Agonists of 8-OXO-guanine DNA glycosylase

Abstract

The present invention is directed to substituted 1-(1H-imidazol-1-yl)-3-methyl-2- phenylbutan-2-ol and 1-cyclopentyl-2-(1H-imidazol-1-yl)-1-phenylethan-1-ol compounds useful as agonists of 8-oxo-guanine DNA glycosylase (OGG1) in humans, as well as pharmaceutical compositions comprising them and methods of their use in treating diseases, including metabolic syndrome, obesity, fatty liver disease, dyslipidemia, insulin resistance, neurodegenerative disorders and cancers.

Description

AGONISTS OF 8-OXO-GUANINE DNA GLYCOSYLASEFIELD OF THE INVENTIONThe present invention concerns compounds that are useful as agonists of 8-oxo-guanine DNA glycosylase (0GG1) in humans, as well as pharmaceutical compositions comprising them and methods of their use in treating diseases, including metabolic syndrome, obesity, fatty liver disease, dyslipidemia, insulin resistance, neurodegenerative disorders and cancers.BACKGROUND OF THE INVENTIONReactive Oxygen Species (ROS) in Disease CausationOne of the greatest threats to public health is the increasing prevalence of adult and pediatric obesity, which brings with it a host of secondary pathologies, including chronic inflammatory liver disease and diabetes, with the term, metabolic syndrome encompassing a number of obesity-related pathologies. Further, severe adverse health consequences also arise following oxidative stress that manifests in neurodegeneration, premature aging, and cancer. Mechanistic studies have revealed that oxidative stress is the central driving factor in the normal aging process, as well as human genetic disorders that manifest as rapid aging. Collectively, these investigations reveal that oxidative stress, arising from endogenous metabolic processes, environmental and dietary factors, as well as pro-inflammatory states driven by viral or bacterial infections, lead to a gradual accumulation of oxidized cellular components. These can be quantitated by measurements of increased levels of DNA base oxidation, protein oxidation, and lipid oxidation. Overall, although manifesting in a wide variety of diseases, there is a single, unifying element to all these pathologies and associated diseases: the generation of Reactive Oxygen Species (ROS). To develop preventive strategies and novel therapeutics for these health conditions, it is necessary to define the molecular mechanisms that lead to their development.ROS-induced DNA damage and its repair. Although ROS induces damage in multiple cellular components, damage to both nuclear and mitochondrial genomes potentially have devastating consequences because DNAs are long-lived molecules that serve as templates from which all other cellular components directly or indirectly arise. In contrast, the life-times of RNAs, proteins and lipids are generally short and thus, even though their oxidized forms may play critical roles in intra- and extra-cellular communications, these are rapidly turned over, thus minimizing longterm effects. While RNAs, protein, and lipids are subject to degradative processes, in the caseof DNA damage, cells have evolved a specific pathway for repair of oxidatively-induced base lesions, the base excision repair (BER) pathway (reviewed in [1]).DNA damage recognition and the initiation of the excision of oxidatively-induced base damage are catalyzed by a class of enzymes, termed DNA glycosylases, that recognize the 23 most common forms of base damage (reviewed in [2, 3]). The majority of purine lesions are repaired by NEIL1 , which is responsible for the initiation of repair of ring-fragmented purines, secondary oxidation products of 8-oxoG, and a subset of ring-saturated pyrimidines (reviewed in [4]). The 0GG1 glycosylase is responsible for the removal of the most prevalent ROS-induced DNA adduct, 7,8-dihydro-8-oxoguanine (8-oxoG), and also the ring-fragmented guanine (FapyG) (reviewed in [4]).Deficiencies in DNA Repair of ROS-induced Damage is Associated with Disease.The role of DNA glycosylases in Metabolic SyndromeWhile replication of nuclear DNA containing unrepaired ROS-induced DNA base damage would be expected to have long-term effects on the overall genetic fitness of a cell, the harmful effects of ROS in mitochondria have the potential to be amplified by leakage of electrons through compromised oxidative phosphorylation and enhanced lipid peroxidation. Although mitochondrial DNA (mtDNA) integrity is buffered by high copy numbers, phylogenetic analyses reveal that all eukaryotic cells use BER to maintain mtDNA integrity. Thus, it is the BER pathway that repairs these lesions in both the nucleus and mitochondria [1 , 3, 5-7],Although deficiencies in 0GG1 have been associated with several diseases including cancers [8-12], Parkinson's disease [13-15], Alzheimer's disease [16-20], and age-related pathologies [21-24], the potential role of oxidatively-induced DNA damage was largely unrecognized as contributing to metabolic disease. In this regard, over the past several years and as described in more detail below, we have shown that two different mouse models lacking DNA repair glycosylases (Neill-'- and Ogg1-'-) are prone to the development of obesity and metabolic syndrome on a chow diet, relative to wild type (WT) controls [25-28] This phenotype is exacerbated by aging and greatly accelerated by high fat diet (HFD), with mice displaying increased hepatic lipid accumulation and impaired glucose tolerance [25-28], More recently, OGG1 polymorphisms have been shown to predispose humans to increased body mass index (BMI) and type 2 diabetes in Japanese and Mexican American populations [29, 30],Further, as will be discussed in the following sections, we previously demonstrated that enhanced expression of mtOGGI also reduces HFD-induced weight gain and changes in bodymass and adiposity

[0031] , We also demonstrated that severe obesity and metabolic syndrome can be greatly attenuated in a mouse model for genetic-induced obesity, the yellow Agouti mouse

[0032] , These studies are significant because they add to a growing understanding of a role for genomic stability in body weight regulation and implicate BER as a critical pathway for the maintenance of metabolic homeostasis. Additionally, using cell culture models, increased expression of mitochondrial 0GG1 (mtOGGI) ameliorated the cellular responses to oxidative stress, including protection from lipid-induced blunting of glucose uptake and apoptosis [33-36].NEIL1 Deficiency Increases Susceptibility to Obesity and HyperlipidemiaWe consistently observed that even on a standard chow diet, the phenotype of Neil7' mice included visceral obesity (40-50 g at adulthood), hyperinsulinemia (increased by 30-50%), hyperlipidemia (increased by 15-30%), and fatty liver disease (extremely severe), predominantly in male mice [25, 28], NeilT7' mice had reduced lean body mass and increased fat mass, compared to WT animals. Total O2 consumption and CO2 production were significantly decreased in Neill'7' mice, across both resting and active periods. To determine their relative sensitivity to HFD-induced disease, WT and Neill'7' mice were fed a HFD for 5 weeks; Neill'7' mice gained significantly more body weight, had higher body fat content, displayed much greater hepatic steatosis, had delayed plasma glucose clearance, and elevated circulating insulin compared to WT counterparts. Given the role of NEIL1 in repairing oxidatively-induced DNA damage, we demonstrated that levels of mtDNA and mitochondrial proteins were significantly decreased in livers of HFD-fed NeilT- vs. WT mice

[0025] ,Novel Roles for the DNA Repair Glycosylase, OGG1 , in the Development of Obesity and Metabolic Syndrome Based on the phenotype of NeilT' mice, we hypothesized that accumulation of the 8-oxoG DNA lesion in OggT' mice may play a critical role in the development of diet-induced obesity and related metabolic pathologies. We observed that OggT7' mice are prone to obesity, even when being fed a low-fat (8%) chow diet, but that the obesity phenotype is a late onset manifestation (>9 months); however, ingestion of a HFD led to a very rapid weight gain

[0027] (Figure 1A, 1 B). To test the role of OGG1 in HFD-induced obesity, young Ogg1~7~ and WT mice were subjected to either a HFD or chow diet for 10 weeks, and metabolic efficiency and susceptibility to HFD-induced disease were measured. Fat accumulation, as measured by NMR, was significantly higher in HFD-fed OggT7' mice (Figure 1 B). Voluntary activity and food intake were not significantly different between WT and OggT7' mice on either a chow or HFD

[0027] , Stained liver sections revealed significant hepatic lipid accumulation in OggT7' mice and a >2-fold higher accumulation of hepatic triglycerides vs. WTmice

[0027] , Despite persistent hyperinsulinemia, HFD-fed Oggt7' mice had significantly delayed glucose clearance compared to WT animals

[0027] , indicating impaired insulin sensitivity in Oggt7' mice. In addition, fasting plasma ketones (Figure 1C) and hepatic glycogen content were reduced in Oggt7' mice, indicating decreased hepatic fatty acid oxidation (FAO) and an increased reliance on carbohydrates for fuel, respectively. There were no significant genotypic differences in metabolic rate in chow-fed animals or in O2 consumption after HFD-feeding. CO2 production was significantly higher during the resting phase in HFD-fed Oggt7' mice, relative to WT controls. Consistently, the respiratory exchange ratio (VCO2 / VO2) was also significantly increased during the resting phase in HFD-fed Ogg1'' mice, indicating a measurable decrease in reliance on FAO for energy needs in Ogg1'' mice (Figure 1 D). Collectively, these data demonstrate that in addition to NEIL1 , 0GG1 plays a key role in regulating cellular energy metabolism, primarily by altering fat oxidation. Since intermediates of the FAO pathway, including lipid hydroperoxides, can increase oxidative stress within the cell and cause further damage [37, 38], it is plausible that this reduction in FAO is a compensatory mechanism to limit the oxidative load within the cell. Notably, levels of the transcriptional co-activator PGC-1a, which regulates a number of genes involved in FAO, were significantly reduced in Oggt7' mice (Figure 1 E).Overexpression of a Mitochondrial Targeted 0GG1 Significantly Protects from Diet-induced Obesity. Given our observations of increased propensity to diet-induced obesity and insulin resistance in Oggt7' mice, especially under conditions of increased oxidative stress, we were interested in understanding the differential contributions of mitochondrial vs. nuclear DNA repair to whole body energy homeostasis. Previous cell culture models had indicated a strong role for mtOGGI in protecting cellular functions such as insulin signaling, glucose uptake, and ATP synthesis in the context of lipid overload [34, 39-41], Therefore, we obtained transgenic animals constitutively overexpressing human 0GG1 in the mitochondria (OggITg). The generation of these mice and confirmation of a selective increase in mtDNA repair activity has been previously reported

[0036] , but these studies had been confined to isolated tissues or cells, and there had been no previous reports on whole body physiology or pathology in these animals. These OggITg mice represented a model of enhanced repair of mitochondrial oxidatively- induced DNA damage and led us to interrogate the specific role of mtDNA repair in regulating body weight and energy balance

[0031] ,To determine if enhanced mtDNA repair was protective against diet-induced obesity, age-matched male WT and OggITg mice were placed on a HFD for 12 weeks. Body weightsand food intake were measured weekly, body composition was measured at 0, 6, and 10 weeks after the start of the HFD, glucose tolerance was measured at 7 weeks, and energy expenditure was measured at 10 weeks. Enhanced mtDNA repair resulted in significantly reduced HFD- induced weight gain in OggITg mice (Figure 2A). This was accompanied by significantly lower fat mass in these mice (Figure 2B), indicating a role for mitochondrial repair of oxidatively- induced DNA lesions in whole body energy and fat balance. It is important to note that this protection from adiposity after HFD feeding was only partial, and distinguishes it from models of cachexia or malabsorption disorders. The differences indicate that this alteration in energy balance due to mtDNA repair is potentially clinically and therapeutically viable While food intake was not altered in OggITg mice, O2 consumption and CO2 respiration were significantly increased across both dark and light cycles, indicating increased energy expenditure correlating with reduced weight gain on HFD (Figure 2C-E). Interestingly, this protection from weight gain did result in a significant enhancement of glucose tolerance (Figure 2F, G). Plasma insulin was also significantly reduced in OggITg mice (Figure 2H).Previous studies conducted in cell culture have suggested that enhancing mtDNA repair may protect various cell types from apoptosis induced by oxidants or free fatty acids [34, 36, 41- 44], For instance, overexpression of mtOGGI in INS-1 cells prevented palmitate-induced mtDNA damage, mitochondrial dysfunction, and apoptosis

[0034] , Similarly, expression of mtOGGI in rat skeletal muscle myotubes

[0044] or primary cultures of mouse skeletal muscle

[0036] , prevented palmitate-induced mtDNA damage, mitochondrial dysfunction, and apoptosis, ultimately resulting in an amelioration of insulin signaling and glucose uptake. However, our studies using the OGG1 Tg mice are the first to report on the effects of enhanced mtDNA repair on whole body physiology and tissue-specific functionality with regard to energy balance. Further, it is already clear that the effects of enhanced DNA repair in a whole animal will likely differ from studies conducted with single cell types in culture. For instance, it is evident that although there is a significant effect of increased DNA repair on reducing body weight and adiposity, these protective effects do not extend to all tissues. Specifically, the results obtained after glucose tolerance testing suggest a possible beta-cell pathology stemming from enhanced mtDNA repair (Figure 2H). Secondly, while the protection from diet-induced obesity in OggITg mice is likely a consequence of increased energy expenditure (Figure 2D, E), it is not yet clear which tissues are primarily responsible for this effect.Unlike in transgenic murine models, in which it was passible to increase the intracellular concentration of mtOGGI and mtDNA DNA repair, such genomic engineering is not possible inhumans. However, an alternative strategy for human applications is to increase the overall catalytic efficiency of OGG 1 , more specifically the mtOGGI . Since the rate-limiting step in the overall rate of repair is at the post-catalytic, enzyme-dissociation step, the overall efficiency of mtOGGI can be accomplished by increasing enzyme turnover via small molecule agonists.Alzheimer’s Disease (AD) as illustrative for ROS-induced neurodeqeneration AD is a neurodegenerative disease characterized by progressive impairments in memory, executive function, language, visuospatial acuity, and decision making. The degree of neuronal loss correlates well with the severity of disease manifestation, duration of dementia, and cortical atrophy. Late-onset AD is sporadic, multifactorial, and represents most of the 1 in 85 adults afflicted globally

[0045] , with economic costs exceeding $300 billion annually in the US

[0046] , The sporadic nature of this disease suggests that there may be complex genetic factors, as well as environmental drivers of the onset and progression of the disease, which when taken in aggregate, contribute to the challenges in target identification and downstream drug discovery platforms

[0047] ,All current clinical treatments are directed toward secondary disease manifestations, and only confer at best, marginal improvement in pathologies, symptoms and mortality. However, it is important to note that the current clinical strategies do not target cellular damage generated by elevated levels of ROS, which may be a key underlying mechanism for the initiation of the cascade of processes which culminate in neurocellular degeneration. Specifically, of the six drugs that have been approved by the US Food and Drug administration, four inhibit acetylcholinesterase, one blocks the NMDA receptor, and one is designed for amyloid-[3 (Ap plaque) clearance

[0048] , Additionally, the results from all clinical trials have been disappointing, highlighting the unmet need for mechanism-based treatments for AD.Support for ROS as the initiating step in AD comes from both fundamental and clinical studies, in which data clearly demonstrate elevated levels of protein oxidation, lipid peroxidation, and oxidatively-induced nuclear and mtDNA damage in AD-affected tissues relative to control. The generation of ROS lies upstream of a cascade of molecular events that leads to bioenergetic failure and cognitive decline, with the role of mitochondrial dysfunction at the epicenter of degenerative processes. Deficiencies in, or loss of, OGG1 result in large increases in cellular 8-oxoG [49-51], Human populations harbouring a highly deleterious OGG1 polymorphic variant Ser236Cys (>8-fold reduction in activity) have a significantly greater risk of developing AD [19, 52, 53], AD neurons accumulate higher levels of 8-oxoG relative to neurotypical ones, thereby impairing mitochondrial function

[0054] , Buildup of mutagenic mtDNA8-oxoG leads to double-stranded DNA breaks [55, 56], loss of energy production, cell death

[0057] and neurodegeneration

[0058] ,ROS, mitochondrial dysfunction, and inflammation produce neuronal death, and thus, are AD causal elements. Since mtDNA is maternally inherited, the central role of mitochondria is supported by findings that individuals with a maternal history of AD have greater risk of developing AD

[0059] , MtDNA haplogroup lineages, rare pathogenic variants and somatic mutations in the replication control region are also linked to AD [60-62], MtDNA copy number is low in AD brains

