Small molecule inhibitors of lanosterol synthase

Abstract

A composition for treating a neurological disease, comprising a lanosterol synthase inhibitor.

Description

[Background technology]

[0001] Introduction Glioblastoma (GBM) is the most common primary malignant brain tumor in the United States (Ostrom et al., 2019). The prognosis for GBM is poor, with a median survival of 12 months, which extends to 14 months with current standard-of-care treatment (Stupp et al., 2005). Standard treatment, consisting of surgical resection followed by radiation therapy and temozolomide, has demonstrated protective antitumor activity but is associated with relapse and tumor recurrence. One of the key factors contributing to the poor outcomes of GBM patients is the scarcity of effective treatments for GBM. Summary of the Invention [Means for solving the problem]

[0002] The present invention provides small molecule inhibitors of lanosterol synthase, a cholesterol biosynthetic enzyme. Inhibiting lanosterol synthase with the small molecule inhibitors of the present invention inhibits lanosterol biosynthesis, thereby inhibiting cholesterol biosynthesis. The small molecule inhibitors of the present invention divert biosynthesis toward the synthesis of the non-canonical sterol 24,25-epoxycholesterol (EPC). Upregulating EPC with small molecule inhibitors of lanosterol synthase can specifically and potently kill glioblastoma cell lines. The present invention also provides representative analogs of lanosterol synthase inhibitors that are capable of killing glioblastoma cell lines at low concentrations in the single-digit nanomolar range. In some embodiments, the inhibitors of the present invention are orally ingestible and / or brain-permeable. Furthermore, the present invention provides methods and compositions for treating glioblastoma, as well as methods and compositions for developing novel therapies for treating glioblastoma.

[0003] In one aspect, the present invention provides a method for producing a pharmaceutical composition comprising: Formula I: [ka] (In the formula, Q is selected from cyclopropane-1,2-diyl, CH2, (CH2)2, and O; X, Y, Z, and W are each independently selected from CR, N, and CH3; R is H or halogen (e.g., F, Cl, Br); X, Y, Z, and W may be fluorinated (e.g., CF3) or deuterated (e.g., CD3); L is -OCHRC(O)-[R=H, Me, CF3, CHF2, CH2F], -NHCH2C(O)-, -NHCHMeC(O)-, -NMeCH2C(O)-, -NMeCHMeC(O)-, -SCH2C(O)-, -SCHMeC(O)-, -CH2OC(O) -, -CHMeOC(O)-, -CH2NHC(O)-, -CHMeNHC(O)-, -OCH2NMeC(O)-, -CHMeNMeC(O)-, -CH2NHSO2-, -CHMeNHSO2-, -CH2NMeSO2-, -CMeNMeSO2-, -O(CH2) n -[n=0~2], -OCHMe-, -OCHMeCH2-, -OCH2CHR-[R=Me, OH, OMe, OCF3, OCHF2, OCH2F], -OCHMeCHR-[R=OH, OMe, OCF3, OCHF2, OCH2F], -(CH2) n C(O)-[n=0~2], -CHRCH2C(O)-[R=Me, OH, OMe, OCF3, OCHF2, OCH2F], -CH2CHRC(O)-[R=Me, OH, OMe, OCF3, OCHF2, OCH2F], -CHORCH 2n -[n=0~2;R=H, Me, CF3, CHF2, CH2F], -(CH2) n CHOR-[n=1-2; R=H, Me, CF3, CHF2, CH2F], -CHORCH2CHOR'-[R and R' are independently selected from H, Me, CF3, CHF2 and CH2F], -CHORCHMeCHOR'-[R and R' are independently selected from H, Me, CF3, CHF2 and CH2F], -CHORCMeCH2-[R=H, Me, CF3, CHF2, CH2F], -CH(OR)CH=CH-[R=H, Me, CF3, CHF2, CH2F], -(CH2)n -[n=0-3], -CH2NR-[R=H, Me]-, -CH=CHC(O)-, CH=CHCHR-[R=OH, OMe, OCF3, OCHF2, OCH2F], -CMe=CHC(O)-, CH=CMeC(O)-, CMe=CHCHOR-[R=H, Me, CF3, CHF2, CH2F], CH=CMeCHOR[R=H, Me, CF3, CHF2, CH2F], -C≡CC(O)-, -C≡CCHR[R=H, Me, OH, OMe, OCF3, OCHF2, OCH2F], -(cyclopropane-1,2-diyl)C(O)-, -(cyclopropane-1,2-diyl)CHR-[R=H , Me, OH, OMe, OCF3, OCHF2, OCH2F], -(oxirane-2,3-diyl)C(O)-, -(oxirane-2,3-diyl)CHR-[R=H, Me, OH, OMe, OCF3, OCHF2, OCH2F], -C(O)(cyclopropane-1,2-diyl)-, -CHR(cyclopropane-1,2-diyl)-[R=H, Me, OH, OMe, OCF3, OCHF2, OCH2F], -C(O)(oxirane-2,3-diyl)-, and -CHR(oxirane-2,3-diyl)-[R=H, Me, OH, OMe, OCF3, OCHF2, OCH2F]; Ar is phenyl that is mono-, di-, or tri-substituted at the 2-, 3-, or 4-position (the substituents are preferably selected from halogen (e.g., F, Cl, Br), Me, OMe, cyclopropyl, CN, and —NHCHO, each of which may be fluorinated or deuterated (e.g., OCF3, CF3, CD3); the phenyl may be a substituted phenyl or a heteroaryl), monocyclic heteroaryl, fused bicyclic heteroaryl, fused heteroaryl (e.g., pyridine, pyrimidine, and fused aryl (naphthyl), each of which may be fluorinated or deuterated (e.g., OCF, CF, CD); the substituents may be selected from halogen (e.g., F, Cl, Br), CF, Me, OMe, cPr, CN, aryl, and heteroaryl, each of which may be fluorinated or deuterated (e.g., OCF, CF, CD). or a salt, hydrate or stereoisomer thereof.

[0004] In some embodiments, Q is cyclopropane-1,2-diyl; X is N and Y, Z and W are each CH; or X, Y, Z and W are each CH; L is -OCHC(O)-, -NHCH2C(O)-, -NHCHMeC(O)-, -NMeCH2C(O)-, -NMeCHMeC(O)-, -CH2OC(O)-, -CHMeOC(O)-, -CH2NHC(O)-, -CHMeNHC(O)-, -OCH2NMeC(O)- , -CHMeNMeC(O)-, -OCHMe-, -OCHMeCH2-, -OCH2CHMe-, -OCHMeCHOH-, -(CH2)C(O)-, -CHMeCH2C(O)-, -CH2CHMeC(O)-, -CHOHCH2-, -CH2CHOH-, -CHOHCH2C is selected from HOH'-, -CHOHCHMeCHOH-, -CHOHCMeCH2-, -CH(OH)CH=CH2-, -CH2NH-, -(cyclopropane-1,2-diyl)C(O)-, -(cyclopropane-1,2-diyl)CH2-, -(oxirane-2,3-diyl)C(O)-, -(oxirane-2,3-diyl)CH2-, -C(O)(cyclopropane-1,2-diyl)-, -CH2(cyclopropane-1,2-diyl)-, -C(O)(oxirane-2,3-diyl)-, and -CH2(oxirane-2,3-diyl)-; and / or Ar is phenyl mono-, di-, or tri-substituted at the 2-, 3-, or 4-position, where the substituents are selected from halogen, Me, OMe, cyclopropyl, CN, and —NHCHO, each of which may be fluorinated or deuterated.

[0005] In embodiments, the compound is having a structure set forth in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8 or Table 9 herein; Inhibits lanosterol synthase (LSS), Is orally bioavailable, and / or Crosses the blood-brain barrier.

[0006] In one aspect, the present invention provides a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0007] In one aspect, the present invention provides a method of inhibiting lanosterol synthase, comprising administering to a human in need of lanosterol synthase inhibition a small molecule inhibitor of lanosterol synthase disclosed herein.

[0008] In one aspect, the present invention provides a method of upregulating 24,25-epoxycholesterol (EPC), comprising administering to a human in need of upregulation of 24,25-epoxycholesterol (EPC) a small molecule inhibitor of lanosterol synthase as disclosed herein.

[0009] In one aspect, the present invention provides a method of treating a neurological disease or condition, the method comprising administering to a human in need of treatment a small molecule inhibitor of lanosterol synthase as disclosed herein.

[0010] In one aspect, the present invention provides a method of screening candidate therapeutic agents for the treatment of a neurological disease or condition, comprising identifying an inhibitor of lanosterol synthase (p75).

[0011] In some embodiments of the methods described herein, the neurological disease or condition is glioblastoma (GBM) or a neurodegenerative disease, such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, or Huntington's disease; and / or The method may further comprise detecting or diagnosing the neurological disease or condition prior to the administering step, and / or detecting an improvement or delay in progression of the neurological disease or condition due to the administration after the administering step.

[0012] The present invention includes all combinations of the specific embodiments described herein as if each combination were specifically described. DETAILED DESCRIPTION OF THE INVENTION

[0013] In the following detailed description, and throughout this specification, unless inappropriate or stated otherwise, "a" and "an" mean one or more, and "or" means "and / or." The examples and embodiments described herein are for illustrative purposes only. Various modifications and variations of these examples and embodiments will be suggested to one of ordinary skill in the art, and these modifications and variations are within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein, including the references cited therein, are hereby incorporated by reference in their entirety for all purposes.

[0014] Herein, we demonstrate that the tetracyclic dicarboximide MM0299 inhibits lanosterol synthase (mouse lanosterol synthase is referred to as "Lss" and human lanosterol synthase is referred to as "LSS"). Lanosterol synthase is the first enzyme in the cholesterol biosynthetic pathway after squalene synthesis to synthesize the tetracyclic sterol skeleton. Like other LSS inhibitors, MM0299 blocks canonical cholesterol biosynthesis and diverts sterol synthesis toward the production of the shunt pathway product, 24(S),25-epoxycholesterol (EPC). EPC inhibits the proliferation of glioblastoma stem-like cells (GSCs) by depleting intracellular cholesterol. Compared to known LSS inhibitors, MM0299 exhibits superior selectivity for LSS over other sterol biosynthetic enzymes. The present inventors have demonstrated that MM0299 derivatives are orally bioavailable, penetrate the blood-brain barrier, and stimulate EPC production in tumors but not in normal brains. The present invention provides novel lanosterol synthase inhibitors as a treatment for glioblastoma or other neurological disorders.

[0015] A selective and brain-penetrant lanosterol synthase inhibitor targets glioma stem-like cells by activating the shunt pathway that generates the toxic metabolite 24(S),25-epoxycholesterol To generate pharmacologically optimized preclinical lead LSSi, medicinal chemistry development activities were conducted and followed up to evaluate target binding, safety, and anti-GBM activity profiles. Structure-activity relationships (SAR) were analyzed for a large number of analogs generated by medicinal chemistry techniques, and EC values ​​were measured in cellular probe-based displacement assays. 50 We distinguished between on-target and off-target binding events by correlating SAR data with cell phenotype. Furthermore, to identify chemicals that compromise GBM cell health, we generated a GBM transgenic mouse model by inducing spontaneous tumor formation in mouse astrocytes through GFAP-Cre-mediated silencing of the tumor suppressors Trp53, Pten, and Nf1. We then performed a high-throughput cell survival screen using the mouse GBM stem cell-like cell (GSC) line Mut6 derived from this GBM transgenic mouse model.

[0016] We investigated the mechanism of action of a tetracyclic dicarboximide (MM0299) identified through screening. MM0299 inhibits lanosterol synthase (mouse lanosterol synthase is referred to as "Lss" and human lanosterol synthase is referred to as "LSS"). Lanosterol synthase is the first enzyme in the cholesterol biosynthetic pathway after squalene synthesis, synthesizing the tetracyclic sterol skeleton. Inhibition of LSS by MM0299 blocks canonical cholesterol biosynthesis and diverts sterol synthesis to the shunt pathway product 24(S),25-epoxycholesterol (EPC), resulting in the inhibition of glioblastoma stem-like cell (GSC) proliferation.

[0017] The present invention provides a novel approach to targeting tumor cellular metabolism for the treatment of brain tumors. Metabolic reprogramming is a fundamental feature of the molecular pathogenesis of gliomas, and numerous therapeutic strategies designed to exploit this process are currently undergoing preclinical and clinical trials (Zhou and Wahl, 2019). One such strategy targets metabolic pathways that exhibit greater flux in glioma cells compared to normal cells. For example, a study evaluating the radiosensitizing effects of inhibiting purine nucleotide synthesis in GBM has been reported (NCT04477200) (Zhou et al., 2020). Another strategy has been reported to block the synthesis of the oncometabolite 2-hydroxyglutarate, which selectively accumulates in gliomas, leading to the formation of gliomas with mutant isocitrate dehydrogenase (IDH) (NCT02481154) (Mellinghoff et al., 2021). Unlike these strategies, our approach demonstrates a new paradigm that activates, rather than inhibits, metabolic pathways in GBM cells to induce the production of tumor-specific cytotoxic metabolites, EPCs.

[0018] Regarding clinical translation, we report a derivative of MM0299 that is orally bioavailable and capable of penetrating the blood-brain barrier. These findings support the development of lanosterol synthase inhibitors as treatments for glioblastoma or other neurological disorders.

[0019] result 1. MM0299 inhibits the proliferation of Mut6 cells by binding to lanosterol synthase Spontaneous tumor formation in mouse astrocytes can be induced by silencing the tumor suppressors Trp53, Pten, and Nf1 via GFAP-Cre, and these tumors are histologically similar to human GBM (Kwon et al., 2008). Next, a glioma stem cell-like cell (GSC) line (hereafter referred to as "Mut6") derived from GBM tumors formed in this model was used in a high-throughput chemical screen to identify small molecules that inhibit GSC proliferation (Shi et al., 2019). MM0299 (1), a tetracyclic dicarboximide obtained from this screen, dose-dependently reduces the viability of Mut6 cells (IC). 50 =0.0182μM). [ka]

[0020] We attempted to elucidate the mechanism of action (MoA) of MM0299 by identifying the protein to which MM0299 binds in Mut6 cells. To achieve this goal, we synthesized the MM0299-probe (2). This MM0299-probe is an analog of MM0299 (IC) that maintains antiproliferative activity in Mut6 cells. 50= 1.18 μM) and contains both diazirine and alkyne functional groups. Exposure of the photoreactive diazirine group to ultraviolet (UV) light forms a reactive carbene, which can react with neighboring amino acid residues and thereby covalently bind to proteins. Mut6 cells were incubated with increasing concentrations of Probe 2 in the presence or absence of UV treatment (306 nm), and the resulting lysates were reacted with fluorescent azides in a copper(I)-catalyzed azide-alkyne cycloaddition reaction (commonly referred to as "click" chemistry). Analysis of the clicked lysates by SDS-PAGE revealed multiple fluorescent protein bands representing various proteins covalently bound to Probe 2. Several of these protein bands showed a dose-dependent increase in fluorescence intensity only under UV conditions, with the most prominent being a protein (p75) migrating at approximately 75 kDa.

