acid, e.g., 1.24 as shown above, followed by a deprotection. Appropriate carboxylic acids are commercially available or prepared by methods known to one of skill in the art. The coupling reaction is carried out in the presence of appropriate coupling reagents, e.g., diisopropylcarbodiimide (DIC) and 1 -hydroxybenzotriazole (HOBt), in an appropriate solvent, e.g., dimethyl formimide (DMF), at an appropriate temperature, e.g., rt. for an appropriate amount of time, e.g., 6 h. The fluorenylmethoxy carbonyl is subsequently removed with an appropriate base, e.g , piperidine, in an appropriate solvent, e.g., dimethyl formimide (DMF). Compounds of ty pe 1.27 can be prepared by coupling an appropriate amine, e.g., 1.25 as shown above, and an appropriate orthoganolly bis protected di-amino acid, e.g, 1.26 as shown above, followed by a mono-deprotection. The coupling reaction is carried out in the presence of appropriate coupling reagents, e.g.. diisopropylcarbodiimide (DIC) and 1 -hydroxybenzotriazole (HOBt), in an appropriate solvent, e.g, dimethyl formimide (DMF), at an appropriate temperature, e.g.. rt, for an appropriate amount of time, e.g., 6 h. The alloc-amine is subsequently protected with an appropriate catalyst, e.g., tetrakis(triphenylphosphine)palladium(0), in the presense of an appropriate scavenger, e.g., dimethylamine borane complex (NfeNH’BFh). Compounds of type 1.29 can be prepared by coupling an appropriate amine, e.g.. 1.27 as shown above, and an appropriate carboxylic acid, e.g, 1.28 as shown above, followed by a deprotection. The coupling reaction is carried out in the presence of appropriate coupling reagents, e.g, diisopropylcarbodiimide (DIC) and 1 -hydroxybenzotriazole (HOBt), in an appropriate solvent, e.g, dimethyl formimide (DMF), at an appropriate temperature, e.g.. rt, for an appropriate amount of time, e.g, 6 h. The fluorenylmethoxy carbonyl is subsequently removed with an appropriate base, e.g, piperidine, in an appropriate solvent, e.g., dimethyl formimide (DMF). Compounds of type 1.31 can be prepared by coupling an appropriate amine, e.g., 1.29 as shown above, and an appropriate orthoganolly bis protected di-amino acid, e.g, 1.30 as shown above, followed by a mono-deprotection. The coupling reaction is carried out in the presence of appropriate coupling reagents, e.g. diisopropylcarbodiimide (DIC) and 1 -hydroxybenzotriazole (HOBt), in an appropriate solvent, e.g, dimethyl formimide (DMF), at an appropriate temperature, e.g, rt, for an appropriate amount of time, e.g, 6 h. The alloc-amine is subsequently deprotected with an appropriate catalyst, e.g, tetrakis(triphenylphosphine)palladium(0). in the presense of an appropriate scavenger, e.g, dimethyl amine borane complex (Me2NH»BHs). Compounds of type 1.33 can be prepared by coupling an appropriate amine, e.g, 1.31 as shown above, and an appropriate carboxylic acid, e.g., 1.32 as shown above, followed by a deprotection. The coupling reaction is carried out in the presence of appropriate coupling reagents, e.g, diisopropylcarbodiimide (DIC) and 1- hydroxybenzotriazole (HOBt), in an appropriate solvent, e.g, dimethyl formimide (DMF), at an appropriate temperature, e.g, rt, for an appropriate amount of time, e.g, 6 h. The fluorenylmethoxy carbonyl is then removed with an appropriate base, e.g., piperidine, in an appropriate solvent, e.g.. dimethyl formimide (DMF). Compounds of type 1.35 can be prepared by coupling an appropriate amine, e.g, 1.33 as shown above, and an appropriate orthoganolly bis protected di-amino acid, e.g., 1.34 as shown above, followed by a monodeprotection. The coupling reaction is carried out in the presence of appropriate coupling reagents, e.g, diisopropylcarbodiimide (DIC) and 1-hydroxybenzotriazole (HOBt), in an appropriate solvent, e.g. dimethyl formimide (DMF). at an appropriate temperature, e.g, rt, for an appropriate amount of time, e.g, 6 h. The alloc-amine is subsequently deprotected with an appropriate catalyst, e.g., tetrakis(triphenylphosphine)palladium(0), in the presense of an appropriate scavenger, e.g. dimethylamine borane complex (Me2NH»BH?). Compounds of type 1.37 can be prepared by coupling an amine, e.g, 1.35 as shown above, and an appropriate carboxylic acid, e.g., 1.36 as shown above, followed by a deprotection. The coupling reaction is carried out in the presence of appropriate coupling reagents, e.g., diisopropylcarbodiimide (DIC) and 1 -hydroxybenzotriazole (HOBt), in an appropriate solvent, e.g., dimethyl formimide (DMF), at an appropriate temperature, e.g.. rt, for an appropriate amount of time, e g., 6 h. The fluorenylmethoxycarbonyl is subsequently removed with an appropriate base, e.g., piperidine, in an appropriate solvent, e.g., dimethyl formimide (DMF). Compounds of type 1.39 can be prepared by coupling an appropriate carboxylic acid, e.g. 1.38 as shown above, followed by deprotection and intramolecular cyclization. The coupling reaction is carried out in the presence of appropriate coupling reagents, e.g., diisopropylcarbodiimide (DIC) and 1 -hydroxybenzotriazole (HOBt), in an appropriate solvent, e.g., dimethyl formimide (DMF), at an appropriate temperature, e. g, it, for an appropriate amount of time, e g., 6 h. Subsequent deprotection of dimethoxytrityl with an appropriate acid, e.g.. 2% trifluoroacetic acid, in the presense of an appropriate scavenger, e.g., triisopropyl silane, in an appropriate solvent, e.g., dichloromethane. Cyclization can be achieved with an appropriate base, e.g., ammonium carbonate, in an appropriate solvent, e.g., 1 : 1 DMF/H20. Compounds of type 1.40 can be prepared by cleavage from resin and global deprotection of an appropriate resin based cyclic peptide, e.g., 1.39 as shown above, with an appropriate acid, e.g., 94 % triflouroacetic acid, in the presence of appropriate radical scavangers, e.g., 2% triisopropylsilane, 2% H2O and 2% thioanisole. As can be appreciated by one skilled in the art the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactions above (compounds similar to 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 1.12, 1.13, 1.14, 1.16, 1.16, 1.17, 1.18, and 1.19) can be substituted in the reaction to provide compounds similar to Formula 1.20.