[0060] and is linked to tau pathology and lower cognitive function

[0063] , SUMMARY OF THE INVENTIONThe efficiency of repair of oxidatively-induced DNA damage in mitochondria is a key rate-limiting process in the development of metabolic syndrome, including obesity, fatty liver disease, dyslipidemia, and insulin resistance. A critical enzyme in this repair process is the DNA glycosylase OGG1 , which when deficient in murine models gives rise to mid-life onset of metabolic syndrome. Further, in humans, there is a common polymorphic variant with significantly reduced catalytic activity that has been associated with increased risk of a variety of metabolic and neurodegenerative diseases, as well as increased risk for a number of cancers [11-27], This disclosure focuses on a small molecule-based, therapeutic strategy that proposes to increase the catalytic efficiency of the DNA repair enzyme, OGG1 , to optimize mitochondrial function for the prevention of metabolic and neurodegeneration disorders and protect nuclear DNA for the prevention of cancers. Specifically, increases in either the catalytic efficiency or the turnover rates of mtOGGI are anticipated to confer disease resistance in humans. Applications include not only HFD-induced obesity and other manifestations of metabolic syndrome, but also genetic predisposition to these conditions. Additional applications extend to cancer therapeutics. Furthermore, humans that are either mono- or bi-allelic for the common polymorphic variant of OGG1 are anticipated to have reduced disease risk if the efficiency of repair can be increased via enhanced OGG1 activity. We have identified a specific small molecule chemotype that stimulates OGG1 activity.Provided herein is a compound of Formula (I):wherein:X is selected from the group of cyclopentyl and isopropylRi, R2, and R3 are independently selected from the group of H, C1-C4 alkyl, -O-C1-C4 alkyl, halogen, CF3, -OH, CN, C(=O)R5, NO2, CO2H, CO2R5, S(O)2OH, S(O)2OR5, NH3, N+R5, and -C(=O)CI;R4is selected from the group of H, CN, halogen, CF3, NO2, NH3, and C1-C4 alkyl;R5is selected from the group of C1-C4 alkyl, C3-Ce cycloalkyl, and -CH2-C3-C6 cycloalkyl; with the proviso that at least one of R1, R2, and R3is not H; and with the proviso that, when X is cyclopropyl, one of R1, R2, and R3is a fluoro substituent in the 2-position of the phenyl ring and R4is 5-CN, then neither of R1, R2, and R3is a fluoro or a chloro substituent in the 4-position of the phenyl ring; and with the proviso that, when X is cyclopropyl and each of R1, R2, and R3is H or when X is cyclopropyl and two of R1, R2, and R3are H and one of R1, R2, and R3is methyl in the 4-position of the phenyl ring, then R5is not 5-CN; and with the proviso that, when X is isopropyl, one of R1, R2, and R3is H and Rs is 5-CN, then the remaining two of R1, R2, and R3do not create a substitution pattern on the phenyl ring selected from the group of 2-chloro-4-trifluoromethyl, 2-chloro-4-fluoro, 2-chloro-4-bromo, 2- chloro-4-chloro, 2-fluoro-4-fluoro, 2-fluoro-4-chloro, 2-bromo-4-chloro, and 2-bromo-4-fluoro; and with the proviso that, when X is isopropyl, two of R1, R2, and R3are H and R5is 5-CN, then the remaining of R1, R2, and R3does not create a substitution pattern on the phenyl ring selected from the group of 2-trifluoromethyl and 4-chloro; andwith the proviso that, when X is isopropyl, each of Ri, R2, and Rs is H and R3 is in the 3- position on the phenyl ring, R3is not selected from the group of butoxy, propoxy, pentyloxy, and hexyloxy; and with the proviso that, when X is isopropyl, R5is H, and R1, R2, and R3, along with the phenyl ring to which they are bound, does not create a 3,4,5-trimethoxyphenyl group; and with the proviso that, when X is isopropyl, R5is H, R1 , R2, and R3, along with the phenyl ring to which they are bound, do not create a 4-chlorophenyl group or a 2,4-dichlorophenyl group; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.BRIEF DESCRIPTION OF THE DRAWINGSFIGURE 1 demonstrates the role of 0GG1 deficiency in the development of diet-induced obesity and related metabolic pathologies.FIGURE 1A represents the fat mass in WT and OggT' mice fed a low-fat chow diet.FIGURE 1 B represents changes in fat mass in chow- or HFD-fed WT and OggT7~ mice.FIGURE 1C represents plasma ketone bodies p-hydroxybutyrate (BHB) (mM) measured in chow- or HFD-fed WT and OggT7- mice.FIGURE 1 D represents the respiratory exchange ratio during the resting phase in HFD- fed OggT- mice, indicating a measurable decrease in reliance on FAO for energy needs in OggT- mice.FIGURE 1 E represents the relative levels of the transcriptional co-activator PGC-1a, which were significantly reduced in OggT7- mice.FIGURE 2 demonstrates the protective role of mitochondrially-targeted 0GG1 against HFD-induced obesity.FIGURE 2A depicts body weight changes in WT and OggITg mice associated with enhanced mtDNA repair.FIGURE 2B represents significantly lower fat mass in OggITg mice, indicating a role for mitochondrial repair of oxidatively-induced DNA lesions in whole body energy and fat balance.FIGURE 2C represents food intake in WT and OggITg mice.FIGURE 2D represents O2 consumption across both dark and light cycles in WT and OggITg mice.FIGURE 2E represents CO2 respiration across both dark and light cycles in WT and OggITg mice.FIGURE 2F represents WT and OggITg mice plasma glucose measurements over time.FIGURE 2G represents glucose tolerance as measured by area under the curve in WT and OggITg mice.FIGURE 2H represents fasting plasma insulin values in WT and OggITg mice.FIGURE 3 represents the assay design for measuring OGG1 activity: a 17-mer oligodeoxynucleotide containing an 8-oxoG lesion positioned 6 nucleotides downstream of a 5'- TAMRA fluorophore and a complementary DNA strand that contains a 3'-Biack Hole Quencher 2 (BHQ2) which is useful for the measurement of OGG1 cleavage of DNA at 8-oxoG sites.FIGURE 4A presents the sequence of a 17-mer 8-oxoG-containing oligodeoxynucleotide substrate with a 5'-TAMRA fluorophore and a complementary strand that contains a 3'-BHQ2.FIGURE 4B provides a bar graph representing the effect of compounds on OGG1 activity with 8-oxoG-containing DNA substrate. Fold change of initial reaction rate of OGG1 (50 nM) with 8-oxoG-containing DNA substrate (50 nM) in the presence of agonists (10 pM) is plotted relative to the DMSO control. Product formation was monitored by measuring TA RA fluorescence every 2 min for 1 h. The initial rate of each reaction was determined by fitting the linear phase of the reaction to a linear equation. The slope of each linear trend line was divided by the slope of the OGG1 + DMSO control reaction to calculate the relative fold change.FIGURES 5A to 5AA present EC50 plots for agonists that stimulated OGG1 activity by 2- fold or greater in the initial screen with 8-oxoG-containing substrate. EC50 values are presented as pM concentrations. EC50 concentrations were determined by analyzing initial reaction rates of OGG1 (50 nM) on 8-oxoG-containing DNA substrate (50 nM) with 9 - 14 agonist concentrations in a fluorescence-based DNA cleavage assay. The slopes of linear trendlines were plotted as a function of agonist concentration and a non-linear regression was performed. Data reflect the mean of three independent experiments with standard deviation unless otherwise noted. Plots for F19, 8-BromoGua and TH 1075 contain data from a single experiment.FIGURE 6A presents the sequence of a 17-mer ThyGly-containing oligodeoxynucleotide substrate with a 5'-TAMRA fluorophore and a complementary strand that contains a 3'-BHQ2.FIGURE 6B presents kinetics of reactions catalyzed by NEIL1 (15 nM) in the presence of selected agonists (10 pM) in a fluorescence-based DNA cleavage assay using the ThyGly DNA substrate (50 nM).FIGURE 6C presents kinetics of reactions catalyzed by NTH1 (11 nM) in the presence of selected agonists (10 pM) in a fluorescence-based DNA cleavage assay using the ThyGly DNA substrate (50 nM).FIGURE 6D presents the sequence of a 17-mer 8-oxoG-containing oligodeoxynucleotide substrate with a 5'-TAMRA fluorophore and the complementary strand that contains a 3'-BHQ2.FIGURE 6E presents kinetics of reactions catalyzed by Escherichia coli Fpg (15 nM) in the presence of selected agonists (10 pM) in a fluorescence-based DNA cleavage assay using the 8-oxoG-containing DNA substrate (50 nM). In Figures 8B, 8C and 8E, product formation was monitored by measuring TAMRA fluorescence every 2 min for 1 h. Data reflect the mean of three independent experiments with standard deviation.FIGURE 7A presents the sequence of a 17-mer AP site-containing oligodeoxynucleotide substrate with a 5'-TAMRA fluorophore annealed to a complementary strand that contains a 3'- BHQ2.FIGURE 7B provides a bar graph representing the effect of compounds on OGG1 activity with AP site-containing DNA substrate. Fold change of initial reaction rate of OGG1 (50 nM) with AP site-containing DNA substrate (50 nM) in the presence of agonists (10 pM) is plotted relative to the DMSO control. Product formation was monitored by measuring TAMRA fluorescence every 2 min for 1 h. The initial rate of each reaction was determined by fitting the linear phase of the reaction to a linear equation. The slope of each linear trend line was divided by the slope of the OGG1 + DMSO control reaction to calculate the relative fold change.FIGURE 8A presents the sequence of a 17-mer AP site-containing oligodeoxynucleotide substrate with a 5'-TAMRA fluorophore annealed to a complementary strand that contains a 3'- BHQ2.FIGURE 8B demonstrates kinetics of reactions of OGG1 agonists (10 pM) with AP sitecontaining substrate (50 nM) for 1 h at 37 °C. Fluorescence signal was measured every 2 min for 1 h using a TECAN plate reader.FIGURE 9A presents the sequence of a 17-mer AP site-containing oligodeoxynucleotide substrate with a 5'-TAMRA fluorophore annealed to a complementary strand that contains a 3'- BHQ2.FIGURE 9B shows product formation observed upon incubation of increasing concentrations of the C253W 0GG1 AP-lyase-only mutant with AP site-containing DNA substrate (50 nM) for 1 h at 37 °C.FIGURE 9C shows product formation observed upon incubation of C253W OGG1 (200 nM) with 8-oxoG-containing DNA substrate (50 nM) for 1 h at 37 °C.FIGURE 9D provides a bar graph of the initial rates of reactions catalyzed by a C253W OGG1 mutant (50nM) on AP site-containing DNA (50 nM) in the presence of 10 pM agonists or DMSO. Product formation was monitored by measuring TAMRA fluorescence every 2 min for 1 h. The initial rate of each reaction was determined by fitting the linear phase of the reaction to a linear equation. The dashed line represents the rate of the OGG1 + DMSO control reaction.FIGURE 10A presents the sequence of a 17-mer 8oxoG-containing oligodeoxynucleotide substrate with a 5'-TAMRA fluorophore annealed to the complementary strand that contains a 3-BHQ2.FIGURE 10B shows product formation observed upon incubation of increasing concentrations of the KCCK OGG1 glycosylase-only mutant with 8-oxoG containing DNA (50 nM) substrate in the presence of APE-1 (0.1 U) for 1 h at 37 °C.FIGURE 10C shows product formation observed upon incubation of the KCCK OGG1 glycosylase-only mutant (25 nM) or APE-1 (0.1 U) with 8-oxoG containing DNA (50 nM) substrate for 1 h at 37 °C.FIGURE 11 A presents the sequence of a 17-mer 8-oxoG-containing oligodeoxynucleotide substrate with a 5'-TAMRA fluorophore annealed to the complementary strand.FIGURE 11 B presents an image of an electrophoresis gel with separated products following reaction of 8-oxoG-containing DNA substrate with KCCK OGG1 , demonstrating that OGG1 agonists do not stimulate the KCCK OGG1 mutant. The KCCK OGG1 mutant (25 nM) was reacted with 8-oxoG-containing DNA substrate (100 nM) for 10 minutes in the presence of 10 pM agonists or DMSO. Products were separated by electrophoreses through a 15% polyacrylamide gel in the presence of 8M urea.FIGURE 110 presents a bar graph showing percent product formation determined by band density analysis of the electrophoresis gel shown in Fig 15B.FIGURE 12A presents a graph of levels of 8-oxoG excised from y-irradiated calf thymus DNA at various 0GG1 concentrations. The released 8-oxoG bases were measured by GC- MS / MS.FIGURE 12B presents a bar graph representing levels of 8-oxoG excised by 2 pg 0GG1 from y-irradiated calf thymus DNA in the presence of agonists at the 2-fold ECso concentrations. Reactions were incubated for 10 min and the released 8-oxoG bases were measured by GC- MS / MS. Significance was calculated relative to the 0GG1 + DMSO control reaction.FIGURE 13A presents a graph of levels of FapyG excised from y-irradiated calf thymus DNA at various 0GG1 concentrations. The released FapyG bases were measured by GC- MS / MS.FIGURE 13B presents a bar graph representing levels of FapyG excised by 2 pg OGG1 from y-irradiated calf thymus DNA in the presence of agonist at the 2-fold ECso concentrations. Reactions were incubated for 10 min and the released FapyG bases were measured by GC- MS / MS. Significance was calculated relative to the OGG1 + DMSO control reaction.FIGURE 14A presents a plot representing the cytotoxicity profile of paraquat in Kasumi-1 cells. Cells were treated with increasing concentrations of paraquat and incubated for 72 h after treatment. Relative metabolic activity was assayed using AlamarBlue and fluorescence readings from paraquat treated cells were normalized to untreated control cells. Means of three biological replicates and standard deviations are plotted.FIGURE 14B presents plots demonstrating the cytotoxicity of OGG1 agonists to Kasumi- 1 cells. Cells were treated with increasing concentrations of the specified agonist. Cells were incubated for 72 h after treatment and relative metabolic activity was assayed using AlamarBlue. Fluorescence readings from agonist treated cells were normalized to control cells treated with 0.1 % (v / v) DMSO. Means of three biological replicates and standard deviations are plotted.FIGURE 14C presents a bar graph demonstrating protection of Kasumi-1 cells from paraquat-induced cytotoxicity by selected 0GG1 agonists. Cells were pre-treated with OGG1 agonists at the specified concentration for 3 h and then treated with 250 pM paraquat. Cells were incubated for 72 h after treatment and relative metabolic activity was assayed using AlamarBlue. Fluorescence readings were normalized to control cells treated with 0.1 % (v / v)DMSO. Means of three biological replicates and standard deviations are plotted with significance calculated using an ordinary one-way ANOVA test.DETAILED DESCRIPTION OF THE INVENTIONProvided herein is a compound of Formula (l-a):wherein:Ri, R2, and R3are independently selected from the group of H, C1-C4 alkyl, -O-C1-C4 alkyl, halogen, CF3,-OH, CN, C(=O)R5, NO2, CO2H, CO2R5, S(O)2OH, S(O)2OR5, NH3, N+R5, and -C(=O)CI;R4is selected from the group of H, CN, halogen, CF3, NO2, NH3, and C1-C4 alkyl;R5is selected from the group of C1-C4 alkyl, C3-Ce cycloalkyl, and -CH2-C3-Ce cycloalkyl; with the proviso that at least one of R1, R2, and R3is not H; and with the proviso that, when one of R1, R2, and R3is a fluoro substituent in the 2-position of the phenyl ring and R4is 5-CN, then neither of R1, R2, and R3is a fluoro or a chloro substituent in the 4-position of the phenyl ring; and with the proviso that, when each of R1, R2, and R3is H or when two of R1, R2, and R3are H and one of R1, R2, and R3is methyl in the 4-position of the phenyl ring, then R5is not 5-CN; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.In one embodiment, the compound of Formula (l-a), or a pharmaceutically acceptable salt, co-crystal, solvate, or hydrate thereof, wherein R4 at the imidazole 5-position, as indicated by Formula (l-b) below, and all provisos and remaining variables, including R1, R2, R3, R4, and Rs, are as defined above for Formula (l-a).Another embodiment provides a compound of Formula (l-a), or a pharmaceutically acceptable salt, co-crystal, solvate, or hydrate thereof, wherein R4is H and all provisos and remaining variables, including Ri, R2, R3, R4, and R5, are as defined above for Formula (l-a).A further embodiment provides a compound of Formula (l-a), wherein:R4is selected from the group of H, CN, halogen, CF3, NO2, NH3, and Ci-C3alkyl;R1 , R2, and R3are independently selected from the group of H, Ci-C3alkyl, -O-Ci-C3alkyl, halogen, CF3,-OH, CN, C(=O)R5, NO2, CO2H, CO2R5, S(O)2OH, S(O)2OR5, NH3, N+R5, and -C(=O)CI;R4is selected from the group of H, CN, halogen, CF3, NO2, NH3, and Ci-C3alkyl;Rs is selected from the group of Ci-C3alkyl, C3-Ce cycloalkyl, and -CH2-C3-Ce cycloalkyl; with the proviso that at least one of R1, R2, and R3is not H; and with the proviso that, when one of R1, R2, and R3is a fluoro substituent in the 2-position of the phenyl ring and R4is 5-CN, then neither of R1, R2, and R3is a fluoro or a chloro substituent in the 4-position of the phenyl ring; and with the proviso that, when each of R1, R2, and R3is H or when two of R1, R2, and R3are H and one of R1, R2, and R3is methyl in the 4-position of the phenyl ring, then R5is not 5-CN; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.A still further embodiment provides a compound of Formula (l-a), wherein:R4is selected from the group of H, CN, halogen, CF3, NO2, NH3, and C1-C2 alkyl;Ri , R2, and R3 are independently selected from the group of H, C1-C2 alkyl, -O-C1-C2 alkyl, halogen, CF3,-OH, CN, C(=O)R5, NO2, CO2H, CO2R5, S(O)2OH, S(O)2OR5, NH3, N+R5, and -C(=O)CI;R4is selected from the group of H, CN, halogen, CF3, NO2, NH3, and C1-C2 alkyl;R5is selected from the group of C1-C2 alkyl; with the proviso that at least one of R1, R2, and R3is not H; and with the proviso that, when one of R1, R2, and R3is a fluoro substituent in the 2-position of the phenyl ring and R4is 5-CN, then neither of 1, R2, and R3is a fluoro or a chloro substituent in the 4-position of the phenyl ring; and with the proviso that, when each of R1, R2, and R3is H or when two of 1, 2, and R3are H and one of R1, R2, and R3is methyl in the 4-position of the phenyl ring, then R5is not 5-CN; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Another embodiment provides a compound of Formula (l-a), wherein:R4is selected from the group of H, CN, CF3, and methyl;R1 , 2, and R3are independently selected from the group of H, halogen, CF3,-OH, CN, C(=O)R5, NO2, CO2H, CO2R5, S(O)2OH, S(O)2OR5, NH3, N+R5, and -C(=O)CI;R4is selected from the group of H, CN, halogen, CF3, NO2, NH3, and Ci-C2alkyl;Rs is selected from the group of Ci-C2alkyl; with the proviso that at least one of R1, R2, and R3is not H; and with the proviso that, when one of R1, R2, and R3is a fluoro substituent in the 2-position of the phenyl ring and R4is 5-CN, then neither of R1, R2, and R3is a fluoro or a chloro substituent in the 4-position of the phenyl ring; and with the proviso that, when each of R1, R2, and R3is H or when two of 1, R2, and R3are H and one of R1, R2, and R3is methyl in the 4-position of the phenyl ring, then R5 is not 5-CN; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Also provided is a compound of Formula (l-c):wherein Ri, R2, and R3are independently selected from the group of H, C1-C3 alkyl, and halogen; with the proviso that at least one of R1, R2, and R3is halogen; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Also provided is a compound of Formula (l-c), above: wherein R1, R2, and R3are independently selected from the group of H, Ci-C2alkyl, and halogen; with the proviso that at least one of R1, R2, and R3is halogen; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Also provided is a compound of Formula (l-c), wherein R1, R2, and R3are each independently selected from the group of H and halogen; with the proviso that at least one of R1, R2, and R3is halogen; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Also provided is a compound of Formula (l-c), wherein R1, R2, and R3are each independently selected from the group of H and halogen; with the proviso that at least two of R1, R2, and R3is halogen; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Also provided is a compound of Formula (l-c), wherein Ri, R2, and R3 are each independently selected from the group of H and Cl; with the proviso that at least one of R1, R2, and R3is Cl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Also provided is a compound of Formula (l-c), wherein 1, R2, and R3are each independently selected from the group of H and Cl; with the proviso that at least two of R1, R2, and R3is Cl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Provided is a compound of Formula (l-d):wherein:R1 is halogen; andR2and R3are each independently selected from the group of H, Ci-C2alkyl, and halogen; or a pharmaceutically acceptable salt, co-crystal, solvate, or hydrate thereof.Also provided is a compound of Formula (l-d), wherein:R1 is Cl; andR2and R3are each independently selected from the group of H, Ci-C2alkyl, and Cl; or a pharmaceutically acceptable salt, co-crystal, solvate, or hydrate thereof.Also provided is a compound of Formula (l-d), wherein:R1 is Cl;R2is Cl; andR3is H; or a pharmaceutically acceptable salt, co-crystal, solvate, or hydrate thereof.Also provided is a compound of Formula (l-e):wherein:Ri is halogen;R2and R3are each independently selected from the group of H, C1-C2 alkyl, and halogen; or a pharmaceutically acceptable salt, co-crystal, solvate, or hydrate thereof.Also provided is a compound of Formula (l-e), wherein:R1 is Cl; andR2and R3are each independently selected from the group of H, C1-C2 alkyl, and Cl; or a pharmaceutically acceptable salt, co-crystal, solvate, or hydrate thereof.Also provided is a compound of Formula (l-e), wherein:R1 is Cl;R2is Cl; andR3is H; or a pharmaceutically acceptable salt, co-crystal, solvate, or hydrate thereof.Also provided compound of Formula (I l-a):wherein:Ri, R2, and R3 are independently selected from the group of H, C1-C4 alkyl, -O-C1-C4 alkyl, halogen, CF3,-OH, CN, C(=O)R5, NO2, CO2H, CO2R5, S(O)2OH, S(O)2OR5, NH3, N+R5, and -C(=O)CI;R4is selected from the group of H, CN, halogen, CF3, NO2, NH3, and C1-C4 alkyl;R5is selected from the group of C1-C4 alkyl, C3-Ce cycloalkyl, and -CH2-C3-C6 cycloalkyl; with the proviso that, when one of R1, R2, and R3is H and R5is 5-CN, then the remaining two of R1, R2, and R3do not create a substitution pattern on the phenyl ring selected from the group of 2-chloro-4-trifluoromethyl, 2-chloro-4-fluoro, 2-chloro-4-bromo, 2-chloro-4-chloro, 2- fluoro-4-fluoro, 2-fluoro-4-chloro, 2-bromo-4-chloro, and 2-bromo-4-fluoro; and with the proviso that, when two of R1, R2, and R3are H and Rs is 5-CN, then the remaining of R1, R2, and R3does not create a substitution pattern on the phenyl ring selected from the group of 2-trifluoromethyl and 4-chloro; and with the proviso that, when each of R1, R2, and R5is H and R3is in the 3-position on the phenyl ring, R3is not selected from the group of butoxy, propoxy, pentyloxy, and hexyloxy; and with the proviso that, when R5is H, R1, R2, and R3, along with the phenyl ring to which they are bound, does not create a 3,4,5-trimethoxyphenyl group; and with the proviso that, when R5is