[0021] To investigate whether binding to the observed bands was related to toxicity, we performed a series of probe-based displacement assays by co-incubating cells with a fixed concentration of probe 2 and an increasing concentration series of competitor compound 1. We hypothesized that compound 1 would reduce the intensity of the fluorescent band of the putative target in a dose-dependent manner. Although probe 2 bound to multiple proteins, we observed a dose-dependent reduction in the fluorescence of only p75. We performed repeated probe displacement assays with 12 structurally related MM0299 derivatives (analogs 3–14 in Table 1; see Supplementary Information for their syntheses and structures) and determined the EC values ​​for binding to p75. 50 Structure-binding relationships were investigated by quantifying the IC value, i.e., the concentration of competitor compound required to displace 50% of the signal bound to the probe. In parallel, the dose-dependent antiproliferative activity of each derivative was measured to determine its IC 50 The structure-activity relationship was obtained by determining the EC values ​​of the displacements of the p75 probe. 50 values ​​and IC of antiproliferative activity 50The relationship between the values ​​was plotted, and the slope of the best-fit line was 1.06, indicating EC 50 The IC values ​​indicate antiproliferative activity. 50 Furthermore, there was a significant correlation (R ) between p75 binding and cytotoxic activity over a 1000-fold effective range. 2 =0.864, p<0.0001), providing evidence that p75 is the functional target of MM0299.

[0022] To determine the identity of p75, we performed large-scale affinity purification of proteins that showed binding to the probe. We performed a 1.0 μM IC400 assay using 0.1 μM probe 2 and 1.0 μM IC400 of analog 11, an active competitor. 50 Mut6 cells were incubated with MM0299 (0.000791 μM) or DMSO, followed by UV crosslinking. The probe-binding proteins were biotinylated by a click reaction using biotin azide in cell lysates, and affinity purified using immobilized streptavidin. Proteins eluted from streptavidin beads were digested with trypsin, and the resulting peptides were identified by liquid chromatography-mass spectrometry (LC-MS). Analysis of the LC-MS data from the above purification revealed that lanosterol synthase (Lss) was the most enriched protein when purified using only the probe, demonstrating a 15.5-fold enrichment compared to purification using the probe and a competitor compound. These data indicated that p75 was Lss (MW = 83.1 kDa). Surprisingly, no other proteins were enriched more than two-fold, suggesting few other targets of MM0299.

[0023] Next, we combined pharmacology and genetics to further test whether p75 is indeed an LSS. First, we investigated whether Ro 48-8071, a structurally distinct LSS inhibitor from MM0299, could displace the MM0299-probe (2) using a method similar to the MM0299-series probe displacement assay described above. The intensity of the p75 band decreased with increasing concentrations of Ro 48-8071, indicating that Ro 48-8071 displaced the MM0299-probe in a dose-dependent manner. Furthermore, Ro 48-8071 was able to displace the MM0299-probe at concentrations (EC ) that were higher than the observed concentration (EC ) of MM0299 binding to p75. 50 = 0.00248 μM) 50 = 0.0112 μM) inhibited the proliferation of Mut6 cells. To further investigate whether p75 is an Lss, we assessed probe binding in HEK293T cells ectopically expressing FLAG epitope-tagged human LSS. Incubation of these HEK293T cells with probe 2 and crosslinking enhanced the p75 band intensity, whereas addition of excess competitor compound 1 reduced the p75 band intensity, demonstrating specificity. These results provide evidence that p75, the direct target of MM0299, is an Lss.

[0024] 2. MM0299(1) inhibits the activity of Lss, thereby suppressing the canonical pathway and inducing the shunt pathway. LSS inhibitors block the canonical cholesterol biosynthetic pathway (known as the Bloch and Kandutsch-Russell pathways) and simultaneously stimulate the production of 24(S),25-epoxycholesterol (EPC) via the "shunt" pathway (Mark et al., 1996; Morand et al., 1997). In sterol synthesis, squalene, a symmetric polyene hydrocarbon intermediate in the cholesterol biosynthetic pathway, is oxidized by squalene epoxidase (SQLE) in the presence of NADPH and oxygen to produce (S)-2,3-oxidosqualene (OS), which is then converted to lanosterol by LSS. Inhibition of LSS allows (S)-2,3-oxidosqualene (OS) to be returned to squalene epoxidase (SQLE), which then catalyzes a second oxidation event to produce (S,S)-2,3:22,23-dioxidosqualene (DOS) with C2 symmetry. DOS is a highly reactive substrate for LSS, and even in the presence of LSS inhibitors, DOS is converted by LSS to produce 24(S),25-epoxylanosterol (EPL) (Boutaud et al., 1992). EPL is further converted to EPC by the same enzymes that convert lanosterol to cholesterol (Nelson et al., 1981a; Nelson et al., 1981b). The overall result of LSS inhibition is a decrease in the concentrations of various intermediates in the canonical pathway and an increase in the concentrations of various intermediates in the shunt pathway. Based on this, to test the hypothesis that compound 1 is an LSS inhibitor, we quantified key intermediates in the canonical and shunt pathways after treatment with various doses of compound 1. Treatment of Mut6 cells with compound 1 dose-dependently increased (up to 6.48-fold) the primary substrate of LSS, (S)-2,3-oxidosqualene, and dose-dependently decreased (up to 24.5-fold) the product, lanosterol (IC). 50= 0.0455 μM). Treatment with compound 1 also dose-dependently increased the shunt pathway intermediates DOS and EPL (up to 17.9- and 25.6-fold, respectively). The concentration of EPC, the end product of the shunt pathway, peaked at 390 ng / mg protein (a 13.9-fold increase) when cells were treated with 0.1 μM compound 1, but gradually decreased with higher concentrations of compound 1. The decrease in EPC with high concentrations of compound 1 was likely due to complete inhibition of LSS. Meanwhile, DOS and EPL concentrations continued to increase even above the dose at which EPC decreased. These data suggest that the decrease in EPC concentration at high doses is likely due to catabolism or excretion, rather than decreased synthesis. Related to this hypothesis, in astrocytes, EPC stimulates the expression of sterol transporters, such as ABCA1, which facilitates the extracellular export of EPC itself (Wong et al., 2007). We hypothesized that a threshold concentration of EPCs obtained by treatment with high concentrations of compound 1 activates sterol transporter expression, leading to the excretion of EPCs and the observed decrease in EPC concentration. Based on these results, we concluded that inhibition of Lss by MM0299 (1) dose-dependently decreases canonical intermediates and increases shunt pathway intermediates.

[0025] Next, we evaluated whether MM0299 (1) and related analogs could directly inhibit recombinant human LSS in cell-free in vitro reactions. Recombinant LSS purified from E. coli converted (S)-2,3-oxidosqualene to lanosterol in a time- and dose-dependent manner. Notably, lanosterol production reached saturation over time, which was attributed to substrate depletion or product inhibition. Enzyme activity was assessed over a 30-minute period using 64 μM substrate, a condition under which the reaction remained linear despite this saturation. Under these conditions, compound 1 dose-dependently inhibited the in vitro activity of LSS, with an IC 50The solubility of LSS was 2.22 μM. Similar experiments with three analogs (3, 6, and 14) supported the notion that inhibition of LSS enzyme activity correlated with anti-GBM activity in Mut6 cells. Notably, the concentrations of compound required to inhibit LSS activity in vitro were found to be significantly higher than those required to inhibit cell proliferation. This discrepancy may be explained by the in vitro reaction conditions, in which a nonionic detergent was added to the aqueous buffer, affecting the solubility or binding of the substrate or compound.

[0026] Regarding the shunt pathway, the question remained as to how LSS was able to convert DOS to EPL, even in the presence of high concentrations of inhibitors. Analysis of the enzyme kinetics in vitro showed that the conversion rate of DOS to EPL was faster than that of OS to lanosterol, suggesting that DOS is a highly reactive substrate for LSS (Boutaud et al., 1992). To address this question, the efficacy of LSS in converting DOS to EPL was evaluated in vitro. Consistent with previously reported results, the conversion rate of DOS to EPL was 2.67-fold faster than that of OS to lanosterol. Despite these results, the efficacy of MM0299(1) in inhibiting the conversion of DOS to EPL and the conversion of OS to lanosterol were comparable (IC ). 50 =1.60 and IC 50 = 2.22 μM). Therefore, the conversion of DOS to EPL by LSS in the presence of MM0299 could not be explained solely by the high affinity of LSS for DOS. A more plausible explanation could be derived from the observation that the concentration of DOS was 375-fold higher than that of OS in cells treated with compound 1. The effective concentration of DOS in the endoplasmic reticulum membrane may be even higher, potentially limiting the access of the inhibitor to the enzyme active site.

[0027] 3. Induction of the shunt pathway by MM0299 contributes to its toxicity to Mut6 cells We next investigated whether the increased EPC concentration resulting from LSS inhibition by MM0299 contributes to the antiproliferative activity observed in Mut6 cells. EPC is a potent ligand for the nuclear hormone transcription factor LXR, which promotes cholesterol efflux by upregulating cholesterol transporters such as ABCA1 and ABCG1 (Janowski et al., 1999; Janowski et al., 1996; Lehmann et al., 1997; Willy et al., 1995). Furthermore, EPC inhibits the activation of SREBP, a master transcription factor that promotes the expression of multiple enzymes involved in cholesterol biosynthesis and uptake (Horton et al., 2003; Radhakrishnan et al., 2007). mRNA sequencing showed that treatment of Mut6 cells with compound 1 upregulated LXR target genes, such as Abca1, Abcg1, and Srebf1, while simultaneously downregulated SREBP target genes, indicating that the concentration of EPCs generated by compound 1 treatment was sufficient to affect these pathways ( Horton et al., 2003 ; Willy et al., 1995 ).

[0028] To further evaluate the role of EPC in the anticancer activity of compound 1, we investigated whether the EPC concentration achieved by treating cells with compound 1 was sufficient to exert toxicity. Incubation of cells with a polydeuterated derivative of 24(S),25-epoxylanosterol (d6-S-EPL) resulted in the time-dependent generation of d6-EPC, which inhibited the proliferation of Mut6 cells, with IC 50 The concentration of d6-EPC produced by incubating cells with an effective dose of d6-S-EPL (1 μM) was 0.483 μM. Notably, the concentration of d6-EPC produced by incubating cells with an effective dose of d6-S-EPL (1 μM) was comparable to the EPC concentration detected after treatment with a lethal dose of compound 1 (0.1 μM) (390 ng of d6-EPC per mg of protein and 342 ng of EPC per mg of protein). These data indicate that the EPC synthesized after treatment with compound 1 is sufficient to inhibit cell proliferation.

[0029] Based on these results, we concluded that the concentration of EPCs generated by treatment with compound 1 was sufficient to downregulate SREBP target genes, upregulate LXR target genes, and inhibit cell proliferation. EPCs could reduce intracellular cholesterol concentrations to lethal levels by exerting a coordinated action on LXR and SREBP, transcriptional regulators crucial for cholesterol homeostasis. To test this hypothesis, we assessed the proliferation of cells treated with increasing concentrations of S-EPL or compound 1 in the presence of exogenous lanosterol or cholesterol bound to methyl-β-cyclodextrin (MCD), which aids in the solubility and delivery of sterols. Addition of lanosterol or cholesterol to the cells rescued Mut6 cells from S-EPL or compound 1-induced toxicity. These observations provided evidence that the antiproliferative activity of compound 1 is due to the generation of EPCs and the resulting depletion of intracellular cholesterol.

[0030] Next, we considered pharmacological tools that could selectively block the shunt pathway to assess whether EPC is required for MM0299 activity. Regarding LSS inhibition, the generation of DOS requires two cycles of oxidation by squalene epoxidase (SQLE), whereas the generation of OS requires only one cycle of oxidation. Based on this, we speculated that coadministration of an SQLE inhibitor would have a more potent effect on DOS concentrations and disrupt flow through the shunt pathway. Consistent with this expectation, simultaneous treatment with a sublethal dose of the SQLE inhibitor NB-598 completely inhibited the accumulation of shunt pathway metabolites by compound 1, but did not reduce canonical sterol concentrations (Horie et al., 1990). From these results, we concluded that NB-598 selectively blocks the shunt pathway and therefore can be used as a pharmacological tool to assess whether EPC is required for MM0299 activity. Furthermore, NB-598 dose-dependently rescued the toxicity of compound 1, thereby reducing IC 50 We found an 11.8-fold increase in LSS levels. In contrast, NB-598 did not rescue the activity of bortezomib, a compound with a mechanism unrelated to cholesterol synthesis, nor did it rescue the activity of TASIN-30, an inhibitor of emopamil-binding protein (EBP), an enzyme downstream of LSS in cholesterol biosynthesis (Theodoropoulos et al., 2020). These observations are consistent with the hypothesis that LSS inhibition and the resulting increase in EPCs are responsible for its toxicity in the low nanomolar range. Furthermore, compound 1 remained toxic to Mut6 cells at high concentrations, even in the presence of NB-598. This toxicity at such high concentrations, which appears pharmacologically unattainable, is likely due to sterol depletion caused by direct inhibition of cholesterol biosynthesis rather than the generation of EPCs. Taken together, these observations led us to conclude that the specific induction of the shunt metabolite EPC is necessary and sufficient to achieve the most potent cytotoxic effect of MM0299 in Mut6 cells.

[0031] 4. Evaluation of LSS selectivity of MM0299 and known LSS inhibitors Enzyme selectivity is a major challenge in developing inhibitors of the cholesterol biosynthetic pathway following squalene synthesis (Korade et al., 2016; Moebius et al., 1998; Wages et al., 2018). This polypharmacology can be particularly problematic when using LSS inhibitors as anti-GBM agents, as inhibition of downstream biosynthetic enzymes also inhibits the production of the key metabolite, EPC (Rabelo et al., 2017). With this in mind, we systematically compared the off-target profile of compound 1 with that of another LSS inhibitor, Ro 48-8071, which has undergone extensive pharmacological and biophysical evaluation, including structural determination of its complex with LSS (Morand et al., 1997; Thoma et al., 2004).

[0032] Treatment with Ro 48-8071, like compound 1, increased shunt pathway intermediates in a dose-dependent manner, and the peak concentration of EPCs generated by treatment with Ro 48-8071 correlated with its toxicity to Mut6 cells (IC 50= 0.0112 μM). Notably, the peak EPC concentration after treatment with Ro 48-8071 was only 62% of that after treatment with compound 1. Based on the peak EPC concentration after treatment with Ro 48-8071, we hypothesized that Ro 48-8071 attenuates EPC synthesis by inhibiting one or more enzymes downstream of LSS. To assess whether Ro 48-8071 inhibits EPC synthesis downstream of EPL, we cultured cells with isotope-labeled EPL (d6-EPL) and treated them with each inhibitor, and then measured the production of d6-EPC. Ro 48-8071 inhibited d6-EPC production, whereas compound 1 had no effect on d6-EPC production. These data suggest that Ro 48-8071 inhibits LSS but also exerts off-target effects on the sterol synthesis pathway downstream of LSS, thereby attenuating EPC synthesis. In the case of small molecule inhibitors that inhibit enzymes downstream of LSS, lanosterol is not expected to rescue toxicity as effectively as cholesterol, because lanosterol is not efficiently converted to cholesterol. Consistent with this hypothesis, the rescue effect of exogenous cholesterol (IC) on Ro 48-8071 was significantly lower than that of cholesterol. 50 The 479.4-fold increase in IL-14 (IC ) was consistent with the rescue effect of exogenous lanosterol (IC 50 The effect of compound 1 on the cytotoxicity of LSS was more potent than that of exogenous lanosterol (a 21.7-fold increase in LSS). In contrast, exogenous lanosterol and exogenous cholesterol showed similar and complete rescue effects in cells treated with compound 1. These findings indicate that compound 1 does not inhibit enzymes downstream of LSS in the cholesterol synthesis pathway, resulting in more efficient production of the toxic metabolite EPC.

