Therapeutic compounds and methods

Abstract

The invention provides a compound of Formula (I)-(VIII): or a salt thereof, wherein R1-R2 and ring A have any of the values described in the specification, as well as compositions comprising a compound of Formula (I)-(VIII) or a salt thereof. The compounds are useful as neuroprotective agents.

Description

[0001] THERAPEUTIC COMPOUNDS AND METHODS CROSS-REFERENCE TO RELATED APPLICATION This application claims priority to United States Provisional Application Number 63 / 534,738 that was filed on August 25, 2023. The entire content of the applications referenced above is hereby incorporated by reference herein. STATEMENTREGARDINGFEDERALLYSPONSOREDRESEARCHThis invention was made with government support under GM138050 awarded by National Institutes of Health. The government has certain rights in the invention. BACKGROUND Numerous insults, both endogenous (e.g., Glu) and exogenous (e.g., pesticides), compromise function of the nervous system by producing an imbalance in reactive oxygen species (ROS) and thereby pose as risk factors for cell injury and later disease (Lau, A.; Tymianski, M., Pflugers Arch 2010, 460 (2), 525-542; Lewerenz, J.; Maher, P.. Front Neurosci 2015, 9, 469; and Nandipati, S.; Litvan, I., Int J Environ Res Public Health 2016, 13 (9)). In particular, extracellular levels of the excitatory neurotransmitter Glu increase in response to injury, such as stroke, as well as several diseases, including amyotrophic lateral sclerosis (ALS), epilepsy, and Alzheimer’s disease (Onaolapo, A. Y.; Onaolapo, O. J., Curr Neuropharmacol 2021, 19 (7), 1069-1089; Belov Kirdajova, D., et al., Front Cell Neurosci 2020, 14, 51; and Barker-Haliski, M.; White, H. S., Cold Spring Harb Perspect Med 2015, 5 (8), a022863). Additionally, aberrant Glu levels and signaling represents a mechanistic component of damage to the nervous system following exposure to chemical threats such as organophosphate nerve agents (Pearson, J. N.; Patel, M., Annals of the New York Academy of Sciences 2016, 1378 (1), 17-24). The aberrant synaptic signaling via Glu leads to what is referred to as excitotoxicity, producing excessive levels of ROS and several other damaging downstream mediators (e.g., inflammatory) (Dong, X. X. , D., et al., Acta Pharmacol Sin 2009, 30 (4), 379-387; and Brandes, M. S.; Gray, N. E., ASN Neuro 2020, 12, 1759091419899782). In addition to Glu, numerous environmental insults, such as pesticides, are also known to induce oxidative stress and cause injury to neurons (Radad, K., et al., Folia Neuropathol 2019, 57 (4), 317-326). An effective cellular mechanism of defense against elevated oxidative stress is through activation of the Kelch-like ECH-associated protein 1 (Keap1), nuclear factor erythroid 2-related factor 2 (Nrf2), and antioxidant response elements (ARE) signaling pathway (Figure 1) (Johnson, J. A., et al., Ann N Y Acad Sci 2008, 1147, 61-69). Under normal conditions, Keap1 exists as a homodimer and forms a complex with Nrf2 with two different affinity binding sites on the Neh2 domain of Nrf2 (ETGE motif and DLG motif). The ETGE motif has stronger binding to Keap1 when compared to the DLG motif and is responsible for recruitment of Nrf2 by Keap1. The DLG motif of the Neh2 domain is responsible for locking in the correct position for ubiquitin signaling for Nrf2 degradation. While complexed together, Keap1 suppresses the activity of Nrf2 by associating with a functional E3 ubiquitin ligase complex by the scaffold protein, Cullin3 (Cul3). Cul3 then facilitates Rbx1-mediated polyubiquitination of Nrf2, thus resulting in the degradation of Nrf2 via 26S proteasome (Johnson, J. A., et al., Ann N Y Acad Sci 2008, 1147, 61-69; Winkel, A. F. , et al., J Biol Chem 2015, 290 (47), 28446-28455; and Nguyen, T. , et al., J Biol Chem 2009, 284 (20), 13291-13295). Following production of excessive ROS, proximal / adjacent Cys residues of Keap1 are oxidized to disulfides, thus resulting in the release of Nrf2 (Tebay, L. E. , et al., Free Radic Biol Med 2015, 88 (Pt B), 108-146). More specifically, oxidative stress prevents Keap1-Nrf2-Cul3 assembly and thus, Nrf2 ubiquitination (Figure 1) (Yamamoto, M. , et al., Physiol Rev 2018, 98 (3), 1169-1203; and Ma, Q., Annu Rev Pharmacol Toxicol 2013, 53, 401-426). In addition, disruption of the complex can occur by covalent modification of the Cys residues, such as sulforaphane (SFN) as an example, or via non-covalent inhibitors targeting the Nrf2-Keap1 interface (Lee, S.; Hu, L., Med Chem Res 2020, 29 (5), 846-867; and Narayanan, D. , et al., J Med Chem 2022, 65 (21), 14481-14526). Upon Nrf2 release, it first accumulates in the cytosol before translocating into the nucleus. In the nucleus, Nrf2 forms a heterodimer with small musculoaponeurotic fibrosarcoma (sMaf) proteins and binds ARE. Subsequently, this modulates the transcription of a vast array of antioxidant genes as a defense against elevated ROS as well as inhibiting inflammatory events given cross-talk with NF-kB signaling (Brandes, M. S.; Gray, N. E., ASN Neuro 2020, 12, 1759091419899782; Wardyn, J. D. , et al., Biochem Soc Trans 2015, 43 (4), 621-626; and Cuadrado, A. , et al., J Biol Chem 2014, 289 (22), 15244-15258). Due to the vital role of Nrf2 in antioxidant-defense against endogenous and exogenous insults, Nrf2-targeting agents have been investigated extensively over the last several years for the potential to mitigate diseases with oxidative stress and inflammation underlying pathology (Ma, Q., Annu Rev Pharmacol Toxicol 2013, 53, 401-426; and Cuadrado, A. , et al., Nat Rev Drug Discov 2019, 18 (4), 295-317). Several Nrf2 activators are being marketed to treat conditions such as multiple sclerosis and psoriasis, and in various stages of development (preclinical to Phase III) to address other disease states such as ALS, subarachnoid hemorrhage and Friedreich Ataxia (Cuadrado, A. , et al., Nat Rev Drug Discov 2019, 18 (4), 295-317; and Robledinos- Anton, N. , et al., Oxid Med Cell Longev 2019, 2019, 9372182). In addition, Nrf2 activators may have promise to mitigate damage from chemical threats, prophylactically or as post- treatment, agents such as organophosphate nerve agents (Simoni, E. , et al., ACS Chem Neurosci 2017, 8 (7), 1618-1627; and Armada-Moreira, A. , et al., Front Cell Neurosci 2020, 14, 90.). In previous reports, limonoids isolated from Dictamnus dasycarpus, such as fraxinellone, showed notable neuroprotective activity against Glu excitotoxicity and oxidative stress in primary cultured rat cortical cells, although no mechanism was proposed (Yoon, J. S. , et al., J Mol Neurosci 2010, 42 (1), 9-16; and Jeong, G. S. , et al., Arch Pharm Res 2010, 33 (8), 1269- 1275). Currently there is a need for new neuroprotective gents. SUMMARY Compounds were synthesized that proved to better protect against endogenous and exogenous toxicants, when compared to fraxinellone and other limonoid natural products (Yoon, J. S. , et al., J Mol Neurosci 2010, 42 (1), 9-16; and Bailly, C.; Vergoten, G., Pestic Biochem Physiol 2020, 168, 104624). In vitro methods were used to assess the protective activity of the novel compounds against Glu excitotoxicity and whether these compounds mitigated oxidative stress. The compound of Example 1 effectively mitigated oxidative stress at low concentrations through rapid and potent activation of the Nrf2 / Keap1 pathway via a potentially novel mechanism compared to known activators, such as SFN (Lazzara, P. R. , et al., ACS Med Chem Lett 2020, 11 (4), 521-527). These results indicate a novel mechanism of action compared to known Nrf2 activators, which are electrophiles or oxidants that rely on thiol modification (Amoroso, R. , et al., Antioxidants (Basel) 2023, 12 (3)). The compound of Example 1 is resistant to thiol reactivity, thereby conferring stability and minimizing off-target reactions as improved characteristics to be considered for therapeutic development. Accordingly, a compound of Formula (I)-(VIII): or a salt thereof, wherein: R1is H or a (C1-C6)alkyl that can optionally be substituted with one or more groups independently selected from the group consisting of halo; R2is a ring selected from the group consisting of 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocycle, and 6-membered heterocycle, which 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocycle, and 6-membered heterocycle is optionally substituted with one or more groups independently selected from the group consisting of halo, cyano, (C1-C6)alkyl that can optionally be substituted with one or more groups independently selected from the group consisting of halo, and (C1-C6)alkoxy that can optionally be substituted with one or more groups independently selected from the group consisting of halo; R3is H, (C1-C6)alkyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, or a hydroxy protecting group (e.g., trimethylsilyl or tert-butyl-dimethylsilyl); and ring A is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkylthio, and (C1-C6)alkoxycarbonyl, wherein any (C1-C6)alkyl, (C1-C6)alkoxy, (C1- C6)alkanoyl, (C1-C6)alkylthio, and (C1-C6)alkoxycarbonyl is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C1-C6)alkoxy, (C1-C6)alkanoyl, and (C1-C6)alkoxycarbonyl. A pharmaceutical composition comprising a compound of formula (I)-(VIII) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient is provided. A method for producing a neuroprotective effect in an animal (e.g., a mammal such as a human) comprising administering a compound of Formula (I)-(VIII) or a pharmaceutically acceptable salt thereof to the animal is provided. A method for producing neuroprotective activity against Glu excitotoxicity and oxidative stress in an animal (e.g., a mammal such as a human) comprising administering a compound of Formula (I)-(VIII) or a pharmaceutically acceptable salt thereof to the animal is provided. A method for treating multiple sclerosis, psoriasis, ALS, subarachnoid hemorrhage, Parkinson’s disease, Alzheimer’s disease, or Friedreich Ataxia in an animal (e.g., a mammal such as a human) comprising administering a compound of Formula (I)-(VIII) or a pharmaceutically acceptable salt thereof to the animal is provided. A method to mitigate damage from chemical exposure (e.g. exposure to an organophosphate nerve agent) in an animal (e.g., a mammal such as a human) comprising administering a compound of Formula (I)-(VIII) or a pharmaceutically acceptable salt thereof to the animal prophylactically or post exposure is provided. A method to produce neuroprotective activity in an animal comprising activating Nrf2 without a covalent thio-modification is provided. A method to produce neuroprotective activity in an animal comprising activating Nrf2 with an agent that is not an electrophile is provided. A method to activate Nrf2 in a cell comprising contacting the cell with a compound or salt as described herein is provided. A method comprising, activating Nrf2 in a cell by contacting the cell with a Nrf2 activating agent that is not an electrophile is provided. A compound of formula (I)-(VIII) or a pharmaceutically acceptable salt thereof to produce a neuroprotective effect in an animal (e.g., a mammal such as a human) is provided. A compound of formula (I)-(VIII) or a pharmaceutically acceptable salt thereof to produce neuroprotective activity against Glu excitotoxicity and oxidative stress is provided. A compound of formula (I)-(VIII) or a pharmaceutically acceptable salt thereof to for treating multiple sclerosis, psoriasis, ALS, subarachnoid hemorrhage, Parkinson’s disease, Alzheimer’s disease, or Friedreich Ataxia is provided. A compound of formula (I)-(VIII) or a pharmaceutically acceptable salt thereof to mitigate damage from chemical exposure (e.g. exposure to an organophosphate nerve agent) in an animal (e.g., a mammal such as a human) comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof to the animal prophylactically or post exposure is provided. The use of a compound of formula (I)-(VIII) or a pharmaceutically acceptable salt thereof to prepare a medicament useful to produce a neuroprotective effect in an animal (e.g., a mammal such as a human) is provided. The use of a compound of formula (I)-(VIII) or a pharmaceutically acceptable salt thereof to prepare a medicament useful to to produce neuroprotective activity against Glu excitotoxicity and oxidative stress in an animal (e.g., a mammal such as a human) is provided. The use of a compound of formula (I)-(VIII) or a pharmaceutically acceptable salt thereof to prepare a medicament useful for treating multiple sclerosis, psoriasis, ALS, subarachnoid hemorrhage, Parkinson’s disease, Alzheimer’s disease, or Friedreich Ataxia in an animal (e.g., a mammal such as a human) is provided. The use of a compound of formula (I)-(VIII) or a pharmaceutically acceptable salt thereof to prepare a medicament useful to mitigate damage from chemical exposure (e.g. exposure to an organophosphate nerve agent) in an animal (e.g., a mammal such as a human) prophylactically or post exposure is provided. Processes and intermediates disclosed herein that are useful for preparing a compound of Formula (I)-(VIII) or a salt thereof are also provided. BRIEF DESCRIPTION OF DRAWINGS Figure 1 illustrates how Nrf2 / Keap1 signaling mediates antioxidant response. Activation and release of Nrf2 occurs via the: 1) reaction of an electrophile with Keap1 thiols, such as SFN; 2) oxidation of Keap1 thiols via ROS; or 3) non-covalent disruption of the Keap1-Nrf2 interaction. Upon dissociation from Keap1, Nrf2 translocates to the nucleus and binds with sMaf to the antioxidant response element (ARE), yielding expression of genes involved in xenobiotic metabolism, ROS mitigation, and GSH synthesis. The interaction of Nrf2 with sMaf and the ARE can be inhibited by ML-385. Figure created with BioRender. Image modified from Curtis D. Klassen, John B. Watkins III: Casarett and Doull’s Essentials of Toxicology, 4e. Figures 2A-2B. MTT analysis to assess cell viability in (A) PC12 and (B) SH-SY5Y cells treated with Glu for 24 hours. Viability is shown as a percent of PC12 or SH-SY5Y cells left untreated. Error bars show standard deviation (SD) for n=3 replicates. **p < 0.05, ***p< 0.01 for ordinary one-way ANOVA comparing Glu-treated PC12 and SH-SY5Y cells to untreated cells with Dunnett correction for multiple comparisons. Figures 3A-3F. Pre-treatment with the compound of Example 1 afforded protection against Glu-induced oxidative toxicity whereas pre-treatment with fraxinellone or Comparison Compound did not. MTT analysis to assess cell viability of (A) PC12 and (B) SH-SY5Y cells pre-treated with a range of doses of fraxinellone for 30 minutes and then Glu (100 ^M) for 24 hours. MTT analysis to assess cell viability of (C) PC12 and (D) SH-SY5Y cells pre-treated with a range of doses of Comparison Compound for 30 minutes and then Glu (100 ^M) for 24 hours. MTT analysis to assess cell viability of (E) PC12 and (F) SH-SY5Y cells pre-treated with a range of concentrations of the compound of Example 1 for 30 minutes and then Glu (100 ^M) for 24 hours. Viability is shown as a percent of PC12 or SH-SY5Y cells left untreated. Error bars show standard deviation (SD) for n=2 replicates. *p < 0.05, **p< 0.01, ***p< 0.0005, ****p<0.0001 for ordinary one-way ANOVA comparing Glu-treated PC12 and SH-SY5Y cells to untreated cells with Dunnett correction for multiple comparisons. Figure 4. Pre-treatment with the