H, R1, R2, and R3, along with the phenyl ring to which they are bound, do not create a 4-chlorophenyl group or a 2,4-dichlorophenyl group; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.In another embodiment, the compound of Formula (ll-a) described above is present with R4at the imidazole 5-position, as indicated by Formula (I l-b) below, and all provisos and variables, including R1, R2, R3, R4, and R5, are as defined above for Formula (ll-a).Another embodiment provides a compound of Formula (I l-a), or a pharmaceutically acceptable salt, co-crystal, solvate, or hydrate thereof, wherein R4is H and all provisos and remaining variables, including Ri, R2, R3, R4, and R5, are as defined above for Formula (ll-a).A further embodiment provides a compound of Formula (I l-b) , wherein:R4is selected from the group of H, CN, halogen, CF3, NO2, NH3, and C1-C3 alkyl;R1 , R2, and R3 are independently selected from the group of H, C1-C3 alkyl, -O-C1-C3 alkyl, halogen, CF3,-OH, CN, C(=O)R5, NO2, CO2H, CO2R5, S(O)2OH, S(O)2OR5, NH3, N+R5, and -C(=O)CI;R4is selected from the group of H, CN, halogen, CF3, NO2, NH3, and C1-C3 alkyl;R5is selected from the group of C1-C3 alkyl, C3-C6 cycloalkyl, and -CH2-C3-C6 cycloalkyl; with the proviso that at least one of R1, R2, and R3is not H; and with the proviso that, when one of R1, R2, and R3is H and R5is 5-CN, then the remaining two of R1, R2, and R3do not create a substitution pattern on the phenyl ring selected from the group of 2-chloro-4-trifluoromethyl, 2-chloro-4-fluoro, 2-chloro-4-bromo, 2-chloro-4-chloro, 2- fluoro-4-fluoro, 2-fluoro-4-chloro, 2-bromo-4-chloro, and 2-bromo-4-fluoro; and with the proviso that, when two of R1, R2, and R3 are H and Rs is 5-CN, then the remaining of R1, R2, and R3does not create a substitution pattern on the phenyl ring selected from the group of 2-trifluoromethyl and 4-chloro; and with the proviso that, when each of R1, R2, and R5is H and R3is in the 3-position on the phenyl ring, R3is not selected from the group of butoxy, propoxy, pentyloxy, and hexyloxy; andwith the proviso that, when Rs is H, Ri, R2, and R3, along with the phenyl ring to which they are bound, does not create a 3,4,5-trimethoxyphenyl group; and with the proviso that, when Rs is H, R1, R2, and R3, along with the phenyl ring to which they are bound, do not create a 4-chlorophenyl group or a 2,4-dichlorophenyl group; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.A still further embodiment provides a compound of Formula (ll-b), wherein:R4is selected from the group of H, CN, halogen, CF3, NO2, NH3, and C1-C2 alkyl;R1 , R2, and R3 are independently selected from the group of H, C1-C2 alkyl, -O-C1-C2 alkyl, halogen, CF3,-OH, CN, C(=O)R5, NO2, CO2H, CO2R5, S(O)2OH, S(O)2ORs, NH3, N+R5, and -C(=O)CI;R4is selected from the group of H, CN, halogen, CF3, NO2, NH3, and C1-C2 alkyl;Rs is selected from the group of C1-C2 alkyl; with the proviso that, when one of R1, R2, and R3 is H and Rs is 5-CN, then the remaining two of R1 , R2, and R3 do not create a substitution pattern on the phenyl ring selected from the group of 2-chloro-4-trifluoromethyl, 2-chloro-4-fluoro, 2-chloro-4-bromo, 2-chloro-4-chloro, 2- fluoro-4-fluoro, 2-fluoro-4-chloro, 2-bromo-4-chloro, and 2-bromo-4-fluoro; and with the proviso that, when two of R1, R2, and R3are H and R5is 5-CN, then the remaining of R1, R2, and R3does not create a substitution pattern on the phenyl ring selected from the group of 2-trifluoromethyl and 4-chloro; and with the proviso that, when each of R1, R2, and R5is H and R3is in the 3-position on the phenyl ring, R3is not selected from the group of butoxy, propoxy, pentyloxy, and hexyloxy; and with the proviso that, when R5is H, R1, R2, and R3, along with the phenyl ring to which they are bound, does not create a 3,4,5-trimethoxyphenyl group; and with the proviso that, when R5is H, R1, R2, and R3, along with the phenyl ring to which they are bound, do not create a 4-chlorophenyl group or a 2,4-dichlorophenyl group; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Another embodiment provides a compound of Formula (I l-b), wherein:R4 is selected from the group of H, CN, CF3, and methyl;R1, R2, and R3 are independently selected from the group of H, halogen, CF3,-OH, CN, C(=O)R5, NO2, CO2H, CO2R5, S(O)2OH, S(O)2OR5, NH3, N+R5, and -C(=O)CI;R4is selected from the group of H, CN, halogen, CF3, NO2, NH3, and C1-C2 alkyl;R5is selected from the group of C1-C2 alkyl; with the proviso that, when one of R1, R2, and R3is H and R5is 5-CN, then the remaining two of R1, R2, and R3 do not create a substitution pattern on the phenyl ring selected from the group of 2-chloro-4-trifluoromethyl, 2-chloro-4-fluoro, 2-chloro-4-bromo, 2-chloro-4-chloro, 2- fluoro-4-fluoro, 2-fluoro-4-chloro, 2-bromo-4-chloro, and 2-bromo-4-fluoro; and with the proviso that, when two of R1, R2, and R3 are H and Rs is 5-CN, then the remaining of R1, R2, and R3 does not create a substitution pattern on the phenyl ring selected from the group of 2-trifluoromethyl and 4-chloro; and with the proviso that, when each of R1, R2, and Rs is H and R3 is in the 3-position on the phenyl ring, R3is not selected from the group of butoxy, propoxy, pentyloxy, and hexyloxy; and with the proviso that, when Rs is H, R1, R2, and R3, along with the phenyl ring to which they are bound, does not create a 3,4,5-trimethoxyphenyl group; and with the proviso that, when Rs is H, R1, R2, and R3, along with the phenyl ring to which they are bound, do not create a 4-chlorophenyl group or a 2,4-dichlorophenyl group; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Provided is a compound of Formula (I l-c):wherein Ri, R2, and R3are independently selected from the group of H, C1-C3 alkyl, and halogen; with the proviso that at least one of R1, R2, and R3 is halogen; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Also provided is a compound of Formula (I l-c), above: wherein R1, R2, and R3 are independently selected from the group of H, Ci-C2alkyl, and halogen; with the proviso that at least one of R1, R2, and R3 is halogen; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Also provided is a compound of Formula (I l-c), wherein R1, R2, and R3are each independently selected from the group of H and halogen; with the proviso that at least one of R1, R2, and R3is halogen; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Also provided is a compound of Formula (I l-c), wherein R1, R2, and R3 are each independently selected from the group of H and halogen; with the proviso that at least two of R1, R2, and R3is halogen; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Also provided is a compound of Formula (ll-c), wherein Ri, R2, and R3 are each independently selected from the group of H and Cl; with the proviso that at least one of R1, R2, and R3is Cl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Also provided is a compound of Formula (ll-c), wherein 1, R2, and R3are each independently selected from the group of H and Cl; with the proviso that at least two of 1, R2, and R3is Cl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Provided is a compound of Formula (I l-d):wherein:R1 is halogen; andR2and R3are each independently selected from the group of H, Ci-C2alkyl, and halogen; or a pharmaceutically acceptable salt, co-crystal, solvate, or hydrate thereof.Also provided is a compound of Formula (I l-d), wherein:R1 is Cl; andR2and R3are each independently selected from the group of H, Ci-C2alkyl, and Cl; or a pharmaceutically acceptable salt, co-crystal, solvate, or hydrate thereof.Also provided is a compound of Formula (I l-d), wherein:R1 is Cl;R2 is Cl; andR3is H; or a pharmaceutically acceptable salt, co-crystal, solvate, or hydrate thereof.Also provided is a compound of Formula (I l-e):wherein:R1 is halogen;R2 and R3are each independently selected from the group of H, C1-C2 alkyl, and halogen; or a pharmaceutically acceptable salt, co-crystal, solvate, or hydrate thereof.Also provided is a compound of Formula (I l-e), wherein:Ri is Cl; andR2and R3are each independently selected from the group of H, C1-C2 alkyl, and Cl; or a pharmaceutically acceptable salt, co-crystal, solvate, or hydrate thereof.Also provided is a compound of Formula (I l-e), wherein:R1 is Cl;R2 is Cl; andR3is H; or a pharmaceutically acceptable salt, co-crystal, solvate, or hydrate thereof.Methods of T reatmentThe methods of treatment herein include different embodiments in which, in separate embodiments, a pharmaceutically effective amount of a compound, or a pharmaceutically acceptable salt, co-crystal, solvate, or hydrate thereof, is utilized from each of the groups of compounds described herein, including those for Formula (I), Formulas (l-a) to (l-e), and Formulas (I l-a) to (I l-e) . Each of the methods herein may be described as a method of treatment of a disease or condition responsive to agonism of 0GG1 glycosylase (0GG1 glycosylase agonist activity) in the subject treated or promoting the activity of 0GG1 glycosylase in the subject treated.Also provided are uses of compounds that are agonists of 0GG1 in methods of medical treatment described herein, the compounds comprising Formula (III):wherein: Ri, R2, and R3 are independently selected from the group of H, C1-C3 alkyl, and halogen; with the proviso that at least one of R1, R2, and R3 is halogen; and R4 is selected from the group of isopropyl and cyclopentyl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Also provided is the use in methods of treatment of a compound of Formula (IV):wherein: Ri, R2, and R3 are independently selected from the group of H, C1-C3 alkyl, and halogen; with the proviso that at least one of R1, R2, and R3is halogen; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Uses are also provided for a compound of Formula (V):wherein: 1 is halogen; and R2and 3 are each independently selected from the group of H, C1- C2alkyl, and halogen; or a pharmaceutically acceptable salt, co-crystal, solvate, or hydrate thereof.Also provided is a compound of Formula (V), wherein: R1 is Cl; and R2and R3are each independently selected from the group of H, Ci-C2alkyl, and Cl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Also provided is a compound of Formula (V), wherein: 1 is Cl; R2is Cl; and R3is H; or a pharmaceutically acceptable salt, co-crystal, solvate, or hydrate thereof.Also provided is a compound of Formula (VI):wherein: Ri is halogen; and R2and R3are each independently selected from the group of H, C1-C2 alkyl, and halogen; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Also provided is a compound of Formula (VI), wherein: R1 is Cl; and R2and R3 are each independently selected from the group of H, Ci-C2alkyl, and Cl; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Also provided is a compound of Formula (VI), wherein: R1 is Cl; R2is Cl; and R3is H; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Non-limiting specific compounds of the invention include those listed below, or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof:1-phenylethan-1-ol -cyclohexyl- 1 -(2,4-dichlorophenyl)-2- (1 H-imidazole-1-yl) ethan-1-ol4-{(1 S* 2R*)-1 -hydroxy-2-[2-2-[2-(2-fluoro-4,5- (2-phenyl-1 ,3-oxazol-4-yl)-1 H- dimethoxyphenyl)- imidazol-1 -yl]propyl}phenol 1 H-imidazol-1 -yl]-1 - phenylethan-1-ol2-[2-(2-cyclohexylpyrimidin-5-yl)- 2-(1-ethyl-5'-phenyl-1 H,3'H-2,4'- H-imidazol-1 -yl]-1 -phenylethan-1 -ol biimidazol-3'-yl)-1 -phenylethan-1 -ol2-chloro-4-[1-(2-hydroxy-2-phenyl 2-{2-[5-fluoro-2-(1 H-pyrazol-1-yl)phenyl]- ethyl )-1 H-imidazol-2-yl]phenol 1 H-imidazol-1 -y I }- 1 -phenylethan-1 -ol4-[(1 S*,2R*)-2-(2'-butyl-1 H, 1 'H-2,4'- 1 -phenyl-2-(2-quinolin-2-yl- biimidazol-1 -yl)-1 -hydroxypropyl]phenol 1 H-imidazol-1 -yl)ethan-1 -ol1 -phenyl-2-(2-quinolin-2-yl- 4-{( 1 S*,2R*)-2-[2-(1 -benzofuran-2-yl)- H-imidazol-1 -yl)ethan-1 -ol 1 H-imidazol-1 -y I]- 1 -hydroxypropyl}phenol4-[1-(2-hydroxy-2-phenylethyl)-4- 2-(1 H,1'H-2,2'-biimidazol-1- phenyl-1 H-imidazol-5-yl]benzonitrile y I )- 1 -phenylethan-1 -ol-[5-(2-fluoro-6-methoxyphenyl)-4-phenyl- 3-[1-(2-hydroxy-2-phenylethyl)-4-1 H-imidazol-1 -y I]- 1 -phenylethan-1 -ol phenyl-1 H-imidazol-5-yl]phenol1 -yn-1 -y I )-2-th ieny I]- 1 H- 2-[5-(1-allyl-1 H-pyrazol-4-yl)-4-phenyl- imidazol-1 -y IJethy I )p henol 1 H-imidazol-1 -yl]-1 -phenylethan-1 -ol4-((1S*,2R*)-2-{2-[2-(ethylamino) 1-phenyl-2-[2-(5,6,7,8-tetrahydro- py ri mid i n-5-y I]- 1 H-imidazol-1 -yl}- 4H-pyrazolo[1 ,5-a][1 ,4]diazepin- 1-hydroxypropyl)phenol 2-y I )- 1 H-imidazol-1 -yl]ethan-1 -ol2-{2-[2-(2-furyl)phenyl]-1 H- 1 -phenyl-2-(4-phenyl-5-pyridin-4- imidazol-1 -y I}- 1 -phenylethan-1 -ol yl-1 H-imidazol-1 -yl)ethan-1 -oln-4-yl)- methyl 3-[1 -(2-hydroxy-2-phenyl 4-phenyl-1 H-imidazol-1 -yl]- ethyl)-1 H-imidazol-2-yl]benzoate 1 -phenylethan-1 -ol(4-fluorophenyl)(1 -methyl- [2-(1 H-imidazol-1 -yl)-1 -phenylethyl]1 H-imidazol-2-yl)methanol amine dihydrochloride hydrate[1 -(1 H-imidazol-1 -ylmethyl) 1 -(1 H-imidazol-1 -yl)-3-phenoxy- propyl]amine dihydrochloride 2-propanol dihydrochloride1 -(2,4-dichlorophenyl)-2- (1-methyl-1 H-imidazol- (1 H-imidazol-1 -yl)ethan-1 -one 2-yl)(phenyl)methanol1 -(4-bromophenoxy)-3- 1 -phenyl-2-(1 H-pyrrol-1 -yl)ethan-1 -one (1 H-imidazol-1 -yl)propan-2-ol1 H-imidazol-1 -ylacetic acid 2-(2-chloro-1 H-imidazol-1 - y I )- 1 -(4-pyridinyl)ethan-1 -ol1 -(4-chlorophenoxy)-3-(2-methyl- 1-(4-chlorophenoxy)-3-(1 H-1 H-imidazol-1-yl)propan-2-ol imidazol-1 -yl)propan-2-ol1 -pyridin-3-y l-2-(2-py ridi n-4- N-[2-(1 H-imidazol-1 -yl)-1- yl-1 H-imidazol-1 -yl)ethan-1 -ol phenylethyl]-2-methoxyacetamide2-(1 H-imidazol-1 -y I )- 1 -phenyl- 2-(1 H-imidazol-1 -yl)- 1 -(pyridin-3-yl)ethan-1 -ol 1 , 1 -diphenylethan-1 -ol2-(1 H-imidazol-1 -y I )- 1 -phenyl- 1 -(2,4-dichlorophenyl)-2- 1 -(pyridin-4-yl)ethan-1 -ol (1 H-imidazol-1 -yl)ethan-1 -ol1 -(4-chlorophenyl)-2-(1 H- 1-(4-fluorophenyl)-2-(1 H- imidazol-1 -yl)ethan-1 -ol imidazol-1 -yl)ethan-1 -ol2-(1 H-imidazol-1 -yl)-1- 1 -(4-bromophenyl)-2- (4-propylphenyl)ethan-1 -ol (1 H-imidazol-1 -yl)ethan-1 -ol1 -(3-bromophenyl)-2-(1 H- 1 -(2,4-dichlorophenyl)-2- im idazol-1 -yl)ethan-1 -ol (1 H-im idazol-1 -yl)ethyl acetate1 -(2,4-dichlorophenyl)-3- 1 -{2-(4-chlorophenyl)-2- [4-(dimethylamino)phenyl]-2- [(2,4-dichlorophenyl)methoxy] (1 H-imidazol-1-yl)propan-1-ol ethyl}- 1 H-imidazole - Nitric Acid (1 / 1 )1-[2-(benzyloxy)-2-(2,4-dichloro 2-(1 H-imidazol-1 -yl)-1 - phenyl)ethyl]-1 H-imidazole phenylethyl acetate-(4-fluorophenyl)-2-(1 H-imidazol- 2-(1 H-imidazol-1-yl)-1-1 -y I )- 1 -(pyridin-2-yl)ethan-1 -ol phenyl-1 -(pyridin-2-yl)ethan-1 -ol1 -(2,4-dichlorophenyl)-2-(1 H- 2-(2,4-dichlorophenyl)-1 -(1 H- imidazol-1 -yl)-1 -phenylethan-1 -ol imidazol-1 -yl)propan-2-ol2-(2,4-dichlorophenyl)-1- 2-(2,4-dichlorophenyl)-1 -(1 H- (1 H-imidazol-1-yl)butan-2-ol imidazol-1-yl)-3-methylbutan-2-ol1 -cyclopentyl-1 -(2,4-dichlorophenyl)- 2-(1 H-imidazol-1 -yl)ethan-1 -olCompounds of Formula (I) may be prepared by methods known in the art, including the reaction scheme below representing the reaction of the relevant chloro-substituted 2-(1H- imidazol-1-yl)-1-phenylethan-1-one compound (1) with cyclopentylmagnesium bromide (2).The compounds described herein are useful in methods of medical treatment for a number of conditions associated with agonism of 0GG1 activity. For each condition or disease mentioned, the method of treatment comprises administering to a human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof. It is understood that, for each method described herein in regard to a disease or condition, including any treatment, inhibition, amelioration, delay of onset, etc., thereof, that reference to use of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, or hydrate thereof, also includes the use of a compound of Formula (l-a), Formula (l-b), Formula (l-c), Formula (l-d), Formula (l-e), Formula (I l-a), Formula (I l-b), Formula (ll-c), Formula (I l-d), Formula (I l-e), Formula (III), Formula (IV), Formula (V), and Formula (VI), and any subset or embodiment thereof, or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof. It is further understood that for each method described herein in regard to a disease or condition, including any treatment,inhibition, amelioration, delay of onset, etc., thereof, that reference to use of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, or hydrate thereof, also includes embodiments in which the specific compounds herein are used, including those for 1- cyclopentyl-1-(2,4-dichlorophenyl)-2-(1 H-imidazol-1-yl)ethan-1-ol and / or 2-(2, 4-dichlorophenyl)- 1-(1 H-imidazol-1-yl)-3-methylbutan-2-ol , or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.In one embodiment is provided a method of promoting the activity of 0GG1 glycosylase in a human subject in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Also provided is a method of Inhibiting or preventing the deleterious consequences of oxidative DNA damage in a human subject in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Also provided is a method of inhibiting or preventing oxidative stress in a human subject in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Another embodiment provides a method of treatment of metabolic syndrome (insulin resistance syndrome) in a human in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.For the treatment of metabolic syndrome / insulin resistance syndrome and / or Type 2 diabetes, the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, or hydrate thereof, may be combined with other treatment agents including, but not limited to: a) biguanides, such as metformin (GLUCOPHAGE®, GLUCOPHAGE XR®, FORTAMET®, GLUMETZA®, and RIOMET®); b) thiazolidinediones (pioglitazone (ACTOS®, rosiglitazone (AVANDIA®), and troglitazone); c) dipeptidyl peptidase (DPP-4) inhibitors, such as vildagliptin (EUCREAS®), sitagliptin (JANUMET®, JANUVIA®), saxagliptin (ONGLYZA®), alogliptin (NESINA®), and linagliptin (TRADJENTA®); d) Sulfonylureas, such as glimepiride (AMARYL®), glyburide (DIABETA®), chlorpropamide (DIABINESE®), glipizide (GLUCOTROL®), tolbutamide, and tolazamide; e) Dopamine receptor agonists, such as bromocriptine (CYCLOSET®); f) Bile acid sequestrants, such as colesevelam (WELCHOL®); g) SGLT2 inhibitors, such as empagliflozin (JARDIANCE®), canagliflozin (INVOKANA®), ertugliflozin (STEGLATRO®), and dapagliflozin (FARXIGA®); h) GLP-1 receptor agonists / lncretin mimetics, such as exenatide (BYETTA® and BYDUREON®), albiglutide (TANZEUM®), dulaglutide (TRULICITY®), liraglutide (VICTOZA®), semaglutide (OZEMPIC®), lixisenatide (ADLYXIN®), and lixisenatide, i) Meglitinides, such as repaglinide (PRANDIN®) and nateglinide (STARLIX®), j) alpha-glucosidase inhibitors, such as miglitol (GLYSET®) and acarbose (PRECOSE®); k) amylin analogs, such as pramlintide acetate (SYMLIN®); and l) insulin products, such as insulin aspart (NOVOLOG®), insulin glulisine (APIDRA®), insulin lispro (HUMLOG®), long-acting insulin products (insulin glargine, insulin degludec, insulin detemir, etc.), insulin regular (HUMULIN R®, LLETIN II REGULAR®, NOVLIN R®, etc.), intermediate-acting insulin products (HUMULIN N®,NOVLIN N®, etc.), inhaled insulin (AFREZZA®), insulin degludec injection (TRESIBA®); m) or combinations thereof.Combinations of the agents above include the non-limiting group of insulin glargine / lixasenatide (SOLIQUA®), alogliptin / metformin (KAZANO®), alogliptin / pioglitazone (OSENI®), glipizide / metformin (METAGLIP®), glyburide / metformin (GLUCOVANCE®), linagliptin / metformin (JENTADUETO®), pioglitazone / glimepiride (DUETACT®), pioglitazone / metformin (ACTOPLUS MET®, ACTOPLUS MET XR®), canagliflozin / metformin (INVOKAMET®), dapagliflozin / metformin (XIGDUO XR®), repaglinide / metformin (PRANDIMET®), rosiglitazone / glimepiride (AVANDARYL®), rosiglitazone / metformin (AVANDAMET®), saxagliptin / metformin (KOMBIGLYZEK XR®), and sitagliptin / metformin (JANUMET® and JANUMET XR®).Another embodiment provides a method of treatment or inhibition of obesity in a human in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Another embodiment provides a method of treatment or inhibition of fatty liver disease in a human in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Another embodiment provides a method of treatment or inhibition of chronic inflammatory liver disease in a human in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Another embodiment provides a method of treatment or inhibition of dyslipidemia in a human in need thereof, the method comprising administering to the human in need thereof apharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.In methods of treating or inhibiting dyslipidemia, the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, or hydrate thereof, may be combined with a statin, such as atorvastatin (LIPITOR®), rosuvastatin (CRESTOR®), simvastatin (ZOCOR®), pravastatin (PRAVACHOL®), pitavastatin (ZYPITAMAG®), lovastatin (M EVACO R®), AND fluvastatin (LESCOL®); or a non-statin drug, such as ezetimibe (ZETIA®); a fibrate, such as fenofibrate (FENOGLIDE®, TRICOR®, and TRIGLIDE®), or a PCSK9 inhibitor, such as evolocumab (REPATHA®), alirocumab (PRALUENT®), or bempedoic acid (NEXLETOL™).The compounds herein are useful in the treatment of cancers associated with 0GG1 deficiency, including kidney and lung cancers. In some embodiments the kidney cancers to be treated include renal cell carcinomas, including renal clear cell carcinomas (RCC), sarcomatoid and rhabdoid RCC, papillary RCC, chromophobe RCC, collecting duct RCC, multiloccular cystic RCC, medullary carcinoma, renal mucinous tubular and spindle cell carcinoma, and RCC associated with neuroblastoma.For renal cell carcinomas, the compound herein, or a pharmaceutically acceptable salt thereof, may be combined with other treatment agents, including pembrolizumab (KEYTRUDA®), avelumab (BAVENCIO®), axitinib (INLYTA®), pazopanib (VOTRIE T®), everolimus, temsirolimus, aldesleukin (IL-12), bevacizumab (AVASTIN®), carbozantinib-S- malate, ipilimumab (YERVOY®), sorafenib tosylate (NEXAVAR®), nivolumab (OPDIVO®), and sunitinib malate (SUTENT®).Another embodiment provides a method of treatment of lung cancer in a human in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof. In some embodiments, the lung cancer to be treated is small cell lung cancer, including small cell carcinoma (oat cell cancer) and combined small cell carcinoma.In other embodiments, the lung cancer to be treated is non-small cell lung cancer (NSCLC), including squamous cell carcinoma (SCC), large ceil carcinoma (LCC), andadenocarcinoma (ADC). In treatments for non-small cell lung cancer, the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, solvate, or hydrate thereof, may be administered in combination with another chemotherapeutic or immunotherapeutic agent, such as cisplatin (PLATINOL®) or carboplatin (PARAPI_ATIN®) plus docetaxel (TAXOTERE), gemcitabine (GEMZAR®), paclitaxel (TAXOL® and others), vinorelbine (NAVELBINE® and others), pemetrexed (ALIMTA®), erlotinib (TARCEVA®), afitinib (GILOTRIF®), gefitinib (IRESSA®), bevacizumab (AVASTIN®), crizotinib (XALKORI®), ceritinib (ZYKADIA®), nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®).Another embodiment provides a method of treatment of head and neck cancer