[0033] To eliminate bias in identifying potential off-targets of Ro 48-8071, we synthesized a derivative of Ro 48-8071 that is amenable to click chemistry reactions. Ro 48-8071 contains a photoreactive benzophenone, which upon UV irradiation is predicted to form a reactive triplet diradical that can covalently bind to neighboring amino acids in the bound protein. The terminal alkene group of Ro 48-8071 was replaced with a terminal alkyne (hereafter referred to as "Ro-alkyne"), which serves as a functional handle for click chemistry reactions. After confirming that this Ro-alkyne retained its antiproliferative activity against Mut6 cells (IC), we performed a click chemistry assay to confirm its activity. 50 Intracellular binding partners of Ro-alkyne were analyzed using 10 μM Ro 48-8071 (=0.396 μM). Incubation of cells with 10 μM Ro 48-8071 resulted in the disappearance of multiple probe- and UV-dependent bands. On the other hand, the band corresponding to LSS was only observed after ectopically expressing LSS in HEK293T cells.

[0034] To determine the identities of putative off-targets of Ro 48-8071, affinity purification of Ro-alkyne-binding proteins was performed in the presence or absence of 10 μM Ro 48-8071. In stark contrast to MM0299, 130 proteins were more strongly enriched than Lss (#131, 1.3-fold enrichment) under the Ro-alkyne-only condition, suggesting the involvement of multiple off-targets. Among the most enriched Ro-alkyne-binding proteins, three enzymes involved in the cholesterol biosynthesis pathway were identified: Ebp (#2, 8.4-fold enrichment), Lbr (#5, 3.1-fold enrichment), and Dhcr7 (#7, 2.5-fold enrichment). These results indicate that, unlike MM0299, Ro 48-8071 has multiple off-targets, including several enzymes involved in cholesterol biosynthesis.

[0035] Inhibition of these various sterol biosynthetic enzymes may explain the observed attenuation of EPC increase after LSS inhibition by Ro 48-8071. To evaluate the effects of compound 1 and Ro 48-8071 on these various enzymes, we utilized a small molecule tool that can investigate the intracellular binding profiles of small molecules to several cholesterol biosynthetic enzymes (Theodoropoulos et al., 2020). First, we tested the binding of compound 1 and Ro 48-8071 to EBP. Specifically, HCT116 cells were incubated with 1 μM TASIN-2 (an EBP-specific photoaffinity probe) in the presence or absence of increasing doses of TASIN-30 (an EBP-specific inhibitor), compound 1, or Ro 48-8071, followed by UV treatment and fluorescent dye binding. Consistent with the proteomic data, Ro 48-8071 and TASIN-30 eliminated TASIN-2 (a band migrating at approximately 20 kDa), whereas compound 1 did not. Furthermore, treatment with Ro 48-8071 led to the accumulation of 8,9-dehydrocholesterol (8,9-DHC), a non-canonical sterol that accumulates upon genetic or pharmacological inhibition of EBP (Braverman et al., 1999; Theodoropoulos et al., 2020), whereas treatment with compound 1 had no effect on intracellular 8,9-DHC levels. These data provide evidence that Ro 48-8071 binds to and inhibits intracellular EBP.

[0036] Next, we performed similar experiments using a probe (known as "4C12") specific for 7-dehydrocholesterol reductase (mouse 7-dehydrocholesterol reductase is referred to as "Dhcr7" and human 7-dehydrocholesterol reductase is referred to as "DHCR7") (Theodoropoulos et al., 2020). 4C12 and Ro 48-8071 eliminated the crosslinked band of Dhcr7 migrating at 40 kDa, whereas compound 1 did not eliminate the Dhcr7 probe at any dose tested. Consistent with the results of the inhibition studies, intracellular concentrations of 7-dehydrodesmosterol, a substrate of Dhcr7, were found to accumulate after treatment with Ro 48-8071, but not with compound 1. Compounds targeting EBP or DHCR7 can also inhibit DHCR24, which converts desmosterol to cholesterol (Theodoropoulos et al., 2020) (Wages et al., 2018). Although we did not have the chemical tools to directly assess binding to DHCR24, we analyzed the concentration of desmosterol in cells treated with compound 1 or Ro 48-8071. We observed accumulation of desmosterol in cells treated with high doses of Ro 48-8071, but not in cells treated with compound 1, supporting the hypothesis that Ro 48-8071 also inhibits Dhcr24. These data indicate that although both compound 1 and Ro 48-8071 inhibit Lss, Ro 48-8071 also inhibits the activity of Ebp, Dhcr7, and Dhcr24, exerting greater potency in that order.

[0037] These observations suggest that Ro 48-8071 has a significantly greater number of off-targets than compound 1, and some of these off-targets attenuate the production of EPC, an antiproliferative metabolite. Consequently, even though Ro 48-8071 inhibits LSS, its antiproliferative effect is likely multifactorial. To assess the contribution of EPC to Ro 48-8071-induced toxicity, Ro 48-8071 was incubated with increasing concentrations of NB-598. NB-598 showed a moderate protective effect against Ro 48-8071-induced toxicity (IC value of Ro 48-8071). 50 This protective effect was not dose-dependent and was abolished by high concentrations of NB-598. In contrast, the toxicity of compound 1 was rescued by NB-598 in a dose-dependent manner, with IC 50 increased by up to 11.8 times.

[0038] 5. MM0299 demonstrates efficacy in human GSC lines Because this study of MM0299 was primarily conducted using Mut6 cells, a GSC line derived from a single gene-defined mouse model, we next sought to evaluate the antiproliferative activity and mechanism of action of MM0299 in various human GSC lines with different driver genes. Two patient-derived GSC lines, designated UTSW63 and UTSW71, were constructed at UT Southwestern Medical Center. UTSW63 was derived from a tumor resected from a 71-year-old male patient with a malignant neoplasm of the temporal lobe. Genomic analysis of the resected tumor revealed genomic alterations in bona-fide GBM cancer drivers. The genomic alterations included, as expected, loss of the tumor suppressor TP53 (deletion at 17p13.3-p11.1), loss of the tumor suppressor RB1 (deletion at 13q13.11-q14.3 with a predicted frameshift canonical splice donor site mutation c.1215+1G>A), and amplification of EGFR (93 copies at 7p11.2). UTSW71, derived from a 52-year-old male patient with glioblastoma, harbored alterations in various cancer drivers, including PTEN gene abnormalities (deletion of 10q21.1-q26.3 and P95S mutation) and amplification of regions containing oncogenes: CDK4 (34 copies at 12q13.3-q14.1), MDM2 (89 copies at 12q15), and c-MYC (51 copies at 8q24.13-q24.21).

[0039] Similar to Mut6 cells, both UTSW63 and UTSW71 grow as neurospheres in serum-free medium (data not shown). MM0299 inhibited the growth of both UTSW63 and UTSW71, and the IC 50The IC values ​​were 0.0222 μM and 0.0212 μM, respectively. The toxicity of MM0299 in these two human GSC lines was fully rescued by exogenous MCD-labeled lanosterol or cholesterol. The natural mechanism for extracellular cholesterol uptake is the uptake of circulating low-density lipoprotein (LDL). Therefore, we investigated whether human LDL could rescue the toxicity of MM0299 in human GBM cells. The toxicity of compound 1 was fully rescued by the addition of 20 μg / ml human LDL in both UTSW63 and UTSW71 cells. Furthermore, to investigate the role of the shunt pathway in MM0299 toxicity, we again used the tool compound NB-598. NB-598 was highly toxic to UTSW63 and UTSW71 cells, with IC values ​​of 0.0222 μM and 0.0212 μM in each cell line. 50 The IC values ​​for UTSW63 cells were 5.56 nM and 8.26 nM, respectively. By adding a low dose of NB-598 that does not affect cell proliferation, the IC values ​​for UTSW63 cells were 50 increased 15.0-fold, and IC 50 The 21.9-fold increase in EPC activity in cultured human GSC lines rescued the toxicity of compound 1. These data suggest that compound 1 exerts its effects by upregulating EPCs via the shunt pathway, thereby depleting the intracellular cholesterol pool.

[0040] 6. Analog 13 exhibits bioavailability and is able to cross the blood-brain barrier With the mechanism of action of MM0299 established, we sought to identify and evaluate analogs with brain bioavailability, a prerequisite for in vivo studies in glioblastoma. In vitro and in vivo pharmacological evaluation of a series of analogs (Table 1) identified analog 13 as a candidate molecule for activating the shunt pathway in mouse brain. [ka]

[0041] Analog 13 competes with p75 / LSS (EC 50=0.0287 μM), possesses drug-like physicochemical properties (MW=468 Da, CLogP=4.3, LogP=3.8, tPSA=64), induces EPC upregulation, and retains antiproliferative activity in Mut6 cells (IC 50 =0.0443 μM), and retained antiproliferative activity in the human GSC line UTSW63 (IC 50 =0.0293 μM). Analog 13 was stable in plasma (>24 hours) and showed superior metabolic stability compared to other analogs when incubated with mouse S9 fraction (Table 1). Pharmacokinetic analysis (PK) of analog 13 administered to mice by intravenous injection (IV) at a dose of 5 mg / kg or orally (PO) at a dose of 20 mg / kg showed AUC 経口 / AUC iv ×Dose iv / dose 経口 Oral bioavailability, as defined by the CI, was shown to be 39% in plasma and 58% in brain. Importantly, analogue 13 administered orally at a dose of 20 mg / kg resulted in a total C max 5 μM (2381 ng / ml), brain-free C max 14 nM, and a brain-blood ratio of 1.8 (free AUC 脳 / Free AUC 血漿 This was calculated as the antiproliferative activity against human GSC lines using a concentration of 0.11 in the unbound fraction (fu) measured in the culture medium. 50This is preferable to the previous value (3 nM). Next, we quantified EPC concentrations in plasma and brain after treatment with analog 13 by mass spectrometry. Plasma EPC concentrations increased time-dependently after a single 20 mg / kg dose. Desmosterol was immediately detected in the brain, but EPC was not. Even at the time point when plasma EPC concentrations significantly increased, brain EPC was not detected. Given the expected low cholesterol biosynthetic flux in the adult brain, this may explain the lack of EPC detection. Alternatively, the concentration of analog 13 in the brain may have been insufficient to inhibit LSS, contrary to our expectations. To evaluate these possibilities, we investigated whether EPC could be detected in orthotopic xenograft tumors derived from UTSW63 cells. Twenty-five days after intracranial injection of UTSW63 cells into mice, analog 13 was orally administered at a dose of 20 mg / kg or vehicle for 3 days on a once-daily or twice-daily dosing schedule. After treatment, EPC levels were analyzed and a dose-dependent increase in EPC levels was observed in both serum and GBM tumors. These findings indicate that administration of analog 13 selectively induced EPCs in glioblastoma cells compared with normal brain, and that EPCs can be used as a pharmacodynamic marker to optimize MM0299 for further preclinical evaluation.

[0042] Consideration Our investigation into the mechanism of action of MM0299 has uncovered a novel approach to targeting tumor cellular metabolism for the treatment of brain tumors. Metabolic reprogramming is a fundamental feature of the molecular pathogenesis of gliomas, and numerous therapeutic strategies designed to exploit this process are currently undergoing preclinical and clinical trials (Zhou and Wahl, 2019). One such strategy targets metabolic pathways that exhibit greater flux in glioma cells compared to normal cells. For example, a study evaluating the radiosensitizing effects of inhibiting purine nucleotide synthesis in GBM has been reported (NCT04477200) (Zhou et al., 2020). Another strategy involves inhibiting the synthesis of the oncometabolite 2-hydroxyglutarate, which selectively accumulates in gliomas, leading to the formation of gliomas with mutant isocitrate dehydrogenase (IDH) (NCT02481154) (Mellinghoff et al., 2021). Unlike these strategies, our approach relies on a novel paradigm that activates, rather than inhibits, metabolic pathways in GBM cells to induce the production of tumor-specific cytotoxic metabolites, EPCs.

[0043] Like most cell types, cancer cells regulate their unesterified cholesterol pool by balancing peripheral uptake, synthesis, and catabolism. Therefore, blocking cholesterol synthesis can induce a negative feedback pathway that maintains homeostasis through increased uptake of low-density lipoprotein (LDL). However, LDL particles cannot cross the blood-brain barrier, so the brain must synthesize its own cholesterol. Most cholesterol synthesis in the brain occurs during embryonic development, and the rate of cholesterol synthesis in the adult brain declines sharply (Dietschy, 2009). However, dividing GBM cells have a higher cholesterol requirement than adult neurons, and are predicted to meet the demand for cell proliferation by relying on de novo cholesterol synthesis and the uptake of exogenous cholesterol (synthesized by astrocytes) (Sassi et al., 2021). By inhibiting LSS, we can exploit the difference in cholesterol synthesis flux between normal brain and tumors. Inhibition of LSS would shift sterol flow from cholesterol synthesis to EPC synthesis, thereby inhibiting cell proliferation and resulting in tumors synthesizing more EPCs than normal brain. Consistent with this hypothesis, in vivo administration of analog 13 failed to detect EPC generation in normal brain, but dose-dependently increased EPCs in orthotopic glioblastoma tumors. Therefore, inhibiting cholesterol biosynthesis via LSS inhibition may selectively target GBM, which undergoes rapid division and exhibits increased sterol synthesis.

[0044] There is now evidence that reducing intracellular cholesterol pools can slow glioblastoma progression. The synthetic LXR agonists GW3965 and LXR-623 promote cholesterol efflux and reduce intracellular cholesterol pools in GBM cells by upregulating the expression of the cholesterol transporter ABCA1 (Guo et al., 2011; Villa et al., 2016). Accordingly, LXR-623 is brain-permeable, delays orthotopic glioblastoma tumor progression, and extends overall survival in glioblastoma tumor-bearing mice (Villa et al., 2016). However, adverse events related to the mechanism of action have hindered clinical development of LXR agonists for the treatment of glioblastoma and other indications. For example, LXR agonists have been reported to stimulate fatty acid synthesis, increasing circulating triglyceride concentrations to clinically unacceptable levels and accelerating the development of fatty liver disease ( Schultz et al., 2000 ; Joseph et al., 2002 ; Bradley et al., 2007 ).

[0045] Another approach to lowering cholesterol levels in GBM cells is to use inhibitors of enzymes crucial to the sterol biosynthesis pathway. Intracellular cholesterol levels are regulated within narrow ranges at the synthesis, LDL uptake, and catabolism (or excretion) stages. Decreased cholesterol levels are detected by the SREBP cleavage-activating protein (SCAP), which promotes the proteolytic cleavage and activation of SREBP-2 (Brown et al., 2018). Activated SREBP-2 is transported to the nucleus and promotes the transcription of genes required for cholesterol synthesis and cholesterol uptake. These feedback pathways therefore counteract the cholesterol-lowering effects of most cholesterol biosynthesis enzyme inhibitors (Brown et al., 1978).