D. TREATING A DISEASE OR DISORDER DISORDER IN A SUBJECT

[00232] In one aspect, disclosed are methods of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a disclosed compound, wherein the disease or disorder is a neurodegenerative disorder (e.g., amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), AD and related dementias (AD/ADRD), Parkinson’s disease (PD), Huntington’s disease, frontotemporal lobar degeneration, chronic traumatic encephalopathy, Parkinsonims linked to chromosome 17, globular glial tauopathy, tauopathies, frontotemperal dementia, PSP with parkinsonism, progressive gait freezing, primary’ progressive apraxia of speech, motor neuron disease, ataxia, progressive supranuclear palsy (PSP), multiple system atrophy, corticobasal degeneration (CBD), argyrophilic grain disease (AGD), Pick’s disease (PiD), dementia, Huntington’s disease (HD), primary’ age-related tauopathy (PART), and aging-related tau astrogliopathy (ART AG)), diabetes (e g., type I diabetes, type II diabetes), or obesity. In a further aspect, the neurodegenerative disorder is selected from amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), motor neuron disease, ataxia, progressive supranuclear palsy (PSP), multiple system atrophy, corticobasal degeneration (CBD), argy rophilic grain disease (AGD), Pick’s disease (PiD), Huntington's disease (HD), primary’ age-related tauopathy (PART), and aging-related tau astrogliopathy (ART AG).

[00233] In one aspect, disclosed are methods of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: wherein r is selected from 2 and 3; wherein R¹ is selected from C1-C4 alkyl, C1-C4 aminoalkyl, -CH2C6H5, and -CH2(unsubstituted indolyl); wherein R⁵ is selected from C2-C4 alkyl, -(C1-C4 alkyl)CO2H, -CH2C6H5, and -CH2(unsubstituted indolyl); wherein R⁶ is selected from C2-C4 alkyl, C2-C4 alkenyl, C2-C4 aminoalkyl, -(C1-C4 alkyl)CO2H, - CH2C6H5, and -CH2(unsubstituted indolyl); wherein R⁷ is selected from -NH2, -CO2H, unsubstituted cyclopropyl, unsubstituted cyclohexyl, unsubstituted phenyl, and unsubstituted indolyl; wherein each of R⁸, R⁹, and R¹⁰ is independently selected from C1-C4 aminoalkyl. - (C1-C4 alkyl)CO2H, and -(Cl-C4 alkyljCy¹; and wherein Cy¹ is selected from cyclopropyl, cyclohexyl, phenyl, and indolyl. and is unsubstituted, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is a neurodegenerative disorder, diabetes, or obesity. [00234] In one aspect, disclosed are methods of treating a neurodegenerative disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: wherein r is selected from 2 and 3; wherein R¹ is selected from C1-C4 alkyl, C1-C4 aminoalkyl, unsubstituted phenyl, and unsubstituted indolyl; wherein R⁵ is selected from C2- C4 alkyl, -(C1-C4 alkyl)CO2H, -CH2C6H5, and -CH2(unsubstituted indolyl); wherein R⁶ is selected from C2-C4 alkyl, C2-C4 alkenyl, C2-C4 aminoalkyl, -(C 1-C4 alkyl)CO2H, - CH2C6H5, and -CH2(unsubstituted indolyl); wherein R⁷ is selected from -NH2, -CO2H, unsubstituted cyclopropyl, unsubstituted cyclohexyl, unsubstituted phenyl, and unsubstituted indolyl; wherein each of R⁸. R⁹, and R¹⁰ is independently selected from C1-C4 aminoalkyl, - (C1-C4 alkyljCChH, and -(Cl-C4 alkyljCy¹; and wherein Cy¹ is selected from cyclopropyl, cyclohexyl, phenyl, and indolyl, and is unsubstituted, or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disorder is selected from amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), motor neuron disease, ataxia, progressive supranuclear palsy (PSP), multiple system atrophy, corti cobasal degeneration (CBD), argyrophilic grain disease (AGD), Pick’s disease (PiD), Huntington’s disease (HD), primary age-related tauopathy (PART), and aging-related tau astrogliopathy (ART AG).

[00235] In various aspects, s is 1.

[00236] In various aspects, R¹ is selected from C1-C4 alkyl and C1-C4 aminoalkyl. In a further aspect, R¹ is selected from C4 alkyl and C3-C4 aminoalkyl. In a still further aspect, R¹ is selected from isobutyl and n-butylamine.

[00237] In various apsects, R⁵ is selected from -(C1-C4 alkyl)CO2H and -CH2C6H5. In a further aspect. R⁵ is selected from -(C2-C3 alkyljCChH and -CH2C6H5. In a still further aspect, R⁵ is selected from -CH2CH2CO2H and -CH2C6H5. [00238] In various aspects, R⁶ is selected from -(C1-C4 alkyl)CC>2H and -CH2C6H5. In a further aspect, R⁶ is selected from -(C2-C3 alkyl)CO2H and -CH2C6H5. In a still further aspect, R⁶ is selected from -CH2CH2CO2H and -CH2C6H5.

[00239] In various aspects, R⁷ is selected from unsubstituted cyclopropyl and unsubstituted phenyl.

[00240] In various aspects, R⁸ is selected from Cl -C4 alkylamino and -(C1-C4 alkyOCy¹. In a further aspect. R⁸ is selected from C3-C4 alkylamino and -ClfcCy¹. In a still further aspect, R⁸ is selected from n-butylamine and -CH2(unsubstituted cyclopropyl).

[00241] In various aspects, R⁹is C1-C4 alkylamino. In a further aspect, R⁹is C3-C4 alkylamino.

[00242] In various aspects, R⁹ is -NH2.

[00243] In various aspects, R¹⁰ is -(C 1-C4 alkyOCy¹. In a further aspect, R¹⁰ is - CFhCy¹. In a still further aspect, -CH2(unsubstituted phenyl).

[00244] In various aspects, the compound has a structure represented by a formula: or a pharmaceutically acceptable salt thereof.

[00245] In various aspects, the compound has a structure represented by a formula: or a pharmaceutically acceptable salt thereof. [00246] In various aspects, the compound has a structure represented by a formula: or a pharmaceutically acceptable salt thereof

[00247] In a further aspect, the compound has a structure represented by a formula: wherein each of m, n, and q is independently selected from 1 , 2, 3, and 4; wherein r is selected from 2 and 3; wherein R¹ is selected from C3-C4 alkyl, C3-C4 aminoalkyl, and unsubstituted benzy l; wherein each of R², R³, and R⁴ is independently selected from -NH2, unsubstituted cyclopropyl, unsubstituted cyclohexyl, and unsubstituted phenyl; wherein R⁵ is selected from C3-C4 alkyl, -(C2-C3 alkyDCChH, and unsubstituted benzyl; wherein R⁶ is selected from C3-C4 aminoalkyl, -(C2-C3 alkyl)CC>2H, and unsubstituted benzyd; and wherein R⁷ is selected from -NH2 and unsubstituted pheny l, or a pharmaceutically acceptable salt thereof, provided that when R¹ is C3-C4 alkyl, R² and R³ are unsubstituted pheny l, R⁴ is unsubstituted cyclopropyL and R⁵ is unsubstituted benzyl, then either (i) R⁷ is unsubstituted phenyl or (ii) R⁶ is C3-C4 aminoalkyl or -(C2-C3 alkyl)CO2H.