in a human in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof. In some embodiments, the head and neck cancer treated in the subject is a squamous cell carcinoma. In different embodiments, the head and neck cancer treated in the subject is, respectively, a laryngeal cancer, an oral cavity cancer, an oropharyngeal cancer, a nasopharyngeal cancer, a hypopharyngeal cancer, a salivary gland cancer, and a nasal cavity and paranasal sinus cancer.Methods using a compound herein for the treatment of head and neck cancer may be combined with additional treatment agents, including one or more selected from the group of cisplatin, nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®), bleomycin sulfate, cetuximab, docetaxel, hydroxyurea, and methotrexate.Another embodiment provides a method of treatment of adenocarcinoma of the gastric cardia in a human in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Another embodiment provides a method of treatment of astrocytoma in a human in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Another embodiment provides a method of treatment of esophageal cancer in a human in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Another embodiment provides a method of treatment of breast cancer in a human in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Another embodiment provides a method of inhibition of breast cancer progression or metastasis in a human in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof. In separate embodiments, the breast cancer to be treated may be selected from the group of metastatic breast cancer, Ductal Carcinoma In Situ (DCIS), Invasive Ductal Carcinoma (IDC), Triple Negative Breast Cancer, Inflammatory Breast Cancer, Medullary Carcinoma, Tubular Carcinoma, Mucinous Carcinoma, and Paget Disease (also known as Paget Disease of the Breast or Nipple).Another embodiment provides a method of treatment of colorectal cancer in a human in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Another embodiment provides a method of inhibition of colorectal cancer progression or metastasis in a human in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, orpharmaceutically acceptable prodrug thereof. In separate embodiments, the colorectal cancer to be treated comprises a colorectal adenocarcinoma (including mucinous adenocarcinoma and Signet ring carcinoma), carcinoid tumors, primary colorectal lymphomas, gastrointestinal stromal tumors, melanomas, and Leiomyosarcomas.Another embodiment provides a method of treatment of COPD in a human in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Methods using a compound herein for the treatment of COPD may be combined with additional treatment agents, including one or more selected from the group of short-acting bronchodilators (such as albuterol, levalbuterol, and ipratropium, or combinations thereof), corticosteroids (such as fluticasone (FLOVENT®), budenoside (PULMICORT®), and prednisolone), a methylxantine agent (such as theophylline), a long-acting bronchodilator (such as aclidinium (TUDORZA®), arformoterol (BROVANA®), formoterol (FORADIL®, PERFORMIST®), glycopyrrolate (SEEBRI NEOHALER®), indacaterol (ARCAPTA®), salmeterol (SEREVANT®), tiotropium (SPIRIVA®), and umeclidinium (INCRUSE ELLIPTA ®), or combinations thereof, and roflumilast (DALIRESP®).A further embodiment provides a method of treatment of Parkinson’s Disease in a human in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Methods using a compound herein for the treatment of Parkinson’s Disease may be combined with additional treatment agents, including one or more selected from the group of levodopa and carbidopa (SINEMET®), inhalable levodopa (INBRIJA®), istradefylline (NOURIANZ®), safinamide (XADAGO®), dopamine agonists (pramipexole (MIRAPEX®), rotigotine (NEUPRO®), and ropinirole (REQUIP®)), amantadine (SYMMETREL®), selegiline, rasagiline, entacapone, and tolcapone.A further embodiment provides a method of treatment of Alzheimer’s Disease in a human in need thereof, the method comprising administering to the human in need thereof apharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof. In some embodiments, the method concerns the treatment of Early-onset Alzheimer’s Disease. In other embodiments, the method is directed to the treatment of Late- onset Alzheimer’s Disease. In still other embodiments, the method is directed to the treatment of Familial Alzheimer’s Disease.Methods using a compound herein for the treatment of Alzheimer’s Disease may be combined with additional treatment agents, including one or more selected from the group of cholinesterase inhibitors (donezpazil (ARICEPT®), rivastigmine (EXELON®), galantamine (RAZADYNE®)), memantine (NAMENDA®), and memantine + donepezil (NAMZARIC®).A further embodiment provides a method of treatment of Huntington’s Disease (also known as Huntington’s chorea) in a human in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof. In some embodiments, the Huntington’s Disease treated by the method is Adult-Onset Huntington’s Disease. In other embodiments, the Huntington’s Disease treated by the method is Juvenile Huntington’s Disease.Methods using a compound herein for the treatment of Huntington’s Disease may be combined with additional treatment agents, including one or more selected from the group of tetrabenazine (XENAZINE®), duetetrabenazine (AUSTEDO®), valbenazine, amantadine, levetiracetam, haloperidol (HALDOL®), chlorpromazine, risperidone (RISPERDAL®), quetiapine (SEROQUEL®), clonazepam (KLONOPIN®), or a selective serotonin reuptake inhibitor, such as fluoxetine (PROZAC®), sertraline (ZOLOFT®), paroxetine (PAXIL®), escitalopram (LEXAPRO®), fluvoxamine (LUVOX®), citalopram (CELEXA®), volazodone (VIIBRID®), and or vortioxetine (BRINTELLIX®), nilotinib, pridopidine (ACR16), resveratrol, fenofibrate, ISIS 443139, IONIS-HTTRX (RO7234292), RG6042, WVE-120102, VX15, SRX246, SOM3355, resveratrol, AMT-130, Sage-718, P110, EHP-102, and Cellavita HD stem-cell therapyAnother embodiment provides a method of treatment of Mild Cognitive Impairment (MCI) in a human in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates,or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof. In some embodiments, the MCI treated by the method is Amnestic MCI. In other embodiments, the MCI treated by the method is Non-Amnestic MCI. In additional embodiments, the MCI treated by the method is Single Domain MCI. In further embodiments, the MCI treated by the method is Multiple Domain MCI.Another embodiment provides a method of treatment of Diffuse Lewy Body Disease (Lewy Body Dementia) in a human in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Another embodiment provides a method of treatment of vascular dementia (also referred to as vascular cognitive impairment) in a human in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Another embodiment provides a method of treatment of mixed vascular dementia and Alzheimer’s Disease in a human in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Another embodiment provides a method of treatment of Frontotemporal Dementia (also known as Pick’s Disease) in a human in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Another embodiment provides a method of treatment of Dystrophic Neurites in a human in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Another embodiment provides a method of treatment of Young-Onset Dementia in a human in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Another embodiment provides a method of treatment of depression in a human in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof. In some embodiments, the depression to be treated is unipolar depression. In other embodiments, the depression to be treated is bipolar depression.Another embodiment provides a method of treatment of normal pressure hydrocephalus in a human in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Another embodiment provides a method of treatment of a prion disease in a human in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof. In some embodiments, the prion disease to be treated in a human in Creutzfeldt-Jakob Disease.The compounds described herein may also be used in veterinary methods of treatment for prion diseases, such as Bovine Spongiform Encephalopathy (BSE) in cattle, Scrapies ingoats and sheep, Feline Spongiform Encephalopathy (FSE) in cats, and Chronic Wasting Disease in deer, elk, and moose.Another embodiment provides a method of treatment of AIDS dementia complex (ADC), also known as HIV-associated dementia (HAD), in a human in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Another embodiment provides a method of treatment of HIV-associated neurocognitive disorder (HAND) in a human in need thereof, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.Pharmaceutical compositionsAlso provided is a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula (I), as defined above, or a pharmaceutically acceptable salt, co-crystal, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier or excipient. It is understood that other separate pharmaceutical compositions are provided the compound within each definition of compounds herein, including the compounds of Formula (I), Formulas (l-a to l-e), and Formula (I l-a to ll-e). Each pharmaceutical formulation comprises a pharmaceutically effective amount of the compound in question, or a pharmaceutically acceptable salt, co-crystal, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.Also described for a compound of Formula (I) and all other formulas and embodiments herein are the pharmaceutically acceptable salts, pharmaceutically acceptable co-crystals, pharmaceutically acceptable esters, pharmaceutically acceptable solvates, hydrates, isomers (including optical isomers, racemates, or other mixtures thereof), tautomers, isotopes, polymorphs, and pharmaceutically acceptable prodrugs of such compounds.The compounds of the disclosure may possess an asymmetric center and can be produced as a racemic mixture or as individual enantiomers. The individual enantiomers may be obtained by asymmetric synthesis or by resolving a racemic or non-racemic mixture of anintermediate at some appropriate stage of the synthesis. The individual enantiomers may also be obtained by resolution of the compound by conventional means, such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high-pressure liquid chromatography (HPLC) column. The individual enantiomers as well as racemic and non- racemic mixtures of enantiomers are within the scope of the present disclosure, all of which are intended to be included within the structures depicted in this specification unless otherwise specifically indicated.Unless specifically defined otherwise, the technical terms, as used herein, have their normal meaning as understood in the art. The following explanations of terms and methods are provided to better describe the present isotopic compounds, compositions and methods, and to guide those of ordinary skill in the art in the practice of the present disclosure. It is also understood that the terminology used in the disclosure is for the purpose of describing particular embodiments and examples only and is not intended to be limiting.As used herein, the term “isotopic” in reference to a compound as disclosed herein means that one or more atoms of the compound is replaced with an isotope of such one or more atoms. An “isotope” refers to any of two or more forms of a chemical element, having the same number of protons in the nucleus, but having different numbers of neutrons in the nucleus. For example, an isotopic compound includes a compound in which one or more hydrogen atoms (H) has been replaced with one or more deuterium atoms (D). In this example, deuterium is an isotope of hydrogen, and replacing a hydrogen atom with deuterium (at one or more positions) renders the resulting compound an isotopic compound. For example, and in reference to Formula (I), replacing the two methyl groups of the isopropyl moiety (-CH(CH3)2) with fully deuterated methyl groups (-CH(CD3)2) would be an isotopic compound of Formula (I). In addition to replacing hydrogen with deuterium, other stable (non-radioactive) isotope substitutions include replacing carbon 12 with carbon 13, while unstable (radioactive) isotopes include replacing hydrogen with tritium, replacing carbon 12 with carbon 14, replacing iodine 127 with iodine 123 or iodine 125, and the like. Accordingly, all reference herein to isotopic compounds of Formula (I), as well as all reference to the various embodiments thereof, refers to a compound having one or more isotopic substitutions, including (but not limited to) substitutions of one or more hydrogen atoms with one or more deuterium atoms and any occurrence(s) in the compound. To this end, the isotopic compounds disclosed herein provide improved advantages relative to their non-isotopic forms. To this end, isotopic modification provides a means of improving existing drugs and / or as a tool in the design of new drugs. For example, isotopic drugdesign has proven successful in the context of the deuterium (D) kinetic isotope effect. Due to the two-fold higher mass of D compared with H, the C-D bond is much more resistant toward oxidative processes (such as its ability to be catalyzed by CYP450 or by other enzymes involved in metabolism), while retaining very similar steric properties. Therefore, H-D isosteric replacement usually retains the pharmacodynamics of the compound, while improving its pharmacokinetics with a repercussion on half-life and / or of area under the curve values and, ultimately, on dose and / or dosing regimen. For example, drug exposure may be enhanced with isotopic modification, and / or a decrease of clearance. Such benefits are provided to the compounds disclosed hereby by way of their isotopic derivation.Compounds of Formula (I), or a pharmaceutically acceptable salt or co-crystal thereof, are usually administered in the form of pharmaceutical compositions. This disclosure therefore provides pharmaceutical compositions that contain, as the active ingredient, one or more of the compounds described, or a pharmaceutically acceptable salt, pharmaceutically acceptable cocrystal or pharmaceutically acceptable ester thereof, and one or more pharmaceutically acceptable vehicle, such as excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. The pharmaceutical compositions may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker & C. T. Rhodes, Eds.)The pharmaceutical compositions may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example through oral, rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.Definitions:"Pharmaceutically acceptable salts" include, for example, salts with inorganic acids and salts with an organic acid. Examples of salts may include hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, nitrate, malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate (mesylate), benzenesuflonate (besylate), p-toluenesulfonate (tosylate), 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, andalkanoate (such as acetate, HOOC--(CH2)n--COOH where n is an integer selected from 0-4). In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts.As used herein, "pharmaceutically acceptable excipient" is a pharmaceutically acceptable vehicle that includes, without limitation, any and all carriers, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.The term "carrier" refers to an excipient or vehicle that includes without limitation diluents, disintegrants, precipitation inhibitors, surfactants, glidants, binders, lubricants, and the like with which the compound is administered. Carriers are generally described herein and also in "Remington's Pharmaceutical Sciences" by E. W. Martin. Examples of carriers include, but are not limited to, aluminum monostearate, aluminum stearate, carboxymethylcellulose, carboxymethylcellulose sodium, crospovidone, glyceryl isostearate, glyceryl monostearate, hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxyoctacosanyl hydroxystearate, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, poloxamer 124, poloxamer 181 , poloxamer 182, poloxamer 188, poloxamer 237, poloxamer 407, povidone, silicon dioxide, colloidal silicon dioxide, silicone, silicone adhesive 4102, and silicone emulsion. It should be understood, however, that the carriers selected for the pharmaceutical compositions, and the amounts of such carriers in the composition, may vary depending on the method of formulation (e.g., dry granulation formulation, solid dispersion formulation).The term "crystal forms" and related terms herein refer to the various crystalline modifications of a given substance, including, but not limited to, polymorphs, solvates, hydrates, co-crystals, and other molecular complexes, as well as salts, solvates of salts, hydrates of salts,other molecular complexes of salts, and polymorphs thereof. Crystal forms of a substance can be obtained by a number of methods, as known in the art. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, recrystallization in confined spaces such as, e.g., in nanopores or capillaries, recrystallization on surfaces or templates, such as, e.g., on polymers, recrystallization in the presence of additives, such as, e.g., co-crystal counter-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, grinding and solvent-drop grinding.The term "subject" or “patient” refers to an animal, such as a mammal, that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in both human therapy and veterinary applications. In some embodiments, the subject or patient is a mammal; in some embodiments the subject or patient is human; and in some embodiments the subject is chosen from cats and dogs. "Subject in need thereof" or "human in need thereof refers to a subject or patient, such as a human, who may have or is suspected to have diseases or conditions that would benefit from certain treatment; for example, treatment with a compound of Formula I, or a pharmaceutically acceptable salt or co-crystal thereof, as described herein. This includes a subject or patient who may be determined to be at risk of or susceptible to such diseases or conditions, such that treatment would prevent the disease or condition from developing.The term "therapeutically effective amount" or "pharmaceutically effective amount" refers to an amount that is sufficient to effect treatment, as defined below, when administered to a subject (e.g., a mammal, such as a human) in need of such treatment. The therapeutically or pharmaceutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. For example, a "therapeutically effective amount" or a "pharmaceutically effective amount" of a compound of Formula I, or a pharmaceutically acceptable salt or co-crystal thereof, is an amount sufficient to modulate, increase, or agonize 0GG1 expression or activity, and thereby treat a subject (e.g., a human) suffering an indication, or to ameliorate or alleviate the existing symptoms of the indication. For example, a therapeutically or pharmaceutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition responsive to agonism of 0GG1 activity.In some embodiments, each dosage unit contains from 0.1 mg to 1 g, 0.1 mg to 700 mg, or 0.1 mg to 100 mg of a compound of Formula (I), or a pharmaceutically acceptable salt or co-crystal thereof. In some embodiments, a therapeutically effective amount or a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, comprises from about 0.1 mg to about 500 mg per dose, given once or twice daily. In some embodiments, the individual dose is selected from 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, and 500 mg per dose.For any of the dosage units as described herein, it will be understood, however, that the amount of the compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual subject, the severity of the subject's symptoms, and the like.The terms “treat”, "treatment," or "treating" is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: (i) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); (ii) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and / or (iii) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival)."Delaying" the development of a disease or condition means to defer, hinder, slow, retard, stabilize, and / or postpone development of the disease or condition. This delay can be of varying lengths of time, depending on the history of the disease or condition, and / or subject being treated. A method that "delays" development of a disease or condition is a method that reduces probability of disease or condition development in a given time frame and / or reduces the extent of the disease or condition in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically significant number of subjects. Disease or condition development can be detectable using standard methods, such as routine physical exams, mammography, imaging, or biopsy. Developmentmay also refer to disease or condition progression that may be initially undetectable and includes occurrence, recurrence, and onset.Numerical values in the specification and claims of this application should be understood to include numerical values which are the same when reduced to the same number of significant figures and numerical values which differ from the stated value by less than the experimental error of conventional measurement technique of the type described in the present application to determine the value.All ranges disclosed and / or claimed herein are inclusive of the recited endpoint and independently combinable (for example, the ranges of "from 2 to 10" and “2-10” are inclusive of the endpoints, 2 and 10, and all the intermediate values).By "significant" is meant any detectable change that is statistically significant in a standard parametric test of statistical significance such as Student's T-test, where p<0.05.The term "alkyl" refers to a straight or branched hydrocarbon. For example, an alkyl group can have 1 to 3 carbon atoms (i.e, C1-C3 alkyl or C1.3 alkyl), which would include methyl, ethyl, n-propyl, and isopropyl groups.The term "halogen" or "halo" refers to F, Cl, Br, or I.TABLES 1-7: Structure activity relationship tables. OGG1 agonist candidates were classified into six chemotypes based on R1 substitutions to a common core molecular structure: phenyls (Table 1), 4-OH-phenyls (Table 2), halogenated phenyls (Table 3), 2,4-dichloro phenyls (Table 4), and CH2-O-phenyl halogens (Table 5) pyridyls (Table 6). 8 compounds that did not share a common core structure were classified separately (Table 7). Tables give fold change of the initial reaction rate of OGG1 (50 nM) with 8oxoG-containing DNA substrate (50 nM) in the presence of agonists (10 pM) relative to the DMSO control and the EC50 concentrations determined by analyzing initial reaction rates of OGG1 (50 nM) with 8-oxoG-containing DNA substrate (50 nM) with a range of agonist concentrations.Agonist F01A publication from the laboratories of Drs. William Rumsey, Glaxo Smith Kline and Vilhelm Bohr, National Institute on Aging has reported the identification of agonists of OGG1, with most of them demonstrating very poor potency, with stimulation observed between 10 to 30 pM