[0046] Inhibition of lanosterol synthase (LSS) is unique in that it can suppress cholesterol synthesis without stimulating these negative feedback pathways. LSS converts linear oxidosqualene to lanosterol, which is the first sterol ring-containing intermediate in cholesterol biosynthesis. Unlike other enzymes in the cholesterol biosynthetic pathway after squalene synthesis, LSS inhibition can inhibit cholesterol synthesis without causing the accumulation of sterol intermediates. Partial inhibition of LSS diverts sterol flow to a "shunt" pathway, inducing the synthesis of the noncanonical sterol EPC. The accumulation of EPC induces a feedback mechanism that inhibits SREBP activation, thereby preventing the upregulation of genes promoting de novo cholesterol biosynthesis and cholesterol uptake in cells (Radhakrishnan et al., 2007). Furthermore, EPC is a potent modulator of LXR, a nuclear hormone transcription factor whose activation induces cholesterol metabolism and efflux (Janowski et al., 1996; Janowski et al., 1999). As a ligand for endogenous LXR, EPC does not induce fatty acid synthesis (Rowe et al., 2003), and LSS inhibitors do not exhibit the adverse effects seen with synthetic LXR agonists in animals. Therefore, LSS inhibition can reduce intracellular cholesterol pools in various ways, including directly inhibiting de novo cholesterol synthesis, inhibiting the feedback pathway that promotes cholesterol biosynthesis, and promoting efflux via LXR activation. This study demonstrated that EPC synthesis via the shunt pathway was necessary and sufficient for the suppression of glioblastoma cell proliferation by the LSS inhibitor MM0299.

[0047] Furthermore, recent evidence suggests that LSS is a potential target for glioblastoma. Allis et al. reported that MI-2, a small molecule LSS inhibitor that increases EPC levels, exhibited antiproliferative activity in glioma. MI-2 has previously been reported to inhibit the protein-protein interaction between menin and MLL, which are important epigenetic regulators in leukemia (Grembecka et al., 2012; Shi et al., 2012). However, MI-2 activity in glioma was not mediated by menin or MLL but rather by direct inhibition of LSS. These findings by Allis et al. not only demonstrated LSS as a potential target for GBM, but also supported the importance of ongoing target deconvolution for compounds evaluated in cancer preclinical trials (Phillips et al., 2019).

[0048] Most LSS inhibitors have been developed to treat atherosclerosis, primarily to lower LDL levels, with little data supporting their efficacy against cancer. One limitation in the development of LSS inhibitors is the difficulty in assessing LSS selectivity. Indeed, most reported small-molecule LSS inhibitors are amphipathic amine drugs, which bind to numerous other proteins, including several enzymes in the cholesterol biosynthetic pathway after squalene synthesis (Rabelo et al., 2017). This polypharmacology is most evident in LSSs, EBPs, and the sterol reductases DHCR7, DHCR14, and DHCR24 (Wages et al., 2018; Korade et al., 2016; Moebius et al., 1998). These enzymes share a common need to stabilize the carbocation charge generated during the conversion of highly lipophilic sterols. This likely explains why amphipathic amines, which are protonated at physiological pH, are able to bind to all or some of these enzymes. Due to the similar substrate structures and the physical proximity of these enzymes, photochemical probes that attribute binding and activity to specific cholesterol biosynthetic enzymes have proven to be useful tools for investigating these enzymes (Theodoropoulos et al., 2020). Using these photochemical probes in conjunction with sterol mass spectrometry, we compared the selectivity of MM0299 with that of Ro 48-8071, an LSS inhibitor that has already been extensively characterized. Our studies demonstrated that Ro 48-8071 binds to and inhibits LSS, but also binds to multiple off-targets, inhibiting multiple enzymes in the cholesterol pathway, including EBP and DHCR7, ultimately impairing EPC production. Similar off-target investigations of MM0299 revealed no off-targets or evidence of binding to or inhibition of other cholesterol biosynthetic enzymes.

[0049] Our research supports LSS as a target for glioblastoma and identifies MM0299 as a highly selective LSS inhibitor. In addition to the aforementioned cholesterol-lowering effects, EPCs have also been shown to stimulate oligodendrocyte myelination via an unknown mechanism (Hubler et al., 2021) and promote midbrain dopaminergic neurogenesis via LXR activation (Theofilopoulos et al., 2013; Theofilopoulos et al., 2019). Among neurodegenerative diseases, multiple sclerosis (MS) develops due to neuronal demyelination, and Parkinson's disease (PD) develops due to the loss of midbrain dopaminergic neurons. Novel treatments for these diseases are needed, and brain-permeable MM0299 derivatives capable of inducing EPC generation may be clinically useful in these diseases.

[0050] A major challenge in developing treatments for GBM and other neurological disorders is identifying small molecule drugs that can cross the blood-brain barrier. Herein, we describe MM0299 derivatives, which are blood-brain barrier-permeable drugs that are orally bioavailable. These derivatives increase EPCs in orthotopic xenograft tumors but not in normal brain.

[0051] References Boutaud, O., Dolis, D., and Schuber, F. (1992). Preferential cyclization of 2,3(S):22(S),23-dioxidosqualene by mammalian 2,3-oxidosqualene-lanosterol cyclase. Biochem Biophys Res Commun 188, 898-904. 10.1016 / 0006-291x(92)91140-l. Bradley, M.N., Hong, C., Chen, M., Joseph, S.B., Wilpitz, D.C., Wang, X., Lusis, A.J., Collins, A., Hseuh, W.A., Collins, J.L., et al. (2007). Ligand activation of LXR beta reverses atherosclerosis and cellular cholesterol overload in mice lacking LXR alpha and apoE. J Clin Invest 117, 2337-2346. 10.1172 / JCI31909. Braverman, N., Lin, P., Moebius, F.F., Obie, C., Moser, A., Glossmann, H., Wilcox, W.R., Rimoin, D.L., Smith, M., Kratz, L., et al. (1999). Mutations in the gene encoding 3 beta-hydroxysteroid-delta 8, delta 7-isomerase cause X-linked dominant Conradi-Hunermann syndrome. Nat Genet 22, 291-294. 10.1038 / 10357. Brown, M.S., Faust, J.R., Goldstein, J.L., Kaneko, I., and Endo, A. (1978). Induction of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in human fibroblasts incubated with compactin (ML-236B), a competitive inhibitor of the reductase. J Biol Chem 253, 1121-1128. Brown, M.S., Radhakrishnan, A., and Goldstein, J.L. (2018). Retrospective on Cholesterol Homeostasis: The Central Role of Scap. Annu Rev Biochem 87, 783-807. 10.1146 / annurev-biochem-062917-011852. Dietschy, J.M. (2009). Central nervous system: cholesterol turnover, brain development and neurodegeneration. Biol Chem 390, 287-293. 10.1515 / BC.2009.035. Grembecka, J., He, S., Shi, A., Purohit, T., Muntean, A.G., Sorenson, R.J., Showalter, H.D., Murai, M.J., Belcher, A.M., Hartley, T., et al. (2012). Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia. Nat Chem Biol 8, 277-284. 10.1038 / nchembio.773. Guo, D., Reinitz, F., Youssef, M., Hong, C., Nathanson, D., Akhavan, D., Kuga, D., Amzajerdi, A.N., Soto, H., Zhu, S., et al. (2011). An LXR agonist promotes glioblastoma cell death through inhibition of an EGFR / AKT / SREBP-1 / LDLR-dependent pathway. Cancer Discov 1, 442-456. 10.1158 / 2159-8290.CD-11-0102. Horie, M., Tsuchiya, Y., Hayashi, M., Iida, Y., Iwasawa, Y., Nagata, Y., Sawasaki, Y., Fukuzumi, H., Kitani, K., and Kamei, T. (1990). NB-598: a potent competitive inhibitor of squalene epoxidase. J Biol Chem 265, 18075-18078. Horton, J.D., Shah, N.A., Warrington, J.A., Anderson, N.N., Park, S.W., Brown, M.S., and Goldstein, J.L. (2003). Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc Natl Acad Sci U S A 100, 12027-12032. 10.1073 / pnas.1534923100. Hubler, Z., Friedrich, R.M., Sax, J.L., Allimuthu, D., Gao, F., Rivera-Leon, A.M., Pleshinger, M.J., Bederman, I., and Adams, D.J. (2021). Modulation of lanosterol synthase drives 24,25-epoxysterol synthesis and oligodendrocyte formation. Cell Chemical Biology 28, 866-875.e865. 10.1016 / j.chembiol.2021.01.025. Janowski, B.A., Grogan, M.J., Jones, S.A., Wisely, G.B., Kliewer, S.A., Corey, E.J., and Mangelsdorf, D.J. (1999). Structural requirements of ligands for the oxysterol liver X receptors LXRalpha and LXRbeta. Proc Natl Acad Sci U S A 96, 266-271. 10.1073 / pnas.96.1.266. Janowski, B.A., Willy, P.J., Devi, T.R., Falck, J.R., and Mangelsdorf, D.J. (1996). An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature 383, 728-731. 10.1038 / 383728a0. Joseph, S.B., Laffitte, B.A., Patel, P.H., Watson, M.A., Matsukuma, K.E., Walczak, R., Collins, J.L., Osborne, T.F., and Tontonoz, P. (2002). Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors. J Biol Chem 277, 11019-11025. 10.1074 / jbc.M111041200. Korade, Z., Kim, H.Y., Tallman, K.A., Liu, W., Koczok, K., Balogh, I., Xu, L., Mirnics, K., and Porter, N.A. (2016). The Effect of Small Molecules on Sterol Homeostasis: Measuring 7-Dehydrocholesterol in Dhcr7-Deficient Neuro2a Cells and Human Fibroblasts. J Med Chem 59, 1102-1115. 10.1021 / acs.jmedchem.5b01696. Kwon, C.H., Zhao, D., Chen, J., Alcantara, S., Li, Y., Burns, D.K., Mason, R.P., Lee, E.Y., Wu, H., and Parada, L.F. (2008). Pten haploinsufficiency accelerates formation of high-grade astrocytomas. Cancer Res 68, 3286-3294. 10.1158 / 0008-5472.CAN-07-6867. Lehmann, J.M., Kliewer, S.A., Moore, L.B., Smith-Oliver, T.A., Oliver, B.B., Su, J.L., Sundseth, S.S., Winegar, D.A., Blanchard, D.E., Spencer, T.A., and Willson, T.M. (1997). Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem 272, 3137-3140. 10.1074 / jbc.272.6.3137. Madhusudhan, N., Hu, B., Mishra, P., Calva-Moreno, J.F., Patel, K., Boriack, R., Ready, J.M., and Nijhawan, D. (2020). Target Discovery of Selective Non-Small-Cell Lung Cancer Toxins Reveals Inhibitors of Mitochondrial Complex I. ACS Chem Biol 15, 158-170. 10.1021 / acschembio.9b00734. Mark, M., Muller, P., Maier, R., and Eisele, B. (1996). Effects of a novel 2,3-oxidosqualene cyclase inhibitor on the regulation of cholesterol biosynthesis in HepG2 cells. J Lipid Res 37, 148-158. Mellinghoff, I.K., Penas-Prado, M., Peters, K.B., Burris, H.A., 3rd, Maher, E.A., Janku, F., Cote, G.M., de la Fuente, M.I., Clarke, J.L., Ellingson, B.M., et al. (2021). Vorasidenib, a Dual Inhibitor of Mutant IDH1 / 2, in Recurrent or Progressive Glioma; Results of a First-in-Human Phase I Trial. Clin Cancer Res 27, 4491-4499. 10.1158 / 1078-0432.CCR-21-0611. Moebius, F.F., Reiter, R.J., Bermoser, K., Glossmann, H., Cho, S.Y., and Paik, Y.K. (1998). Pharmacological analysis of sterol delta8-delta7 isomerase proteins with [3H]ifenprodil. Mol Pharmacol 54, 591-598. 10.1124 / mol.54.3.591. Morand, O.H., Aebi, J.D., Dehmlow, H., Ji, Y.H., Gains, N., Lengsfeld, H., and Himber, J. (1997). Ro 48-8.071, a new 2,3-oxidosqualene:lanosterol cyclase inhibitor lowering plasma cholesterol in hamsters, squirrel monkeys, and minipigs: comparison to simvastatin. J Lipid Res 38, 373-390. Nelson, J.A., Steckbeck, S.R., and Spencer, T.A. (1981a). 24(S),25-Epoxycholesterol is a natural product of mammalian steroid biosynthesis. Journal of the American Chemical Society 103, 6974-6975. 10.1021 / ja00413a040. Nelson, J.A., Steckbeck, S.R., and Spencer, T.A. (1981b). Biosynthesis of 24,25-epoxycholesterol from squalene 2,3;22,23-dioxide. J Biol Chem 256, 1067-1068. Ostrom, Q.T., Cioffi, G., Gittleman, H., Patil, N., Waite, K., Kruchko, C., and Barnholtz-Sloan, J.S. (2019). CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2012-2016. Neuro Oncol 21, v1-v100. 10.1093 / neuonc / noz150. Phillips, R.E., Yang, Y., Smith, R.C., Thompson, B.M., Yamasaki, T., Soto-Feliciano, Y.M., Funato, K., Liang, Y., Garcia-Bermudez, J., Wang, X., et al. (2019). Target identification reveals lanosterol synthase as a vulnerability in glioma. Proc Natl Acad Sci U S A 116, 7957-7962. 10.1073 / pnas.1820989116. Rabelo, V.W., Romeiro, N.C., and Abreu, P.A. (2017). Design strategies of oxidosqualene cyclase inhibitors: Targeting the sterol biosynthetic pathway. J Steroid Biochem Mol Biol 171, 305-317. 10.1016 / j.jsbmb.2017.05.002. Radhakrishnan, A., Ikeda, Y., Kwon, H.J., Brown, M.S., and Goldstein, J.L. (2007). Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: oxysterols block transport by binding to Insig. Proc Natl Acad Sci U S A 104, 6511-6518. 10.1073 / pnas.0700899104. Rowe, A.H., Argmann, C.A., Edwards, J.Y., Sawyez, C.G., Morand, O.H., Hegele, R.A., and Huff, M.W. (2003). Enhanced Synthesis of the Oxysterol 24( S ),25-Epoxycholesterol in Macrophages by Inhibitors of 2,3-Oxidosqualene:Lanosterol Cyclase. Circulation Research 93, 717-725. 10.1161 / 01.res.0000097606.43659.f4. Sassi, K., Nury, T., Samadi, M., Fennira, F.B.A., Vejux, A., and Lizard, G. (2021). Cholesterol Derivatives as Promising Anticancer Agents in Glioblastoma Metabolic Therapy. In Gliomas, W. Debinski, ed. 10.36255 / exonpublications.gliomas.2021.chapter6. Schultz, J.R., Tu, H., Luk, A., Repa, J.J., Medina, J.C., Li, L., Schwendner, S., Wang, S., Thoolen, M., Mangelsdorf, D.J., et al. (2000). Role of LXRs in control of lipogenesis. Genes Dev 14, 2831-2838. 10.1101 / gad.850400. Shi, A., Murai, M.J., He, S., Lund, G., Hartley, T., Purohit, T., Reddy, G., Chruszcz, M., Grembecka, J., and Cierpicki, T. (2012). Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia. Blood 120, 4461-4469. 10.1182 / blood-2012-05-429274. Shi, Y., Lim, S.K., Liang, Q., Iyer, S.V., Wang, H.Y., Wang, Z., Xie, X., Sun, D., Chen, Y.J., Tabar, V., et al. (2019). Gboxin is an oxidative phosphorylation inhibitor that targets glioblastoma. Nature 567, 341-346. 10.1038 / s41586-019-0993-x. Stupp, R., Mason, W.P., van den Bent, M.J., Weller, M., Fisher, B., Taphoorn, M.J., Belanger, K., Brandes, A.A., Marosi, C., Bogdahn, U., et al. (2005). Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352, 987-996. 10.1056 / NEJMoa043330. Theodoropoulos, P.C., Wang, W., Budhipramono, A., Thompson, B.M., Madhusudhan, N., Mitsche, M.A., McDonald, J.G., De Brabander, J.K., and Nijhawan, D. (2020). A Medicinal Chemistry-Driven Approach Identified the Sterol Isomerase EBP as the Molecular Target of TASIN Colorectal Cancer Toxins. J Am Chem Soc 142, 6128-6138. 10.1021 / jacs.9b13407. Theofilopoulos, S., Abreu de Oliveira, W.A., Yang, S., Yutuc, E., Saeed, A., Abdel-Khalik, J., Ullgren, A., Cedazo-Minguez, A., Bjorkhem, I., Wang, Y., et al. (2019). 24(S),25-Epoxycholesterol and cholesterol 24S-hydroxylase (CYP46A1) overexpression promote midbrain dopaminergic neurogenesis in vivo. J Biol Chem 294, 4169-4176. 10.1074 / jbc.RA118.005639. Theofilopoulos, S., Wang, Y., Kitambi, S.S., Sacchetti, P., Sousa, K.M., Bodin, K., Kirk, J., Salto, C., Gustafsson, M., Toledo, E.M., et al. (2013). Brain endogenous liver X receptor ligands selectively promote midbrain neurogenesis. Nat Chem Biol 9, 126-133. 10.1038 / nchembio.1156. Thoma, R., Schulz-Gasch, T., D'Arcy, B., Benz, J., Aebi, J., Dehmlow, H., Hennig, M., Stihle, M., and Ruf, A. (2004). Insight into steroid scaffold formation from the structure of human oxidosqualene cyclase. Nature 432, 118-122. 10.1038 / nature02993. Villa, G.R., Hulce, J.J., Zanca, C., Bi, J., Ikegami, S., Cahill, G.L., Gu, Y., Lum, K.M., Masui, K., Yang, H., et al. (2016). An LXR-Cholesterol Axis Creates a Metabolic Co-Dependency for Brain Cancers. Cancer Cell 30, 683-693. 10.1016 / j.ccell.2016.09.008. Wages, P.A., Kim, H.H., Korade, Z., and Porter, N.A. (2018). Identification and characterization of prescription drugs that change levels of 7-dehydrocholesterol and desmosterol. J Lipid Res 59, 1916-1926. 10.1194 / jlr.M086991. Willy, P.J., Umesono, K., Ong, E.S., Evans, R.M., Heyman, R.A., and Mangelsdorf, D.J. (1995). LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev 9, 1033-1045. 10.1101 / gad.9.9.1033. Wong, J., Quinn, C.M., Guillemin, G., and Brown, A.J. (2007). Primary human astrocytes produce 24(S),25-epoxycholesterol with implications for brain cholesterol homeostasis. J Neurochem 103, 1764-1773. 10.1111 / j.1471-4159.2007.04913.x. Zhou, W., and Wahl, D.R. (2019). Metabolic Abnormalities in Glioblastoma and Metabolic Strategies to Overcome Treatment Resistance. Cancers (Basel) 11. 10.3390 / cancers11091231. Zhou, W., Yao, Y., Scott, A.J., Wilder-Romans, K., Dresser, J.J., Werner, C.K., Sun, H., Pratt, D., Sajjakulnukit, P., Zhao, S.G., et al. (2020). Purine metabolism regulates DNA repair and therapy resistance in glioblastoma. Nat Commun 11, 3811. 10.1038 / s41467-020-17512-x.