[00248] In various aspects, the compound is selected from:

or a pharmaceutically acceptable salt thereof.

[00249] In various aspects, the compound is: or a pharmaceutically acceptable salt thereof.

[00250] In various aspects, the compound is selected from:

or a pharmaceutically acceptable salt thereof.

[00251] In various aspects, the compound is: or a pharmaceutically acceptable salt thereof.

[00252] In various aspects, the subject is a mammal. In a further aspect, the mammal is human.

[00253] In various aspects, the subject has been diagnosed with a need for treatment of the disease or disorder prior to the administering step. In various further aspects, the subject has been diagnosed with a need for treatment of the neurodegenerative disorder prior to the administering step.

[00254] In various aspects, the method further comprises the step of identifying a subject in need of treatment of the disease or disorder. In various further aspects, the method further comprises the step of identifying a subject in need of treatment of the neurodegenerative disorder.

[00255] In various aspects, the effective amount is a therapeutically effective amount. [00256] In various aspects, the effective amount is a prophylactically effective amount.

[00257] In various aspects, the disease or disorder (e.g., the neurodegenerative disorder) is associated with dysregulation of GAS5 IncRNA signaling.

[00258] In various aspects, the disease or disorder (e.g., the neurodegenerative disorder) is associated with a decrease in GAS5 IncRNA signaling.

[00259] In various aspects, the disease or disorder is a neurodegenerative disorder. In a further aspect, the neurodegenerative disorder is selected from amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease (PD), motor neuron disease, ataxia, progressive supranuclear palsy (PSP), multiple system atrophy, corticobasal degeneration (CBD), argyrophilic grain disease (AGD), Pick's disease (PiD), dementia, Huntington's disease (HD), primary age-related tauopathy (PART), and aging-related tau astrogliopathy (ART AG). In a still further aspect, the neurodegenerative disorder is selected from amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), AD and related dementias (AD/ADRD), Parkinson’s disease (PD), Huntington’s disease, frontotemporal lobar degeneration, chronic traumatic encephalopathy, Parkinsonims linked to chromosome 17, globular glial tauopathy. tauopathies, frontotemperal dementia. PSP with parkinsonism, progressive gait freezing, primary progressive apraxia of speech, motor neuron disease, ataxia, progressive supranuclear palsy (PSP), multiple system atrophy, corticobasal degeneration (CBD). argyrophilic grain disease (AGD), Pick's disease (PiD), dementia, Huntington’s disease (HD), primary age-related tauopathy (PART), and aging-related tau astrogliopathy (ART AG). In yet a aspect, the neurodegenerative disorder is selected from amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), Huntington’s disease, frontotemporal lobar degeneration, chronic traumatic encephalopathy, Parkinsonims linked to chromosome 17, globular glial tauopathy, tauopathies, PSP with parkinsonism, progressive gait freezing, primary progressive apraxia of speech, motor neuron disease, ataxia, progressive supranuclear palsy (PSP), multiple system atrophy, corticobasal degeneration (CBD), argyrophilic grain disease (AGD), Pick's disease (PiD). dementia, Huntington's disease (HD), primary age-related tauopathy (PART), and aging-related tau astrogliopathy (ART AG). In an even further aspect, the neurodegenerative disorder is selected from amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), motor neuron disease, ataxia, progressive supranuclear palsy (PSP), multiple system atrophy, corticobasal degeneration (CBD). argyrophilic grain disease (AGD), Pick's disease (PiD), Huntington’s disease (HD), primary age-related tauopathy (PART), and aging-related tau astrogliopathy (ART AG). [00260] In various aspects, the disease or disorder is diabetes. In a further aspect, diabetes is type I diabetes or type II diabetes.

[00261] In various aspects, the disease or disorder is obesity.

E. ADDITIONAL METHODS OF USING THE COMPOUNDS

[00262] The compounds and pharmaceutical compositions of the invention are useful in treating or controlling conditions associated with dysregulation of GAS5 IncRNA signaling. Examples of diseases and disorders associated with dysregulation of GAS5 IncRNA for which the compounds and compositions can be useful in treating include, but are not limited to, neurodegenerative diseases (e.g., amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson’s disease (PD), motor neuron disease, ataxia, progressive supranuclear palsy (PSP), multiple system atrophy, corticobasal degeneration (CBD), argyrophilic grain disease (AGD), Pick’s disease (PiD), dementia, Huntington’s disease (HD), primary age-related tauopathy (PART), and aging-related tau astrogliopathy (ART AG)), diabetes (e.g, type I diabetes, type II diabetes), and obesity'.

[00263] To treat or control the condition, the compounds and pharmaceutical compositions comprising the compounds are administered to a subject in need thereof, such as a vertebrate, e g., a mammal, a fish, a bird, a reptile, or an amphibian. The subject can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. The subject is preferably a mammal, such as a human. Prior to administering the compounds or compositions, the subject can be diagnosed with a need for treatment of a condition associated with GAS5 IncRNA signaling dysfunction such as, for example, neurodegenerative diseases (e.g., amyotrophic lateral sclerosis (ALS). Alzheimer’s disease (AD), Parkinson’s disease (PD), motor neuron disease, ataxia, progressive supranuclear palsy (PSP), multiple system atrophy, corticobasal degeneration (CBD), argyrophilic grain disease (AGD), Pick’s disease (PiD), dementia, Huntington’s disease (HD), primary' age-related tauopathy (PART), and aging- related tau astrogliopathy (ART AG)), diabetes (e.g., type I diabetes, type II diabetes), and obesity.

[00264] The compounds or compositions can be administered to the subject according to any method. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. A preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. A preparation can also be administered prophylactically; that is, administered for prevention of a condition associated with dysregulation of GAS5 IncRNA signaling such as, for example, neurodegen erative diseases (e.g, amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease (PD), motor neuron disease, ataxia, progressive supranuclear palsy (PSP), multiple system atrophy, corticobasal degeneration (CBD). argyrophilic grain disease (AGD). Pick’s disease (PiD), dementia, Huntington’s disease (HD), primary age-related tauopathy (PART), and aging-related tau astrogliopathy (ART AG)), diabetes (e.g, type I diabetes, type II diabetes), and obesity.