[0057] , Although multiple compounds were identified that enhanced OGG1 activity, one molecule was reported to show OGG1 stimulation at ~1 pM

[0066] , We considered this small molecule agonistfrom the perspectives of chemical properties: 1-cyclohexyl-1-(2,4-dichlorophenyl)-2-(1 H- imidazol-1-yl) ethanol (F01 , below) [CAS Reg. No. 2241587-66-4], F01 was used as a parent compound for the derivation of the other compounds described herein.Development of a Screen for Activators and Inhibitors of the 0GG1 DNA GlycosylaseOur lab has designed a low volume, high throughput screen (HTS) for agonists of 0GG1 based on our previous HTS design for the identification of inhibitors of human NEIL1 and 0GG1 DNA glycosylases [67, 68], The 0GG1 activity assay utilizes a 17-mer oligodeoxynucleotide containing an 8-oxoG lesion positioned at the 6thnucleotide downstream of a 5'-TAMRA fluorophore and a complementary DNA strand that contains a 3'-Black Hole Quencher 2 (BHQ2) (Figure 4). While the TAMRA fluorescence signal is quenched by BHQ2 in substrate DNA, addition of purified human 0GG1 results in base release and subsequent strand scission, leading to the dissociation of the TAMRA-labeled 5-mer into bulk solution, where the TAMRA fluorescence is no longer quenched. Increasing concentrations of human 0GG1 resulted in a dose-dependent increase in TAMRA fluorescence. Identical reactions are routinely analyzed by gel electrophoresis, with similar dose-response curves observed, indicating that a measured increase in fluorescence can reliably be used as a readout for the combined glycosylase and apurinic / apyrimidinic (AP) site lyase activities of 0GG1

[0067] , Therefore, 0GG1 agonists enhance the rate of fluorescence acquisition over time compared to the 0GG1 only control, while inhibitors reduce this rate.Identification and Characterization of High Potency Activators of 0GG1.Synthesis of F01 and structural derivativesAs described above, a prior publication revealed a starting small molecule agonist of 0GG1 , F01 , that both increased biochemical catalytic activity and demonstrated efficacy in cell biology assays