compound of Example 1 afforded protection against Glu-induced oxidative toxicity whereas pre-treatment with Comparison Compound did not. Cell-Titer Glo assay to assess viability of PC12 cells pre-treated with a range of doses of the compound of Example 1 (four center) or Comparison Compound (four right) for 30 minutes and then Glu (100 ^M) for 24 hours. Viability is shown as a percent of PC12 cells left untreated. Error bars show standard deviation (SD) for n=5 replicates. ****p<0.0001 for ordinary one-way ANOVA comparing Glu-treated PC12 cells to untreated cells with Dunnett correction for multiple comparisons. Figures 5A-5C. Pre-treatment with the compound of Example 1 afforded protection against rotenone-induced oxidative toxicity whereas pre-treatment with Comparison Compound did not. MTT analysis to assess cell viability of PC12 treated with a range of doses of rotenone for 12 hours (A). MTT analysis to assess cell viability of PC12 cells pre-treated with the compound of Example 1 or Comparison Compound for 30 minutes and then 0.1 ^M (B) or 1.0 μM (C) rotenone for 12 hours. Viability is shown as a percent of PC12 cells left untreated. Error bars show standard deviation (SD) for n=3 replicates. *p < 0.05, **p< 0.01, ***p< 0.0005, ****p<0.0001 for ordinary one-way ANOVA comparing Rotenone + / - the compound of Example 1 or Comparison Compound treated cells to untreated cells with Dunnett correction for multiple comparisons. Figure 6. Glu-mediated ROS production is attenuated by the compound of Example 1. Mean H2DCFDA fluorescence of PC12 cells treated with Glu, pre-treated with Comparison Compound (Analog 1) followed by Glu, pre-treated with the compound of Example 1 (Analog 2) followed by Glu, pre-treated with Comparison Compound (Analog 1), pre-treated with the compound of Example 1 (Analog 2) only, or left untreated. Error bars show SEM for n=12 replicates. Figure 7. Preincubation (30 minutes) with SFN or the compound of Example 1 mitigates production of ROS in SH-SY5Y cells treated with 100 μM Glu for 4horrs. Show are images of cells co-stained with both CellROX (top) and DAPI (bottom) following 4 hours of incubation: (A) Untreated control; (B) 100 μM Glu; (C) 10 μM menadione (positive control); (D) 100 μM Glu + 1 μM SFN; (E) 100 μM Glu + 1 μM SFN; (F) 100 μM Glu + 100 nM Comparison Compound (Analog 1); (G) 100 μM Glu + 100 nM the compound of Example 1 (Analog 2). Figures 8A-8C. Pre-treatment with the compound of Example 1 alone induces upregulation of Nrf2-dependent oxidative stress response genes in PC12 cells after 4 hours. Expression of Nrf2 target genes, (A) GPX4, (B) NQO1, and (C) SOD1, as measured by qPCR, in PC12 cells pre-treated with the compound of Example 1 (Center) or Comparison Compound (Right) (0.05 or 1.0 ^M) for 4 hours. Error bars show for SEM for n=3 replicates. Figures 9A-9C. Pre-treatment with the compound of Example 1 followed by 4 hours Glu exposure induces upregulation of Nrf2-dependent oxidative stress response genes in PC12 cells. Expression of Nrf2 target genes, (A) GPX4, (B) NQO1, and (C) SOD1, as measured by qPCR, in PC12 cells pre-treated with the compound of Example 1 (third and fourth columns from the left) or the Comparison Compound (fifth and sixth columns from the left) (0.05 or 1.0 ^M) before Glu (100 ^M) for 4 hours. Error bars show for SEM for n=4 replicates. Figure 10. Upregulation of Nrf2-related genes is time dependent. Induction of GPX4 expression is seen in PC12 cells pretreated with 100 nM the Comparison Compound or the compound of Example 1 followed by 1 or 2 hours exposure to 100 μM Glu. Expression of Nrf2 target gene GPX4, as measured by qPCR, in PC12 cells pre-treated with the Comparison Compound (third and seventh columns from the left) or the compound of Example 1 (fourth and eight columns from the left) before Glu for 1 or 2 hours. Error bars show SEM for n=3 replicates. Figure 11. SFN protects against Glu excitotoxicity, but at higher concentrations when compared to the compound of Example 1. MTT analysis of treatment with the Comparison Compound or the compound of Example 1 (50 or 100 nM) or SFN (1 and 10 ^M) followed by Glu for 24 hours. Viability is shown as a percent of PC12 cells left untreated. Error bars show standard deviation (SD) for n=3 replicates. **p< 0.01, ***p< 0.0005, ****p<0.0001 for ordinary one-way ANOVA comparing Glu-treated PC12 cells to untreated, SFN, and cells treated with the Comparison Compound or the compound of Example 1 with Dunnett correction for multiple comparisons. Figure 12. ML-385 antagonized the activity of the compound of Example 1 in the presence of Glu. MTT analysis of treatment with the Comparison Compound (50 or 100 nM) + / - ML-385 (1 or 10 ^M), Comparison Compound (50 or 100 nM) + / - ML-385 (1 or 10 ^M), or ML-385 (1 and 10 ^M) followed by Glu for 24 hours. Viability is shown as a percent of PC12 cells left untreated. Error bars show standard deviation (SD) for n=3 replicates. **p< 0.01, ***p< 0.0005, ****p<0.0001 for ordinary one-way ANOVA comparing Glu-treated PC12 cells to untreated and ML-385 + / - and cells treated with the Comparison Compound or the compound of Example 1 with Dunnett correction for multiple comparisons. Figure 13A-13B. The compound of Example 1 and SFN induce Nrf2 expression in PC12 cells whereas the Comparison Compound does not. PC12 cells were treated with SFN (1 or 10 ^M), the compound of Example 1, or the Comparison Compound (50 or 100 nM) or left untreated for (A) 1 hour or (B) 4 hours. Nuclear lysates were prepared and levels of active Nrf2 binding to DNA were measured with TransAM Nrf2 assay kit. Error bars show standard deviation (SD) for n=3 replicates. **p< 0.01, ***p< 0.0005, ****p<0.0001 for ordinary one- way ANOVA comparing SFN, the compound of Example 1, or the Comparison Compound to untreated treated cells with Dunnett correction for multiple comparisons. Figure 14A-14C. Treatment with SFN or the compound of Example 1 induces upregulation of Nrf2-dependent oxidative stress response genes in PC12 cells after 4 hr. When cells are pre-treated with NAC, SFN induced upregulation of Nrf2-dependent AREs is eliminated but remains in cells treated with the compound of Example 1. Expression of Nrf2 target genes, (A) GPX4, (B) NQO1, and (C) SOD1, as measured by qPCR, in PC12 cells pre- treated with 10 ^M SFN (columns 2 and 4 from the left) or 100 nM the compound of Example 1 (columns 3 and 5 from the left) + / - 1 mM NAC for 4 hr. Error bars show for SEM for n=3. DETAILED DESCRIPTION The following definitions are used, unless otherwise described: halo or halogen is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, alkenyl, alkynyl, etc. denote both straight and branched groups; but reference to an individual radical such as propyl embraces only the straight chain radical, a branched chain isomer such as isopropyl being specifically referred to. The term "alkyl", by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e., C1-8 means one to eight carbons). Examples include (C1-C8)alkyl, (C2-C8)alkyl, C1-C6)alkyl, (C2-C6)alkyl and (C3-C6)alkyl. Examples of alkyl groups include methyl, ethyl, n- propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and and higher homologs and isomers. The term "alkoxy" refers to an alkyl groups attached to the remainder of the molecule via an oxygen atom (“oxy”). The term “heteroaryl” as used herein refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur. “Heteroaryl” also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a single heteroaryl ring, as defined above, is condensed with one or more rings selected from cycloalkyl, aryl, heterocycle, and heteroaryl. Exemplary heteroaryl ring systems include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, and quinazolyl. The term “alkanoyl” as used herein refers to a group (alkyl)-C(=O)-, wherein the term alkyl has the meaning defined herein. The term “alkoxycarbonyl” as used herein refers to a group (alkyl)-O-C(=O)-, wherein the term alkyl has the meaning defined herein. The term “alkanoyloxy” as used herein refers to a group (alkyl)-C(=O)-O-, wherein the term alkyl has the meaning defined herein. As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si). As used herein, the term "protecting group" refers to a substituent that is commonly employed to block or protect a particular functional group on a compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9- fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A "carboxy-protecting group" refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy- protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2- (trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2- (diphenylphosphino)-ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see P.G.M. Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis 4thedition, Wiley-Interscience, New York, 2006. As used herein a wavy line “ ” that intersects a bond in a chemical structure indicates the point of attachment of the bond that the wavy bond intersects in the chemical structure to the remainder of a molecule. The terms “treat”, “treatment”, or “treating” to the extent it relates to a disease or condition includes inhibiting the disease or condition, eliminating the disease or condition, and / or relieving one or more symptoms of the disease or condition. The terms “treat”, “treatment”, or “treating” also refer to both therapeutic treatment and / or prophylactic treatment or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as, for example, the development or spread of cancer. For example, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease or disorder, stabilized (i.e., not worsening) state of disease or disorder, delay or slowing of disease progression, amelioration or palliation of the disease state or disorder, and remission (whether partial or total), whether detectable or undetectable. “Treat”, “treatment”, or “treating,” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the disease or disorder as well as those prone to have the disease or disorder or those in which the disease or disorder is to be prevented. In one embodiment “treat”, “treatment”, or “treating” does not include preventing or prevention, The phrase "therapeutically effective amount" or “effective amount” includes but is not limited to an amount of a compound of the that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The term “mammal” as used herein refers to humans, higher non-human primates, rodents, domestic, cows, horses, pigs, sheep, dogs and cats. In one embodiment, the mammal is a human. The term “patient” as used herein refers to any animal including mammals. In one embodiment, the patient is a mammalian patient. In one embodiment, the patient is a human patient. The compounds disclosed herein can also exist as tautomeric isomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention. It is understood by one skilled in the art that this invention also includes any compound claimed that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium (2H or D). As a non-limiting example, a -CH3 group may be substituted with -CD3. The pharmaceutical compositions of the invention can comprise one or more excipients. When used in combination with the pharmaceutical compositions of the invention the term “excipients” refers generally to an additional ingredient that is combined with the compound of formula (I)-(VIII) or the pharmaceutically acceptable salt thereof to provide a corresponding composition. For example, when used in combination with the pharmaceutical compositions of the invention the term “excipients” includes, but is not limited to: carriers, binders, disintegrating agents, lubricants, sweetening agents, flavoring agents, coatings, preservatives, and dyes. Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity. It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase. When a bond in a compound formula herein is drawn in a non-stereochemical manner (e.g. flat), the atom to which the bond is attached includes all stereochemical possibilities. Bold- rectangles and dashed-rectangles designate relative stereochemistry. When a bond in a compound formula herein is drawn as a bold-wedge or a dashed-wedge t is to be understood that the atom to which the stereochemical bond is attached ed in the absolute stereoisomer depicted unless otherwise noted. In one embodiment, the compound may be at least 51% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 60% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 80% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 90% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 95 the absolute stereoisomer depicted. In another embodiment, the compound may be at least 99% the absolute stereoisomer depicted. Specific values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents. It is to be understood that two or more values may be combined. It is also to be understood that the values listed herein below (or subsets thereof) can be excluded. Specifically, (C1-C6)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec- butyl, pentyl, 3-pentyl, or hexyl; (C1-C6)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; (C1-C6)alkanoyl can be acetyl, propanoyl or butanoyl; (C1-C6)alkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, or hexyloxycarbonyl; and (C2-C6)alkanoyloxy can be acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, or pentanoyloxy. A specific compound or salt is a compound of Formula (I): or a salt thereof, wherein: R1is H or a (C1-C6)alkyl that can optionally be substituted with one or more groups independently selected from halo; R2is a ring selected from the group consisting of 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocycle, and 6-membered heterocycle; R3is H, (C1-C6)alkyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, or a hydroxy protecting group (e.g., trimethylsilyl or tert-butyl-d ring A is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkylthio, and (C1-C6)alkoxycarbonyl, wherein any (C1-C6)alkyl, (C1-C6)alkoxy, (C1- C6)alkanoyl, (C1-C6)alkylthio, and (C1-C6)alkoxycarbonyl is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C1-C6)alkoxy, (C1-C6)alkanoyl, and (C1-C6)alkoxycarbonyl. A specific compound or salt is a compound of Formula (I) or a salt thereof. A specific compound or salt is a compound of Formula (II) or a salt thereof. A specific compound or salt is a compound of Formula (III) or a salt thereof. A specific compound or salt is a compound of Formula (IV) or a salt thereof. A specific compound or salt is a compound of Formula (V) or a salt thereof. A specific compound or salt is a compound of Formula (VI) or a salt thereof. A specific compound or salt is a compound of Formula (VII) or a salt thereof. A specific compound or salt is a compound of Formula (VIII) or a salt thereof. A specific value for R1is (C1-C6)alkyl that can optionally be substituted with one or more groups independently selected from halo. A specific value for R1is (C1-C6)alkyl. A specific value for R1is methyl. A specific value for R2is a ring selected from the group consisting of pyrazinyl, thienyl, thiazolyl, furyl, and tetrahydrofuryl. A specific value for R2is a furyl ring. A specific value for R2is a 2-furyl ring. A specific value for 3-furyl ring. A specific value for ring A is substituted with one or more groups. A specific value for ring A is not substituted with one or more groups. A specific compound or salt is a compound of the following formula:

[0002] or a salt thereof. A specific compound or salt is a compound of the following formula: or a salt thereof. A specific compound or salt is a compound of the following formula:

[0003] or a salt thereof. A specific compound or salt is a compound of the following formula: or a salt thereof. A specific compound or salt is a compound of the following formula: or a salt thereof. In one embodiment, the compound is not: In one embodiment, the compound is not: . In one embodiment, the compound is not: . In cases where compounds are sufficiently basic or acidic, a salt of a compound of Formula (I)-(VIII) can be useful as an intermediate for isolating or purifying a compound of Formula (I). Additionally, administration of a compound of Formula (I)-(VIII) as a pharmaceutically acceptable acid or base salt may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts. Salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made. The compounds or salts can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes. Thus, the present compounds or salts may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound or salts may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound or salt in such therapeutically useful compositions is such that an effective dosage level will be obtained. The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices. The active compound or salt may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salt can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active compound or salt in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions. For topical administration, the present compounds or salts may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid. Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol / glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers. Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user. Examples of useful dermatological compositions which can be used to deliver the compounds or salts to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No.4,992,478), Smith et al. (U.S. Pat. No.4,559,157) and Wortzman (U.S. Pat. No.4,820,508). Useful dosages of the compounds or salts can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No.4,938,949. The amount of the compound, or an active salt required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye. The invention will now be illustrated by the following non-limiting Examples. EXAMPLES General Alkylation procedure (step 1): In a three-neck round-bottom flask equipped with a magnetic stir bar and an addition funnel, diisopropylamine (4.0 g, 5.6 mL, 39.5 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL). The solution was cooled down to 0 °C, and then using the addition funnel, n-BuLi (2.5 M in hexane, 14.0 mL, 35.2 mmol) was added dropwise. The resulting solution was allowed to stir at this temperature for 30 minutes. Then, the reaction mixture was cooled down to -78 °C, and a solution of cyclohexenone (2.0 g, 2.0 mL, 20.8 mmol) in THF (5 mL) was added dropwise. After 30 minutes, iodomethane (7.38 g, 3.24 mL, 51.9 mmol) was added dropwise at -78 °C and stirred for 30 minutes. N,N′-Dimethylpropylene urea, DMPU, (15 mL) was then added, and the reaction mixture was allowed to gradually reach the room temperature. After 12 hours, saturated NH4Cl solution (20 mL) was slowly added at 0 °C, and the reaction mixture was extracted with diethyl ether (2 ^ 20 ml). The combined organic layers were washed with brine, and dried with sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel and hexane / diethyl ether (90:10) as the eluent to afford 6-methylcyclohex-2-en-1-one as a colorless liquid (1.5 g, 65%). NMR data were in accordance with literature values (Marques, F. A. et al., J Nat Prod 2004, 67, 1939-1941).1H NMR (500 MHz, CDCl3): δ = 6.92 - 6.89 (m, 1H), 5.95 (dt, J = 10.0, 2.0 Hz, 1H), 2.39 - 2.35 (m, 3H), 2.08 - 2.02 (m, 1H), 1.76 - 1.68 (m, 1H), 1.11 (d, J = 6.8 Hz, 3H). Aldol reaction (step 2): In a three-neck round-bottom flask equipped with a magnetic stir bar, diisopropylamine (0.25 g, 0.35 mL, 2.49 mmol) was dissolved in anhydrous tetrahydrofuran (12 mL). The solution was cooled down to 0 °C, and then n-BuLi (2.5 M in hexane, 1.04 mL, 2.49 mmol) was added dropwise. The resulting solution was allowed to stir at this temperature for 15 minutes. Then, the reaction mixture was cooled down to -78 °C, and methylcyclohexenone (0.25 g, 2.26 mmol) in THF was added dropwise. After 30 minutes, solution of aldehyde RCHO (1.1 eqv.) in THF was added dropwise at -78 °C and stirred for 45 minutes before quenching the reaction mixture with saturated NH4Cl solution (10 mL). After stirring at 25 °C for 1 h, the reaction mixture was diluted with diethyl ether (15 ml) and the resulting biphasic reaction mixture was then poured into a separatory funnel, and the layers were separated. After extracting the aqueous layer with diethyl ether (3 ^ 15 mL), the combined organic layers were washed with brine, and dried with sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford aldol intermediates. Reduction reaction (step 3): To a 20 mL-glass vial equipped with a magnetic stir bar, the aldol intermediate (0.277 g, 1.342 mmol) and palladium on carbon (27.7 mg, 10% w / w) were added and the mixture was first flushed with nitrogen gas. Ethanol (6.71 mL) was then added, and the mixture was flushed with hydrogen gas using a balloon. The resulting mixture was stirred at room temperature until TLC showed the full consumption of the starting material (ca.2 h). The reaction mixture was filtered over a pad of Celite, and was sequentially washed with diethyl ether and dichloromethane. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography to afford the final desired product. Example 1. Preparation of: The aldol intermediate was synthesized using the general aldol procedure and purified by column chromatography using silica gel and hexane / ethyl acetate (85:15) as the eluent to afford the aldol intermediate as a white solid (0.78 g, 84%).1H NMR (400 MHz, CDCl3): δ = 7.38 (dt, J = 1.5, 0.8 Hz, 1H), 7.37 (t, J = 1.7 Hz, 1H), 7.00 – 6.92 (m, 1H), 6.38 (dd, J = 1.9, 0.9 Hz, 1H), 5.96 (ddd, J = 10.0, 2.5, 1.5 Hz, 1H), 4.91 (s, 1H), 4.40 (s, 1H), 2.46 – 2.28 (m, 2H), 1.74 (ddd, J = 13.5, 10.0, 6.2 Hz, 1H), 1.55 (dddd, J = 13.6, 4.7, 3.3, 1.3 Hz, 1H), 1.20 (s, 3H).13C NMR (101 MHz, CDCl3): δ = 207.1, 150.6, 142.7, 140.8, 128.4, 124.0, 110.3, 71.6, 47.7, 31.1, 23.1, 14.7. HRMS-ESI calcd for C12H14O3Na [M+Na]+229.0835, found 229.0832. The final product was synthesized using the general reduction procedure and purified by column chromatography using silica gel and hexane / diethyl ether (7:3) as the eluent to afford the final desired product (Example 1; 212.7 mg, 76%) as a white solid (upon standing in freezer overnight).1H NMR (600 MHz, CDCl3): δ = 7.37 (s, 1H), 7.36 (s, 1H), 6.37 (dd, J =1.4 Hz, 1H), 4.90 (s, 1H), 3.86 (s, 1H), 2.63 – 2.55 (m, 1H), 2.38 – 2.32 (m, 1H), 2.07 – 2.00 (m, 1H), 1.77 – 1.64 (m, 3H), 1.53 – 1.48 (m, 2H), 1.22 (s, 3H).13C NMR (151 MHz, CDCl3): δ = 219.43, 142.60, 140.66, 123.89, 110.39, 71.77, 52.39, 39.16, 36.72, 27.37, 20.79, 16.48. HRMS-ESI calcd for C12H16O3Na [M+Na]+231.0992, found 231.0990. Example 2. Preparation of: The aldol intermediate was synthesized using the general aldol procedure and purified by column chromatography using silica gel and hexane / diethyl ether (85:15) as the eluent to afford the aldol intermediate as a yellow solid (0.618 g, 32%).1H NMR (500 MHz, CDCl3): δ = 7.36 (dd, J = 1.8, 0.9 Hz, 1H), 6.97 (dddd, J = 10.0, 4.6, 3.3, 1.2 Hz, 1H), 6.35 (dd, J = 3.3, 1.8 Hz, 1H), 6.31 (dt, J = 3.4, 0.7 Hz, 1H), 5.98 (ddd, J = 10.0, 2.4, 1.7 Hz, 1H), 4.95 (s, 1H), 4.35 (s, 1H), 2.38 (dddd, J = 6.5, 5.4, 4.6, 2.3 Hz, 2H), 1.79 (ddd, J = 13.7, 9.5, 6.5 Hz, 1H), 1.42 (dddd, J = 13.7, 4.8, 3.6, 1.2 Hz, 1H), 1.28 (s, 3H). The final product was synthesized using the general reduction procedure and purified by column chromatography using silica gel and hexane / diethyl ether (85:15) as the eluent to afford the final desired product (Example 2: 18.2 mg, 71%) as a white solid (upon standing in freezer overnight).1H NMR (500 MHz, CDCl3): δ = 7.35 (dd, J = 1.9, 0.9 Hz, 1H), 6.33 (dd, J = 3.2, 1.8 Hz, 1H), 6.28 (dt, J = 3.2 , 0.7 Hz, 1H), 4.95 (d, J = 3.1 Hz, 1H), 3.75 (d, J = 3.5 Hz, 1H), 2.58 (ddd, J = 14.5, 12.1, 6.2 Hz, 1H), 2.39 – 2.32 (m, 1H), 2.05 – 1.96 (m, 1H), 1.78 – 1.65 (m, 3H), 1.63 – 1.55 (m, 1H), 1.39 – 1.33 (m, 1H), 1.30 (s, 3H). Example 3. Preparation of: The final product was synthesized from the appropriate aldol intermediate using the general reduction procedure with an extended reaction time (24 hours) to achieve reduction of the furan ring. Two separable diastereomers were formed. The crude product mixture was purified by preparative TLC using hexane / ethyl acetate (85:15) as eluent to afford to afford the final desired product (Example 3, 8.2 mg, 18%) as a colorless oil. Diastereomer 1:1H NMR (500 MHz, CDCl3): ^ = 3.94 – 3.87 (m, 2H), 3.87 – 3.83 (m, 1H), 3.79 (td, J = 7.9 , 5.0 Hz, 1H), 2.78 (d, J = 7.2 Hz, 1H), 2.48 (ddd, J = 14.5, 9.9, 6.0 Hz, 1H), 2.42 – 2.34 (m, 1H), 1.97 – 1.66 (m, 10 H), 1.23 (s, 3H). Example 4. Preparation of: Following the procedure described above for Example 3, the second separable diastereomer was isolated as a colorless oil. Diastereomer 2:1H NMR (500 MHz, CDCl3): ^ = 3.94 – 3.87 (m, 2H), 3.81 – 3.75 (m, 1H), 3.68 (ddd, J = 8.1 , 7.4, 5.8 Hz, 1H), 2.91 (d, J = 3.9 Hz, 1H), 2.53 – 2.45 (m, 1H), 2.42 – 2.35 (m, 1H), 1.97 – 1.69 (m, 10 H), 1.20 (s, 3H). Example 5. Preparation of: The aldol intermediate was synthesized using the general aldol procedure and purified by column chromatography using silica gel and hexane / ethyl acetate (94:6) as the eluent to afford the aldol intermediate as a colorless liquid in 71% yield.1H NMR (500 MHz, CDCl3): δ = 8.76 (s, 1H), 8.50 (s, 2H), 6.97 – 6.94 (m, 1H), 5.98 (dt, J = 10.0, 2.0 Hz, 1H), 5.18 (s, 1H), 4.60 (br s, 1H), 2.39 - 2.34 (m, 2H), 1.83 - 1.77 (m, 1H), 1.57 - 1.53 (m, 1H), 1.25 (s, 3H).13C NMR (125 MHz, CDCl3): δ = 204.95, 154.67, 150.45, 145.03, 143.60, 142.59, 128.43, 75.77, 48.87, 29.73, 22.90, 16.54. HRMS-ESI calcd for C12H14N2O2 [M+H]+219.1133, found 219.1130 and [M+Na]+241.0952, found 241.0948. The final product was synthesized using the general reduction procedure and purified by column chromatography using silica gel and hexane / ethyl acetate (90:10) as eluent to afford the desired product (Example 5) as a colorless liquid in 80% yield.1H NMR (500 MHz, CDCl3): δ = 8.73 (d, J = 1.4 Hz, 1H), 8.51 - 8.49 (m, 2H), 5.18 (s, 1H), 4.18 (br s, 1H), 2.61 - 2.55 (m, 1H), 2.46 - 2.41 (m, 1H), 2.03 - 1.95 (m, 1H), 1.81 - 1.70 (m, 4H), 1.41 - 1.38 (m, 1H), 1.19 (s, 3H).13C NMR (125 MHz, CDCl3): δ = 217.22, 154.68, 144.88, 143.58, 142.77, 76.04, 53.06, 38.95, 35.71, 26.99, 20.60, 17.23. HRMS-ESI calcd for C12H16N2O2 [M+H]+221.1290, found 221.1286 and [M+Na]+243.1109, found 243.1105. Example 6. Preparation of: In a 50 mL round-bottom flask equipped with a magnetic stir bar, the appropriate aldol product (0.100 g, 1 eqv.), acetic anhydride (1 mL), and pyridine (1 mL) were added. The reaction was allowed to stir at room temperature for 2h. After completion of reaction, as monitored on TLC, ice was added to it. The layers were separated, and workup was done using DCM and water. Dried and concentrated the organic layer and the crude product mixture was purified by column chromatography using hexane:ethyl acetate (95:5) as eluent to get the desired acetate intermediate as a colorless oil in 89% yield.1H NMR (500 MHz, CDCl3): δ = 7.36 (s, 1H), 6.92 - 6.89 (m, 1H), 6.34 - 6.33 (m, 2H), 6.31 - 6.30 (m, 1H), 5.96 - 5.93 (m, 1H), 2.54 - 2.50 (m, 1H), 2.36 - 2.32 (m, 1H), 2.07 (s, 3H), 1.85 (t, J = 5.1 Hz, 2H), 1.24 (s, 3H).13C NMR (150 MHz, CDCl3): δ = 200.60, 169.74, 150.73, 148.53, 142.19, 128.42, 110.27, 109.29, 70.93, 48.77, 30.72, 22.89, 20.83, 17.98. HRMS-ESI calcd for C14H16O4 [M+Na]+271.0946, found 271.0940. The final product was synthesized using the general reduction procedure and purified by column chromatography using silica gel and hexane:ethyl acetate (95:5) as eluent to afford the final desired product (Example 6) as a colorless oil in 90% yield.1H NMR (600 MHz, CDCl3): δ = 7.38 (s, 1H), 6.40 (s, 1H), 6.35 - 6.32 (m, 2H), 2.61 - 2.56 (m, 1H), 2.45 - 2.41 (m, 1H), 2.03 (s, 3H), 1.96 - 1.92 (m, 1H), 1.89 - 1.85 (m, 1H), 1.82 - 1.77 (m, 1H), 1.72 - 1.67 (m, 2H), 1.47 - 1.42 (m, 1H), 1.24 (s, 3H).13C NMR (150 MHz, CDCl3): δ = 212.64, 169.83, 150.31, 142.40, 110.22, 109.64, 70.99, 52.59, 38.68, 36.75, 27.60, 20.84, 20.82, 17.98. HRMS-ESI calcd for C14H18O4 [M+Na]+273.1102, found 273.1097. E In a 20 mL glass vial equipped with a magnetic stir bar, the appropriate aldol product (100 mg, 0.485 mmol) was dissolved in CH2Cl2 (6 mL) and treated with NEt3 (0.020 mL, 0.146 mmol) and 1-hexanethiol (0.080 mL, 0.534 mmol). The reaction mixture was stirred at room temperature for 20 hours and the volatiles were removed under vacuum. The crude residue wasdiluted with diethyl ether (5 ml) and water (5 mL) the resulting biphasic reaction mixture was then poured into a separatory funnel, and the layers were separated. After extracting the aqueous layer with diethyl ether (2 x 5 mL), the combined organic layers were washed with brine, and