[00265] The therapeutically effective amount or dosage of the compound can vary within wide limits. Such a dosage is adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg or more, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, as a continuous infusion. Single dose compositions can contain such amounts or submultiples thereof of the compound or composition to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days.

1. USE OF COMPOUNDS

[00266] In one aspect, the invention relates to the use of a disclosed compound or a product of a disclosed method. In a further aspect, a use relates to the manufacture of a medicament for the treatment of a condition associated with GAS5 IncRNA signaling dysfunction such as, for example, neurodegenerative diseases (e.g, amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease (PD), motor neuron disease, ataxia, progressive supranuclear palsy (PSP), multiple system atrophy, corticobasal degeneration (CBD). argyrophilic grain disease (AGD). Pick’s disease (PiD), dementia, Huntington’s disease (HD), primary age-related tauopathy (PART), and aging-related tau astrogliopathy (ARTAG)), diabetes (e.g., type I diabetes, type II diabetes), and obesity. [00267] Also provided are the uses of the disclosed compounds and products. In one aspect, the invention relates to use of at least one disclosed compound; or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In a further aspect, the compound used is a product of a disclosed method of making. [00268] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, for use as a medicament. [00269] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of the compound or the product of a disclosed method of making. [00270] In various aspects, the use relates to a treatment of a condition associated with GAS5 lncRNA signaling dysfunction in a subject. In one aspect, the use is characterized in that the subject is a human. In one aspect, the use is characterized in that the condition associated with GAS5 lncRNA signaling dysfunction is a neurodegenerative disease (e.g., amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease (PD), motor neuron disease, ataxia, progressive supranuclear palsy (PSP), multiple system atrophy, corticobasal degeneration (CBD), argyrophilic grain disease (AGD), Pick’s disease (PiD), dementia, Huntington’s disease (HD), primary age-related tauopathy (PART), and aging- related tau astrogliopathy (ARTAG)), diabetes (e.g., type I diabetes, type II diabetes), or obesity. [00271] In a further aspect, the use relates to the manufacture of a medicament for the treatment of a condition associated dysregulation of GAS5 lncRNA signaling in a subject. [00272] It is understood that the disclosed uses can be employed in connection with the disclosed compounds, products of disclosed methods of making, methods, compositions, and kits. In a further aspect, the invention relates to the use of a disclosed compound or a disclosed product in the manufacture of a medicament for the treatment of a condition associated with dysregulation of GAS5 lncRNA signaling in a mammal. In a further aspect, the condition associated with dyresgulation of GAS5 lncRNA signaling is a neurodegenerative disease (e.g., amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson’s disease (PD), motor neuron disease, ataxia, progressive supranuclear palsy (PSP), multiple system atrophy, corticobasal degeneration (CBD), argyrophilic grain disease (AGD), Pick’s disease (PiD), dementia, Huntington’s disease (HD), primary age-related tauopathy (PART), and aging-related tau astrogliopathy (ART AG)), diabetes (e.g., type I diabetes, type II diabetes), or obesity.

2. MANUFACTURE OF A MEDICAMENT

[00273] In one aspect, the invention relates to a method for the manufacture of a medicament for treating a condition associated with dysregulation of GAS5 IncRNA signaling in a subject having the condition, the method comprising combining a therapeutically effective amount of a disclosed compound or product of a disclosed method with a pharmaceutically acceptable carrier or diluent.

[00274] As regards these applications, the present method includes the administration to an animal, particularly a mammal, and more particularly a human, of a therapeutically effective amount of the compound effective in the treatment of a condition associated with dysregulation of GAS5 IncRNA signaling. The dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to affect a therapeutic response in the animal over a reasonable timeframe. One skilled in the art will recognize that dosage will depend upon a variety of factors including the condition of the animal and the body weight of the animal.

[00275] The total amount of the compound of the present disclosure administered in a ty pical treatment is preferably between about 0.05 mg/kg and about 100 mg/kg of body weight for mice, and more preferably between 0.05 mg/kg and about 50 mg/kg of body weight for mice, and between about 100 mg/kg and about 500 mg/kg of body weight for humans, and more preferably between 200 mg/kg and about 400 mg/kg of body weight for humans per daily dose. This total amount is ty pically, but not necessarily, administered as a series of smaller doses over a period of about one time per day to about three times per day for about 24 months, and preferably over a period of twice per day for about 12 months.