[0066] , The OHSU Medicinal Chemistry Core laboratory synthesized compound F01 as follows.The compounds herein can be prepared using techniques known in the art, such as the reaction of the relevant chloro-substituted 2-(1 H-imidazol-1-yl)-1-phenylethan-1-one compound (1) with cyclopentylmagnesium bromide (2). For the isopropyl analogs noted herein, isopropyl magnesium bromide may be used.The following scheme represents the reaction of 2-bromo-1-(2,4-dichlorophenyl)ethenone with imidazole and DCM followed by the reaction of 1-(2,4-dichlorophenyl)-2-(1 / - / -imidazol-1- yl)ethenone with THF and alkyl magnesium bromide.1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanone.Imidazole (4.9 g, 72 mmol) was dissolved in 20 ml_ of DCM. 2-Chloro-1-(2,4- dichlorophenyl)ethanone (5.36 g, 24 mmol) was dissolved in 10 mL of DCM, then added dropwise to the imidazole mixture. The solution was stirred for 2 hr at 40° C, then RT for 18 hr. The reaction was concentrated, redissolved in 200 mL of EtOAc, washed 3X with 50 mL of H2O and 2X with 50 mL of brine. The organic layer was concentrated, then redissolved in hot MeOH and recrystallized overnight. The resulting product was collected by filtration and dried to give 2.91 g of 2 (47% yield). 1 H NMR (400 MHz, CDCI3) 6 7.55 (d, 1H); 7.53 (d, 2H); 7.40 (dd, 1 H); 7.14 (s, 1H); 6.96 (s, 1 H); 5.35 (s, 2H).General F-series procedure.A flask was loaded with molecular sieves, then flame-dried under vacuum. After cooling, 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanone (0.1 g, 0.39 mmol) was loaded, then the flask was sealed, evacuated, and flushed with argon. 4 mL of Dry THF were added and degassed, then the solution was cooled to -78° C. Alkylmagnesium bromide (1.6 mL, 4 mmol)was added dropwise, then the reaction was stirred to 0° C for two hours (Figure 5B). The reaction was quenched with 5 ml_ of sat. aq. NH4CI. The aqueous layer was extracted 3X with 10 mL of EtOAc. The organic fractions were combined, washed 2X with 5 mL of brine, then dried with MgSO4, filtered, and concentrated. The crude was redissolved in Et2O, then HCI / dioxane was added and the mixture was cooled to -20°C for 18 hr.1-(2,4-dichlorophenyl)-1-cyclohexyl-2-(1 / 7-imidazol-1-yl)ethanol.The resulting yellow-orange crystals were collected by filtration and dried to give 15 mg of product as the HCI salt (10% yield). 1 H NMR (400 MHz, d6-DMSO) 5 8.90 (d, 1 H); 7.55 (dd, 1 H); 7.52 (m, 2H); 7.46 (d, 1 H); 7.35 (dd, 1 H); 4.56 (dd, 1H); 4.38 (dd, 1 H).Examples of useful chloro-substituted 2-(1 H-imidazol-1-yl)-1-phenylethan-1-one compounds include:1-(2,3-dichlorophenyl)-2-(1 H-imidazol-1-yl)ethan-1-one (CAS Reg. No. 1999227-90-5);2-(1 H-imidazol-1-yl)-1-(2,3,4-trichlorophenyl)ethan-1-one (CAS Reg. No. 1353585-96-2);1-(2,5-dichlorophenyl)-2-(1 H-imidazol-1-yl)ethan-1-one (CAS Reg. No. 1353585-84-8);1-(3,4-dichlorophenyl)-2-(1 H-imidazol-1-yl)ethan-1-one (CAS Reg. No. 1348139-02-5);1-(4-chlorophenyl)-2-(1 H-imidazol-1-yl)ethan-1-one (CAS Reg. No. 763921-00-2);1-(2-chlorophenyl)-2-(1 H-imidazol-1-yl)ethan-1-one (CAS Reg. No. 27087-95-2);1-(3-chlorophenyl)-2-(1 H-imidazol-1-yl)ethan-1-one (CAS Reg. No. 128563-40-6);1-(4-chlorophenyl)-2-(1 H-imidazol-1-yl)ethan-1-one (CAS Reg. No. 128563-38-2);2-(1 H-imidazol-1-yl)-1-(2,4,5-trichlorophenyl)ethan-1-one (CAS Reg. No. 98164-61-5);1-(2,4-dichlorophenyl)-2-(1 H-imidazol-1-yl)ethan-1-one (CAS Reg. No. 98164-08-0); and1-(2,6-dichlorophenyl)-2-(1 H-imidazol-1-yl)ethan-1-one (CAS Reg. No. 94038-29-6.Synthetic oliqodeoxynucleotidesThroughout this investigation, synthetic oligodeoxynucleotides were used for DNA cleavage assays including: (1) 5'-TAMRA-labeled 17-mer containing an internal 8-oxoG (5’- TAMRA-TCACC(8-oxoG)TCGTACGACTC-3’); (2) 5'-TAMRA-labeled 17-mer containing an internal deoxyuridine (dU) (5'-TAMRA-TCACC(dU)TCGTACGACTC-3'); [6] 5'-TAMRA-labeled 17-mer containing an internal thymine glycol (ThyGly) (5'-TAMRA- TCACCT(ThyGly)CGTACGACTC-3'); (4) a complementary 17-mer conjugated with BHQ2 at its 3' terminus and a cytosine deoxynucleotide opposite 8-oxoG or dU or an adenine opposite ThyGly (5 - GAGTCGTACGACGGTGA-BHQ2-3'). To prepare double-stranded DNA substrates, 1 pM 5’-TAMRA conjugated 8-oxoG-, dU-, or ThyGly-containing oligodeoxynucleotides were combined with 1.2 pM BHQ2 conjugated complementary oligodeoxynucleotides in 20 mM Tris- HCI buffer (pH 7.4) containing 100 mM KCI and 0.01% (v / v) Tween-20 and heated to 90 °C for 2 min then slowly cooled to 4 °C. AP sites were produced from dU-containing oligodeoxynucleotides by incubation of 100 nM DNA with UDG (0.5 U / pl) for 30 min at 37 °C in 20 mM Tris-acetate (pH 7.9), 50 mM potassium acetate, 10 mM magnesium acetate, and 100 pg / ml bovine serum aluminum (BSA) (CutSmart buffer from New England Biolabs Inc.).Purification of hOGG1 and separation-of-function mutants.The vectors for the expression of human OGG1 and the separation-of-function mutants were engineered to encode a N-terminal 6-His affinity purification tag and were introduced into BL21 (DE3) E. coli (New England Biolabs). Individual clones were obtained on LB-agar plates containing 50 pg / mL ampicillin. Colonies were inoculated into 20 mL LB media (1 % tryptone, 0.5 % yeast extract, 1 % NaCI (w / v), pH 7.0) containing 50 pg / mL ampicillin and grown overnight at 37 °C. The overnight culture was used to inoculate 2 L of LB media and the culture was incubated at 37 °C until the ODeoo reached 0.8. Expression of OGG1 and mutants were induced by addition of isopropyl 1-thio-p-D-galactopyranoside to a final concentration of 0.5 mM and incubation continued for 6 h at 20 °C. Cells were pelleted by centrifugation at -4000 x g for 10 min and stored at -80 °C. The frozen pellet was resuspended to a single-cell suspension on ice in a binding buffer for Ni2+chromatography (50 mM sodium phosphate (pH 8), 300 mM sodium chloride, 50 mM imidazole, 5 mM [3-mercaptoethanol), followed by lysis using a French pressure cell at 96.5 MPa (14,000 psi), and brief sonication (3 times 10 s each). Cellular debris was removed by centrifugation at -22,000 x g for 20 min, and the supernatant was loaded onto a 10 mL Qiagen Ni-NTA agarose column that was pre-equilibrated with binding buffer. The column was washed with -25 column volumes using binding buffer until the optical density at 280 nm was < 0.05. OGG1 and mutants were eluted with 150 mL binding buffer containing agradient of 50 to 500 mM imidazole. Fractions (3 mL) were collected, and the protein concentration of each fraction was measured with the Bradford reagent (Bio-Rad) using an Infinite M200 Tecan system. The purity of OGG1 in each fraction was evaluated by gel electrophoresis with a NuPAGE 4-12 % Bis-Tris gel under denaturing conditions. Gels were stained with Bio-Safe Coomassie Blue (Bio-Rad). All fractions comprising visibly pure protein were pooled for long-term storage and dialyzed against 50 mM Tris-HCI, pH 7.4, 150 mM sodium chloride, 0.1 mM ethylenediaminetetraacetic acid (EDTA), and 10 % (v / v) glycerol. Aliquots were flash-frozen and stored at -80 °C.Identification of compounds that stimulate the overall kinetic rate of OGG1Consistent with the previous report

[0066] , independent synthesis and analyses of the activity of F01 confirmed its activity as an activator of OGG1 with 8-oxoG-containing DNA (Figure 6B; Figure 7).To address our hypothesis that structural derivatives of F01 (Figure 3B; Tables 1-7) may stimulate OGG1 activity, all compounds were screened at 10 pM for stimulation of OGG1 activity in a fluorescence-based DNA cleavage assay with a 17-mer 8-oxoG-containing oligodeoxynucleotide substrate. Specifically, screening reactions were performed at 37 °C in a reaction volume of 20 pl. WT OGG1 or C253W OGG1 mutant was diluted to 125 nM in buffer containing 20 mM Tris (pH7.4), 100 mM KCI, 0.01 % Tween-20 and 100 pg / mL BSA. Test compounds were diluted to 100 pM in 100% DMSO prior to screening. For each reaction, 32 pl of 125 nM WT OGG1 or C253W OGG1 mutant was pre-mixed with 8 pl of 100 pM test compound. Reactions were initiated by adding 10 pl of the OGG1 + compound mixture to 10 pL of 100 nM AP site- or 8-oxoG-containing oligodeoxynucleotides in a 384 well black bottom microplate using a multichannel pipette. Reaction plates were centrifuged for 1 min at 200 x g prior to measurement at 37 °C in a TECAN INFINITE M NANO instrument. The final concentrations of reactants in all screening reactions were as follows: 50 nM WT OGG1 or C253W mutant OGG1 , 50 nM 8-oxoG- or AP-site-containing oligodeoxynucleotide substrate, 10 pM test compound and 10% (v / v) DMSO. Fluorescence readings were taken every two min for 1 h using a 525 nm (9 nm bandwidth) excitation filter and a 598 nm (20 nm bandwidth) emission filter. All reactions were performed in technical duplicate. Readings from technical duplicates were averaged and the initial rate was determined by fitting the data of the linear phase of the reaction to linear function using Excel. The initial rate was divided by that of the OGG1 + DMSO control reaction to calculate relative fold change. Agonists (10 pM) were also screened with human WT edited NEIL1 (15 nM) and human Endonuclease Ill-like protein 1 (NTH1; 11 nM)using ThyGly-containing oligodeoxynucleotide substrate (50 nM) and E. coli formamidopyrimidine / 8-oxoguanine DNA N-glycosylase (Fpg; 15 nM) using 8-oxoG-containing oligodeoxynucleotide substrate under the reaction and reading conditions described above.The screen with 8-oxoG-containing substrate (Figure 6A) identified 23 lead compounds that stimulated OGG1 activity by at least 2-fold (Figure 6B). Six molecules with Ri phenyl substitutions, five molecules with Ri halogenated phenyl substitutions and nine molecules with Ri 2,4-dichloro phenyl substitutions were identified that stimulated OGG1 activity 8-oxoG- containing substrate. At 10 pM, molecules with Ri 4-OH-phenyl (Table 2) or pyridyl (Table 6) substitutions provided minimal or no stimulation to OGG1 activity. Additionally, compounds with any R5, Re, or R7substitutions to the core molecular structure did not stimulate OGG1 activity with 8-oxoG-containing substrates. Rs, Re, and R? positions correspond to substitutions on the imidazole ring of the core molecular structure.From this initial screen with 8-oxoG-containing DNA, the 23 compounds that stimulated OGG1 activity 2-fold or greater were further characterized by measurements of ECso concentration (Figure 7; Tables 1-7). In this context, the ECso is the concentration of a compound required to produce 50% of the maximum stimulation observed. ECso concentrations were determined using the same fluorescence-based DNA cleavage assay with 8-oxoG- containing DNA substrate and increasing concentrations of agonist. ECso curves were generated for selected agonist using 9 - 14 agonist concentrations. OGG1 agonists were diluted to 10-fold the final concentration in 100% DMSO. Reactions were performed and initial rates calculated as described above. The rates for each agonist concentration were plotted and a non-linear regression was performed to determine the ECso concentration using the ATT Bioquest ECso calculator [https: / / www.aatbio.eom / 1. Each agonist was tested in three independent experiments and the mean with standard deviation was calculated.ECso concentrations ranged from 0.29 ± 0.05 pM (F51) to 36.1 ± 3.0 pM (F38) (Figure 7). Nine compounds were identified with lower ECso concentrations than F01 (F01 : ECso = 9.1 ± 0.5 pM). Molecules with Ri 2,4-dichloro phenyl and R3benzyl containing substitutions were notable with low ECso concentrations (F51 : ECso = 0.29 ± 0.05 pM, F50: ECso = 2.8 ± 0.5 pM) (Table 4). Interestingly, the ECso concentration of molecules with Ri halogenated phenyl substitutions, specifically molecules with halogens at the C4 position of the phenyl (F43, F44 and F46), depended on the type of halogen on the phenyl with more electronegative halogens providing lower ECso concentrations (Table 3). When taken all together or parsed by Ri substitution, there was no correlation between ECso concentration and the magnitude of fold-increase provided to0GG1 activity by compounds at 10 pM (analyses not shown). The ECso concentration was also determined for two previously described agonists of OGG1 , 8-bromoGua (9.3 pM)

[0069] and TH10785 (3.0 pM)

[0070] (Figure 7). These comparative analyses revealed a superior potency of several compounds in our set relative to previously identified OGG1-stimulating molecules.OGG1 agonists do not stimulate the activity of other qlycosylases with overlapping substrate specificities To investigate the specificity of agonists to OGG1 , fluorescence-based DNA cleavage assays were performed with human NEIL1 , human NTH1 and E. coli Fpg in the presence of agonists. Evaluating the effects of OGG1 agonists on NEIL1 , NTH1 and Fpg activity was of interest because these glycosylases share substrate specificity with OGG1. NEIL1 , NTH1 and OGG1 excise FapyG while Fpg and OGG1 both excise 8-oxoG. DNA cleavage assays with WT edited NEIL1 (15 nM) or NTH1 (11 nM) and the same group of agonists (10 pM) were performed using a ThyGly-containing oligodeoxynucleotide substrate (Figure 8A). These agonists did not significantly stimulate NEIL1 or NTH1 activity (Figure 8B; 80). However, F02 (10 pM) completely inhibited NEIL1 activity with ThyGly-containing DNA substrate (Figure 8B). Inhibition of NEIL1 by F02 was found to be concentration dependent with an IC50 of 2.0 pM. DNA cleavage assays with Fpg (15 nM) and a selected group of OGG1 agonists (10 pM) were performed using 8-oxoG-containing oligodeoxynucleotide substrates (Figure 8D). These agonists did not significantly stimulate Fpg activity with 8-oxoG-containing oligodeoxynucleotide substrates (Figure 8E). The lack of stimulation of Fpg, NTH1 and NEIL1 activity by OGG1 agonists demonstrates the specificity of these molecules to the enhancement of OGG1 activity. This result also provides evidence that these agonists do not decrease the thermal denaturation temperature of oligodeoxynucleotide substrates in the fluorescence-based DNA cleavage assay.OGG1 agonists stimulate AP lyase but not qlycosylase OGG1 activityKinetic rates derived from the fluorescence-based DNA cleavage assay with 8-oxoG- containing DNA described above reflect the combined rate of the glycosylase reaction in which OGG1 hydrolyzes the N-glycosidic bond between the deoxyribose and 8-oxoG, the [3- elimination (AP lyase) reaction, catalyzed by the K249 residue of OGG1 , and the thermal denaturation of duplex DNA necessary to release fluorescent signal for detection. To evaluate the mechanism by which agonists stimulate OGG1, it was necessary to isolate each step of the reaction. We hypothesized that agonists may stimulate the AP lyase activity of OGG1. To test this hypothesis, the same fluorescence-based DNA cleavage assay described above was performed with a 17-mer AP site-containing oligodeoxynucleotide substrates (Figure 9A) andagonists at 10 pM final concentration. AP sites were generated from dll-containing duplex DNAs by incubation with UDG. These analyses revealed that all compounds that stimulated OGG1 activity with 8-oxoG-containing substrate also stimulated OGG1 activity with AP sitecontaining substrate (Figure 9B). In all cases where stimulation was observed, the magnitude of OGG1 stimulation with AP site-containing DNA was either equal to or greater than the magnitude of stimulation observed with 8-oxoG-containing DNA. To control for the possibility that OGG1 agonists cleave AP site DNA on their own, 10 pM agonists were incubated with AP site-containing DNA substrate (Figure 10A) with fluorescence monitored every 2 min for 1 h. Fluorescence levels did not increase in the presence of agonists indicating that OGG1 agonists do no cleave AP sites on their own (Figure 10B).In 2011 , Dalhus et al. used site-directed mutagenesis to create separation of function OGG1 mutants that effectively disentangled the glycosylase and AP lyase activity of OGG1 . The C253W mutant retains AP lyase activity, but cannot perform the glycosylase step of the reaction