[0052] Method References 1. Theodoropoulos, P. C. et al. Discovery of tumor-specific irreversible inhibitors of stearoyl CoA desaturase. Nat Chem Biol 12, 218-225, doi:10.1038 / nchembio.2016 (2016). 2. McDonald, J. G., Smith, D. D., Stiles, A. R. & Russell, D. W. A comprehensive method for extraction and quantitative analysis of sterols and secosteroids from human plasma. J Lipid Res 53, 1399-1409, doi:10.1194 / jlr.D022285 (2012). 3. Kurten, C., Uhlen, M. & Syren, P. O. Overexpression of functional human oxidosqualene cyclase in Escherichia coli. Protein Expr Purif 115, 46-53, doi:10.1016 / j.pep.2015.04.015 (2015). 4. McNaney, C. A. et al. An automated liquid chromatography-mass spectrometry process to determine metabolic stability half-life and intrinsic clearance of drug candidates by substrate depletion. Assay Drug Dev Technol 6, 121-129, doi:10.1089 / adt.2007.103 (2008). 5. Kalvass, J. C. & Maurer, T. S. Influence of nonspecific brain and plasma binding on CNS exposure: implications for rational drug discovery. Biopharm Drug Dispos 23, 327-338, doi:10.1002 / bdd.325 (2002). 6. Louis, D. N. et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol 23, 1231-1251, doi:10.1093 / neuonc / noab106 (2021).

[0053] synthesis All reactions were carried out under anhydrous conditions using dry solvents under a nitrogen atmosphere unless otherwise noted. Anhydrous solvents were obtained by passing through commercially available alumina columns (Innovative Technology, Massachusetts). All reagents were the highest purity commercially available compounds. Analytical thin-layer chromatography (TLC) was performed on aluminum plates coated with Merck Silica Gel 60F254 and visualized by ultraviolet irradiation (254 nm) or staining with potassium permanganate solution. Flash column chromatography was performed under pressure using Merck Silica Gel 60 (230-400 mesh). Infrared spectra were measured on thin films mounted on NaCl glass using a Perkin-Elmer I1000 FTIR series. Optical rotations were measured at 20 °C using a Rudolph Research Analytical Autopol® IV polarimeter. 1 H NMR spectra were measured using a 400 MHz Varian Inova-400 spectrometer in CDCl3, CD3OD, DMSOd6, or (CD3)2CO solvents, with the residual proton in the solvent as the internal standard (CDCl3, d H = 7.26 ppm; (CD3)2CO, d H = 2.05 ppm; CD3OD, d H = 3.31 ppm; DMSO-d6, d H = 2.50 ppm) and recorded at ambient temperature. Chemical shifts (d) are expressed in parts per million (ppm) and coupling constants (J) are expressed in Hertz (Hz). Proton spectra are reported as d (multiplicity, coupling constant J, number of protons). Multiplicities are indicated by the following abbreviations: app = apparent, b = broad, d = doublet, dd = doublet of doublets, ddd = doublet of doublet of doublets, dddd = doublet of doublet of doublet of doublets, m = multiplet, s = singlet, t = triplet. 13 C NMR spectra were obtained using the same type of spectrometer at 100 MHz in CDCl3, CD3OD, DMSO-d6, or (CD3)2CO solvents. C=77.0 ppm), CD3OD(d C =49.0 ppm), DMSO-d6 (d C =39.4 ppm) or (CD3)2CO(d C The central peak (A = 30.8 ppm) was used as an internal standard and recorded at ambient temperature. Electrospray ionization mass spectra (ESI-MS) were recorded using a Shimadzu 2010-LCMS. HRMS was performed using a Shimadzu IT-TOF. Microwave reactions were performed using a Biotage® Initiator Classic. The following abbreviations are used: DMAP = 4-(dimethylamino)pyridine, DMF = N,N-dimethylformamide, DIPEA = N,N-diisopropylethylamine, DHP = tetrahydro-2H-pyran, EDC = N-ethylcarbodiimide hydrochloride, HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, MW = microwave, NMP = 1-methyl-2-pyrrolidinone, py = pyridine, TBDMS = tert-butyldimethylsilyl, THF = tetrahydrofuran, THP = 3,4-dihydro-2H-pyran. Unless otherwise noted, commercially available materials were used without purification. All solvents were HPLC or ACS grade. Solvents used in moisture-sensitive procedures were distilled under a nitrogen atmosphere with a drying agent as follows: EtO and THF were distilled over sodium and benzophenone ketyl. Benzene and toluene were distilled over sodium. CHCl was distilled over CaH. Pyridine was distilled over solid KOH. Anhydrous N,N-dimethylformamide and CHCN were purchased from commercial suppliers. Reactions were carried out under argon atmosphere with magnetic stirring unless otherwise noted. Flash chromatography (FC) was performed using E. Merck silica gel 60 (240-400 mesh) according to the protocol of Still, Kahn, and Mitra.

[0054] General Procedure A for the Condensation of Anhydride 97 with (Hetero)aromatic Amines (Schemes 1-2) A mixture of anhydride 97 (1.0 equiv.) and the corresponding (hetero)aromatic amine (1.0 equiv.) in pyridine (0.1 M) was heated at 140 °C in a pressure sealed tube. The reaction was monitored by TLC analysis. The reaction was cooled to room temperature, diluted with CHCl (10 mL), and washed with excess 10% aqueous CuSO. The organic phase was washed with H2O, dried over anhydrous MgSO, and filtered. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography as described above to give the corresponding dicarboximide.

[0055] General Procedure B for the Condensation of Anhydride 97 with (Hetero)aromatic Amines (Schemes 1-2) A mixture of anhydride 97 (1.0 equiv.) and the corresponding (hetero)aromatic amine (1.0 equiv.) in AcOH (0.5 M) was heated to 90 °C by conventional heating or to 100 °C in a microwave reactor for 45 min. The reaction was monitored by TLC analysis. The reaction was cooled to room temperature and allowed to crystallize. The crystals were collected by filtration, and the residue was washed with EtO / hexane (1:1) to remove excess AcOH. No further purification was necessary. If crystallization did not occur, the mixture was diluted with EtOAc and neutralized with saturated aqueous NaHCO3. The organic phase was washed with brine, dried over anhydrous Na2SO4, and filtered. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography as described above to give the corresponding dicarboximide.

[0056] General Procedure C for the Synthesis of Compounds 92–95, 10, 11, 15, 16, 20, 29, 30a–45a, 47a–64a, 52b, 55b–58b, 60b–63b, and 71–86 by Alkylation (Scheme 1) A solution of (optionally substituted) nitrophenol or intermediates 98–106 (1.0 equiv.), the corresponding bromide (1.5 equiv.), KCO (1.5 equiv.), and NaI (0.5 equiv.) in acetone (0.1 M) was heated to 80°C and stirred overnight. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography as described above to give the alkylated product.

[0057] General procedure D for the one-pot reduction and cycloaddition of compounds 7–9 from nitroarenes 93–95 (Scheme 1) To a suspension of Fe (5 equiv.) in AcOH (1.0 M) was added the corresponding nitroarenes 93–95 (1.0 equiv.), maleic anhydride (1.2 equiv.), and 1,3,5-cycloheptatriene (3.0 equiv.). The mixture was heated to 120 °C and stirred for 24 h. The mixture was cooled to room temperature, filtered through a pad of Celite, and the residue was washed with EtOAc (twice). The combined organic phase was washed with saturated aqueous NaHCO3, then brine, dried over anhydrous MgSO4, and filtered. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography as described above to give the cycloadducts 7–9.

[0058] General Procedure E for the Synthesis of Enones 110 and 111a-f via Wittig Olefination (Scheme 2) A mixture of the corresponding benzaldehyde 107 or 108 (1 equiv.) and the corresponding ylide (1.5 equiv.) in CHCl (0.2 M) was refluxed at 70 °C. The reaction was monitored by TLC. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography as described above to give enones 110 or 111a–f.

[0059] General Procedure F for the Synthesis of Cyclopropane Analogues via Cyclopropanation Using the Corey-Tchaikovsky Reaction (Scheme 2) A flame-dried flask was charged with trimethylsulfoxonium iodide (1.5 equiv.) and NaH (1.5 equiv., 60% oil dispersion). The mixture was dissolved in anhydrous DMSO (0.5 M) with stirring at room temperature for 30 min. After 30 min, the reaction mixture became homogeneous. The corresponding enone (1.0 equiv.) was added to the reaction mixture in one portion. The resulting mixture was heated to 85 °C and stirred overnight. After cooling to room temperature, the reaction was quenched with cold H2O. The mixture was extracted with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography as described above to give the cyclopropyl derivative.

[0060] 1-(4-Methoxyphenyl)-2-(4-nitrophenoxy)ethan-1-one (92) [ka] Basic Procedure CPurification by silica gel flash chromatography (gradient elution, 0% to 30% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 92 (3.8 g, 13.2 mmol, 92%) as a pale yellow solid. IR (cm -1 ) 2914, 2842, 1690, 1600, 1509, 1341, 1231, 1172, 1112, 970, 836; 1 H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 9.2 Hz, 2H), 7.97 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 9.2 Hz, 2H), 6.98 (d, J = 9.2 Hz, 2H), 5.36 (s, 2H), 3.90 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 191.5, 164.6, 163.2, 130.6 (2C), 127.2, 126.1 (2C), 115.0 (2C), 114.5 (2C), 110.2, 70.7, 55.8; ES-API MS: m / z calcd for C 15 H 14 NO5288.1, found 288.1 [M+H] + .

[0061] 2-(2-fluoro-4-nitrophenoxy)-1-(4-methoxyphenyl)ethan-1-one (93) [ka] Basic Procedure C Purification by silica gel flash chromatography (gradient elution, 0 to 25% EtOAc in hexanes) afforded the title compound 93 (45 mg, 0.14 mmol, 96%) as a yellow solid. IR (cm -1 ) 1686, 1600, 1508, 1346, 1293, 1239, 1171, 970; 1H NMR (400 MHz, DMSO-d6) δ 8.20 (dd, J = 11.1, 2.6 Hz, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.99 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 8.9 Hz, 1H), 7.11 (d, J = 8.8 Hz, 2H), 5.88 (s, 2H), 3.87 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 191.3, 163.8, 152.0 (d, J = 10.0 Hz, 1C), 150.2 (d, J = 246.9 Hz, 1C), 140.3 (d, J = 7.0 Hz, 1C), 130.3 (2C), 126.8, 121.1 (d, J = 2.7 Hz, 1C), 114.7, 114.1 (2C), 112.1 (d, J = 21.3 Hz, 1C), 70.9, 55.7; ES-API MS: m / z calcd for C 15 H 13 FNO5306.1, found 306.1 [M+H] + .