[00276] The size of the dose also will be determined by the route, timing and frequency of administration as well as the existence, nature and extent of any adverse side effects that might accompany the administration of the compound and the desired physiological effect. It will be appreciated by one of skill in the art that various conditions or disease states, in particular chronic conditions or disease states, may require prolonged treatment involving multiple administrations. [00277] Thus, in one aspect, the invention relates to the manufacture of a medicament comprising combining a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, with a pharmaceutically acceptable carrier or diluent. 3. K^ITS [00278] In one aspect, disclosed are kits comprising a disclosed compound or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an agent associated with the treatment of a neurodegenerative disorder; (b) an agent associated with the treatment of diabetes (c) an agent associated with the treatment of obesity; (d) instructions for administering the compound in connection with treating a neurodegenerative disorder, diabetes, and/or obesity; and (e) instructions for treating a neurodegenerative disorder, diabetes, and/or obesity. [00279] Thus, in one aspect, disclosed are kits comprising a compound having a structure represented by a formula: , wherein r is selected fro m 2 and 3; wherein R¹ is selected from C1-C4 alkyl, C1-C4 aminoalkyl, –CH2C6H5, and –CH2(unsubstituted indolyl); wherein R⁵ is selected from C2-C4 alkyl, –(C1-C4 alkyl)CO₂H, –CH₂C₆H₅, and –CH₂(unsubstituted indolyl); wherein R⁶ is selected from C2-C4 alkyl, C2-C4 alkenyl, C2-C4 aminoalkyl, –(C1-C4 alkyl)CO2H, – CH₂C₆H₅, and –CH₂(unsubstituted indolyl); wherein R⁷ is selected from –NH₂, –CO₂H, unsubstituted cyclopropyl, unsubstituted cyclohexyl, unsubstituted phenyl, and unsubstituted indolyl; wherein each of R⁸, R⁹, and R¹⁰ is independently selected from C1-C4 aminoalkyl, – (C1-C4 alkyl)CO2H, and –(C1-C4 alkyl)Cy¹; and wherein Cy¹ is selected from cyclopropyl, cyclohexyl, phenyl, and indolyl, and is unsubstituted, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an agent associated with the treatment of a neurodegenerative disorder; (b) an agent associated with the treatment of diabetes (c) an agent associated with the treatment of obesity; (d) instructions for administering the compound in connection with treating a neurodegenerative disorder, diabetes, and/or obesity; and (e) instructions for treating a neurodegenerative disorder, diabetes, and/or obesity. [00280] In one aspect, disclosed are kits a compound having a structure represented by a formula: , wherein r is selected fro 1-C4 alkyl, C1-C4 aminoalkyl, –CH₂C₆H₅, and –CH₂(unsubstituted indolyl); wherein R⁵ is selected from C2-C4 alkyl, –(C1-C4 alkyl)CO2H, –CH2C6H5, and –CH2(unsubstituted indolyl); wherein R⁶ is selected from C2-C4 alkyl, C2-C4 alkenyl, C2-C4 aminoalkyl, –(C1-C4 alkyl)CO₂H, – CH2C6H5, and –CH2(unsubstituted indolyl); wherein R⁷ is selected from –NH2, –CO2H, unsubstituted cyclopropyl, unsubstituted cyclohexyl, unsubstituted phenyl, and unsubstituted indolyl; wherein each of R⁸, R⁹, and R¹⁰ is independently selected from C1-C4 aminoalkyl, – (C1-C4 alkyl)CO₂H, and –(C1-C4 alkyl)Cy¹; and wherein Cy¹ is selected from cyclopropyl, cyclohexyl, phenyl, and indolyl, and is unsubstituted, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an agent associated with the treatment of a neurodegenerative disorder selected from amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), motor neuron disease, ataxia, progressive supranuclear palsy (PSP), multiple system atrophy, corticobasal degeneration (CBD), argyrophilic grain disease (AGD), Pick’s disease (PiD), Huntington’s disease (HD), primary age-related tauopathy (PART), and aging- related tau astrogliopathy (ARTAG); (b) instructions for administering the compound in connection with treating the neurodegenerative disorder; and (c) instructions for treating the neurodegenerative disorder. [00281] In various aspects, the agent associated with the treatment of a neurodegenerative disorder is selected from kinase inhibitors (e.g., fyn inhibitors such as saracatinib. GSK-3P inhibitors such as tideglusib, and tyrosine kinase inhibitors such as nilotinib and masitinib), immunotherapies (e.g, antibodies such as zagotenemab. gosuranemab, donanemab, lecanemab, remtemetug, aducanumab, and gantenerumab), tau aggregation inhibitors (e.g., TRxO237), cholinesterase inhibitors, and memantine [00282] In various aspects, the agent associated with the treatment of diabetes is selected from insulin, an amylinomimetic (e.g, pramlintide), an alpha-glucosidase inhibitor (e.g. acarbose. miglitol), a biguanide (e.g, metformin), a dopamine agonist (e.g, bromocriptine), a dipeptidyl peptidase-4 (DPP-4) inhibitor (e.g, alogliptin, linagliptin, saxagliptin, sitagliptin), a glucagon-like peptide-1 (GLP-1) receptor agonist (e.g, albiglutide, dulaglutide, exenatide, liraglutide, semaglutide), a meglitinide (e.g., nateglinide, repaglinide, a sodium-glucose transporter (SGLT) 2 inhibitor (e.g, dapagliflozin, canagliflozin, empagliflozin, ertugliflozin), a sulfonylurea (e.g, glimepiride, gliclazide, glipizide, glyburide, chlorpropamide, tolazamide, tolbutamide), and a thiazolidinedione (e.g., rosiglitazone, pioglitazone).

[00283] In various aspects, the agent associated with the treatment of obesity is selected from orlistat, phentermine-topiramate, naltrexone-bupropion, liraglutide, and semaglutide.

[00284] In a further aspect, the compound and the agent are co-formulated. In a further aspect, the compound and the agent are co-packaged.

[00285] The kits can also comprise compounds and/or products co-packaged, coformulated, and/or co-delivered with other components. For example, a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound and/or product and another component for delivery' to a patient.

[00286] It is understood that the disclosed kits can be prepared from the disclosed compounds, products, and pharmaceutical compositions. It is also understood that the disclosed kits can be employed in connection with the disclosed methods of using.

[00287] The foregoing description illustrates and describes the disclosure. Additionally, the disclosure shoyvs and describes only the preferred embodiments but, as mentioned above, it is to be understood that it is capable to use in various other combinations, modifications, and environments and is capable of changes or modifications within the scope of the invention concepts as expressed herein, commensurate with the above teachings and/or the skill or knowledge of the relevant art. The embodiments described herein above are further intended to explain best modes known by applicant and to enable others skilled in the art to utilize the disclosure in such, or other, embodiments and with the various modifications required by the particular applications or uses thereof. Accordingly, the description is not intended to limit the invention to the form disclosed herein. Also, it is intended to the appended claims be construed to include alternative embodiments.

[00288] All publications and patent applications cited in this specification are herein incorporated by reference, and for any and all purposes, as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. In the event of an inconsistency between the present disclosure and any publications or patent application incorporated herein by reference, the present disclosure controls.

F. EXAMPLES

[00289] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and/or methods claimed herein are made and evaluated, and are intended to be purely exemplary⁷ of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g, amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric.

[00290] The Examples are provided herein to illustrate the invention, and should not be construed as limiting the invention in any way. Examples are provided herein to illustrate the invention and should not be construed as limiting the invention in any way.

1. CHEMISTRY EXPERIMENTALS a. SYNTHESIS OF CYCLIC GAMMA-AA PEPTIDES

[00291] The synthesis of the cyclic y-AA library and methods to identify putative positive hits for GAS5 binding was previously described in Shi, Y. et al, J. Med. Chem. 2017 60(22): 9290-9298 and Shi, Y., et al., (2019) Cell Chem. Bio. 26, 310-330. The structures of exemplary compounds prepared are shown in Table 1.

TABLE 1.

b. SYNTHESIS OF FITC-LABELED ANALOGUES

[00292] After the structures of the putative hits were determined by MALDI MS/MS, the hits and its Fluorescein (FITC) labeled analogues were resynthesized on the Rink amide resin and confirmed by Applied Biosystems 4700 Proteomics analyzer. For the synthesis of the fluorescent cyclic peptide, the Fmoc-Lys(Dde)-OH was first attached to the Rink amide resin. The Fmoc protection group was then removed, followed by the desired building blocks needed for the sequence synthesis. After the y-AA peptides were cyclized, the Dde group was removed. Then, fluorescein isothiocyanate (2 equiv) and DIPEA (6 equiv) in DMF were added to the resin and shaken for 12 h at room temperature. The FITC labeled cyclic y- peptide was cleaved by 1 : 1 (v/v) DCM/TFA containing 2% triisopropylsilane. The crude product was purified by the Waters HPLC system with a flow rate of 0.8 mL/min with a linear gradient from 5% to 100% (CH3CN in water) in 40 min.

[00293] A list of exemplary FITC-labeled analogues that were prepared as detailed above is shown in Table 2. TABLE 2.