[0071] (Figure 11 B; 11C). Conversely, the KCCK OGG1 double mutant (K249C / C253K) is capable of excising oxidatively-damaged bases, but cannot catalyze the AP lyase reaction (Figure 12B; 12C). The KCCK OGG1 mutant provides a method to isolate the glycosylase step of the overall reaction, while the C253W OGG1 mutant provides a method to isolate the AP lyase step.To provide further evidence that agonists stimulate the OGG1 catalyzed AP lyase reaction, the activity of selected agonists was evaluated at 10 pM with the C253W OGG1 mutant in a fluorescence-based DNA cleavage assay with AP site-containing DNA substrate. In the presence of F50, F51 and F55, the kinetic rate of [3-elimination reaction catalyzed by the C253W OGG1 mutant was significantly increased (Figure 11 D). Notably, the magnitude of C253W OGG1 mutant stimulation by F50, F51 and F55 with AP site-containing DNA was much lower than the magnitude of WT OGG1 stimulation observed with AP site-containing DNA. This result provided confirmation of the stimulation of AP lyase activity by F50, F51 and F55. Additionally, since the 8-oxoG recognition pocket of the C253W OGG1 mutant is blocked by the tryptophan side chain, the observed stimulation may suggest that F50, F51 and F55 bind outside of the product recognition pocket. Other agonists tested (F01, F02, F26, F29, F58, F59, TH10785) did not significantly stimulate the activity of the C253W OGG1 mutant (Figure 11 D). Since these agonists were found to stimulate WT OGG1 activity with AP-containing DNA, the lack of stimulation of C253W OGG1 activity may suggest that blockage of the product recognition pocket prevents the interaction of agonists at this site. However, otherconformational differences between WT OGG1 and C253W OGG1 could explain the observed lack of stimulation.We hypothesized that 0GG1 agonists could increase the overall rate of 0GG1 through stimulation of the glycosylase step of the reaction. To test this hypothesis, the effects of selected agonists were evaluated at 10 pM in a gel-based DNA-cleavage assay with the KCCK OGG1 mutant and 8-oxoG-containing oligodeoxynucleotide substrate (Figure 13A). Since the KCCK OGG1 mutant cannot catalyze the AP lyase chemistry, sodium hydroxide was used to hydrolyze AP sites and terminate reactions. Gel-based DNA cleavage assays were performed using the KCCK OGG1 mutant and selected agonists with 8-oxoG-containing oligodeoxynucleotide substrate. KCCK OGG1 was diluted to 62.5 nM in buffer containing 20 mM Tris (pH7.4), 100 mM KCI, 0.01% Tween-20 and 100 pg / mL BSA. Test compounds were diluted to 100 pM in 100% DMSO. For each reaction, 32 pl of 62.5 nM KCCK OGG1 was premixed with 8 pl of 100 pM agonist or 100% DMSO. Reactions were performed in a 37 °C manifold heat block. Reactions were initiated by the addition of 10 pl of 200 nM 8-oxoG- containing oligodeoxynucleotide substrate to 10 pl of each KCCK OGG1 mutant and agonist mixture. After 15 min, reactions were terminated with the addition of 20 pl of 0.5 M NaOH and incubated at 90 °C for 2 min. Two volumes of formamide solution with 10 mM EDTA were added to each reaction. DNAs were resolved by electrophoresis through a 15% polyacrylamide gel in the presence of 8 M urea. TAMRA conjugated DNAs were visualized using a FluorChem M imager (Protein Simple) with a 534 nm LED light source and 593 nM emission filter. The intensities of TAMRA fluorescence of DNA bands were measured by the FluorChem M built-in software. Data was analyzed and plotted using Graph Pad Prism software.After 15-min reactions, equivalent product formation was observed in the presence or absence of F01 , F02, F26, F29, F50, F51 , F55, F58 and F59 (Figures 13B, 13C). This result indicates that these agonists did not stimulate the glycosylase activity of the KCCK OGG1 mutant with 8-oxoG-containing DNA.OGG1 agonists increase the turnover rate of OGG1 : OGG1 agonists increase OGG 1 -catalyzed release of 8-oxoG and FapyG from high molecular weight DNATaken together, our data suggest that OGG1 agonists function to increase the overall rate of OGG1 activity by increasing the rate of the OGG1 catalyzed AP lyase reaction and not the rate of the glycosylase reaction. We hypothesized that by increasing the kinetics of the AP lyase reaction, OGG1 agonists could increase the rate of OGG 1 -catalyzed release of 8-oxoGand FapyG from high molecular weight DNA. To evaluate this hypothesis, OGG1 was incubated in the presence of selected agonists with y-irradiated calf thymus DNA and the amount of released 8-oxoG and FapyG bases were measured by gas chromatography / tandem mass spectrometry (GC-MS / MS) analyses. Since this assay directly quantitates the amount of 8-oxoG and FapyG excised from DNA by 0GG1 , the AP lyase activity of 0GG1 will not be reflected. Thus, any stimulation of 0GG1 activity in this assay can be accounted for by either an increased rate of the glycosylase activity of 0GG1 or by an increased rate of turnover. Since our analysis with the KCCK 0GG1 lyase-deficient mutant demonstrated that agonists do not stimulate the glycosylase reaction, increased amounts of released bases observed in this assay can be interpreted as an enhanced rate of enzyme turnover.Calf thymus DNA in a N2O-saturated buffered aqueous solution was y-irradiated in a60Co-y source at a dose of 5 Gy and then dialyzed. Unirradiated control samples were also dialyzed. Aliquots of 50 pg of DNA samples were dried in a SpeedVac. For each data point, a triplicate of 50 pg of DNA samples were supplemented with aliquots of FapyG-13C,15N2 and 8- oxoG15Ns as internal standards. The samples were then dissolved in 50 pL of an incubation buffer consisting of 50 mM phosphate buffer (pH 7.4), 100 mM KCI, 1 mM EDTA, and 0.1 mM dithiothreitol. The samples were incubated as described below at 37 °C. Control unirradiated samples without OGG1 ± agonists were also incubated. After incubations, an aliquot of 125 pL ethanol was added to the samples to precipitate DNA and to stop the reaction. The samples were kept at -25 °C for 60 min. After centrifugation, the supernatant fractions were separated, lyophilized, derivatized by trimethylsilylation and then analyzed by GC-MS / MS using multiple reaction monitoring as described previously [2],Specifically, reactions (10 min) were performed with various concentrations of OGG1 to establish limiting enzyme conditions for the excision of 8-oxoG (Figure 14A) and FapyG (Figure 15A). Limiting enzyme OGG1 concentrations facilitated a dynamic window for observation of stimulated OGG1 activity. OGG1 agonists were tested at concentrations 2-fold higher than their respective ECso concentrations, which is comparable with the lowest concentration that provided maximum stimulation of OGG1 activity in the previously described fluorescence-based DNA cleavage assays with 8-oxoG-containing substrate. In 10-min reactions with 2 pg of OGG1 , significantly more 8-oxoG was excised from DNA by OGG1 in the presence of F01 , F02, F26, F50, F51 and F55 relative to the DMSO control reaction (Figure 14B). F29, F49 and F58 did not increase the amount of 8-oxoG excised by OGG1 (Figure 14B). Under the same conditions, F26 and F51 significantly increased the amount of FapyG excised from DNA relative to the OGG1DMSO control (Figure 15B). TH10785 significantly inhibited the amount of 8-oxoG and FapyG excised by 0GG1 (Figure 14B; 15B). Additionally, F58 significantly inhibited the amount of FapyG excised by 0GG1 (Figure 15B).F01 , F02, F50, and F55 significantly increased the release of 8-oxoG, but not the release of FapyG by 0GG1 (Figure 14B; 15B). The substrate-specific activity of these agonists may be explained by the preferential affinity of 0GG1 for 8-oxoG lesions over FapyG lesions and the greater abundance of 8-oxoG relative to FapyG in this DNA. With these factors in mind, it is plausible that an increased rate of 0GG1 turnover will not be reflected in the amount of FapyG excised from DNA by 0GG1 . Thus, the observed increase in the amount of 8-oxoG excised from DNA by 0GG1 in the presence of F01 , F02, F26, F50, F51 and F55 relative to the DMSO remains consistent with interpretation that agonist provide increased rate of 0GG1 turnover. The inhibition of OGG 1 -catalyzed base release by F58 and TH10785 could indicate that the released 8-oxoG or FapyG remains bound to 0GG1 in the presence of these agonists thus preventing detection of these bases by GC-MS / MS. Alternatively, if F58 and TH 10785 remain tightly bound in the active site of OGG1 turnover could be prevented.OGG1 agonists protect against paraquat-induced cytotoxicityConditions of oxidative stress can be modeled in human cell lines through chemical treatment. Paraquat (PQ) is an herbicide that exerts toxic effects through production of superoxide anions in the mitochondria

[0072] , We hypothesized that agonists could mitigate the impact of paraquat-induced cytotoxicity by stimulating OGG1 turnover and thus, enhancing the removal of oxidatively-induced lesions from the nuclear and mitochondrial genomes.The human leukemia cell line Kasumi-1 was generously provided by Dr. Jeffery Tyner, OHSU. The Kasumi-1 cell line is characterized by RUNX1-RUNX1T1 fusion and reduced levels of nuclear OGG1

[0073] , Kasumi-1 cells were cultured under sterile conditions in T25 and T75 flasks (Greiner Bio-One) using RPMI 1640 culture media (HyClone) supplemented with 20% fetal bovine serum (FBS; Corning). Kasumi-1 cells were maintained in suspension culture at density of 0.5 x 106- 1.5 x 106cells / mL in a humidified ambient oxygen incubator at 37 °C with 5% CO2. Cells were counted using a hemocytometer and trypan blue exclusion. Kasumi-1 cells were routinely tested for mycoplasma contamination.Initially, toxicities of paraquat and selected OGG1 agonists for the Kasumi-1 cell line were established individually. Exponentially growing Kasumi-1 cells were seeded in 96 well plates at 10,000 cells per well in 90 pl of RPMI-1640 media and incubated overnight at 37 °Cand 5% CO2. Cells were treated with increasing concentrations of agonists (0 - 10 pM) or paraquat (0 - 500 pM) by adding 10 pl of OGG1 agonists or paraquat diluted in culture media to a concentration 10-fold higher than the final concentration. All treatments were performed in technical triplicates. DMSO concentration was held constant at 0.1 % (v / v) between agonist concentrations. After 72 hours at 37 °C and 5% CO2, metabolic activity was assayed by adding 10 pl of AlamarBlue to each well and incubating cells for five hours. Fluorescence was measured on a TECAN INFINITE M NANO plate reader using a 545 nm (9 nm bandwidth) excitation filter and a 590 nm (20 nm bandwidth) emission filter. Fluorescence readings from technical triplicate wells were averaged and the background fluorescence of culture media alone was subtracted. The experimental wells containing agonist treated cells were normalized to control cells treated with 0.1% DMSO. The experimental wells containing paraquat treated cells were normalized to untreated control cells. All cytotoxicity assays were performed in biological triplicates. Data were analyzed using Graph Pad Prism software.Paraquat treatment of Kasumi-1 cells resulted in decreased metabolic activity in a dosedependent manner with a D50 of -200 pM (Figure 16A). Treatment of cells with F01, F49, F50, F55, F58 and F59 at concentrations up to 10 pM resulted in no or minimal reduction in metabolic activity relative to control cells (Figure 16B). Treatment of cells with F51 sharply reduced metabolic activity at concentrations above 2.5 pM with no metabolic activity detected in cells treated with 10 pM F51 (Figure 16B). Treatment of cells with F50 at 10 pM and F51 at 2.5 pM resulted in increased metabolic activity relative to control cells (Figure 16B). F51 and F49 showed limited solubility in aqueous culture media at concentrations above 100 pM. None of the agonists reduced the Alamarblue fluorescence on its own (data not shown).For combination treatments of paraquat and agonists, exponentially growing Kasumi-1 cells were seeded as described above. Cells were treated with agonists and 3 h later with paraquat. Treatments were performed by adding 10 pl of agonist compounds diluted in culture media to 10-fold the final concentration to each well in technical triplicate. DMSO was held constant at a final concentration of 0.1% (v / v) between agonist concentrations. After 3 hours, cells were treated with paraquat at a final concentration of 250 pM. After 72 h at 37 °C and 5% CO2, metabolic activity was assayed by AlamarBlue as described above. The metabolic activity of cells treated with 250 pM paraquat and 10 pM F49, F50, F58 or F59 was significantly increased as compared to cells treated with 250 pM paraquat and DMSO (Figure 16C). F51 significantly enhanced metabolic activity at a 250 nM concentration (Figure 16C). The metabolic activity of cells treated with F01 and 250 pM paraquat trended to be higher than that of cellstreated with 250 pM paraquat but the difference was not statistically significant (p = 0.0915).F55 did not increase metabolic activity of cells treated with paraquat relative to control. F49, F50 and F51 offered the most robust protection of paraquat-induced cytotoxicity with ~2-fold enhancement of metabolic activity compared to the control.TABLES 1-7. Structure activity relationshipsTable 1: Ri phenylCompound R2Table 2: Ri 4-OH-phenylTable 3: Ri halogenated phenylTable 4: Ri 2,4-dichloro phenylTable 5: Ri CH2-0-phenyl halogensAfold 8oxoGTable 6: R1 pyridylAfold 8oxoGCompound R2R3 R4 RsTable 7: OtherREFERENCE TO SEQUENCE LISTINGThe nucleic acid sequences described herein are shown using standard letter abbreviations, as defined in 37 C.F.R. §1.822. The nucleic acid strands and their complementary strand sequences of each double-stranded nucleic acid substrate are shown in Table #8, as included in embodiments where appropriate. The sequence of each nucleic acid strand in the table is indicated in a 5’ to 3’ direction.Table #8: Nucleic acid sequences of DNA substratesIn particular embodiments, a 17mer DNA strand may include an internal modified base (SEQ ID NOs. 1 , 3, and 6). Underlined nucleotide residue (N), in the appropriate sequences, refers to the nucleotide with a modified base, which may include an 8-oxoguanine, thymine glycol, or AP (apurinic / apyrimidinic) site. It is to be understood that although Table #8 shows nucleotide with a modified base as underlined residue “N”, it may also be represented by nucleotide residue “X” in figures 4A, 6A, 6D, 7A, 8A, 9A, 10A, and 11A. The nucleotide residues “X” and “N” may be used interchangeably throughout these figures.In particular embodiments herein, the nucleic acid strands may include a 5’ fluorescentabel, e.g., TAMRA (SEQ ID NOs. 1 , 3, and 6). Other example fluorophores may be used by one skilled in the art, including fluorescein isothiocyanate (FITC), hydroxy coumarin, Aminocoumarin, methoxycoumarin, Cascade Blue, Pacific Blue, Pacific Orange, 3-hydroxyisonicotinaldehyde, Lucifer yellow, NBD, R-Phycoerythrin (PE), PE-Cy5 conjugates, PE-Cy7 conjugates, Red 613, PerCP, TruRed, FluorX, BODIPY-FL, G-Dye100, G-Dye200, G-Dye300, G-Dye400, Cy2, Cy3, Cy3B, Cy3.5, Cy5, Cy5.5, Cy7, TRITC, X-Rhodamine, lissamine Rhodamine B, Texas Red, Allophycocyanin (APC), or APC-Cy7.

[0001] In some embodiments herein, the complementary strands may include a 3’ quencher e.g., BHQ2 (SEQ ID NOs. 2 and 4). Other example quenchers may be used by one skilled in the art, including BHQ1 , Eclipse, Dabcyl, Iowa Black FQ / RQ, and Tide Quenchers.SEQUENCE LISTING