dried with sodium sulfate, and concentrated under reduced pressure. The crude product mixture was purified by column chromatography using silica gel and hexane / ethyl acetate (80:20) as eluent to afford to afford the final desired product (Example 7, 16.4 mg, 10%) as a colorless oil.1H NMR (500 MHz, CDCl3): δ = 7.37 (d, J = 1.9 Hz, 1H), 6.35 (dd, J = 3.3, 1.8 Hz, 1H), 6.30 (d, J = 3.2 Hz, 1H), 5.06 (d, J = 3.5 Hz, 1H), 3.44 (d, J = 3.6 Hz, 1H), 3.35 – 3.31 (m, 1H), 2.92 (dd, J = 14.7, 4.9 Hz, 1H), 2.58 – 2.49 (m, 3H), 2.14 – 2.07 (m, 1H), 2.02 – 1.96 (m, 1H), 1.92 – 1.86 (m, 1H), 1.60 – 1.55 (m, 2H), 1.43 – 1.29 (m, 5H), 1.25 (s, 3H), 1.23 – 1.20 (m, 2H), 0.89 (t, J = 6.9 Hz, 3H). Example 8. Preparation of: The aldol intermediate was synthesized using the general aldol procedure and purified by column chromatography using silica gel and hexane / diethyl ether (20:80) as the eluent to afford the aldol intermediate as a white solid (0.282 g, 28%).1H NMR (500 MHz, CDCl3): ^ = 8.73 (d, J = 2.1 Hz, 1H), 7.33 (dd, J = 2.2, 0.8 Hz, 1H), 6.96 (dddd, J = 10.1, 4.9, 3.0, 1.1 Hz, 1H), 5.97 (ddd, J = 10.0, 2.6, 1.5 Hz, 1H), 5.27 (s, 1H), 4.47 (s, 1H), 2.46 – 2.29 (m, 2H), 1.89 (ddd, J = 13.8, 9.7, 6.0 Hz, 1H), 1.60 (dddd, J = 13.8, 4.9, 3.6, 1.2 Hz, 1H), 1.19 (s, 3H). The final product was synthesized using the general reduction procedure and purified by preparative TLC using dichloromethane / methanol (97.5 : 2.5) to afford the final desired product (Example 8: 56.7 mg, 55%) as a white solid.1H NMR (500 MHz, CDCl3): ^ = 8.74 (d, J = 2.1 Hz, 1H), 7.32 (dd, J = 2.1, 0.8 Hz, 1H), 5.29 (d, J = 3.7 Hz, 1H), 3.98 (d, J = 3.8 Hz, 1H), 2.58 (ddd, J = 14.6, 11.6, 7.5 Hz, 1H), 2.44 – 2.36 (m, 1H), 2.05 – 1.95 (m, 1H), 1.80 – 1.67 (m, 4H), 1.47 (dt, J = 11.4, 2.4 Hz, 1H), 1.21 (s, 3H). Example 9. Preparation of: The aldol intermediate was synthesized using the general aldol procedure and purified by column chromatography using silica gel and hexane / ethyl acetate (80:20) as the eluent to afford the aldol intermediate as a yellow oil in 84% yield.1H NMR (600 MHz in acetone-d6): δ = 7.31 (d, J = 6.2 Hz, 1H), 6.99-6.96 (m, 1H), 6.94 (d, J = 5.5 Hz, 1H), 6.90 (dd, J = 6.2, 5.5 Hz, 1H), 5.87 (d, J = 4.5 Hz, 1H), 5.40 (d, J = 4.5 Hz, 1 H), 4.93 (d, J = 4.5 Hz, 1H), 2.87-2.84 (m, 1H), 2.40-2.36 (m, 1H), 1.79-1.76 (m, 1H), 1.71-1.68 (m, 1H), 1.21 (s, 3H).13C NMR (150 MHz, Acetone): δ = 203.81, 150.40, 146.06128.50, 126.44, 125.19, 124.62, 73.41, 49.90, 29.89, 23.00, 17.67. HRMS-ESI calcd for C12H14O2S [M+Na]+245.0612, found 245.0604. The final product was synthesized using the general reduction procedure and purified by column chromatography using silica gel and dichloromethane / ethyl acetate (7:3) as eluent, afforded the final desired product final desired product in 92% yield as a white solid.1H NMR (500 MHz in CDCl3): δ = 7.25 (d, J = 5.1 Hz, 1H), 6.99 (dd, J = 5.1, 3.5 Hz, 1H), 6.98 (d, J = 3.5 Hz, 1H), 5.20 (s, 1 H), 4.84 (s, 1H), 2.64-2.62 (m, 1H), 2.39-2.37 (m, 1H), 2.06-2.04 (m, 1H), 1.75-1.72 (m, 3H), 1.71-1.69 (m, 1H), 1.49-1.47 (m, 1H), 1.47 (s, 3H).13C NMR (150 MHz, CDCl3): δ = 219.09, 142.28, 126.00125.76, 124.87, 74.90, 52.56, 39.00, 36.73, 27.17, 20.71, 16.36. HRMS-ESI calcd for C12H14O2S [M+Na]+247.0763, found 247.0762. Example 10. Preparation of: The aldol intermediate was synthesized using the general aldol procedure using cyclohexenone in place of 6-methylcyclohexenone and purified by column chromatography using silica gel and hexane / ethyl acetate (94:6) as the eluent to afford the aldol intermediate as a colorless liquid in 70% yield.1H NMR (500 MHz, CDCl3): δ = 7.40 (dd, J = 1.8, 0.9 Hz, 1H), 7.06 - 7.02 (m, 1H), 6.34 (dd, J = 3.3, 1.8 Hz, 1H), 6.31 (dd, J = 3.2, 0.9 Hz, 1H), 6.08 (ddd, J = 10.0, 2.5, 1.6 Hz, 1H), 4.90 (d, J = 8.8 Hz, 1H), 4.64 (br s, 1H), 2.87 (dd, J = 18.4, 8.9 Hz, 1H), 2.42 - 2.37 (m, 2H), 1.63 - 1.59 (m, 2H).13C NMR (125 MHz, CDCl3): δ = 203.12, 153.53, 151.73, 142.43, 129.57, 110.10, 108.24, 68.97, 50.62, 25.79, 25.25. HRMS-ESI calcd for C11H12O3 [M+Na]+215.0683, found 215.0681. The final product was synthesized using the general reduction procedure and purified by column chromatography using silica gel and hexane / ethyl acetate (90:10) as the eluent to afford the desired product (Example 10) as a colorless liquid in 72% yield.1H NMR (500 MHz, CDCl3): δ = 7.38 (dd, J = 1.9, 0.9 Hz, 1H), 6.33 (dd, J = 3.2, 1.8 Hz, 1H), 6.28 (dd, J = 3.2, 0.8 Hz, 1H), 4.82 (d, J = 8.4 Hz, 1H), 2.94 - 2.89 (m, 1H), 2.49 - 2.45 (m, 1H), 2.41 - 2.34 (m, 1H), 2.14 - 2.09 (m, 1H), 1.86 - 1.82 (m, 1H), 1.72 - 1.63 (m, 3H), 1.39 - 1.33 (m, 1H).13C NMR (125 MHz, CDCl3): δ = 214.96, 153.67, 142.30, 110.10, 107.97, 68.27, 54.89, 42.63, 30.64, 27.82, 24.72. HRMS-ESI calcd for C11H14O3 [M+Na]+217.0840, found 217.0837. Example 11. Preparation of: The aldol intermediate was synthesized using the general aldol procedure using cyclohexenone in place of 6-methylcyclohexenone and purified by column chromatography using silica gel and hexane / ethyl acetate (94:6) as the eluent to afford the aldol intermediate as a colorless liquid in 73% yield.1H NMR (500 MHz, CDCl3): δ = 8.81 (d, J = 1.4 Hz, 1H), 8.51 - 8.50 (m, 2H), 7.01 - 6.98 (m, 1H), 6.10 (ddd, J = 10.0, 2.8, 1.2 Hz, 1H), 5.64 (d, J = 3.1 Hz, 1H), 3.04 - 3.00 (m, 1H), 2.45 - 2.31 (m, 2H), 2.10 - 2.02 (m, 1H), 1.65 - 1.60 (m, 1H).13C NMR (125 MHz, CDCl3): δ = 200.21, 156.50, 150.91, 143.49, 143.20, 143.14, 129.91, 70.32, 52.20, 25.68, 21.88. HRMS-ESI calcd for C11H12N2O2[M+H]+205.0977, found 205.0971 and [M+Na]+227.0796, found 227.0789. The final product was synthesized using the general reduction procedure and purified by column chromatography using silica gel and hexane / ethyl acetate (90:10) as the eluent to afford the desired product (Example 11) as a colorless liquid in 68% yield.1H NMR (500 MHz, CDCl3): δ = 8.82 (s, 1H), 8.49 (s, 2H), 5.45 (d, J = 2.9 Hz, 1H), 3.30 (br s, 1H), 3.06 - 3.02 (m, 1H), 2.50 - 2.45 (m, 1H), 2.43 - 2.33 (m, 1H), 2.13 - 2.08 (m, 1H), 1.88 - 1.84 (m, 1H), 1.74 - 1.58 (m, 4H).13C NMR (125 MHz, CDCl3): δ = 213.87, 156.32, 143.53, 143.22, 70.47, 55.43, 42.52, 27.81, 26.52, 24.75. HRMS-ESI calcd for C11H14N2O2 [M+H]+207.1133 found 207.1128 and [M+Na]+229.0952, found 229.0947. Example 12. Preparation of: The aldol intermediate was synthesized using the general aldol procedure using cyclohexenone in place of 6-methylcyclohexenone and purified by column chromatography using silica gel and hexane / ethyl acetate (80:20) as the eluent to afford the aldol intermediate as a white solid in 30% yield.1H NMR (500 MHz in CDCl3): δ = 7.88 (d, J = 6.2 Hz, 1H), 7.30 (d, J = 6.2 Hz, 1H), 7.04 (m, 1H), 6.15 (d, J = 5.5 Hz, 1H), 5.74 (d, J = 4.1 Hz, 1H), 3.50-3.47 (m, 1 H), 2.05-2.02 (m, 2H), 2.00-1.65 (m, 2H). The final product was synthesized using the general reduction procedure and purified by column chromatography using silica gel and hexane / ethyl acetate (8:2) as eluent, afforded the final desired product in 92% yield as a light purple solid.1H NMR (500 MHz in CDCl3): δ = 7.68 (d, J = 6.3 Hz, 1H), 7.46 (d, J = 6.3 Hz, 1H), 5.65 (d, J = 4.1 Hz, 1H), 3.25-3.22 (m, 1 H), 2.49-2.47 (m, 2 H), 2.20-2.02 (m, 1H), 1.95-1.92 (m, 2H), 1.75-1.73 (m, 2H), 1.63-1.60 (m, 1H). Example 13. Preparation of: The aldol intermediate was synthesized using the general aldol procedure and purified by column chromatography using silica gel and hexane / ethyl acetate (80:20) as the eluent to afford the aldol intermediate as a white solid in 41 % yield.1H NMR (600.21 MHz in CDCl3): δ = 7.25 (m, 1H), 7.19 (s, 1H), 7.04 (d, J = 5 Hz, 1H), 6.95 (d, J = 5 Hz, 1H), 5.96 (d, J = 10 Hz, 1 H), 5.03 (s, 1H), 2.32-2.29 (m, 2H), 1.79-1.74 (m, 1H), 1.43-1.40 (m, 1H), 1.18 (s, 3H).13C NMR (150 MHz,CDCl3): δ = 200.44, 143.93, 133.89, 121.67, 120.55, 117.93, 70.23, 67.79, 41.11, 24.25, 16.31, 7.90.HRMS-ESI calcd for C12H14O2S [M+Na]+245.0612, found 245.0604 and [M+H-H2O]+205.0642, found 205.0680. The final product was synthesized using the general reduction procedure and purified by column chromatography using silica gel and hexane / ethyl acetate (80:20) as the eluent to afford the final desired product as a white solid in 93 % yield.1H NMR (500 MHz in CDCl3): δ = 7.25 (d, J = 8.6 Hz, 1H), 7.17 (s, 1H), 7.03 (d, J = 8.6 Hz, 1H), 5.06 (s, 1 H), 2.62-2.57 (m, 1H), 2.38-2.34 (m, 1H), 2.03-1.99 (m, 1H), 1.70-1.64 (m, 3H), 1.57-1.54 (m, 1H), 1.37-1.34 (m, 1H), 1.19 (s, 3H).13C NMR (150 MHz, CDCl3): δ = 219.27, 140.60, 127.47124.63, 122.63, 74.60, 52.58, 39.04, 36.80, 27.28, 20.67, 16.24. HRMS-ESI calcd for C12H16O2S [M+Na]+247.0769, found 247.0760, and [M+H-H2O]+207.0871, found 207.0835. Example 14. Preparation of: The aldol intermediate was synthesized using the general aldol procedure and purified by column chromatography using silica gel and hexane / ethyl acetate (80:20) as the eluent to afford the aldol intermediate as a white solid in 56 % yield.1H NMR (600.21 MHz in CDCl3): δ = 6.98 (m, 1H), 6.7(d, J = 3.4 Hz 1H), 6.5(d, J = 3.4 Hz, 1H), 5.97 (d, J = 11 Hz, 1H), 5.09 (s, 1 H), 5.03 (s, 1H), 4.58 (s, 1H), 2.44 (s, 3H), 2.38-3.34 (m, 2H), 1.79-1.74 (m, 1H), 1.55-1.52 (m, 1H), 1.26 (s, 3H).13C NMR (150 MHz, CDCl3): δ = 206.82, 150.72, 139.72, 139.41, 128.19, 125.76, 124.83, 124.09, 74.79, 60.15, 47.87, 31.16, 23.03, 15.30, 14.56. HRMS-ESI calcd for C13H18O2S [M+Na]+259.0768, found 259.0760 and [M+H-H2O]+219.0871, found 219.0836. The final product was synthesized using the general reduction procedure and purified by column chromatography using silica gel and hexane / ethyl acetate (80:20) as the eluent to afford the final desired product as a white solid in 98 % yield.1H NMR (500 MHz in CDCl3): δ = 6.71 (d, J = 4.2 Hz, 1H), 6.60 (d, J = 4.21H), 5.09 (s, 1 H), 3.90 (s, 1H), 2.62-2.57 (m, 1H), 2.45 (s, 3H), 2.38- 2.34 (m, 1H), 2.04-2.01 (m, 1H), 1.73-1.59 (m, 3H), 1.54-1.50 (m, 1H), 1.46-1.44 (m, 1 H), 1.27 (s, 3H).13C NMR (150 MHz, CDCl3): δ = 219.809, 139.74, 139.41, 125.83, 124.07, 75.06, 52.58, 38.98, 36.79, 27.20, 20.73, 16.45, 15.28. HRMS-ESI calcd for C13H18O2S [M+Na]+261.0925, found 261.0916and [M+H-H2O]+221.1028, found 221.0992. The synthesis of Example 15 and several subsequent analogs was completed beginning with the synthesis of intermediates reported in the literature by Fernández-Mateos et al. (Fernández- Mateos, A. et al., Tetrahedron 1995, 51, 7521-7526). General condensation procedure (step 5): The aldol intermediate was added to an oven-dried 100 mL round bottom flask and backfilled with nitrogen three times. The starting material in the round bottom flask was dissolved with 4 mL of THF and 0.08ml of pyridine was added. The reaction mixture was placed in ice and stirred for 10 minutes to ensure the temperature had reached 0 °C. SOCl2 (2.1 eqv) was then added and the reaction mixture was stirred for 5 minutes. Ice cubes were then added to the mixture and warmed to room temperature. The mixture was extracted with dichloromethane (3 ^ 15 mL) and washed with 2N HCl, 5% Na2CO3 and brine. The extract was further dried with Na2SO4 and purified using column chromatography to obtain the unsaturated lactone product. Example 15. Preparation of: To an oven-dried 100 ml round bottom flask, was added aldol intermediate (0.18 g, 0.68 mmol, 1 eqv). The compound and the dried round bottom flask were backfilled three times using nitrogen. Dry DCM was added and allowed to be stirred for 10 minutes to ensure complete dissolution of the starting material. Afterward, meta-chloroperoxybenzoic acid (m-CPBA) (0.37g, 2.15 mmol, 3.13 eqv), was added in drops and the reaction mixture was allowed to stir for 22 hours and was keenly monitored with TLC. The reaction was quenched with 10 mL of 5% NaHSO3 and extracted with DCM (3 ^ 10 mL). The combined DCM extract was washed with brine, dried with Na2SO4, and concentrated under reduced pressure. The crude extract was finally purified using column chromatography using diethyl ether:hexanes (1:1) to obtain epoxide intermediate as a white solid (0.086 g, 45%).1H NMR (500 MHz, Chloroform-d) δ 7.49 (d, 1H), 7.44 (s, 1H), 6.43 (dd, J=2.0, 0.9 Hz, 1H), 5.25 (s, 1H), 3.41 (d, J =2.1 Hz, 1H), 3.01 (d, 1H), 2.89 (d,1H), 2.09 (ddt, J=16.0, 6.3, 2.0 Hz, 1H), 1.96 (m, 1H), 1.59 (ddd, J = 14.8, 12.4, 6.3 Hz, 2H), 1.46 (s, 3H), 1.08 (ddd, J=14.8,6.3, 2.3 Hz, 1H), 0.97 (s, 3H). The final epoxide product (Example 15) was synthesized following the general condensation procedure with a yield of 0.0163 g (76%), as a white amorphous solid.1H NMR (500 MHz, Chloroform-d) δ 7.50 – 7.44 (m, 1H), 7.43 – 7.39 (m, 1H), 6.51 – 6.39 (m, 1H), 6.25 (s, 1H), 5.04 (s, 1H), 3.40 (s, 1H), 2.05 – 1.87 (m, 1H), 1.54 (s, 4H), 1.50 – 1.37 (m, 3H), 1.16 (s, 3H), 0.93 – 0.85 (m, 1H). Example 16. Preparation of: To an oven-dried 100 ml round bottom flask, was added unsaturated lactone (0.026 g, 0.11 mmol, 1 eqv). The compound and the dried round bottom flask were purged three times using nitrogen. Dry DCM was added and allowed to be stirred for 10 minutes to ensure complete dissolution of the starting material. Then, meta-chloroperoxybenzoic acid (m-CPBA) (0.059g, 0.34 mmol, 3.13 equivalents) was added dropwise, and the reaction mixture was stirred for 22 hours, with TLC closely monitoring the progress. The reaction was quenched with 10 mL of 5% NaHSO3 and extracted with DCM (3 ^ 10 mL). The combined DCM