2. EVALUATION OF THE IN VIVO EFFICACY OF NPC86 IN MOUSE MODELS a. MODE OF DELIVERY 1: SUBCUTANEOUS INJECTION

[00294] An insulin resistant mouse model was used to evaluate s.c. injection of NPC86 in vivo. Briefly, GAS5 IncRNA levels were compared for diabetic vs normal patients. In various tissue samples from normal nondiabetic mice showed greater levels of GAS5 than diabetic mice (FIG. 8). C57BL6 mice (6 months age) on a normal lean diet or a high fat diet in a DIO mouse model were utilized to evaluate subcutaneous administration of NPC86.

NPC86 was administered by subcutaneous injections at different doses on alternate days x 5 (N = 6). GAS5 levels were measured by SYBR Green qPCR and absolute quantities (AQ in ng) was calculated. NPC86 was shown to increase GAS5 in a dose dependent manner (FIG. 9 A) and did not result in weitght loss in DIO mice (FIG. 9B). Glucose tolerance was also improved with NPC86 in vivo in a diabetic, obese mouse model (FIG. 10). [00295] RNAseq analysis of adipose tissue following subcutaneous administration of NPC86 500 pg/kg to C57BL6 mice (FIG. 11A-D and FIG. 12A and 12B) shows representative RNA-sequencing data of adipose tissue in DIO murine model.

[00296] However, subcutaneous administration of NPC86 did not provide any mediation of GAS5 levels in the cortex (FIG. 13) b. MODE OF DELIVERY 2: INTRANASAL ADMINISTRATION

[00297] An aged mouse model was used to evaluate intranasal administration of NPC86 in vivo. Previously, it was demonstrated that intranasal insulin directly improves learning and memory where age-matched control and db/db mice cohorts were treated with intranasal insulin (1 unit/ml, daily for 3 weeks) and the radial arm water maze (RAWM) was used for cognitive assessment. Errors (incorrect arm choices) and escape latency were recorded for each daily trial (FIG. 14). It was found that serum levels of GAS5 of aged mice is significantly lower than young mice but that intranasal administration of NPC86 can rescue and increase GAS5 level and similar results were obtain in the hippocampus and cortex (FIG. 15)

[00298] The efficacy and safety of NPC86 was also evaluated in mice. Increasing doses of NPC86 (100 nmol, 200 nmol or 500 nmol) or 100 nmol of PBS vehichle was administered intranasally to young mice. RNA was isolated from hippocampus and qPCR performed using primers specific to GAS 5 and insulin receptor and normalized to |3-actin levels. Relative quantification (RQ) was determined using control as reference. Statistical analysis was performed by one-way ANOVA, ***p < 0.001 (FIG. 16). Results indicated that 100 nmol was an optimal dose as our goal is to increase GAS5 to physiological levels and not have sustained over-expression which could be detrimental, as observed in certain cancers. Coronal section of the brain from the 100 nmol NPC86 treated mice were imaged using Keyence BX810 microscope. Results (FIG. 17A and FIG. 17B) show that intranasal delivery of NPC86 crossed the blood brain barrier with distribution across all regions of the brain. Less than 5% of fluorescein label was detected in liver and spleen sections while it was not observed in the other organs Section of tissues were treated with Sudan black B (SBB) dye to eliminate autofluorescence and nuclear counterstained with DAPI. Histochemistry of brain (scale bar 1 mm) from control mice and NPC86-FITC treated mice, liver (scale bar 100 pm), and spleen (scale bar 100 pm) from mice treated with NPC86-FITC (n = 5) and analyzed. In addition, hematoxy lin and eosin staining of brain (hippocampus), liver, spleen, kidney, and adipose tissue sections indicated no toxicity in NPC86 treated mice (FIG. 18). Attorney Docket No.37759.0548P1 3. EVALUATION OF INTRANASAL ADMINISTRATION OF NPC86 IN MODELS OF N^{EUROGENERATION} a. A^GING M^ODEL [00299] Comparision of GAS5 levels from both subcutaneous and intranasal administration of NPC86 shows that only the intranasal administration provides increase in the GAS5 levels in the cortex and also in a dose dependent increase (FIG.19). [00300] Evaluation of the transcriptomic effects of NPC86 treatment using mRNAseq analysis on hippocampal tissue from young, aged, and aged mice treated with NPC86 was performed. The RNAseq results demonstrate that treatment with NPC86 increased GAS5 levels in aged mice while levels of other lncRNAs such as Malat1 and Neat1 were not affected. Heatmap with hierarchal clustering analysis ((FIG.20A) show differentially expressed mRNAs that changed significantly between young and aged, and we identified genes whose expression was reversed with NPC86 treatment compared to the age-related changes in Up, Down, Up (UDU) or Down, Up, Down (DUD) patterns. These were further identified and grouped into pathways using Ingenuity Pathway Analysis (IPA). Top ten canonical pathways that changed in response to NPC86 treatment in UDU or DUD pattern were identified that were distinguished by Z-score comparing aged mice to aged + NPC86 (FIG.20B). Further analysis of the neuroinflammation pathways identified the top genes that were changed in aged mice and levels reversed with NPC86 treatment and a similar analysis identified the top genes that changed downstream in the insulin signaling pathway (FIG. 20C). b. T^AUOPATHY M^ODEL [00301] Decreased GAS5 levels has been shown to promote tau phosphorylation that further leads to tau aggregation and formation of neurofibrillary tangles. The tangles significantly correlate to neurodegeneration and cognitive decline in ADRD and other tauopathies (FIG.21) [00302] Previous research in human adipocytes had indicated that GAS5 regulated the expression of insulin receptor (IR) and insulin signaling pathway. HT22 cells (mouse hippocampal) were transfected with GAS5 siRNA and whole cell lysates were collected from GAS5 siRNA transfected cells and results by western blot (FIG.22A and FIG.22B) show decrease in insulin receptor and phosphorylation of Akt, a downstream mediator of insulin signaling. Cell lysate was harvested, and western blot was performed using antibodies against IR, pAKT, AKT, pTau, Tau, pGSK3β, pGSK3α/β, GSK3α/β, and β-actin. Graph shows relative densitometric analysis of individual bands as indicated with phosphorylated protein normalized to total protein (n = 3). Statistical analysis was performed by two-tail Student’s t-test, ***p < 0.001. i. LPS ^{CHRONIC TREATMENT DECREASES} GAS5 ^{LEVELS IN} HT22 CELLS. [00303] Chronic low-grade inflammation in the brain is a hallmark of aging and neurodegeneration. To mimic a microenvironment of low-grade inflammation, HT22 neuronal cells were treated with low levels of lipopolysaccharide (LPS; 5 ng/mL) for 4 days. Real time qPCR results demonstrate that chronic treatment of LPS decreases GAS5 levels with concurrent increase of the inflammatory cytokine IL1β (FIG.23A). To determine if NPC86 could protect the cells from the LPS mediated inflammation NPC86 (20 nM) was added to the cells along with LPS and maintained for 4 days (LPS + NPC86 (4 days)). Results demonstrate that co-treatment of cells with NPC86 inhibited LPS induced decline in GAS5 cells and decreased IL1β levels. Separately, to determine if treatment with NPC86 could rescue LPS mediated inflammation, HT22 cells were treated with LPS for 3 days, media changed and then administered NPC86 (20 nM) and cells were harvested on day 4 (LPS + NPC86 (24 h)). Results demonstrate that LPS induced decline of GAS5 was significantly rescued by 24-h treatment with NPC86 along with decrease in IL1β levels. ii. H₂O₂ INDUCED OXIDATIVE STRESS DECREASES GAS5 LEVELS I^N HT22 ^CELLS. [00304] Oxidative stress is a key hallmark of aging. To evaluate the effect of oxidative stress on GAS5 levels, 100 μM H2O2 was added to HT22 cells for 1 h followed by treatment with NPC86 for 7 h. Results demonstrated that H2O2 significantly decreases GAS5 levels with concurrent decrease in pro-survival Bcl2 levels and treatment with NPC86 post H2O2 increases levels of GAS5 and Bcl2 (FIG.23B). Separately, HT22 cell viability was evaluated using the AOPI assay.100 μM H2O2 was added to HT22 cells for 1 h followed by treatment with NPC86 for 7 h. Results demonstrate that treatment with NPC86 rescued the viability of cells concurrent with increase in levels of GAS5 and Bcl2 (FIG.23C). [00305] PS19 mouse models express the disease associated with human tau P301S mutation (FTLD-associated). Mice from age 3 months onwards progressively develop tauopathy and neurotangles, impaired memory, abnormal morphology in hippocampus, cortex, entorhinal, dentate gyrus and have a life expectancy of 10-12 months average. PS19 mice were purchased from Jackson Labs (Tg(Pmp-MAPT*P301S)PS19Vle/J5) along with the control non-transgenic strain Ntg (Non Carrier for Tg(Pmp-MAPT*P301S)PS19Vle).