[0001] The Sequence Listing is submitted as an XML file in the form of the file named “Sequence. xml” (10,000 bytes), which was created on May 15, 2025, which is incorporated by reference herein.REFERENCES1. Sampath, et al., Regulation of DNA glycosylases and their role in limiting disease. Free Radic Res, 2012. 46(4): p. 460-78.2. Dizdaroglu, et al., Measurement of oxidatively induced DNA damage and its repair, by mass spectrometric techniques. Free Radic Res, 2015. 49(5): p. 525-48.3. Dizdaroglu, et al., Repair of oxidatively induced DNA damage by DNA glycosylases: Mechanisms of action, substrate specificities and excision kinetics. Mutat Res Rev Mutat Res, 2017. 771 : p. 99-127.4. Lloyd, R.S., Complex Roles of NEIL1 and OGG1: Insights Gained from Murine Knockouts and Human Polymorphic Variants. DNA, 2022. 2(4): p. 279-301.5. Sahan, et al., The Pivotal Role of DNA Repair in Infection Mediated-lnflammation and Cancer. Front Microbiol, 2018. 9: p. 663.6. Tiwari, V. and D.M. Wilson, 3rd, DNA Damage and Associated DNA Repair Defects in Disease and Premature Aging. Am J Hum Genet, 2019. 105(2): p. 237-257.7. Wallace, S.S., Base excision repair: a critical player in many games. DNA Repair (Amst), 2014. 19: p. 14-26.8. Chevillard, et al., Mutations in OGG1 , a gene involved in the repair of oxidative DNA damage, are found in human lung and kidney tumours. Oncogene, 1998. 16(23): p. 3083-6.9. Lu, et al., A mammalian DNA repair enzyme that excises oxidatively damaged guanines maps to a locus frequently lost in lung cancer. Curr Biol, 1997. 7(6): p. 397-407.10. Okasaka, T., et al., hOGG1 Ser326Cys polymorphism and risk of lung cancer by histological type. J Hum Genet, 2009. 54(12): p. 739-45.Paz-Elizur, T., et al., DNA repair of oxidative DNA damage in human carcinogenesis: potential application for cancer risk assessment and prevention. Cancer Lett, 2008. 266(1): p. 60-72. 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Boldogh, 8-Oxo-7,8-dihydroguanine: links to gene expression, aging, and defense against oxidative stress. Free Radic Biol Med, 2010. 49(4): p. 587-96. Radak, Z., et al., Age-dependent changes in 8-oxoguanine-DNA glycosylase activity are modulated by adaptive responses to physical exercise in human skeletal muscle. Free Radic Biol Med, 2011. 51(2): p. 417-23.Radak, Z., et al., Exercise training decreases DNA damage and increases DNA repair and resistance against oxidative stress of proteins in aged rat skeletal muscle. Pflugers Arch, 2002. 445(2): p. 273-8. Sampath, H., et al., Variable penetrance of metabolic phenotypes and development of high-fat diet-induced adiposity in N El L1 -deficient mice. Am J Physiol Endocrinol Metab, 2011. 300(4): p. E724-34. Sampath, H. and R.S. Lloyd, Roles of OGG1 in transcriptional regulation and maintenance of metabolic homeostasis. DNA Repair (Amst), 2019. 81 : p. 102667. Sampath, H., et al., 8-Oxoguanine DNA glycosylase (OGG1) deficiency increases susceptibility to obesity and metabolic dysfunction. PLoS One, 2012. 7(12): p. e51697. Vartanian, V., et al., The metabolic syndrome resulting from a knockout of the NEIL1 DNA glycosylase. Proc Natl Acad Sci U S A, 2006. 103(6): p. 1864-9. Daimon, M., et al., Association of the Ser326Cys polymorphism in the OGG1 gene with type 2 DM. Biochem Biophys Res Commun, 2009. 386(1): p. 26-9. Thameem, F., et al., The Ser(326)Cys polymorphism of 8-oxoguanine glycosylase 1 (OGG1) is associated with type 2 diabetes in Mexican Americans. Hum Hered, 2010. 70(2): p. 97-101. Komakula, S.S.B., et al., The DNA repair protein OGG1 protects against obesity by altering mitochondrial energetics in white adipose tissue. Sci Rep, 2018. 8(1): p. 14886. Burchat, N., et al., Maternal transmission of human OGG1 protects mice against genetically- and diet-induced obesity through increased tissue mitochondrial content. 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Marnett, L.J., Oxyradicals and DNA damage. Carcinogenesis, 2000. 21(3): p. 361-70. Rachek, L.I., et al., Conditional targeting of the DNA repair enzyme hOGG1 into mitochondria. J Biol Chem, 2002. 277(47): p. 44932-7. Rachek, L.I., et al., Palmitate induced mitochondrial deoxyribonucleic acid damage and apoptosis in I6 rat skeletal muscle cells. Endocrinology, 2007. 148(1): p. 293-9. Rachek, L. I., et al., Role of nitric oxide-induced mtDNA damage in mitochondrial dysfunction and apoptosis. Free Radic Biol Med, 2006. 40(5): p. 754-62. Kim, J., et al., Mitochondrial DNA damage is involved in apoptosis caused by pro- inflammatory cytokines in human OA chondrocytes. Osteoarthritis Cartilage, 2010. 18(3): p. 424-32. Ricci, C., et al., Mitochondrial DNA damage triggers mitochondrial-superoxide generation and apoptosis. Am J Physiol Cell Physiol, 2008. 294(2): p. C413-22. 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Mizuno, Y., et al., Deficiency of MTH1 and / or OGG1 increases the accumulation of 8- oxoguanine in the brain of the App(NL-G-FZNL-G-F) knock-in mouse model of Alzheimer's disease, accompanied by accelerated microgliosis and reduced anxiety-like behavior. Neurosci Res, 2022. 177: p. 118-134. Sliwinska, A., et al., The levels of 7,8-dihydrodeoxyguanosine (8-oxoG) and 8- oxoguanine DNA glycosylase 1 (OGG1) - A potential diagnostic biomarkers of Alzheimer's disease. J Neurol Sci, 2016. 368: p. 155-9.Lillenes, M.S., et al., Altered DNA base excision repair profile in brain tissue and blood in Alzheimer's disease. Mol Brain, 2016. 9(1): p. 61. Dincer, Y., et al., DNA repair gene OGG1 polymorphism and its relation with oxidative DNA damage in patients with Alzheimer's disease. Neurosci Lett, 2019. 709: p. 134362. Jacob, K.D., et al., Alzheimer's disease-associated polymorphisms in human OGG1 alter catalytic activity and sensitize cells to DNA damage. Free Radic Biol Med, 2013. 63: p. 115-25. Miller, M.B., et al., Somatic genomic changes in single Alzheimer's disease neurons. Nature, 2022. 604(7907): p. 714-722. Kennedy, L.J., et al., Quantitation of 8-oxoguanine and strand breaks produced by four oxidizing agents. Chem Res Toxicol, 1997. 10(4): p. 386-92. Swerdlow, et al., The Alzheimer's disease mitochondrial cascade hypothesis: progress and perspectives. Biochim Biophys Acta, 2014. 1842(8): p. 1219-31. Oka, S., et al., Two distinct pathways of cell death triggered by oxidative damage to nuclear and mitochondrial DNAs. EMBO J, 2008. 27(2): p. 421-32. Sheng, Z.H. and Q. Cai, Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration. Nat Rev Neurosci, 2012. 13(2): p. 77-93. Edland, S.D., et al., Increased risk of dementia in mothers of Alzheimer's disease cases: evidence for maternal inheritance. Neurology, 1996. 47(1): p. 254-6. Coskun, P.E., M.F. Beal, and D.C. 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Claims

1. What is claimed:

1. A method of treatment in a human subject of a disease or condition responsive to agonism of 0GG1 glycosylase activity, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a compound of selected from the group of:or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

2. The method of treatment of Claim 1 , wherein the disease or condition responsive to agonism of 0GG1 glycosylase activity treated in the subject in need thereof is metabolic syndrome.

3. The method of treatment of Claim 1 , wherein the disease or condition responsive to agonism of 0GG1 glycosylase activity treated in the subject in need thereof is dyslipidemia4. The method of treatment of Claim 1 , wherein the disease or condition responsive to agonism of 0GG1 glycosylase activity treated in the subject in need thereof is selected from the group of non-small cell lung cancer, head and neck cancer, adenocarcinoma of the gastric cardia, astrocytoma, breast cancer, esophageal cancer, colorectal cancer, and kidney cancer.

5. The method of treatment of Claim 1 , wherein the disease or condition responsive to agonism of 0GG1 glycosylase activity treated in the subject in need thereof is selected from the group of Parkinson’s Disease, Alzheimer’s Disease, Huntington’s Disease, Mild Cognitive Impairment, Diffuse Lewy Body Disease, vascular dementia, Frontotemporal Dementia, Dystrophic Neurites, Young-Onset Dementia, and HIV-associated neurocognitive disorder.

6. A compound of Formula (I):wherein:X is selected from the group of cyclopentyl and isopropylRi, R2, and R3are independently selected from the group of H, C1-C4 alkyl, -O-C1-C4 alkyl, halogen, CF3,-OH, CN, C(=O)R5, NO2, CO2H, CO2R5, S(O)2OH, S(O)2OR5, NH3, N+R5, and -C(=O)CI;R4is selected from the group of H, CN, halogen, CF3, NO2, NH3, and C1-C4 alkyl;Rs is selected from the group of C1-C4 alkyl, C3-Ce cycloalkyl, and -CH2-C3-Ce cycloalkyl; with the proviso that at least one of R1, R2, and R3is not H; and with the proviso that, when X is cyclopropyl, one of R1, R2, and R3is a fluoro substituent in the 2-position of the phenyl ring and R4is 5-CN, then neither of R1, R2, and R3is a fluoro or a chloro substituent in the 4-position of the phenyl ring; and with the proviso that, when X is cyclopropyl and each of R1, R2, and R3is H or when X is cyclopropyl and two of R1, R2, and R3are H and one of R1, R2, and R3is methyl in the 4-position of the phenyl ring, then R5is not 5-CN; and with the proviso that, when X is isopropyl, one of R1, R2, and R3is H and R5 is 5-CN, then the remaining two of R1, R2, and R3do not create a substitution pattern on the phenyl ring selected from the group of 2-chloro-4-trifluoromethyl, 2-chloro-4-fluoro, 2-chloro-4-bromo, 2- chloro-4-chloro, 2-fluoro-4-fluoro, 2-fluoro-4-chloro, 2-bromo-4-chloro, and 2-bromo-4-fluoro; andwith the proviso that, when X is isopropyl, two of Ri, R2, and R3 are H and Rs is 5-CN, then the remaining of R1, R2, and R3does not create a substitution pattern on the phenyl ring selected from the group of 2-trifluoromethyl and 4-chloro; and with the proviso that, when X is isopropyl, each of R1, R2, and R5is H and R3is in the 3- position on the phenyl ring, R3 is not selected from the group of butoxy, propoxy, pentyloxy, and hexyloxy; and with the proviso that, when X is isopropyl, Rs is H, and 1, R2, and R3, along with the phenyl ring to which they are bound, does not create a 3,4,5-trimethoxyphenyl group; and with the proviso that, when X is isopropyl, R5is H, R1, R2, and R3, along with the phenyl ring to which they are bound, do not create a 4-chlorophenyl group or a 2,4-dichlorophenyl group; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

7. The compound of Claim 6, wherein:X is cyclopentyl;R4is selected from the group of H, CN, halogen, CF3, NO2, NH3, and Ci-C2alkyl;R1 , R2, and R3are independently selected from the group of H, Ci-C2alkyl, -O-Ci-C2alkyl, halogen, CF3,-OH, CN, C(=O)R5, NO2, CO2H, CO2R5, S(O)2OH, S(O)2OR5, NH3, N+R5, and -C(=O)CI;R4is selected from the group of H, CN, halogen, CF3, NO2, NH3, and C1-C2 alkyl;Rs is selected from the group of Ci-C2alkyl; with the proviso that at least one of R1, R2, and R3is not H; and with the proviso that, when one of 1, R2, and R3is a fluoro substituent in the 2-position of the phenyl ring and R4is 5-CN, then neither of R1, R2, and R3is a fluoro or a chloro substituent in the 4-position of the phenyl ring; and with the proviso that, when each of R1, R2, and R3is H or when two of R1 , R2, and R3are H and one of R1, R2, and R3is methyl in the 4-position of the phenyl ring, then R5is not 5-CN;or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

8. The compound of Claim 6, wherein:X is cyclopentyl;R4 is selected from the group of H, CN, CF3, and methyl;R1, R2, and R3 are independently selected from the group of H, halogen, CF3,-OH, CN, C(=O)R5, NO2, CO2H, CO2R5, S(O)2OH, S(O)2OR5, NH3, N+R5, and -C(=O)CI;R4 is selected from the group of H, CN, halogen, CF3, NO2, NH3, and C1-C2 alkyl;R5is selected from the group of C1-C2 alkyl; with the proviso that at least one of R1, R2, and R3is not H; and with the proviso that, when one of R1, R2, and R3is a fluoro substituent in the 2-position of the phenyl ring and R4is 5-CN, then neither of R1, R2, and R3is a fluoro or a chloro substituent in the 4-position of the phenyl ring; and with the proviso that, when each of R1, R2, and R3is H or when two of R1, R2, and R3are H and one of R1, R2, and R3is methyl in the 4-position of the phenyl ring, then R5is not 5-CN; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

9. The compound of Claim 6, wherein:X is cyclopentyl;R4is selected from the group of H, CN, halogen, CF3, NO2, NH3, and C1-C3 alkyl;R1, R2, and R3 are independently selected from the group of H, C1-C3 alkyl, -O-C1-C3 alkyl, halogen, CF3,-OH, CN, C(=O)R5, NO2, CO2H, CO2R5, S(O)2OH, S(O)2OR5, NH3, N+R5, and -C(=O)CI;R4is selected from the group of H, CN, halogen, CF3, NO2, NH3, and C1-C3 alkyl;R5is selected from the group of C1-C3 alkyl, C3-C6 cycloalkyl, and -CH2-C3-C6 cycloalkyl; with the proviso that at least one of R1, R2, and R3is not H; and with the proviso that, when one of R1, R2, and R3is a fluoro substituent in the 2-position of the phenyl ring and R4is 5-CN, then neither of R1, R2, and R3is a fluoro or a chloro substituent in the 4-position of the phenyl ring; and with the proviso that, when each of R1, R2, and R3 is H or when two of R1, R2, and R3are H and one of R1, R2, and R3 is methyl in the 4-position of the phenyl ring, then R5 is not 5-CN; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

10. The compound of Claim 6, wherein R1, R2, and R3are independently selected from the group of H, C1-C2 alkyl, and halogen; with the proviso that at least one of R1, R2, and R3is halogen; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

11. The compound of Claim 6, wherein:X is isopropyl;R1, R2, and R3are independently selected from the group of H, C1-C4 alkyl, -O-C1-C4 alkyl, halogen, CF3,-OH, CN, C(=O)R5, NO2, CO2H, CO2R5, S(O)2OH, S(O)2OR5, NH3, N+R5, and -C(=O)CI;R4is selected from the group of H, CN, halogen, CF3, NO2, NH3, and C1-C4 alkyl;Rs is selected from the group of C1-C4 alkyl, C3-Ce cycloalkyl, and -CH2-C3-C6 cycloalkyl; with the proviso that, when one of R1, R2, and R3is H and R5is 5-CN, then the remaining two of R1, R2, and R3do not create a substitution pattern on the phenyl ring selected from the group of 2-chloro-4-trifluoromethyl, 2-chloro-4-fluoro, 2-chloro-4-bromo, 2-chloro-4-chloro, 2- fluoro-4-fluoro, 2-fluoro-4-chloro, 2-bromo-4-chloro, and 2-bromo-4-fluoro; andwith the proviso that, when two of Ri, R2, and R3 are H and Rs is 5-CN, then the remaining of R1, R2, and R3does not create a substitution pattern on the phenyl ring selected from the group of 2-trifluoromethyl and 4-chloro; and with the proviso that, when each of R1, R2, and R5is H and R3is in the 3-position on the phenyl ring, R3 is not selected from the group of butoxy, propoxy, pentyloxy, and hexyloxy; and with the proviso that, when Rs is H, R1, R2, and R3, along with the phenyl ring to which they are bound, does not create a 3,4,5-trimethoxyphenyl group; and with the proviso that, when each of R1, R2, and Rs is H and R3 is in the 3-position on the phenyl ring, R3is not selected from the group of butoxy, propoxy, pentyloxy, and hexyloxy; and with the proviso that, when R5is H, R1, R2, and R3, along with the phenyl ring to which they are bound, do not create a 4-chlorophenyl group or a 2,4-dichlorophenyl group; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

12. The compound of Claim 6, wherein:X is isopropyl;R4 is selected from the group of H, CN, CF3, and methyl;R1, R2, and R3are independently selected from the group of H, halogen, CF3,-OH, CN, C(=O)R5, NO2, CO2H, CO2R5, S(O)2OH, S(O)2OR5, NH3, N+RS, and -C(=O)CI;R4is selected from the group of H, CN, halogen, CF3, NO2, NH3, and C1-C2 alkyl;Rs is selected from the group of Ci-C2alkyl; with the proviso that, when one of R1, R2, and R3is H and R5is 5-CN, then the remaining two of R1, R2, and R3do not create a substitution pattern on the phenyl ring selected from the group of 2-chloro-4-trifluoromethyl, 2-chloro-4-fluoro, 2-chloro-4-bromo, 2-chloro-4-chloro, 2- fluoro-4-fluoro, 2-fluoro-4-chloro, 2-bromo-4-chloro, and 2-bromo-4-fluoro; and with the proviso that, when two of R1, R2, and R3are H and R5is 5-CN, then the remaining of R1, R2, and R3does not create a substitution pattern on the phenyl ring selected from the group of 2-trifluoromethyl and 4-chloro; andwith the proviso that, when each of Ri, R2, and Rs is H and R3 is in the 3-position on the phenyl ring, R3is not selected from the group of butoxy, propoxy, pentyloxy, and hexyloxy; and with the proviso that, when R5is H, R1, R2, and R3, along with the phenyl ring to which they are bound, does not create a 3,4,5-trimethoxyphenyl group; and with the proviso that, when R5is H, 1, R2, and R3, along with the phenyl ring to which they are bound, do not create a 4-chlorophenyl group or a 2,4-dichlorophenyl group; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

13. The compound of Claim 6, wherein:X is isopropyl;R1 is selected from the group of H, Ci-C3alkyl, and halogen;R2is selected from the group of H, Ci-C3alkyl, and halogen;R3is selected from the group of H, Ci-C3alkyl, and halogen; and 4 is H; with the proviso that at least one of R1, R2, and R3is halogen; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

14. The compound of Claim 6 selected from the group of:pharmaceutically acceptable salt, co- crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

15. A method of treatment in a human subject of a disease or condition responsive to agonism of OGG1 glycosylase activity, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a compound of Claim 6, or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

16. The method of treatment of Claim 15, wherein the disease or condition responsive to agonism of 0GG1 glycosylase activity treated in the subject in need thereof is metabolic syndrome.

17. The method of treatment of Claim 15, wherein the disease or condition responsive to agonism of 0GG1 glycosylase activity treated in the subject in need thereof is dyslipidemia.

18. The method of treatment of Claim 15, wherein the disease or condition responsive to agonism of OGG1 glycosylase activity treated in the subject in need thereof is selected from the group of non-small cell lung cancer, head and neck cancer, adenocarcinoma of the gastric cardia, astrocytoma, breast cancer, esophageal cancer, colorectal cancer, and kidney cancer.

19. The method of treatment of Claim 15, wherein the disease or condition responsive to agonism of OGG1 glycosylase activity treated in the subject in need thereof is selected from the group of Parkinson’s Disease, Alzheimer’s Disease, Huntington’s Disease, Mild Cognitive Impairment, Diffuse Lewy Body Disease, vascular dementia, Frontotemporal Dementia, Dystrophic Neurites, Young-Onset Dementia, and HIV-associated neurocognitive disorder.

20. The method of Claim 15, wherein the compound of Claim 6 is selected from the grouppharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

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