extract was washed with brine, dried with Na2SO4, and concentrated under reduced pressure. The crude extract was finally purified using column chromatography with diethyl ether:hexanes (1:1) as mobile phase to obtain the epoxide (Example 16) as a white amorphous solid (0.016 g, 58%). NMR data were in accordance with literature values (Fernández-Mateos, A. et al., Tetrahedron 1995, 51, 7521- 7526).1H NMR (500 MHz, Chloroform-d) δ 7.46 (t, 1H), 7.42 (t, 1H), 6.42(dd, J = 1.9, 0.9 Hz, 1H), 6.29 (s, 1H), 5.12 (s, 1H), 3.28 (t, J = 1.8 Hz, 1H), 2.12 – 2.17 (ddd, J = 15.5, 4.9, 2.4 Hz, 1H), 1.92 – 1.99 (m, 1H), 1.55 (s, 3H), 1.44-1.50 (td, J = 13.0, 5.0 Hz, 1H), 1.08-1.12 (ddd, J = 13.1, 5.0, 2.2 Hz, 1H), 1.02 (s, 3H). Example 17. Preparation of: Example 17 was synthesized following the reduction procedure reported by Guo et al. (Guo, Y. et al. J Agric Food Chem 2013, 61, 11937-11944). NMR data were in accordance with literature values. Example 18. Preparation of: Example 18 was prepared as illustrated below. Synthesis of aldol intermediate (step 2): In a three-neck round-bottom flask equipped with a magnetic stir bar, diisopropylamine (0.97 g, 1.3 mL, 9.6 mmol) was dissolved in anhydrous tetrahydrofuran (22 mL). The solution was cooled down to 0 °C, and then n-BuLi (2.5 M in hexane, 3.8 mL, 9.6 mmol) was added dropwise. The resulting solution was allowed to stir at this temperature for 15 minutes. Then, the reaction mixture was cooled down to -78 °C, and 2,6- dimethylcyclohexenone (0.98 g, 7.9 mmol) was added dropwise. After 30 minutes, freshly distilled 2-furaldehyde (0.92 g, 0.84 mL, 9.6 mmol) was added dropwise at -78 °C and stirred for 45 minutes before quenching the reaction mixture with saturated NH4Cl solution (10 mL). After stirring at 25 °C for an hour, the reaction mixture was extracted with ethyl acetate (3 ^ 10 mL), and the combined organic layers were washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel and hexane / ethyl acetate (92:8) as the eluent to afford aldol intermediate as a white solid (0.97 g, 56%).1H NMR (500 MHz, CDCl3): ^ = 7.36 (d, J = 1.0 Hz, 1H), 6.73 (dq, J = 4.1, 1.4 Hz, 1H), 6.34 (dd, J = 3.2, 1.9 Hz, 1H), 6.30 (d, J = 3.2 Hz, 1H), 4.94 (s, 1H), 4.46 (s, 1H), 2.43 – 2.24 (m, 2H), 1.84 – 1.74 (m, 4H), 1.38 (dddd, J = 13.6, 4.8, 3.3, 1.2 Hz, 1H), 1.27 (s, 3H).13C NMR (101 MHz, CDCl3): ^ = 206.9, 153.4, 145.8, 141.7, 133.8, 110.1, 108.3, 72.5, 47.8, 31.3, 22.6, 16.2, 14.8. Reduction reaction (step 3): To an 8 mL-glass vial equipped with a magnetic stir bar and a hydrogen balloon, aldol intermediate (0.11 g, 0.50 mmol) and palladium on activated charcoal (0.011 g, 10% w / w) were added and the mixture was pumped and back filled with hydrogen (three times). Ethanol (2.5 mL) was then added, and the resulting mixture was stirred at room temperature until TLC showed the full consumption of the starting material (ca.1 h). The reaction mixture was filtered over a pad of Celite, and was sequentially washed with ethanol, ethyl acetate and dichloromethane. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography using silica gel and hexane / ethyl acetate (from 100:0 to 93:7) as the eluent to afford products Diastereomer 1 (33 mg, 30%) and Diastereomer 2 (22 mg, 20%) as white solids. Dia11H NMR (400 MHz, CDCl3): δ = 7.35 (dd, J = 1.8, 0.9 Hz, 1H), 6.33 (dd, J = 3.3, 1.8 Hz, 1H), 6.27 (dd, J = 3.3, 0.7 Hz, 1H), 4.89 (s, 1H), 2.73 (dt, J = 12.7, 6.3 Hz, 1H), 2.12 – 2.03 (m, 1H), 1.83 (tt, J = 13.6, 3.8 Hz, 1H), 1.72 – 1.63 (m, 1H), 1.60 (m, 1H), 1.41 – 1.31 (m, 5H), 1.03 (d, J = 6.4 Hz, 3H). Dia21H NMR (500 MHz, CDCl3): δ = 7.39 (dd, J = 1.9, 0.8 Hz, 1H), 6.37 (dd, J = 3.2, 1.8 Hz, 1H), 6.30 (d, J = 3.2 Hz, 1H), 5.32 (s, 1H), 2.81 (dp, J = 12.6, 6.4 Hz, 1H), 2.13 (dtt, J = 10.4, 5.8, 2.4 Hz, 1H), 2.01 (dtt, J = 14.1, 12.3, 4.3 Hz, 1H), 1.85 (dtd, J = 14.4, 4.1, 2.4 Hz, 1H), 1.72 – 1.64 (m, 2H), 1.47 – 1.33 (m, 3H), 1.08 (d, J = 6.5 Hz, 3H), 1.02 (s, 3H).13C NMR (151 MHz, CDCl3): δ = 215.4, 153.5, 142.0, 110.2, 107.9, 71.2, 53.6, 41.5, 37.2, 35.9, 20.6, 17.1, 15.3. Hydrazone formation (step 4): To an ethanolic solution (2.4 mL) of Diasteromer 2 (0.25 g, 1.1 mmol), hydrazine monohydrate (1.7 g, 1.6 mL, 34 mmol) and acetic acid (0.56 g, 0.53 mL, 9.3 mmol) were added, and the resulting mixture was heated to 40 °C for 4 h. After cooling to 25 °C, water (3.0 mL) and ethyl acetate (3.0 mL) were added. The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 3.0 mL). The combined organic layers were washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. The crude material was dissolved in ethyl acetate, quickly passed through a short plug of silica, and concentrated under reduced pressure. The crude hydrazone was azeotropically dried with benzene, and used for the next step without further purification. Vinyl iodide formation (step 5): The resulting hydrazone and anhydrous triethylamine (1.1 g, 01.5 mL, 11 mmol) were dissolved in anhydrous tetrahydrofuran (12 mL), followed by the dropwise addition of a solution of iodine (1.1 g, 4.3 mmol) in anhydrous tetrahydrofuran (7.7 mL). The addition of iodine was continued until the brown color of the solution remained stable for around 30 sec. The reaction mixture was then diluted with ethyl acetate (15 mL) and washed with saturated sodium thiosulfate solution (15 mL). The aqueous layer was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel and hexane / ethyl acetate (94:6) to afford the vinyl iodide as an off-white solid (0.14 g, 37% over 2 steps).1H NMR (400 MHz, CDCl3): δ = 7.35 (dd, J = 1.8, 0.9 Hz, 1H), 6.31 (dd, J = 3.3, 1.8 Hz, 1H), 6.28 (dt, J = 3.3, 0.8 Hz, 1H), 5.02 (s, 1H), 2.03 – 1.99 (m, 1H), 1.94 (ddd, J = 13.7, 10.6, 3.5 Hz, 1H), 1.84 (d, J = 0.8 Hz, 3H), 1.65 (dddd, J = 13.4, 7.3, 3.3, 1.2 Hz, 2H), 1.54 – 1.42 (m, 2H), 1.32 (s, 4H).13C NMR (151 MHz, CDCl3): δ = 154.1, 141.2, 141.0, 112.1, 110.5, 107.5, 76.4, 46.9, 34.3, 31.5, 30.0, 27.0, 19.1. Carbonylation reaction (step 6): In a 25 mL Schlenk flask, a mixture of the vinyl iodide (0.057 g, 0.18 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.013 g, 0.018 mmol) and potassium carbonate anhydrous (0.075 g, 0.54 mmol) in anhydrous N,N-dimethylformamide (1.2 mL) was degassed via three cycles of “freeze-pump-thaw”. The reaction vessel was filled with carbon monoxide using a balloon, and was then heated to 100 °C in an oil bath for 16 h. After cooling to room temperature, brine (10 mL) and ethyl acetate (10 mL) were added and the layers were separated. The aqueous layer was then extracted with ethyl acetate (2 10 mL). The combined organic layers were washed with an aqueous solution of LiCl (5%), dried with sodium sulfate, and concentrated under reduced pressure. The crude material was purified by column chromatography using silica gel and hexane / ethyl acetate (95:5) to obtain the lactone product (Example 18) as a white solid (21 mg, 50%).1H NMR (400 MHz, CDCl3): δ = 7.41 (dd, J = 1.8, 0.9 Hz, 1H), 6.42 (dt, J = 3.3, 0.9 Hz, 1H), 6.39 (dd, J = 3.3, 1.8 Hz, 1H), 4.92 (d, J = 0.9 Hz, 1H), 2.33 – 2.15 (m, 2H), 2.13 (d, J = 0.9 Hz, 3H), 1.93 (dt, J = 12.4, 3.4 Hz, 1H), 1.89 – 1.79 (m, 1H), 1.74 (ddtd, J = 17.5, 14.0, 7.0, 3.4 Hz, 1H), 1.50 (td, J = 13.0, 4.0 Hz, 1H), 0.88 (d, J = 0.6 Hz, 3H).13C NMR (101 MHz, CDCl3): δ = 169.4, 149.7, 149.1, 142.4, 126.9, 110.3, 108.0, 83.4, 43.4, 32.1, 31.9, 20.5, 18.5, 18.3. HRMS (ESI) m / z calcd for C14H16O3 ([M+H]+) 233.1172, found 233.1169. Example 19. Preparation of: Example 19 and Example 20 were synthesized with the following route. To an oven-dried 250 mL round-bottom flask was added, 2,4-pentadienoic acid (1g, 10.2 mmol, 1 eqv), and p-Toluensulfonic acid monohydrate (0.053g, 0.31 mmol, 0.03 eqv), which was then pumped / backfilled three times with nitrogen. To the mixture, 3 mL (51 mmol, 5 equivalents) of ethanol was added and connected to a Dean-Stark apparatus along with a condenser. The reaction mixture was then refluxed overnight for 18 hours. After cooling to room temperature, the mixture was extracted with water and diethyl ether (3 ^ 10 mL). The organic layer was dried with Na2SO4 and purified on column chromatography using diethyl ether: hexane (2:8) to obtain compound the ester as an oil (0.520 g, 40%).1H NMR (500 MHz, Chloroform-d) δ 7.28-7.24 (m, 1H), 6.48-6.42 (m, 1H), 5.90 (d, J = 15.5, 0.9 Hz, 1H), 5.60 (d, 1H), 5.50 (d, 1H), 4.20 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1Hz, 3H). An oven-dried 100 mL round bottom flask was pumped / backfilled with nitrogen three times before methacrolein (0.073 g, 1.044 mmol, 1.49 eqv) and boron trifluoride diethyl etherate (0.11 mL, 0.969 mmol, 1 eqv) were added. The mixture was stirred for 10 minutes at room temperature before the ester (0.088g, 0.7 mmol, 1 eqv) was added dropwise. The reaction mixture was then stirred for 21 hours. The crude was concentrated under reduced pressure and dried further under high vacuum to obtain compound the Diels-Alder product as an oil (0.129 g, 94%). NMR data were in accordance with literature values (Tokoroyama, T. et al., J Chem Soc, Perkin Trans I 1981, 1556- 1562).1H NMR (600 MHz, Chloroform-d) δ 9.70 (d, J = 1.1 Hz, 1H), 5.90 (dt, J = 9.9 Hz, 3.1 Hz, 1H), 5.80 (ddd, J = 10.2, 4.4, 2.6 Hz, 1H), 4.50 – 4.00 (m, 2H), 3.10 (t, J = 3.5 Hz, 1H), 2.14 (ddd, J = 20.7, 6.3, 3.5 Hz, 2H), 2.08 – 2.04 (m, 1H), 1.69 (dt, J = 12.5, 5.7 Hz, 1H), 1.26 (td, J = 7.1, 1.1 Hz, 3H), 1.12 (d, J = 2.0 Hz, 3H). An empty 100 mL round bottom flask was oven-dried and backfilled three times with nitrogen. n-BuLi (0.21 mL, 0.526 mmol, 1 eqv) and dry ether (5 mL) were added and placed in an acetone-dry ice bath to cool to -78 °C.3-bromofuran (47 µL, 0.526 mmol, 1 eqv) was added and allowed to stir at that temperature for 20 minutes. Afterward, the Diels-Alder product (0.102 g, 0.5216 mmol, 1 eqv) was dissolved in dry THF and added dropwise within 3 minutes, and stirred for 3 hours at room temperature. The reaction mixture was quenched using HCl after 3 hours and extracted with diethyl ether (3 ^ 10 mL). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated under reduced pressure. The crude was purified on column chromatography using hexanes:diethyl ether (1:1) and preparative TLC with diethyl ether:hexanes (1:3) as the mobile phase to afford diastereomer 1 (0.0126 g, 11% yield) and diastereomer 2 (0.0127 g, 11% yield). Diastereomer 11H NMR (600 MHz, Chloroform-d) δ 7.43 (d, J = 1.7 Hz, 1H), 7.40 (s, 1H), 6.31 (s, 1H), 6.08 – 5.90 (m, 1H), 5.77 (ddt, J = 10.0, 4.1, 2.0 Hz, 1H), 5.22 (s, 1H), 2.91 (dd, J = 4.4, 2.4 Hz, 1H), 2.18 (dt, J = 6.6, 3.3 Hz, 2H), 1.87 – 1.71 (m, 1H), 1.62 – 1.57 (m, 1H), 0.89 (d, J = 1.3 Hz, 3H). Example 20. Preparation of: Following the procedure described above for Example 19, the second separable diastereomer 2 was isolated as a colorless oil (0.0127 g, 11% yield). Diastereomer 21H NMR (600 MHz, chloroform-d) δ7.46 (s,1H), 7.44 (m,1H), 6.37 (d, J = 2.0 Hz, 1H), 5.93 (d, J = 11.5Hz, 1H), 5.88 (m, 1H), 5.14 (d, J = 3.2 Hz, 1H), 2.90(d, J = 4.9 Hz, 1H), 2.3 (td, J = 7.5, 3.2 Hz, 1H), 2.10. – 2.0 (m, 2H), 1.2 (s, 3H). Example 21. Preparation of: To an oven-dried 100 mL round bottom flask, was added compound 5 (0.054g, 0.21 mmol, 1 eqv) and evacuated / backfilled three times with nitrogen. To the round bottom flask added dry CH2Cl2 (8 mL), this was cooled to 0 ºC for 10 minutes and diethyl zinc (0.08g, 0.63 mmol, 3 eqv) was added and allowed to stir at 0 °C for an additional 10 minutes. Diiodomethane (0.17 g, 0.63 mmol, 3 eqv) was added dropwise and the mixture was allowed to stir for 48 hours.1M HCl (10 mL) was used to quench the reaction and extracted with diethyl ether (3 ^ 15 mL). The combined extracts were washed with brine, dried with Na2SO4, and concentrated under reduced pressure. The crude was purified using column chromatography using diethyl ether:hexanes (1:1) as mobile phase to obtain the cyclopropane intermediate as a white amorphous solid (0.020 g, 35%).1H NMR (600 MHz, Chloroform-d) δ 7.48 (s, 1H), 7.41 (d, J = 1.5 Hz, 1H), 6.97 (s, 1H), 6.45 (d, J = 1.7 Hz, 1H), 5.43 (s, 1H), 3.06 (d, J = 17.0 Hz, 1H), 2.88 (d, J = 17.2 Hz, 1H), 1.92 (dq, J = 13.3, 6.9, 5.8 Hz, 1H), 1.74 (d, J = 5.9 Hz, 2H), 1.17 (s, 3H), 1.15 – 1.08 (m, 2H), 0.92 (s, 3H), 0.73 (t, J = 5.3 Hz, 1H), 0.44 (dd, J = 9.0, 4.9 Hz, 1H). To an oven-dried 100 mL round bottom flask, was added compound the cyclopropane intermediate (0.02g, 0.07 mmol, 1 eqv). The round bottom flask was evacuated / backfilled three times with nitrogen. To the round bottom flask added dry THF (3 mL) and 0.02ml of pyridine. The reaction mixture was cooled to 0 °C and allowed to stir for 10 minutes. SOCl2 (0.01 mL, 0.15 mmol, 2.1 eqv) was then added and the reaction mixture was stirred for 5 minutes. Ice cubes were then added to the mixture and warmed to room temperature. The mixture was extracted with dichloromethane (3 ^ 10 mL) and washed with 2N HCl, 5% Na2CO3, and brine. The extract was further dried with Na2SO4 and purified on a column using diethyl ether:hexanes (1:1) to obtain the final cyclopropane product (Example 21) as a white solid (0.0103 g, 55%).1H NMR (600 MHz, Chloroform-d) δ 7.45 (s, 1H), 7.40 (s, 1H), 6.43 (s, 1H), 5.97 (s, 1H), 5.05 (s, 1H), 1.95 – 1.86 (m, 1H), 1.70 – 1.59 (m, 2H), 1.52 – 1.40 (m, 2H), 1.28 (s, 3H), 1.14 (t, J = 5.4 Hz, 1H), 1.05 (s, 3H), 1.01 – 0.94 (m, 1H).