4. EVALUATION OF THE ABILITY OF NPC67 TO INCREASE GAS5 LEVELS

[00306] Mouse hippocampal cell line HT22 was treated were initially treated with increasing doses (20 nM, 50 nM, 100 nM and 200 nM) of NPC67 showing a dose response for increasing both GAS5 and the insulin receptor (FIG. 24). In addition, mouse hippocampal cell line HT22 was treated with increasing doses (20 nM, 50 nM, 100 nM) of either NPC86 or NPC67 for 18 hours. SYBR Green real time qPCR was performed with GAS5-specific primers amplifying exon 12 and relative quantities (RQ) was calculated with control set as reference using the comparative (DDCT) method. Repeated 4 times.

**p<0.001. As shown in FIG. 25, both compounds showed increased levels of GAS5 IncRNA and insulin receptor at each concentration, although NPC86 demonstrated a higher efficacy to increase GAS5 levels.

5. EFFICACY OF INTRANASAL ADMINISTRATION OF NPC86 AND NPC76 IN A TAUOPATHY MOUSE MODEL

[00307] To evaluate effect of treatment with NPC86 or NPC67 to PS 19 mice as their disease progressed, 8 month old PS 19 mice were treated intranasally with 200 ng/kg bodyweight of NPC86 or 200 ng/kg bodyweight of NPC67 or PBS (control) every 3 days and brain tissue collected after 4 weeks. The qPCR results show that both NPC86 and NPC67 increased levels of Gas5 significantly in the cortex (FIG. 26), NPC67 had higher efficacy compared to NPC86. Results also demonstrate that NPC86 and NPC67 decreases neuroinflammation by decreasing IL1|3 and TNFa in PS 19 mice (FIG. 27A and FIG. 27B).

6. EVALUATION OF TAU PHOSPHORYLATION

[00308] The cortex from PS 19 mice treated with either PBS or 200 ng/kg bw NPC86 or 200 ng/kg bw NPC67 was analyzed by western blotting to evaluate tau phosphorylation (FIG. 28). The western blot results show phosphorylation of tau at S214 was decreased significantly. The levels of ptau S202/T205 were also decreased with NPC67 and NPC86, with NPC67 showing a higher efficacy. Both NPC67 and NP86 showed significantly increase insulin signaling as shown by phosphorylation of AKT. GASK3(3 is active when it is dephosphorylated and active GSK3|3 is shown to phosphorylate tau. The phosphorylation of GSK3P was also increased indicating that it was de-activated. Without wishing to be bound by theory, these results show that increasing insulin signaling resulted in decrease in pTau. [00309] To accomplish the above analysis, the cortex was separated and analyzed for levels of GAS5, the inflammatory markers IL1 (3 and TNFa. RNA was isolated from cortex using automated QiaCube MDx and cDNA was synthesized using 1 pg RNA (260/230 > 1.8 and 260/290 > 1.8) and iScript™ (Bio-Rad #1,708,891). Target was amplified with Maxima SYBR green/Rox qPCR master mix (Thermo Scientific #K0222) and qPCR was performed on the ViiA 7 (ABI). GAS5 primers were developed to amplify exon 12 to measure total GAS5 levels. Ill P-speicific and TNFa-specific primers were used for amplification. Primer concentrations were optimized for a single melt curve and consistent amplification. Plate set up included a standard series, no template control and no reverse transcriptase control and samples were run in triplicate. A standard curve was generated for GAS5 and ILip, TNFa and used to calculate absolute quantities (AQ) of target expression normalized to P- Actin expression. Samples run in triplicate.

[00310] Whole cell lysates were harvested from the cortex using lysis buffer (Cell Signaling 9803S) + 10% protease/phosphatase inhibitor (Pierce A32957. A32953). Lysates were kept on ice or stored in the freezer for an hour, then sonicated briefly. Automated western blot analysis using Simple JESS system (ProteinSimple, Santa Clara, CA, USA) was used. The amount of ly sate to antibody was optimized as per manufacturer’s instructions. A concentration of 0.4 mg/mL was found optimal to be used on all antibodies. The samples were separated on 12-230 kDa Wes Separation Module capillary cartridges of Simple Protein JESS system and each antibody was used at a dilution of 1 :50. GAPDH (Cell Signaling #D16H11) was used as a loading control (1:250 dilution of antibody). Anti-rabbit detection module kits were specific for Jess (ProteinSimple) and include Luminol-S, Peroxide. Streptavidin-HRP and anti-rabbit secondary antibody. The proteins are separated by capillary technology and analyzed based on the chemiluminescence signal peaks generated, shown as digital images representing bands as observed in traditional western blot analysis. Jess blots show 3 mice per treatment cohort. Using Compass software (ProteinSimple). the peak areas of were estimated and normalized against GAPDH. Graph shows peaks from 6 mice per cohort.