[0062] 2-(3-fluoro-4-nitrophenoxy)-1-(4-methoxyphenyl)ethan-1-one (94) [ka] Basic Procedure C Purification by recrystallization in acetone / H2O gave the title compound 94 (376 mg, 1.23 mmol, 83%) as a brownish solid. IR (cm -1 ) 1678, 1600, 1511, 1332, 1243, 1171, 1098, 829; 1H NMR (400 MHz, DMSO-d6) δ 8.15 (dd, J = 9.2, 9.2 Hz, 1H), 8.00 (dd, J = 8.8 Hz, 2H), 7.29 (d, J = 14.0 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 9.2 Hz, 1H), 5.78 (s, 2H), 3.87 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 192.0, 164.9 (d, J = 11.3 Hz, 1C), 164.4, 157.3 (d, J = 260.0 Hz, 1C), 131.0 (2C), 128.6 (2C), 127.5, 114.8 (2C), 112.5 (d, J = 2.0 Hz, 1C), 104.8 (d, J = 24.6 Hz, 1C), 71.5, 56.3 (d, J = 2.3 Hz, 1C); ES-API MS: m / z calcd for C 15 H 13 FNO5306.1, found 306.1 [M+H] + .

[0063] 1-(4-Methoxyphenyl)-2-(4-nitro-3-(trifluoromethyl)phenoxy)ethan-1-one (95) [ka] Basic Procedure C Purification by silica gel flash chromatography (gradient elution, 0% to 30% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 95 (802 mg, 2.26 mmol, 94%) as a yellow-orange solid. IR (cm -1 ) 2940, 1690, 1601, 1534, 1314, 1229, 1174, 1149, 974, 834; 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 2.8 Hz, 1H), 7.08 (dd, J = 9.2, 2.4 Hz, 1H), 7.00 (d, J = 8.4 Hz, 2H), 5.41 (s, 2H), 3.90 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 190.8, 164.8, 161.4, 130.6 (2C), 130.2, 128.3, 126.9, 126.6, 121.9 (q, J = 272.1 Hz, 1C), 117.0, 115.6 (q, J = 5.9 Hz, 1C), 114.6 (2C), 70.7, 55.9; ES-API MS: m / z calcd for C 16 H 13 F3NO5356.1 , found 356.1 [M+H] + .

[0064] 2-(4-aminophenoxy)-1-(4-methoxyphenyl)ethan-1-one (96) [ka] A mixture of nitroarene 92 (1.0 equiv.) and iron powder (5.0 equiv.) in 1.0 M NH4Cl and saturated 1.0 M EtOH was heated to 70 °C and stirred until complete conversion was observed by TLC. The mixture was cooled to room temperature, filtered through a pad of Celite, and the residue was washed with EtOAc (twice). The combined organic layers were washed with saturated aqueous NaHCO3, then brine, dried over anhydrous MgSO4, and filtered. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (gradient elution, 0% to 70% EtOAc in hexanes) to give the title aniline 96 (78 mg, 0.30 mmol, 90%) as a yellow solid. IR (cm -1 ) 3408, 3334, 1600, 1506, 1258, 1213, 1172, 828; 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.76 (d, J = 8.8 Hz, 2H), 6.59 (d, J = 8.8 Hz, 2H), 5.10 (s, 2H), 3.84 (s, 3H), 3.42 (br, 2H); 13 C NMR (100 MHz, CDCl3) δ 193.8, 164.1, 151.4, 141.0, 130.7 (2C), 127.9, 116.4 (2C), 116.3 (2C), 114.1 (2C), 71.9, 55.7; ES-API MS: m / z calcd for C 15 H 16 NO3258.1, found 258.1 [M+H] + .

[0065] (3aR,4R,4aR,5aS,6S,6aS)-4,4a,5,5a,6,6a-hexahydro-1H-4,6-ethenocyclopropa[f]isobenzofuran-1,3(3aH)-dione; (3aR,4S,4aS,5aR,6R,6aS)-4,4a,5,5a,6,6a-hexahydro-1H-4,6-ethenocyclopropa[f]isobenzofuran-1,3(3aH)-dione (97) [ka] A solution of 1,3,5-cycloheptatriene (10 g, 0.108 mol) and maleic anhydride (12.0 g, 0.122 mol) in xylene (50 mL) was heated to 150 °C and reacted for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel flash chromatography (gradient elution, 0% to 10% EtOAc in hexanes, then 10% to 30% EtOAc in hexanes) to give the exo isomer, titled 97-exo (1 g, 5.25 mmol, 5%), and the endo isomer, titled 97-endo (14 g, 73.6 mmol, 70%), both as white solids. 97-endo: IR (cm -1) 3008, 2945, 1856, 1823, 1774, 1376, 1227, 1093, 1078, 952, 915; 1 1H NMR (500 MHz, CDCl3) δ 5.87 (m, 2H), 3.45 (m, 2H), 3.23 (dd, J = 7.5, 1.5 Hz, 2H), 1.10 (m, 2H), 0.35 (m, 1H), 0.25 (m, 1H); 13 13C NMR (100 MHz, CDCl3) δ 172.5 (2C), 128.6 (2C), 46.0 (2C), 33.8 (2C), 9.7 (2C), 5.3; ES-API MS: m / z calcd for C 11 12H 10 O3, found 191.1 [M+H] + . 97-exo isomer: IR (cm -1 ) 3016, 2983, 1848, 178, 1305, 1221, 1086, 1072, 1042, 960, 915, 851; 1 1H NMR (500 MHz, CDCl3) δ 5.94 (dd, J = 4.0, 4.0 Hz, 2H), 3.41 (m, 2H), 3.08 (m, 2H), 1.12 (m, 2H), 0.21 (dd, J = 13.5, 7.0 Hz, 1H), 0.13 (m, 1H); 13 13C NMR (100 MHz, CDCl3) δ 172.5 (2C), 129.4 (2C), 46.7 (2C), 32.7 (2C), 5.6 (2C), 1.9; ES-API MS: m / z calcd for C 11 12H 11 O3 191.1, found 191.1 [M+H] + .

[0066] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(4-methoxyphenyl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (1) [ka] A mixture of the endo isomer of anhydride 97 (1.0 equiv.) and the corresponding aniline (1.0 equiv.) in AcOH (0.2 M) was heated to 120°C for 30 min. The mixture was cooled to room temperature, quenched with saturated aqueous NaHCO3, and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and filtered. The solvent was removed under reduced pressure, and the residue was purified by crystallization in EtOAc / hexane to give the title compound 1 (40 mg, 0.093 mmol, 35%) as a white solid. IR (cm -1 ) 1704, 1601, 1511, 1389, 1224, 1172; 1 H NMR (400 MHz, DMSO-d6) δ 8.00 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 6.98 (s, 4H), 5.82 (m, 2H), 5.54 (s, 2H), 3.85 (s, 3H), 3.27 (m, 2H), 3.16 (m, 2H), 1.17 (m, 2H), 0.25 (m, 1H), 0.07 (m, 1H); 13 C NMR (100 MHz, DMSO-d6) δ 192.8, 177.9 (2C), 163.8, 157.8, 130.4 (2C), 128.1 (2C), 127.7 (2C), 127.4, 125.2, 115.0 (2C), 114.3 (2C), 70.2, 55.8, 45.0 (2C), 33.4 (2C), 9.7 (2C), 4.5; ES-API MS: m / z calcd for C 26 H 24 NO5430.2, found 430.2 [M+H] + .

[0067] (3aR,4S,4aS,5aR,6R,6aS)-2-(4-(2-(4-methoxyphenyl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (2) [ka] A mixture of the exo form of anhydride 97 (1.0 equiv.) and the corresponding aniline (1.0 equiv.) in AcOH (0.2 M) was heated to 120 °C for 30 min. The mixture was cooled to room temperature, quenched with saturated aqueous NaHCO3, and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and filtered. The solvent was removed under reduced pressure, and the residue was purified by crystallization in EtOAc / hexane to give the title compound 2 (35 mg, 0.081 mmol, 33%) as a white solid. IR (cm -1 ) 1702, 1599, 1510, 1387, 1308, 1228, 1172; 1 H NMR (500 MHz, DMSO-d6) δ 8.00 (d, J = 9.0 Hz, 2H), 7.12 (d, J = 9.5 Hz, 2H), 7.09 (d, J = 9.5 Hz, 2H), 7.02 (d, J = 8.5 Hz, 2H), 5.95 (m, 2H), 5.56 (s, 2H), 3.86 (s, 3H), 3.24 (m, 2H), 2.89 (m, 2H), 0.95 (m, 2H), 0.12 (m, 1H), -0.02 (m, 1H); 13 C NMR (100 MHz, DMSO-d6) δ 192.3, 177.3 (2C), 163.2, 157.3, 129.9 (2C), 128.8 (2C), 127.7 (2C), 126.8, 124.8, 114.5 (2C), 113.7 (2C), 69.5, 55.2, 44.7 (2C), 31.5 (2C), 4.7 (2C), 0.86; ES-API MS: m / z calcd for C 26 H 24 NO5430.2, found 430.2 [M+H] + .

[0068] 1-(4-(2-(4-methoxyphenyl)-2-oxoethoxy)phenyl)-1H-pyrrole-2,5-dione (5) [ka] A mixture of aniline 96 (219 mg, 0.851 mmol) and maleic anhydride (100 mg, 1.02 mmol) in AcOH (8.5 mL) was heated to 120 °C and stirred for 12 h. The mixture was cooled to room temperature, quenched with cold saturated aqueous NaHCO3, and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and filtered. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (gradient elution, 0 to 40% EtOAc in hexanes) to give the title compound 5 (148 mg, 0.44 mmol, 52%) as a yellow solid. IR (cm -1 ) 1714, 1601, 1511, 1397, 1224, 1172; 1 H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 9.2 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.83 (s, 2H), 5.23 (s, 2H), 3.89 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 192.8, 169.9 (2C), 164.4, 157.8, 134.4 (2C), 130.8 (2C), 127.8 (2C), 127.7, 124.9, 115.6 (2C), 114.3 (2C), 71.1, 55.8; ES-API MS: m / z calcd for C 19 H 16 NO5338.1, found 338.1 [M+H] + .

[0069] (3aR,4S,7R,7aS)-2-(4-(2-(4-methoxyphenyl)-2-oxoethoxy)phenyl)-3a,4,7,7a-tetrahydro-1H-4,7-ethanoisoindole-1,3(2H)-dione (3) [ka] To a solution of maleimide 5 (1 equiv.) in CHCl (0.1 M) was added cyclohexadiene (5.0 equiv.). The resulting mixture was heated at 60°C until TLC showed complete consumption of the starting material. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography (gradient elution, 0% to 40% EtOAc in hexanes) to give the title cycloadduct 3 (9.0 mg, 0.021 mmol, 36%) as a white solid. IR (cm -1 ) 2954, 1707, 1601, 1512, 1389, 1299, 1233, 1172; 1 H NMR (500 MHz, CDCl3) δ 7.98 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 9.0 Hz, 2H), 6.98 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 6.27 (dd, J = 4.0, 3.5 Hz, 2H), 5.19 (s, 2H), 3.89 (s, 3H), 3.24 (m, 2H), 2.99 (m, 2H), 1.65 (d, J = 7.5 Hz, 2H), 1.43 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 192.8, 178.4 (2C), 164.3, 158.1, 132.6 (2C), 130.8 (2C), 128.0 (2C), 125.6, 115.5 (2C), 114.3 (2C), 105.0, 71.2, 55.8, 44.4 (2C), 32.2 (2C), 23.9 (2C); ES-API MS: m / z calcd for C 25 H 24 NO5418.2, found 418.2 [M+H] + .

[0070] (3aR,4S,7R,7aS)-2-(4-(2-(4-methoxyphenyl)-2-oxoethoxy)phenyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione (4) [ka] To a solution of maleimide 5 (1 equiv.) in CHCl (0.1 M) was added cyclopentadiene (5.0 equiv.). The resulting mixture was heated at 60°C until TLC showed complete consumption of the starting material. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography (gradient elution, 0% to 70% EtOAc in hexanes) to give the title cycloadduct 4 (30 mg, 0.074 mmol, 63%) as a pale yellow solid. IR (cm -1 ) 2843, 1706, 1601, 1512, 1386, 1263, 1227, 1173; 1H NMR (500 MHz, CDCl3) δ 7.98 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 9.0 Hz, 2H), 6.97 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 8.5 Hz, 2H), 6.24 (s, 2H), 5.18 (s, 2H), 3.89 (s, 3H), 3.49 (m, 2H), 3.41 (m, 2H), 1.78 (d, J = 9.0 Hz, 1H), 1.60 (d, J = 9.0 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 192.8, 177.2 (2C), 164.3, 158.1, 134.8 (2C), 130.8 (2C), 128.1 (2C), 127.6, 125.5, 115.5 (2C), 114.2 (2C), 71.1, 55.7, 52.4, 45.8 (2C), 45.6 (2C); ES-API MS: m / z calcd for C 24 H 22 NO5, found 404.1 [M+H] + .

[0071] (3aR,4R,4aR,5aS,6S,6aS)-2-(2-fluoro-4-(2-(4-methoxyphenyl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (7) [ka] Method D Purification by silica gel flash chromatography (gradient elution, 0 to 50% EtOAc in hexanes) afforded the title compound 7 (30 mg, 0.067 mmol, 14%) as a white solid. IR (cm -1 ) 1707, 1693, 1600, 1518, 1385, 1291, 1243, 1166; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.8 Hz, 2H), 7.06 (m, 1H), 6.97 (d, J = 8.8 Hz, 2H), 6.78 (m, 1H), 6.75 (m, 1H), 5.85 (dd, J = 4.4, 3.6 Hz, 2H), 5.19 (s, 2H), 3.89 (s, 3H), 3.48 (m, 2H), 3.15 (m, 2H), 1.14 (m, 2H), 0.35-0.26 (m, 2H); 13 C NMR (100 MHz, DMSO-d6) δ 192.6, 177.5 (2C), 164.1, 160.0, 159.1, 156.6, 130.7 (2C), 128.0, 127.8, 127.6 (2C), 114.5 (2C), 110.0, 103.4, 70.7, 56.1, 45.7, 45.2, 33.7, 33.6, 9.9 (2C), 4.9; ES-API MS: m / z calcd for C 26 H 23 FNO5448.2, found 448.2 [M+H] + .

[0072] (3aR,4R,4aR,5aS,6S,6aS)-2-(3-fluoro-4-(2-(4-methoxyphenyl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (8) [ka] Method D Purification by silica gel flash chromatography (gradient elution, 0 to 50% EtOAc in hexanes) afforded the title compound 8 (183 mg, 0.40 mmol, 59%) as a white solid. IR (cm -1 ) 1774, 1709, 1600, 1515, 1441, 1388, 1268, 1240, 1174; 1H NMR (400 MHz, DMSO-d6) δ 7.99 (d, J = 8.8 Hz, 2H), 7.15 (dd, J = 9.2, 9.2 Hz, 1H), 7.10 (d, J = 8.8 Hz, 2H), 7.04 (dd, J = 11.6, 2.0 Hz, 1H), 6.84 (ddd, J = 8.8, 1.6, 1.6 Hz, 1H), 5.82 (dd, J = 4.4, 3.6 Hz, 2H), 5.68 (s, 2H), 3.86 (s, 3H), 3.28 (m, 2H), 3.18 (m, 2H), 1.18 (m, 2H), 0.26 (dd, J = 12.8, 7.3 Hz, 1H), 0.08 (dd, J = 8.8, 3.7 Hz, 1H); 13 C NMR (100 MHz, DMSO-d6) δ 192.2, 177.4 (2C), 163.7, 150.7 (d, J = 243.5 Hz, 1C), 145.8 (d, J = 10.1 Hz, 1C), 130.2 (2C), 127.5 (2C), 127.1, 124.8 (d, J = 9.1 Hz, 1C), 123.1 (d, J = 3.3 Hz, 1C), 115.0, 114.8, 114.1 (2C), 70.5, 55.7, 44.8 (2C), 33.3 (2C), 9.5 (2C), 4.4; ES-API MS: m / z calcd for C 26 H 23 FNO5448.2, found 448.1 [M+H]+.