[0004] Example 22. Preparation of: In a 25 mL Schlenk flask, a mixture of vinyl iodide intermediate (16.1 mg, 0.05 mmol), bis(triphenylphosphine)palladium(II) dichloride (3.2 mg, 0.005 mmol) and potassium carbonate anhydrous (20.7 mg, 0.150 mmol) in anhydrous N,N-dimethylformamide (0.33 mL) was degassed via three cycles of “freeze-pump-thaw”. The reaction vessel was filled with carbon monoxide using a balloon, and was then heated to 105 °C in an oil bath for 20 h. After cooling to room temperature, brine (5 mL) and ethyl acetate (5 mL) were added and the layers were separated. The aqueous layer was then extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with an aqueous solution of LiCl (5%), dried with sodium sulfate, and concentrated under reduced pressure. The crude material was purified by column chromatography using silica gel and hexane / ethyl acetate (90:10) to obtain the final compound Example 22 (7.5 mg, 65%). 1H NMR (500 MHz, Chloroform-d) δ 8.82 (d, J = 2.08 Hz, 1H), 7.45 (dd, J = 2.18, 1.17 Hz, 1H), 5.19 (s, 1H), 2.27 (d, J = 6.67 Hz, 1H), 2.24 – 2.18 (m, 1H), 1.86 (dddd, J = 12.18, 5.97, 3.37, 1.68 Hz, 2H), 1.74 (ddq, J = 13.11, 6.53, 3.26 Hz, 1H), 1.68 (dd, J = 12.10, 3.25 Hz, 1H), 1.55 (s, 3H), 0.71 (s, 3H).13C NMR (126 MHz, Chloroform-d) δ 169.66, 153.49, 149.52, 127.34, 123.75, 115.01, 86.26, 43.41, 32.44, 29.86, 20.44, 18.71, 18.42. Example 23. Preparation of: In an oven-dried 100 mL round bottom flask, 88.1 mg (0.4 mmol, 6 eqv) of trimethylsolfoxonium iodide was added and backfilled with nitrogen three times. Next, 3 mL of dimethyl sulfoxide (DMSO) was added, followed by potassium bis(trimethyl)silyl amide (83 µL, 0.4 mmol, 5.7 eqv). The reaction mixture was stirred at room temperature for 1 hour. Afterward, the unsaturated lactone (16.3 mg, 0.07 mmol, 1 eqv) was added dropwise and allowed to stir for 3 days, ultimately quenched with ice and 1M HCl. The heterogenous reaction mixture was extracted with diethyl ether (3 × 15 mL). The combined extract was washed with 1M NaOH, and brine, and concentrated under reduced pressure. The crude extract was purified using column chromatography using diethyl ether:hexanes (1:1) to obtain the desired compound as a white solid (8.6 mg, 48%).1H NMR (600 MHz, Chloroform-d) δ 7.48-7.43 (m, 1H), 7.40 (s, 1H), 6.42 (d, J = 1.8 Hz, 1H), 6.06 (s, 1H), 4.99 (s, 1H), 1.99 (tt, J = 13.7, 4.9 Hz, 1H), 1.88-1.82 (m, 1H), 1.31 (s, 3H), 1.22 – 1.13 (m, 2H), 1.10 (dd, J = 13.6, 5.0 Hz, 1H), 1.04 (s, 3H), 0.81 (dd, J = 8.3, 4.9 Hz, 1H), 0.71 (t, J=5.4 Hz, 1H). Example 24. Preparation of: An empty 100 mL round bottom flask was oven-dried and backfilled three times with nitrogen. To it was added the unsaturated lactone (0.103 g, 0.422 mmol, 1 eqv), OsO4 (10.73 mg, 10 mol %,) and allowed to stir in acetone: tert-butanol: water (1:1:1). The reaction temperature was reduced to 0 °C using ice and allowed to stir for 10 minutes. After 10 minutes, NMO (0.13 mL, 1.5 eqv) was added dropwise and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched using NaHSO3 and extracted with ethyl acetate (3 ^ 15 mL). The combined organic layers were combined, washed with brine, dried with Na2SO4, and concentrated under reduced pressure. The crude was purified on column chromatography using hexane: diethyl ether (1:1) to afford the diol product (Example 24) as a white solid (0.109 g, 93%).1H NMR (600 MHz, chloroform-d) δ7.51-7.50 (m,1H), 7.42 (d, J= 1.71 Hz, 1H), 6.49 (s, 1H), 6.47-6.43 (m, 1H), 5.12 (s, 1H), 3.85 (t, J = 2.74 Hz, 1H), 2.74 (s, 1H), 2.37 (s, 1H), 1.94-1.88 (m, 2H), 1.46 (s, 3H), 1.26 (dd, J= 7.52, 2.29 Hz, 2H), 1.14 (s, 3H). Example 25. To a 20 mL-glass vial equipped with a magnetic stir bar, the unsaturated lactone (0.039 g, 0.15 mmol, 1 eqv) and palladium on carbon (11.6 mg, 30% w / w) were added and the mixture was first evacuated / backfilled with nitrogen three times. Dry ethanol (4 mL) was then added, and the mixture was flushed with hydrogen gas using a balloon. The resulting mixture was stirred at room temperature until TLC showed the full consumption of the starting material (ca.2 h). The reaction mixture was filtered using Celite and was sequentially washed with diethyl ether and dichloromethane. The filtrate was concentrated under reduced pressure and purified by column chromatography to yield the reduced product (Example 25) as a white solid (0.013 g, 35%, relative stereochemistry at the methyl group not determined).1H NMR (500 MHz, Chloroform-d) δ 7.46 (dt, J = 1.6, 0.7 Hz, 1H), 7.42 (t, J = 1.7 Hz, 1H), 6.43 (dd, J = 1.9, 0.9 Hz, 1H), 6.25 (s, 1H), 5.04 (s, 1H), 3.40 (t, J = 2.9 Hz, 1H), 2.00 (dd, J = 5.6, 3.0 Hz, 1H), 1.54 (s, 3H), 1.51 – 1.36 (m, 2H), 1.16 (s, 3H), 0.88 (t, J = 6.9 Hz). Preparation of Comparison Compound The Comparison Compound has the following structure. The Comparison Compound was prepared as illustrated below. The aldol product was synthesized according to a modified literature procedure from Fernández-Mateos (Fernández-Mateos, A.; de la Fuente Blanco, J. A. J. Org. Chem.1991, 56, 7084–7092). In a round-bottom flask equipped with a magnetic stir bar, diisopropylamine (0.672 g, 0.937 mL, 6.64 mmol) was dissolved in anhydrous diethyl ether (12.08 mL). The solution was cooled down to 0 °C, and then n-BuLi (2.5 M in hexane, 2.66 mL, 6.64 mmol) was added dropwise. The resulting solution was allowed to stir at this temperature for 15 minutes. Then, the reaction mixture was cooled down to -78 °C, and 2,6-dimethylcyclohexanone (0.75 g, 0.811 mL, 6.04 mmol) was added dropwise. After 20 minutes, freshly distilled benzaldehyde (0.64 g, 0.615 mL, 6.04 mmol) was added dropwise at -78 °C and stirred for 1 minute before quenching the reaction mixture with saturated NH4Cl solution (12 mL). After stirring at 25 °C for an hour, the reaction mixture was extracted with diethyl ether (3 x 20 mL), and the combined organic layers were washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel and hexane / ethyl acetate (9:1) as the eluent to afford the aldol product (1.097 g, 78%).1H NMR (500 MHz, CDCl3): ^ = 7.33- 7.29 (m, 4H), 7.29 – 7.27 (m, 1H), 4.92 (s, 1H), 4.21 (s, 1H), 2.80 – 2.71 (m, 1H), 2.11 – 2.05 (m, 1H), 1.83 -1.72 (m, 1H), 1.67 – 1.56 (m, 2H), 1.43 – 1.31 (m, 1H), 1.31 – 1.28 (m, 1H), 1.24 (s, 3H), 1.05 (d, J = 6.4 Hz, 3H). To an ethanolic solution (4.97 mL) of aldol product (0.52 g, 2.34 mmol), hydrazine monohydrate (3.476 g, 3.37 mL, 69.44 mmol) and acetic acid (1.184 g, 1.11 mL, 19.72 mmol) were added, and the resulting mixture was heated to 42 °C for 3.5 h. After cooling to 25 °C, water (3.0 mL) and ethyl acetate (3.0 mL) were added. The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 x 3.0 mL). The combined organic layers were washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. The crude material was dissolved in ethyl acetate, quickly passed through a short plug of silica, and concentrated under reduced pressure. The crude hydrazine was azeotropically dried with benzene and used for the next step without further purification (422.7 mg, 73%). The resulting hydrazine (422.7 mg, 1.71 mmol) and anhydrous triethylamine (1.696 g, 2.33 mL, 16.758 mmol) were dissolved in anhydrous tetrahydrofuran (19 mL), followed by the dropwise addition of a solution of iodine (1.692 g, 6.669 mmol) in anhydrous tetrahydrofuran (11.9 mL). The addition of iodine was continued until the brown color of the solution remained stable for around 30 sec. The reaction mixture was then diluted with ethyl acetate (5 mL) and washed with saturated sodium thiosulfate solution (3 mL). The aqueous layer was extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel and hexane / ethyl acetate (80:20) to afford the vinyl iodide intermediate (198 mg, 34%).1H NMR (500 MHz, CDCl3): ^ = 7.54 – 7.46 (m, 2H), 7.32 – 7.19 (m, 3H), 5.13 (s, 1H), 1.99 – 1.90 (m, 2H), 1.85 (s, 3H), 1.77 (dt, J = 17.2, 5.7 Hz, 2H), 1.46 (ddd, J = 13.7, 10.2, 3.6 Hz, 2H), 1.34 (s, 3H). In a 25 mL Schlenk flask, a mixture of vinyl iodide (17 mg, 0.05 mmol), bis(triphenylphosphine)palladium(II) dichloride (3.51 mg, 0.005 mmol) and potassium carbonate anhydrous (23 mg, 0.163 mmol) in anhydrous N,N-dimethylformamide (0.36 mL) was degassed via three cycles of “freeze-pump-thaw”. The reaction vessel was filled with carbon monoxide using a balloon, and was then heated to 105 °C in an oil bath for 20 h. After cooling to room temperature, brine (5 mL) and ethyl acetate (5 mL) were added and the layers were separated. The aqueous layer was then extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with an aqueous solution of LiCl (5%), dried with sodium sulfate, and concentrated under reduced pressure. The crude material was purified by column chromatography using silica gel and hexane / ethyl acetate (95:5) to obtain the comparison compound (8.3 mg, 68%).1H NMR (500 MHz, CDCl3): ^ = 7.40 – 7.30 (m, 5H), 4.99 (s, 1H), 2.28 (dd, J = 19.8, 6.8 Hz, 1H), 2.22 – 2.17 (m, 1H), 2.16 (s, 3H), 1.88 – 1.80 (m, 2H), 1.77 – 1.66 (m, 1H), 1.62 – 1.55 (m, 1H), 0.69 (s, 3H) .13C NMR (101 MHz, CDCl3): ^ = 170.16, 148.58, 135.97, 128.41, 128.04, 127.94, 125.65, 88.53, 43.75, 32.21, 32.10, 20.39, 18.65, 18.33. Example 26. Biological Data Protection against Glu toxicity in PC12 and SH-SY5Y cells. Previous reports demonstrated treatment with fraxinellone prior to Glu significantly protected against toxicity in vitro (Yoon, J. S. , et al., J Mol Neurosci 2010, 42 (1), 9-16). These findings were further explored using two different neuronal-like cell lines, i.e., PC12 (rat) and SH-SY5Y (human), as in vitro models. Initially, the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay was used to monitor the viability of both cell lines incubated with fraxinellone, the Comparison Compound, and the compound of Example 1 for 24 hours to verify cell viability is minimally impacted at concentrations used in experiments.24-Hour treatment with Glu reduced viability of PC12 cells by roughly 40-50% (Figure 2A) and SH- SY5Y cells by roughly 50% (Figure 2B), as measured by MTT. Given this, the activity of fraxinellone and several other compounds against Glu- mediated toxicity (i.e., 100 μM Glu, 24 hours) was determined in PC12 and SH-SY5Y cells (Kritis, A. A. , et al., Front Cell Neurosci 2015, 9, 91). A 30-minute pre-treatment with fraxinellone at ≤1 μM did not provide any significant protection against Glu toxicity in PC12 (Figure 3A) or SH-SY5Y cells (Figure 3B). Fraxinellone at significantly higher concentrations (i.e., μM range) mitigated Glu-mediated toxicity for PC12 cells (data not shown), as seen in previous reports (Jeong, G. S. , et al., Arch Pharm Res 2010, 33 (8), 1269-1275). It was also found that pre-treatment with Comparison Compound did not provide protection against Glu toxicity in PC12 (Figure 3C) or SH-SY5Y (Figure 3D) cells; however, incubation with the compound of Example 1 prior to addition of Glu yielded significant protection in a dose- dependent manner in both PC12 (Figure 3E) and SH-SY5Y cells (Figure 3F). For this compound, an EC50 of 44 nM and 39 nM was measured for PC12 and SH-SY5Y cells, respectively. Of note, fraxinellone and the other two compounds were washed from the cells following the 30 minute incubation, thereby indicating significant cellular uptake and / or potent and rapid interaction with the molecular target(s). To enhance rigor of the work, the cell viability experiments were repeated using an assay for an alternative endpoint, i.e., ATP production. Using a commercial kit, cell viability (i.e., ATP) was measured following pre-treatment with the compound of Example 1 (columns 3-6 from the left) or Comparison Compound (columns 7-10 from the left) for 30 minutes followed by Glu for 24 hours in PC12 cells. This experiment yielded similar results to the MTT assay, as the compound of Example 1 (EC50= 45 nM) provided significant protection against the Glu insult, but Comparison Compound did not (Figure 4). Protection against the toxicant rotenone in PC12 cells. To test whether protection afforded by the compound of Example 1 is generalizable and applicable to other oxidative insults, rotenone treatment was employed as a model toxicant using the same methods as previously reported (Bailly, C.; Vergoten, G., Pestic Biochem Physiol 2020, 168, 104624). Rotenone is a neurotoxicant used in vitro and in vivo to model parkinsonism with a mechanism of action involving potent inhibition of Complex 1, yielding mitochondrial ROS and a loss of matrix NAD production (Radad, K. , et al., Neurochem Int 2006, 49 (4), 379-386; and Harris, G. , et al., Arch Toxicol 2018, 92 (8), 2587-2606). Cell viability was assessed following treatment with rotenone, a widely used pesticide, at a range of doses (Figure 5A). The activities of the compound of Example 1 and Comparison Compound were investigated against rotenone at a low (0.1 ^M) (Figure 5B) and high (1 ^M) (Figure 5C) dose. The cells were pre-treated with the compound of Example 1 or the Comparison Compound for 30 minutes and then washed cells before incubating with rotenone for 12 hours. The compound of Example 1 significantly protected against 0.1 ^M rotenone at as low as 0.05 ^M, whereas the Comparison Compound did not. The compound of Example 1 also significantly protected against 1.0 ^M rotenone at as low as 0.1 ^M, whereas the Comparison Compound did not. These results suggest a broader application of the compounds of formulas (I)-(VIII) against different modulators of oxidative cell death, and in this case, one that targets the mitochondria (Complex 1); however, higher concentrations were needed to mitigate rotenone-mediated loss of cell viability compared to that seen following Glu treatment. Mitigation of time-dependent ROS production following Glu treatment. The ability of the compound of Example 1 to reduce Glu-mediated ROS production in PC12 cells, thereby, providing cytoprotection (Eruslanov, E.; Kusmartsev, S., Methods Mol Biol 2010, 594, 57-72) was investigated. In untreated cells (open circle), accumulation of ROS occurred over the course of 24 hours as measured using DCFDA (Figure 6). PC12 cells showed a significant increase in ROS as early as 4 hours following Glu exposure alone (open square). Treatment with Comparison Compound prior to Glu did not attenuate oxidative stress in Glu- treated cells (black hexagon); however, incubation with the compound of Example 1 before the Glu insult significantly attenuated ROS production as early as 2 hours (grey triangle), indicating the compound of Example 1 rapidly reduces oxidative stress caused by Glu. Interestingly, treatment with the compound of Example 1 alone (in the absence of excess Glu) also significantly reduced basal ROS production in PC12 cells as early as 2 hours (black triangle) whereas Comparison Compound did not (diamond). Collectively, these results demonstrate that