[00311] It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

I l l

Claims

CLAIMS What is claimed is: 1. A method for treating a neurodegenerative disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: , wherein s is selected from 1, 2, and 3; wherein R¹ is selected from C1-C4 alkyl, C1-C4 aminoalkyl, –CH2C6H5, and – CH₂(unsubstituted indolyl); wherein R⁵ is selected from C2-C4 alkyl, –(C1-C4 alkyl)CO₂H, –CH₂C₆H₅, and – CH2(unsubstituted indolyl); wherein R⁶ is selected from C2-C4 alkyl, C2-C4 alkenyl, C2-C4 aminoalkyl, –(C1-C4 alkyl)CO2H, –CH2C6H5, and –CH2(unsubstituted indolyl); wherein R⁷ is selected from –NH2, –CO2H, unsubstituted cyclopropyl, unsubstituted cyclohexyl, unsubstituted phenyl, and unsubstituted indolyl; wherein each of R⁸, R⁹, and R¹⁰ is independently selected from C1-C4 aminoalkyl, –(C1- C4 alkyl)CO2H, and –(C1-C4 alkyl)Cy¹; and wherein Cy¹ is selected from cyclopropyl, cyclohexyl, phenyl, and indolyl, and is unsubstituted, or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disorder is selected from amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), motor neuron disease, ataxia, progressive supranuclear palsy (PSP), multiple system atrophy, corticobasal degeneration (CBD), argyrophilic grain disease (AGD), Pick’s disease (PiD), Huntington’s disease (HD), primary age-related tauopathy (PART), and aging-related tau astrogliopathy (ARTAG).

2. The method of claim 1, wherein s is 1.

3. The method of claim 1, wherein R¹ is selected from C1-C4 alkyl and C1-C4 aminoalkyl.

4. The method of claim 1, wherein R¹ is selected from C4 alkyl and C3-C4 aminoalkyl.

5. The method of claim 1, wherein R¹ is selected from isobutyl and n-butylamine.

6. The method of claim 1, wherein R⁵ is selected from –(C1-C4 alkyl)CO₂H and – CH2C6H5.

7. The method of claim 1, wherein R⁵ is selected from –(C2-C3 alkyl)CO2H and – CH₂C₆H₅.

8. The method of claim 1, wherein R⁵ is selected from –CH2CH2CO2H and –CH2C6H5.

9. The method of claim 1, wherein R⁶ is selected from –(C1-C4 alkyl)CO2H and – CH₂C₆H₅.

10. The method of claim 1, wherein R⁶ is selected from –(C2-C3 alkyl)CO2H and – CH₂C₆H₅.

11. The method of claim 1, wherein R⁶ is selected from –CH₂CH₂CO₂H and –CH₂C₆H₅.

12. The method of claim 1, wherein R⁷ is selected from unsubstituted cyclopropyl and unsubstituted phenyl.

13. The method of claim 1, wherein R⁸ is selected from C1-C4 alkylamino and –(C1-C4 alkyl)Cy¹.

14. The method of claim 1, wherein R⁸ is selected from C3-C4 alkylamino and –CH2Cy¹.

15. The method of claim 1, wherein R⁸ is selected from n-butylamine and – CH₂(unsubstituted cyclopropyl).

16. The method of claim 1, wherein R⁹ is C1-C4 alkylamino.

17. The method of claim 1, wherein R⁹ is C3-C4 alkylamino.

18. The method of claim 1, wherein R¹⁰ is –(C1-C4 alkyl)Cy¹.

19. The method of claim 1, wherein R¹⁰ is –CH₂Cy¹.

20. The method of claim 1, wherein R¹⁰ is –CH₂(unsubstituted phenyl).

21. The method of claim 1, wherein the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.

22. The method of claim 1, wherein the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.

23. The method of claim 1, wherein the compound has a structure represented by a formula: or a pharmaceutically acceptable salt thereof.

24. The method of claim 1, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

25. The method of claim 1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

26. The method of claim 1, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

27. The method of claim 1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

28. The method of claim 1, wherein the subject is a mammal.

29. The method of claim 28, wherein the mammal is a human.

30. The method of claim 1, wherein the subject has been diagnosed with a need for treatment of the neurodegenerative disorder prior to the administering step.

31. The method of claim 1 , further comprising the step of identifying a subj ect in need of treatment of the neurodegenerative disorder.

32. The method of claim 1, wherein the effective amount is a therapeutically effective amount.

33. The method of claim 1, wherein the effective amount is a prophylactically effective amount.

34. The method of claim 1, wherein the neurodegenerative disorder is associated with dysregulation of GAS5 IncRNA signaling.

35. The method of claim 1, wherein the neurodegenerative disorder is associated with a decrease in GAS5 IncRNA signaling.

36. A kit comprising a compound having a structure represented by a formula: , wherein r is selected o a ; wherein R¹ is selected from C1-C4 alkyl, C1-C4 aminoalkyl, –CH₂C₆H₅, and – CH2(unsubstituted indolyl); wherein R⁵ is selected from C2-C4 alkyl, –(C1-C4 alkyl)CO2H, –CH2C6H5, and – CH₂(unsubstituted indolyl); wherein R⁶ is selected from C2-C4 alkyl, C2-C4 alkenyl, C2-C4 aminoalkyl, –(C1-C4 alkyl)CO₂H, –CH₂C₆H₅, and –CH₂(unsubstituted indolyl); wherein R⁷ is selected from –NH₂, –CO₂H, unsubstituted cyclopropyl, unsubstituted cyclohexyl, unsubstituted phenyl, and unsubstituted indolyl; wherein each of R⁸, R⁹, and R¹⁰ is independently selected from C1-C4 aminoalkyl, –(C1- C4 alkyl)CO2H, and –(C1-C4 alkyl)Cy¹; and wherein Cy¹ is selected from cyclopropyl, cyclohexyl, phenyl, and indolyl, and is unsubstituted, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an agent associated with the treatment of a neurodegenerative disorder selected from amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), motor neuron disease, ataxia, progressive supranuclear palsy (PSP), multiple system atrophy, corticobasal degeneration (CBD), argyrophilic grain disease (AGD), Pick’s disease (PiD), Huntington’s disease (HD), primary age-related tauopathy (PART), and aging-related tau astrogliopathy (ARTAG); (b) instructions for administering the compound in connection with treating the neurodegenerative disorder; and

(c) instructions for treating the neurodegenerative disorder.