[0073] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(4-methoxyphenyl)-2-oxoethoxy)-2-(trifluoromethyl)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (9) [ka] Method DPurification by silica gel flash chromatography (gradient elution, 0 to 30% EtOAc in hexanes) afforded the title compound 9 (432 mg, 0.87 mmol, 72%) as a white solid. IR (cm -1 ) 3062, 3016, 1715, 1694, 1600, 1506, 1316, 1174; 1 H NMR (500 MHz, CDCl3) δ 7.97 (d, J = 9.2 Hz, 2H), 7.31 (d, J = 2.8 Hz, 1H), 7.12 (dd, J = 8.4, 2.8 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 8.8 Hz, 2H), 5.86 (m, 2H), 5.25 (s, 2H), 3.89 (s, 3H), 3.47 (m, 2H), 3.16 (m, 2H), 1.12 (m, 2H), 0.35-0.26 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 191.8, 177.8 (2C), 164.5, 158.9, 132.5, 132.1, 130.8 (2C), 128.2, 127.8, 127.4, 118.8, 118.6, 114.7 (q, J = ES-API MS: m / z calcd for C 27 H 23 F3NO5498.2, found 498.1 [M+H] + .

[0074] (3aR,4R,4aR,5aS,6S,6aS)-2-(3-chloro-4-hydroxyphenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (98) [ka] Method B(Microwave) crystallization gave the title compound 98 (466 mg, 1.48 mmol, 94%) as a white solid. IR (cm -1 ) 3396, 1694, 1496, 1291, 1195, 1166, 736; 1 H NMR (400 MHz, CDCl3) δ 7.08 (d, J = 2.4 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 6.87 (dd, J = 8.8, 2.4 Hz, 1H), 5.81 (dd, J = 4.8, 3.2 Hz, 2H), 3.43 (m, 2H), 3.08 (dd, J = 1.6, 1.6 Hz, 2H), 2.66 (br, 1H), 1.11 (m, 2H), 0.31-0.21 (m, 2H); 13 C NMR (100MHz, CDCl3) δ 178.2 (2C), 152.8, 128.0, 127.9 (2C), 126.4, 124.1, 120.7, 116.7, 45.4 (2C), 33.9 (2C), 10.0 (2C), 4.8; MS: m / z calcd for C 17 H 15 ClNO3316.1, found 316.1 [M+H] + .

[0075] (3aR,4R,4aR,5aS,6S,6aS)-2-(3,5-dichloro-4-hydroxyphenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (99) [ka] Method B (Microwave) crystallization afforded the title compound 99 (423 mg, 1.21 mmol, 77%) as a light brown solid. IR (cm -1 ) 3234, 1699, 1489, 1416, 1184, 1162, 732; 1H NMR (400 MHz, CDCl3) δ 7.13 (s, 2H), 6.08 (br, 1H), 5.86 (dd, J = 4.4, 3.2 Hz, 2H), 3.49 (m, 2H), 3.13 (dd, J = 1.6, 1.6 Hz, 2H), 1.15 (m, 2H), 0.36-0.26 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 177.5 (2C), 148.3, 128.1 (2C), 126.8 (2C), 124.7, 121.4 (2C), 45.5 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 17 H 14 Cl2NO3350.0 found 350.2 [M+H] + .

[0076] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-mercaptophenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (100) [ka] Method B (Microwave) crystallization gave the title compound 100 (80%) as yellow crystals. IR (cm -1 ) 3003, 2942, 1704, 1496, 1389, 1193, 1172, 812, 733; 1 H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 5.84 (dd, J = 4.8, 3.2 Hz, 2H), 3.50 (s, 1H), 3.48 (m, 2H), 3.12 (dd, J = 1.6, 1.6 Hz, 2H), 1.14 (m, 2H), 0.35-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 177.7 (2C), 132.1, 129.9 (2C), 129.6, 128.0 (2C), 127.2 (2C), 45.5 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 17 H 16 NO2S 298.1, found 298.1 [M+H] + .

[0077] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-aminophenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (101) [ka] Method A Purification by silica gel flash chromatography (gradient elution, 0 to 75% EtOAc in hexanes) afforded the title compound 101 (97 mg, 0.35 mmol, 66%) as a yellow solid. IR (cm -1 ) 3336, 3060, 3029, 2948, 1699, 1517, 1404, 1199, 1165, 916, 734; 1 H NMR (400 MHz, CDCl3) δ 6.90 (d, J = 8.8 Hz, 2H), 6.67 (d, J = 8.8 Hz, 2H), 5.83 (dd, J = 4.8, 3.2 Hz, 2H), 3.76 (br, 2H), 3.47 (m, 2H), 3.09 (dd, J = 2.0, 1.6 Hz, 2H), 1.13 (m, 1H), 0.29 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 178.1 (2C), 146.7, 127.8 (2C), 127.5 (2C), 122.2, 115.1 (2C), 45.2 (2C), 33.8 (2C), 9.9 (2C), 4.6; ES-API MS: m / z calcd for C17 H 17 N2O2281.1, found 281.1 [M+H] + .

[0078] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-hydroxyphenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (102a) [ka] Method B (Microwave) crystallization afforded the title compound 102a (145 mg, 0.52 mmol, 98%) as a white solid. IR (cm -1 ) 3398, 1772, 1692, 1517, 1188; 1 H NMR (500 MHz, DMSO-d6) δ 9.71 (s, 1H), 6.87 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 9.0 Hz, 2H), 5.81 (dd, J = 4.0, 4.0 Hz, 2H), 3.27 (m, 2H), 3.15 (m, 2H), 1.17 (m, 2H), 0.26 (dd, J = 13.0, 7.0 Hz, 1H), 0.08 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ 177.8 (2C), 157.2, 128.0 (2C), 127.5 (2C), 123.3, 115.3 (2C), 44.7 (2C), 33.2 (2C), 9.5 (2C), 4.3; ES-API MS: m / z calcd for C 17 H 16 NO3282.1, found 282.1 [M+H] + .

[0079] (3aR,4R,4aR,5aS,6S,6aS)-2-(2-fluoro-4-hydroxyphenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (102b) [ka] Method B Purification by silica gel flash chromatography (gradient elution, 0 to 55% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes afforded the title compound 102b (95%) as a brown solid. IR (cm -1 ) 3372, 1698, 1518, 1401, 1311, 1186; 1 H NMR (500 MHz, CDCl3) δ 6.86 (ddd, J = 67.5, 8.0, 7.5 Hz, 1H), 6.51 (m, 2H), 5.94 (br, 1H), 5.86 (m, 2H), 3.48 (m, 2H), 3.17 (d, J = 18.0 Hz, 1H), 1.15 (m, 2H), 0.35-0.27 (m, 2H); 13 C NMR (100 MHz, DMSO-d6) δ 177.6 (2C), 159.5 (d, J = 63.0 Hz, 1C), 156.7, 135.5, 130.8, 128.0, 127.7, 112.1 (d, J = 20.8 Hz, 1C), 103.5 (d, J = 9.7 Hz, 1C), 45.7, 45.1, 33.7, 33.5, 9.8 (2C), 4.8; ES-API MS: m / z calcd for C 17 H 15 FNO3300.1, found 300.1 [M+H] + .

[0080] (3aR,4R,4aR,5aS,6S,6aS)-2-(5-hydroxypyridin-2-yl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (103) [ka] Method B (Microwave) Purification by silica gel flash chromatography (gradient elution, 0% to 70% EtOAc in CH2Cl2) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 103 (1.64 g, 5.81 mmol, 72%) as an orange solid. IR (cm -1 ) 3290, 3010, 2360, 1710, 1580, 1488, 1288, 1181; 1 H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 2.8 Hz, 1H), 7.08 (dd, J = 8.4, 2.8 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 5.68 (dd, J = 4.0, 4.0 Hz, 2H), 3.26 (m, 2H), 2.96 (m, 2H), 0.96 (m, 2H), 0.15-0.06 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 177.8 (2C), 154.1, 137.1, 136.7, 127.5 (2C), 124.8, 122.8, 45.2 (2C), 33.4 (2C), 9.5 (2C), 4.4; ES-API MS: m / z calcd for C 16 H 15 N2O3283.1, found 283.1 [M+H] + .

[0081] (3aR,4R,4aR,5aS,6S,6aS)-2-(5-hydroxypyrimidin-2-yl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (104) [ka] Method A Purification by silica gel flash chromatography (gradient elution, 0% to 5% MeOH in CH2Cl2) followed by recrystallization in MeOH / CH2Cl2 / hexanes gave the title compound 104 (1.08 g, 3.81 mmol, 48%) as an orange solid. IR (cm -1 ) 3008, 1710, 1567, 1422, 1291, 1183, 731; 1 H NMR (400 MHz, CD3OD) δ 8.38 (s, 1H), 5.86 (dd, J = 4.8, 3.6 Hz, 2H), 3.39 (m, 2H), 3.26 (dd, J = 1.6, 1.6 Hz, 2H), 1.21 (m, 2H), 0.36-0.26 (m, 2H); 13 C NMR (100 MHz, CD3OD) δ 177.5 (2C), 152.2, 145.7 (2C), 144.3, 127.4 (2C), 45.6 (2C), 33.5 (2C), 9.3 (2C), 3.7; ES-API MS: m / z calcd for C 15 H 14 N3O3284.1, found 284.1 [M+H] + .

[0082] (3aR,4R,4aR,5aS,6S,6aS)-2-(3-chloro-4-(2-(4-methoxyphenyl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (10) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0% to 50% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 10 (112 mg, 0.24 mmol, 77%) as a white solid. IR (cm-1 ) 2957, 1711, 1601, 1505, 1233, 1174, 972, 733; 1 H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 2.4 Hz, 1H), 7.00 (dd, J = 8.8, 2.4 Hz, 1H), 6.96 (d, J = 9.2 Hz, 2H), 6.88 (d, J = 8.8 Hz, 1H), 5.84 (dd, J = 4.8, 3.2 Hz, 2H), 5.26 (s, 2H), 3.88 (s, 3H), 3.47 (m, 2H), 3.11 (dd, J = 1.6, 1.6 Hz, 2H), 1.14 (m, 2H), 0.35-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 192.4, 177.6 (2C), 164.4, 153.9, 131.0 (2C), 128.8, 128.0 (2C), 127.5, 126.1, 125.9, 123.7, 114.3 (2C), 114.0, 72.1, 55.8, 45.4 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 26 H 23 ClNO5264.1 found 464.1 [M+H] + .

[0083] (3aR,4R,4aR,5aS,6S,6aS)-2-(3,5-dichloro-4-(2-(4-methoxyphenyl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (11) [ka] Method CPurification by silica gel flash chromatography (gradient elution, 0 to 35% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 11 (121 mg, 0.24 mmol, 85%) as a white solid. IR (cm -1 ) 3077, 3010, 2954, 1714, 1601, 1471, 1172, 971, 733; 1 H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 9.2 Hz, 2H), 7.22 (s, 2H), 6.96 (d, J = 8.8 Hz, 2H), 5.86 (dd, J = 4.4, 3.6 Hz, 2H), 5.20 (s, 2H), 3.88 (s, 3H), 3.50 (m, 2H), 3.14 (dd, J = 1.6, 1.6 Hz, 2H), 1.16 (m, 2H), 0.37-0.26 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 191.2, 177.1 (2C), 164.2, 151.1, 130.7 (2C), 129.8 (2C), 128.9, 128.1 (2C), 127.6, 127.3 (2C), 114.2 (2C), 74.7, 55.8, 45.5 (2C), 34.1 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 26 H 22 Cl2NO5498.1, found 498.1 [M+H] + .

[0084] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-((2-(4-methoxyphenyl)-2-oxoethyl)thio)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (15) [ka] Method CPurification by silica gel flash chromatography (gradient elution, 0 to 55% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 15 (88 mg, 0.20 mmol, 59%) as a pale yellow solid. IR (cm -1 ) 2955, 2358, 1706, 1669, 1599, 1497, 1379, 1261, 1175, 733; 1 H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 9.2 Hz, 2H), 7.43 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 5.84 (dd, J = 4.8, 3.6 Hz, 2H), 4.26 (s, 2H), 3.87 (s, 3H), 3.48 (m, 2H), 3.12 (dd, J = 1.6, 1.6 Hz, 2H), 1.14 (m, 2H), 0.35-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 192.6, 177.6 (2C), 164.1, 136.3, 131.2 (2C), 130.5, 130.3 (2C), 128.5, 128.0 (2C), 127.1 (2C), 114.1 (2C), 55.7, 45.5 (2C), 41.0, 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 26 H 23 NO4SNa 468.1, found 468.1 [M+Na] + .

[0085] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-((2-(4-methoxyphenyl)-2-oxoethyl)amino)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (16) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0 to 45% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 16 (32 mg, 0.07 mmol, 71%) as a white solid. IR (cm -1 ) 3394, 2959, 2924, 2852, 1702, 1602, 1524, 1260, 1172, 818, 735; 1 H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 4H), 6.70 (d, J = 8.8 Hz, 2H), 5.85 (dd, J = 4.8, 3.6 Hz, 2H), 5.12 (br, 1H), 4.52 (s, 2H), 3.89 (s, 3H), 3.48 (m, 2H), 3.10 (dd, J = 1.6, 1.6 Hz, 2H), 1.13 (m, 2H), 0.33-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 193.0, 178.2 (2C), 164.1, 147.2, 130.1 (2C), 127.7 (3C), 127.5 (2C), 121.4, 114.1 (2C), 113.0 (2C), 55.6, 49.6, 45.2 (2C), 33.8 (2C), 9.9 (2C), 4.6; ES-API MS: m / z calcd for C 26 H 25 N2O4429.2 found 429.1 [M+H] + .

[0086] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-oxo-2-phenylethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (20) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0 to 45% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 20 (32 mg, 0.08 mmol, 45%) as a pale yellow solid. IR (cm -1 ) 1704, 1513, 1218, 1184, 734; 1 H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 7.2 Hz, 2H), 7.62 (t, J = 7.6 Hz, 1H), 7.50 (dd, J = 8.0, 7.6 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 5.84 (dd, J = 4.0, 4.0 Hz, 2H), 5.25 (s, 2H), 3.48 (m, 2H), 3.12 (m, 2H), 1.14 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 194.3, 178.0 (2C), 158.0, 134.6, 134.2, 129.1 (2C), 128.4 (2C), 128.00 (2C), 127.98 (2C), 125.6, 115.5 (2C), 71.2, 45.5 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 25 H 21 NO4Na 422.1 found 422.1 [M+Na] + .