the compound of Example 1 rapidly attenuates Glu-induced oxidative stress in PC12 cells in a time-dependent manner (Figure 6). To visualize ROS production and mitigation, SH-SY5Y cells were pre-treated with 1 or 10 μM SFN or 100 nM of the Comparison Compound or the compound of Example 1 for 30 minutes prior to incubation with 100 μM Glu. ROS was detected via CellROX after 4hours with 100 μM Glu or 10 μM menadione (positive control). As shown in Figure 7, pre-treatment with either 10 μM SFN or 100 nM. The compound of Example 1 yielded significant reduction in CellROX staining, even less than that observed for the negative control. Pre-treatment with the compound of Example 1 enhances expression of several antioxidant genes, a key mechanism of Nrf2 activation. In reasoning a mechanism of action for the compound of Example 1, the following were considered: 1) direct antioxidant activity; 2) Glu receptor antagonism; 3) activation of the Nrf2 antioxidant response. Given the potency of the compound of Example 1 (i.e., 44 and 39nM) in the presence of an excess of Glu (i.e., 100 μM), it was unlikely that direct antioxidant activity played a key role in its mechanism of protection. In addition, the compound’s structure does not feature common antioxidant motifs, such as a free thiol, a hydroxylated chromane ring or a polyphenol (Flora, S. J., Oxid Med Cell Longev 2009, 2 (4), 191-206). With the lack of a nitrogen atom, it seemed unlikely that the compound of Example 1was an effective Glu receptor antagonist. The structure of the compound appeared dissimilar to other known Glu antagonists, such as ketamine, memantine and riluzole (Niciu, M. J. , et al., Annu Rev Pharmacol Toxicol 2014, 54, 119-139). Based on such rationale, the possibility that Nrf2 activation was a mechanistic target for the compound of Example 1 was investigated. The antioxidant response is primarily regulated by the transcription factor Nrf2 binding to the antioxidant response element (ARE) sequences within the promoter region of target genes to induce their expression (Nguyen, T. , et al., J Biol Chem 2009, 284 (20), 13291-13295; and Ma, Q., Annu Rev Pharmacol Toxicol 2013, 53, 401- 426). Since the compound of Example 1 potently and rapidly mitigates Glu-mediated ROS production, it was investigated whether the mechanism of action of the compound of Example 1 involved activation of Nrf2, whether (either) upstream or downstream. qPCR was used to show the compound of Example 1 induces expression of Nrf2 target genes including Gpx4, Nqo1, and Sod1, whereas inactive Comparison Compound did not, as a control (Rosarda, J. D. , et al., ACS Chem Biol 2021, 16 (12), 2852-2863). Incubation with the compound of Example 1 (center column) alone significantly increased expression of Gpx4 (Figure 8A), Nqo1 (Figure 8B), and Sod1 (Figure 8C) after 4 hours whereas Comparison Compound (right column) did not. Pre-treatment with the compound of Example 1 (third and fourth columns from the left) followed by incubation with Glu for 4 hours increased expression of Gpx4 (Figure 9A), Nqo1 (Figure 9B), and Sod1 (Figure 9C) whereas Comparison Compound (fifth and sixth columns from the left) did not. Lastly, pre-treatment with the compound of Example 1 (fourth and eighth columns from the left) followed by Glu for 1 or 2 hours enhanced expression of Gpx4 (Figure 10) in a time- dependent manner whereas Comparison Compound (third and seventh columns from the left) did not. As noted in Figure 10, the increase in gene expression was seen as early as 1hour following incubation. These data indicate the compound of Example 1 strongly and rapidly enhances ARE expression alone or in response to elevated levels of Glu, with the mechanism of action likely through Nrf2 activation, and in a time-dependent manner. To confirm induction of protein expression, Western blog analysis was performed demonstrating treatment of PC12 cells with the compound of Example 1 but not Comparison Compound yields increased levels of GPX4. The cytoprotective activity of the compound of Example 1 can be replicated using SFN, a Nrf2 activator. Nrf2 activity is regulated through its interaction with redox sensor E3 ligase protein KEAP1. KEAP1 promotes the ubiquitination of Nrf2 in the absence of oxidative stress; however, in response to inflammatory, environmental, or oxidative stressors, sensor Cys residues on KEAP1 are covalently modified by these stressors, thus stabilizing Nrf2 to promote its transcriptional activity (Ma, Q., Annu Rev Pharmacol Toxicol 2013, 53, 401-426; and Liu, P.; , et al., Cell Chem Biol 2019, 26 (10), 1427-1435 e1425). A notable Nrf2 activator is SFN, an isothiocyanate that readily induces KEAP1-Nrf2 signaling and enhancement of ARE gene expression (Houghton, C. A. , et al., Oxid Med Cell Longev 2016, 2016, 7857186). SFN was used as a positive control for protection against Glu-excitotoxicity through Nrf2 activation, and furthermore. Results in Figure 11 represent outcomes of experiments involving pre-treatment with SFN or test compounds before addition of 100 μM Glu for 24 hours. As shown in Figure 11, SFN replicated the protective activity of the compound of Example 1; however, higher concentrations of SFN were required (1 and 10 ^M) for significant protection, compared to the compound of Example 1 (50 and 100 nM). The Comparison Compound showed no activity. In addition, to achieve measurable and significant activity of SFN, the treatment protocol needed to be modified to remove the wash step prior to the 30 minute pre-treatment. Washing the cells prior to addition of 100 μM Glu significantly attenuated the protective activity of SFN. The Nrf2 inhibitor ML-385 antagonizes the activity of the compound of Example 1. Upon activation, Nrf2 readily accumulates in the cytosol followed by translocation to the nucleus. Once in the nucleus, Nrf2 interacts with sMaf proteins to form the Nrf2-MafG protein complex, which is required for Nrf2 to bind the ARE and induce expression of antioxidant genes. ML-385 is a Nrf2 inhibitor that blocks downstream ARE-mediated gene expression by disrupting the formation of the Nrf2-MafG complex, thereby preventing the binding of Nrf2 to the ARE (Singh, A, et al., ACS Chem Biol 2016, 11 (11), 3214-3225). To further demonstrate involvement of Nrf2 activation in the mechanism of action of the compound of Example 1, ML- 385 was employed in experiments to determine whether or not it antagonized the protective activity of the compound of Example 1. As shown in Figure 12, pre-treatment with ML-385 significantly attenuated protection towards Glu excitotoxicity afforded by the compound of Example 1. Interestingly, ML-385 augmented the toxicity of Glu, likely by antagonizing the basal Nrf2 response. Treatment with the compound of Example 1 induces nuclear translocation of Nrf2 and binding to the ARE. To further elucidate the mechanism of action for the compound of Example 1, the Nrf2 DNA-binding activity from cells treated with SFN was assessed with the compound of Example 1 and the Comparison Compound. Following incubation with SFN, the compound of Example 1, or Comparison Compound for 1 hour (Figure 13A) or 4 hours (Figure 13B), enhancement of Nrf2 nuclear translocation and DNA-binding is seen in cells treated with the positive control, SFN (1 and 10 μM) and the compound of Example 1 (50 and 100 nM). Nrf2 translocation is greater in cells treated with 100 nM of the compound of Example 1 for 4 hours when compared to the positive control (SFN). Enhancement of Nrf2 expression is also seen in cells treated with 1 and 10 ^M SFN at both 1 and 4 hours, but not as great as compared to the compound of Example 1. Treatment with Comparison Compound at both time points yielded similar results to the untreated control, indicating no activation of Nrf2. These findings demonstrate that treatment of cells with the compound of Example 1 yields Nrf2 nuclear translocation and binding to the ARE. The compound of Example 1 likely activates Nrf2 in a thiol-independent manner. N-acetylcysteine (NAC) is a reactive thiol scavenger that serves as a precursor to L- cysteine, resulting in elevated biosynthesis of glutathione (Mokhtari, V. , et al., Cell J 2017, 19 (1), 11-17; and Zhitkovich, A., Chem Res Toxicol 2019, 32 (7), 1318-1319). To determine the thiol-dependence for the protective activity of the compound of Example 1, cells were treated with 1 mM NAC for 1 hour followed by incubation with SFN or the compound of Example 1 for 4 hours. Treatment with SFN or the compound of Example 1 alone increased expression of GPX4 (Figure 14A), NQO1 (Figure 14B), and SOD1 (Figure 14C) after 4 hours; however, pre- treatment with 1 mM NAC for 1 hour completely antagonized gene expression by SFN but had no effect on the activity of the compound of Example 1. Since NAC readily reacts with thiols, it was predicted NAC would readily react with SFN, although it was unknown whether or not the thiol would block gene expression by the compound of Example 1. Such data suggest the compound of Example 1 is acting via a thiol-independent mechanism. Conclusion In summary, the compound of Example 1 protects against both endogenous (Glu) and exogenous (rotenone) toxicants through Nrf2 activation at nM concentrations. The compound of Example 1 decreased Glu-mediated ROS levels via inducing the expression of Nrf2-dependent genes GPX4, NQO1, and SOD1, whereas inactive Comparison Compound did not. These findings could be replicated via a known Nrf2 activator, SFN. ML-385, an inhibitor of the Nrf2- MafG complex binding the ARE, antagonized the activity of the compound of Example 1. SFN also enhances expression of AREs GPX4, NQO1, and SOD1. However, pre-treatment with NAC eliminates ARE enhancement in SFN treated cells but not the compound of Example 1 treated cells. Findings suggest the compound of Example 1 protects against exogenous and endogenous insults through Nrf2 activation and induction of an antioxidant response, potentially via a novel non-covalent mechanism (Figure 1). Materials and Methods Synthesis The Comparison Compound and the compound of Example 1 were synthesized starting from 2,6-dimethylcyclohexanone or cyclohexenone. Key steps involved a diastereoselective aldol reaction with 3-furaldehyde, alkene reduction, formation of a vinyl iodide and lactone formation. Cell Culture 4.2.1 PC12 rat cells were obtained from American Type Culture Collection (Manassas, VA, U.S.A.) and were grown in tissue culture flasks in RPMI 1140 supplemented with 10% horse serum, 5% fetal bovine serum (FBS), 1% penicillin / streptomycin at 37 ^C in a humidified atmosphere of 5% CO2. All experiments on these cells were performed between passage 9-14 to reduce inter-experimental variability. All cells were treated with equal volumes of DMSO prior to harvesting for analysis. 4.2.2 SH-SY5Y human neuroblastoma cells were obtained from American Type Culture Collection (Manassas, VA, U.S.A.) and were grown in Opti-MEM supplemented with 10% FBS, 1% MEM-nonessential amino acids, 1% penicillin / streptomycin, and 1mM sodium pyruvate at 37 ^C in a humidified atmosphere of 5% CO2. All experiments on these cells were performed between passage 8-10 to reduce inter-experimental variability. All cells were treated with equal volumes of DMSO prior to harvesting for analysis. Viability Assays Cell viability was assessed using Cell-Titer Glo reagent (Promega) or the colorimetric reagent, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) (Sigma Aldrich). Cell-Titer Glo was performed following the manufacturer’s protocol. For MTT analysis, cultures were incubated in HBSS / glucose with 2 mg / mL MTT for 2 hours at 37 ^C. Following incubation, 0.4 mL DMSO was added to each well to solubilize the formazan product. Reduced MTT was measured on a microplate reader (Molecular Devices Spectra Max 190) at 570nm with a reference of 650nm. Toxicity Cells were pre-treated with fraxinellone, the Comparison Compound, or the compound of Example 1 at a range of 0 to 1 ^M for 30 minutes. The compoundss were then washed from the cells before adding 100 ^M Glu for 24 hours. Cell-Titer Glo and MTT were both used to assess cell viability. Exogenous Toxicants Cells were pre-treated with the Comparison Compound or the compound of Example 1 at a range of 0 to 1 ^M for 30 minutes. The compounds were then washed from the cells before adding a low (0.1 ^M) or high (1.0 ^M) dose of Rotenone as previously described. MTT analysis was performed to assess cell viability. Quantification of ROS by DCFDA Fluorescence Cells were collected, resuspended in 10 mL fresh media containing 25 ^M DCFDA, and incubated for 30 minutes in this solution. DCFDA was then washed from the cells. The cells were then plated in a 96-well black plate non-treated (Thermo Fisher Scientific) and treated as previously described in 3.3.1. Images were taken on a BioTek Synergy 2 using ex.485 nm and em.535 / 30 channel at 0, 2, 4, 8, 12, and 24 hours. CellROX ROS production was detected using CellROX green reagent (Thermo Fisher). Briefly, SH-SY5Y cells were stained with 5 µM CellROX for 30 minutes prior to 30 minutes treatment with 1 or 10 µM SFN, or 100 nM the Comparison Compound or the compound of Example 1 and then exposure to 100 μM Glu for 4 hours. In addition, cells were incubated with 10 μM menadione as a positive control for ROS production. Following treatment, live cell images were taken to measure ROS production using Evos FL Auto 2 (Thermo Fisher). Cells were stained 15 minutes prior to imaging with NucBlue Live ReadyProbes Reagent. Quantitative PCR (qPCR) PC12 cells were subjected to two different experimental conditions. Cells were Pre- treated with the compound of Example 1, the Comparison Compound, or DMSO vehicle for 30 minutes before Glu for 1, 2, or 4 hours. Treated with SFN or the compound of Example 1 + / - NAC. Cells were then lysed, and total RNA was extracted using the RNeasy Mini Kit (Qiagen) according to the manufacturer’s instructions. RNA yield was quantified using Nanodrop (Thermo Fisher). cDNA was generated using from 2 ^g using High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems, cat.4311235). qPCR reactions were prepared using PowerUp SYBR Green PCR Master Mix (Applied Biosystems) and primers (Table 1) obtained from Integrated DNA Technologies. Amplifications were run in an Applied Biosystems QuantStudio 3 plate reader with an initial melting period of 95 ^C for 2 minutes and then 40 cycles of 2 minutes at 50 ^C, 2 minutes at 95 ^C, 15 seconds at 95 ^C, 15 seconds at 58 ^C, 1 minutes at 72 ^C, 15 seconds at 95 ^C, 1 minutes at 60 ^C, and 15 seconds at 95 ^C. Housekeeping genes used to normalize the control were TBP and ^-actin. Table 1: Forward and Reverse Primers Data for representative compounds of the invention is provided in the following Table.

[0005]

[0006] Example 27. The following illustrate representative pharmaceutical dosage forms, containing a compound of Formula (I)-(VIII) ('Compound X'), for therapeutic or prophylactic use in humans.

[0007] The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. All publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

Claims

CLAIMS What is claimed is:

1. A compound of Formula (I)-(VIII):or a salt thereof, wherein: R1 is H or a (C1-C6)alkyl that can optionally be substituted with one or more groupsindependently selected from the group consisting of halo; R2is a ring selected from the group consisting of 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocycle, and 6-membered heterocycle, which 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocycle, and 6-membered heterocycle is optionally substituted with one or more groups independently selected from the group consisting of halo, cyano, (C1-C6)alkyl that can optionally be substituted with one or more groups independently selected from the group consisting of halo, and (C1-C6)alkoxy that can optionally be substituted with one or more groups independently selected from the group consisting of halo; R3is H, (C1-C6)alkyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, or a hydroxy protecting group; andring A is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkylthio, and (C1-C6)alkoxycarbonyl, wherein any (C1-C6)alkyl, (C1-C6)alkoxy, (C1- C6)alkanoyl, (C1-C6)alkylthio, and (C1-C6)alkoxycarbonyl is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C1-C6)alkoxy, (C1-C6)alkanoyl, and (C1-C6)alkoxycarbonyl; provided the compound is not:

2. A compound of Formula (I) as described in claim 1 or a salt thereof.

3. A compound of Formula (I) as described in claim 1 or a salt thereof, wherein: R1is H or a (C1-C6)alkyl that can optionally be substituted with one or more groups independently selected from halo; R2is a ring selected from the group consisting of 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocycle, and 6-membered heterocycle; R3is H, (C1-C6)alkyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, or a hydroxy protecting group (e.g., trimethylsilyl or tert-butyl-dimethylsilyl); and ring A is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkylthio, and (C1-C6)alkoxycarbonyl, wherein any (C1-C6)alkyl, (C1-C6)alkoxy, (C1- C6)alkanoyl, (C1-C6)alkylthio, and (C1-C6)alkoxycarbonyl is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C1-C6)alkoxy, (C1-C6)alkanoyl, and (C1-C6)alkoxycarbonyl.

4. A compound of Formula (II) as described in claim 1 or a salt thereof.

5. A compound of Formula (III) as described in claim 1 or a salt thereof.

6. A compound of Formula (IV) as described in claim 1 or a salt thereof.

7. A compound of Formula (V) as described in claim 1 or a salt thereof.

8. A compound of Formula (VI) as described in claim 1 or a salt thereof.

9. A compound of Formula (VII) as described in claim 1 or a salt thereof.

10. A compound of Formula (VIII) as described in claim 1 or a salt thereof.

11. The compound or salt of any one of claims 1-3, wherein R1is (C1-C6)alkyl that can optionally be substituted with one or more groups independently selected from halo.

12. The compound or salt of any one of claims 1-3, wherein R1is (C1-C6)alkyl.

13. The compound or salt of any one of claims 1-3, wherein R1is methyl.

14. The compound or salt of any one of claims 1-13, R2is a ring selected from the group consisting of pyrazinyl, thienyl, thiazolyl, furyl, and tetrahydrofuryl.

15. The compound or salt of any one of claims 1-13, R2is a furyl ring.

16. The compound or salt of any one of claims 1-13, R2is a 2-furyl ring.

17. The compound or salt of any one of claims 1-13, R2is a 3-furyl ring.

18. The compound or salt of any one of claims 1-17, wherein the ring A is substituted with one or more groups.

19. The compound or salt of any one of claims 1-17, wherein the ring A is not substituted with one or more groups.

20. The compound or salt of claim 1, which is a compound of the following formula:or a salt thereof.

21. The compound or salt of claim 1, which is a compound of the following formula:or a salt thereof. 2 The compound or salt of claim 1, which is a compound of the following formula:or a salt thereof.

23. The compound or salt of claim 1, which is a compound of the following formula:or a salt thereof.

24. The compound or salt of claim 1, which is a compound of the following formula:or a salt thereof.

25. A pharmaceutical composition comprising a compound of Formula (I)-(VIII):or a pharmaceutically acceptable salt thereof, wherein: R1is H or a (C1-C6)alkyl that can optionally be substituted with one or more groups independently selected from the group consisting of halo; R2is a ring selected from the group consisting of 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocycle, and 6-membered heterocycle, which 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocycle, and 6-membered heterocycle is optionally substituted with one or more groups independently selected from the group consisting of halo, cyano, (C1-C6)alkyl that can optionally be substituted with one or more groups independently selected from the group consisting of halo, and (C1-C6)alkoxy that can optionally be substituted with one or more groups independently selected from the group consisting ofhalo; R3is H, (C1-C6)alkyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, or a hydroxy protecting group; and ring A is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkylthio, and (C1-C6)alkoxycarbonyl, wherein any (C1-C6)alkyl, (C1-C6)alkoxy, (C1- C6)alkanoyl, (C1-C6)alkylthio, and (C1-C6)alkoxycarbonyl is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C1-C6)alkoxy, (C1-C6)alkanoyl, and (C1-C6)alkoxycarbonyl; and a pharmaceutically acceptable excipient.

26. A pharmaceutical composition comprising a compound as described in any one of claims 1-24 or a pharmaceuticallly acceptable salt thereof and a pharmaceutically acceptable excipient.

27. A method for producing a neuroprotective effect in an animal comprising administering a compound as described in any one of claims 1-25 or a pharmaceutically acceptable salt thereof to the animal.

28. A method for producing neuroprotective activity against Glu excitotoxicity or oxidative stress in an animal comprising administering a compound as described in any one of claims 1-25 or a pharmaceuticallly acceptable salt thereof to the animal.

29. A method for treating multiple sclerosis, psoriasis, ALS, subarachnoid hemorrhage, Parkinson’s disease, Alzheimer’s disease, or Friedreich Ataxia in an animal comprising administering a compound as described in any one of claims 1-25 or a pharmaceuticallly acceptable salt thereof to the animal.

30. A method to mitigate damage from chemical exposure in an animal comprising administering a compound as described in any one of claims 1-25 or a pharmaceuticallly acceptable salt thereof to the animal prophylactically or post exposure.

31. A compound as described in any one of claims 1-25 or a pharmaceuticallly acceptable salt thereof to produce a neuroprotective effect in an animal.

32. A compound as described in any one of claims 1-25 or a pharmaceuticallly acceptable salt thereof to produce neuroprotective activity against Glu excitotoxicity or oxidative stress.

33. A compound as described in any one of claims 1-25 or a pharmaceuticallly acceptable salt thereof for treating multiple sclerosis, psoriasis, ALS, subarachnoid hemorrhage, Parkinson’s disease, Alzheimer’s disease, or Friedreich Ataxia.

34. A compound as described in any one of claims 1-25 or a pharmaceuticallly acceptable salt thereof to mitigate damage from chemical exposure prophylactically or post exposure.

35. The use of a compound as described in any one of claims 1-25 or a pharmaceuticallly acceptable salt thereof to prepare a medicament useful to produce a neuroprotective effect in an animal.

36. The use of a compound as described in any one of claims 1-25 or a pharmaceuticallly acceptable salt thereof to prepare a medicament useful to produce neuroprotective activity against Glu excitotoxicity or oxidative stress in an animal.

37. The use of a compound as described in any one of claims 1-25 or a pharmaceuticallly acceptable salt thereof to prepare a medicament useful for treating multiple sclerosis, psoriasis, ALS, subarachnoid hemorrhage, Parkinson’s disease, Alzheimer’s disease, or Friedreich Ataxia in an animal.

38. The use of a compound as described in any one of claims 1-25 or a pharmaceuticallly acceptable salt thereof to prepare a medicament useful to mitigate damage from chemical exposure in an animal prophylactically or post exposure.

39. A method to produce neuroprotective activity in an animal comprising activating Nrf2 without a covalent thio-modification.

40. A method to produce neuroprotective activity in an animal comprising activating Nrf2 with an agent that is not an electrophile.

41. A method to activate Nrf2 in a cell comprising contacting the cell with a compound as described in any one of claims 1-25 or a salt thereof.

42. A method comprising, activating Nrf2 in a cell by contacting the cell with a Nrf2 activating agent that is not an electrophile.

Images