[0087] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(4-methoxyphenethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (29) [ka] Method CPurification by silica gel flash chromatography (gradient elution, 0 to 35% EtOAc in hexanes) afforded the title compound 29 (77 mg, 0.19 mmol, 52%) as a white solid. IR (cm -1 ) 3007, 2953, 1705, 1513, 1245, 1180, 1031, 826; 1 H NMR (400 MHz, CDCl3) δ 7.19 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 9.2 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 5.85 (dd, J = 4.8, 3.6 Hz, 2H), 4.12 (t, J = 7.2 Hz, 2H), 3.79 (s, 3H), 3.48 (m, 2H), 3.11 (dd, J = 1.6, 1.6 Hz, 2H), 3.03 (t, J = 7.2 Hz, 2H), 1.14 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 178.1 (2C), 158.9, 158.5, 130.2, 130.1 (2C), 127.94 (2C), 127.86 (2C), 124.6, 115.2 (2C), 114.1 (2C), 69.3, 55.5, 45.4 (2C), 34.9, 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 26 H 26 NO4416.2, found 416.2 [M+H] + .

[0088] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(3-methoxyphenyl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (30a) [ka] Method C After purification by silica gel flash chromatography (gradient elution, 0 to 50% EtOAc in hexanes) and recrystallization in CH2Cl2 / hexanes, the title compound 30a (140 mg, 0.33 mmol, 92%) was obtained as a pale yellow foam. IR (cm -1 ) 2954, 2359, 1704, 1512, 1392, 1236, 1185, 1041, 735; 1 H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.0 Hz, 1H), 7.47 (dd, J = 2.4, 1.2 Hz, 1H), 7.36 (dd, J = 8.4, 7.6 Hz, 1H), 7.13 (dd, J = 8.0, 2.4 Hz, 1H), 7.06 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 5.81 (dd, J = 4.8, 3.6 Hz, 2H), 5.21 (s, 2H), 3.82 (s, 3H), 3.43 (m, 2H), 3.08 (dd, J = 1.6, 1.6 Hz, 2H), 1.11 (m, 2H), 0.31-0.22 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 193.9, 177.9 (2C), 160.0, 157.9, 135.7, 129.9, 127.9 (2C), 127.8 (2C), 125.5, 120.6, 120.5, 115.3 (2C), 112.4, 71.0, 55.6, 45.3 (2C), 33.9 (2C), 10.0 (2C), 4.7; ES-API MS: m / z calcd for C 26 H 23 NO5Na 452.1, found 452.1 [M+Na] + .

[0089] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(2-methoxyphenyl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (31a) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0% to 60% EtOAc in hexanes) gave a mixture of starting phenol and product. The resulting mixture was further repurified by HPLC (reverse phase, MeCN / HO / 0.1% TFA) to give the title product 31a (33 mg, 0.077 mmol, 43%) as a pale yellow foam. IR (cm -1 ) 3053, 3008, 2952, 1706, 1597, 1512, 1184, 973, 735; 1 H NMR (400 MHz, CDCl3) δ 7.93 (dd, J = 8.0, 1.6 Hz, 1H), 7.54 (ddd, J = 8.0, 8.0, 1.6 Hz, 1H), 7.06 (d, J = 8.8 Hz, 2H), 7.06 (m, 1H), 7.01 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 9.2 Hz, 2H), 5.84 (dd, J = 4.8, 3.6 Hz, 2H), 5.22 (s, 2H), 3.95 (s, 3H), 3.47 (m, 2H), 3.12 (m, 2H), 1.13 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 195.1, 178.1 (2C), 159.3, 158.2, 135.0, 131.1, 127.7 (2C), 127.6 (2C), 124.9, 124.6, 121.2, 115.4 (2C), 111.5, 74.4, 55.7, 45.2 (2C), 33.8 (2C), 9.9 (2C), 4.7; ES-API MS: m / z calcd for C26 H 23 NO5Na 452.1, found 452.2 [M+Na] + .

[0090] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(4-ethoxyphenyl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (32a) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0 to 45% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 32a (93 mg, 0.21 mmol, 73%) as a yellow solid. IR (cm -1 ) 1705, 1600, 1511, 1393, 1226, 1172; 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 9.2 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 5.84 (dd, J = 4.4, 3.2 Hz, 2H), 5.18 (s, 2H), 4.11 (q, J = 6.8 Hz, 2H), 3.48 (m, 2H), 3.11 (m, 2H), 1.45 (t, J = 7.2 Hz, 3H), 1.14 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 192.8, 178.0 (2C), 163.8, 158.1, 130.8 (2C), 128.1, 128.0 (4C), 127.5, 125.5, 116.1, 115.5 (2C), 114.7 (2C), 71.1, 64.1, 45.5 (2C), 34.0 (2C), 14.9, 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 27 H 25 NO5Na 466.2, found 466.1 [M+Na] + .

[0091] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-oxo-2-(4-(prop-2-yn-1-yloxy)phenyl)ethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (33a) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0% to 50% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 33a (32 mg, 0.07 mmol, 86%) as a colorless solid. IR (cm -1 ) 3298, 3052, 3011, 2956, 1772, 1704, 1600, 1511, 1223, 1173, 734; 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 9.2 Hz, 2H), 6.96 (d, J = 9.2 Hz, 2H), 5.82 (dd, J = 4.8, 3.2 Hz, 2H), 5.17 (s, 2H), 4.76 (d, J = 2.4 Hz, 2H), 3.46 (m, 2H), 3.10 (dd, J = 2.0, 2.0 Hz, 2H), 2.55 (t, J = 2.4 Hz, 1H), 1.12 (m, 2H), 0.32-0.23 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 192.9, 178.0 (2C), 162.1, 158.1, 130.8 (2C), 128.4, 128.1, 127.99 (2C), 127.98, 125.6, 115.5 (2C), 115.1 (2C), 76.6, 71.2, 56.1, 45.5 (2C), 34.0 (2C), 10.1 (2C); ES-API MS: m / z calcd for C 28 H 24 NO5454.2, found 454.1 [M+H] + .

[0092] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(4-butoxyphenyl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (34a) [ka] Method C After purification by silica gel flash chromatography (gradient elution, 0 to 45% EtOAc in hexanes) and recrystallization in CH2Cl2 / hexanes, the title compound 34a (110 mg, 0.23 mmol, 56%) was obtained as colorless needles. IR (cm -1) 2957, 2874, 1705, 1601, 1512, 1224, 1173, 965, 830, 734; 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 9.2 Hz, 2H), 6.97 (d, J = 9.2 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 5.84 (dd, J = 4.4, 3.2 Hz, 2H), 5.18 (s, 2H), 4.04 (t, J = 6.8 Hz, 2H), 3.48 (m, 2H), 3.11 (dd, J = 2.0, 2.0 Hz, 2H), 1.79 (pent, J = 7.2 Hz, 2H), 1.50 (hex, J = 7.6 Hz, 2H), 1.14 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 192.8, 178.0 (2C), 164.0, 158.1, 130.8 (2C), 128.0 (4C), 127.4, 125.5, 115.5 (2C), 114.7 (2C), 71.1, 68.2, 45.5 (2C), 34.0 (2C), 31.3, 19.4, 14.0, 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 29 H 29 NO5Na 494.2, found 494.1 [M+Na] + .

[0093] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(4-フルオロフェニル)-2-オキソエトキシ)フェニル)-4, 4a,5,5a,6,6a-ヘキサヒドロ-4,6-エテノシクロプロパ[f]イソインドール-1,3(2H,3aH)-ジオン(35a)

change

[0094] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(4-chlorophenyl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (36a) [ka] Method C After purification by silica gel flash chromatography (gradient elution, 0 to 45% EtOAc in hexanes) and recrystallization in CH2Cl2 / hexanes, the title compound 36a (223 mg, 0.51 mmol, 51%) was obtained as a colorless solid. IR (cm -1 ) 1704, 1515, 1397, 1219, 1174, 1087, 966, 736; 1 H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 9.2 Hz, 2H), 5.84 (dd, J = 4.8, 3.6 Hz, 2H), 5.18 (s, 2H), 3.48 (m, 2H), 3.12 (dd, J = 1.6, 1.6 Hz, 2H), 1.14 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 193.2, 177.8 (2C), 157.6, 140.5, 132.7, 129.7 (2C), 129.2 (2C), 127.84 (2C), 127.76 (2C), 125.6, 115.2 (2C), 71.1, 45.2 (2C), 33.8 (2C), 9.9 (2C), 4.7; ES-API MS: m / z calcd for C 25 H 21 ClNO4434.1, found 434.1 [M+H] + .

[0095] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(4-bromophenyl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (37a) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0% to 40% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 37a (35 mg, 0.073 mmol, 69%) as a pale yellow solid. IR (cm -1 ) 1703, 1585, 1514, 1399, 1229, 1194, 984, 822; 1 H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 9.2 Hz, 2H), 5.84 (dd, J = 4.0, 3.6 Hz, 2H), 5.18 (s, 2H), 3.47 (m, 2H), 3.11 (m, 2H), 1.14 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 193.6, 178.0 (2C), 157.8, 133.3, 132.4 (2C), 130.0 (2C), 129.5, 128.04 (2C), 127.96 (2C), 125.8, 115.4 (2C), 71.2, 45.4 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 25 H 20 BrNO4Na 500.0, found 500.0 [M+Na] + .

[0096] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-oxo-2-(p-tolyl)ethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (38a) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0% to 40% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 38a (100 mg, 0.24 mmol, 65%) as a white solid. IR (cm -1 ) 3055, 3008, 2952, 1705, 1609, 1514, 1386, 1310, 1228, 1183, 964, 818, 734; 1 H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 5.84 (dd, J = 4.8, 3.6 Hz, 2H), 5.22 (s, 2H), 3.48 (m, 2H), 3.11 (dd, J = 1.6, 1.2 Hz, 2H), 2.43 (s, 3H), 1.14 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 193.9, 178.0 (2C), 158.1, 145.2, 132.2, 129.7 (2C), 128.5 (2C), 128.0 (4C), 125.6, 115.5 (2C), 71.2, 45.5 (2C), 34.0 (2C), 22.0, 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 26 H 24 NO4414.2, found 414.1 [M+H] + .

[0097] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (39a) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0% to 50% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 39a (25 mg, 0.053 mmol, 30%) as a colorless solid. IR (cm -1 ) 1704, 1516, 1326, 1176, 1123, 1067, 718; 1 H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 9.2 Hz, 2H), 5.84 (d, J = 4.4, 3.2 Hz, 2H), 5.23 (s, 2H), 3.48 (m, 2H), 3.12 (dd, J = 1.6, 1.6 Hz, 2H), 1.14 (m, 2H), 0.35-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 193.9, 178.0 (2C), 157.7, 129.0 (2C), 128.1 (2C), 128.0 (2C), 126.19, 126.15, 126.11, 126.07, 125.9, 115.5 (2C), 71.5, 45.5 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 26 H 20 F3NO4Na 490.1, found 490.1 [M+Na] + .

[0098] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-oxo-2-(4-(trifluoromethoxy)phenyl)ethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (40a) [ka] Method C After purification by silica gel flash chromatography (gradient elution, 0% to 40% EtOAc in hexanes) and recrystallization in CH2Cl2 / hexanes, the title compound 40a (35 mg, 0.072 mmol, 51%) was obtained as a colorless solid. IR (cm -1 ) 1704, 1515, 1398, 1260, 1230, 1194, 1174, 989, 734; 1 H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 5.84 (dd, J = 4.8, 3.6 Hz, 2H), 5.19 (s, 2H), 3.48 (m, 2H), 3.12 (dd, J = 1.6, 1.6 Hz, 2H), 1.14 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 193.2, 178.0 (2C), 157.8, 153.4, 132.8, 130.7 (2C), 128.08 (2C), 127.98 (2C), 125.8, 121.7, 120.8 (2C), 115.5 (2C), 71.3, 45.5 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 26 H 20 F3NO5Na 506.1, found 506.1 [M+Na] + .

[0099] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(4-hydroxyphenyl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (41a) [ka] Acetate ester 42a (530 mg, 1.16 mmol) was dissolved in MeOH (4.0 mL) and KCO (320 mg, 2.31 mmol) was added. The resulting mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography (gradient elution, 0% to 70% EtOAc in hexanes) to give the title phenol 41a (375 mg, 0.90 mmol, 78%) as a white solid. IR (cm -1 ) 3334, 1704, 1700, 1602, 1512, 1392, 1186, 1173, 735; 1 H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 9.2 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 5.84 (dd, J = 4.8, 3.6 Hz, 2H), 5.18 (s, 2H), 3.48 (m, 2H), 3.12 (dd, J = 1.6, 1.6 Hz, 2H), 1.15 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 192.8, 178.2 (2C), 161.0, 158.2, 131.1 (2C), 128.03 (2C), 127.99 (2C), 127.7, 125.5, 115.9 (2C), 115.5 (2C), 71.0, 45.5 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 25 H 22 NO5416.1, found 416.1 [M+H] + .

[0100] 4-(2-(4-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-ethenocyclopropa[f]isoindol-2(1H)-yl)phenoxy)acetyl)phenyl acetate (42a) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0% to 50% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 42a (45 mg, 0.098 mmol, 55%) as a white solid. IR (cm -1 ) 1760, 1705, 1600, 1513, 1193, 1166; 1 H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 9.2 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 5.84 (dd, J = 4.4, 3.6 Hz, 2H), 5.21 (s, 2H), 3.48 (m, 2H), 3.12 (dd, J = 1.6, 1.2 Hz, 2H), 2.33 (s, 3H), 1.14 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 193.1, 178.0 (2C), 168.9, 157.9, 155.2, 132.2, 130.2 (2C), 128.03 (2C), 127.98 (2C), 125.7, 122.3 (2C), 115.5 (2C), 71.2, 45.5 (2C), 34.0 (2C), 21.4, 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 27 H 23 NO6Na 480.1, found 480.1 [M+Na] + .

[0101] Methyl 4-(2-(4-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-ethenocyclopropa[f]isoindol-2(1H)-yl)phenoxy)acetyl)phenyl carbonate (43a) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0 to 55% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 43a (47 mg, 0.099 mmol, 56%) as a white solid. IR (cm -1 ) 1770, 1704, 1508, 1262, 1216, 734; 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 9.2 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 5.84 (dd, J = 4.8, 3.6 Hz, 2H), 5.21 (s, 2H), 3.93 (s, 3H), 3.48 (m, 2H), 3.12 (dd, J = 1.6, 2.0 Hz, 2H), 1.15 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 193.1, 178.0 (2C), 157.9, 155.3, 153.6, 132.3, 130.3 (2C), 128.04 (2C), 127.98 (2C), 125.7, 121.7 (2C), 115.5 (2C), 71.2, 55.9, 45.5 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 27 H 23 NO7Na 496.1, found 496.1 [M+Na] + .

[0102] Methyl (4-(2-(4-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-ethenocyclopropa[f]isoindol-2(1H)-yl)phenoxy)acetyl)phenyl)carbamate (44a) [ka] Method C After purification by silica gel flash chromatography (gradient elution, 0% to 60% EtOAc in hexanes) and recrystallization in CH2Cl2 / hexanes, the title compound 44a (55 mg, 0.11 mmol, 68%) was obtained as a pale yellow solid. IR (cm -1 ) 3315, 2954, 1706, 1683, 1516, 1393, 1224, 1190, 1084, 972; 1 H NMR (400 MHz, CDCl3 / CD3OD) δ 7.83 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 9.2 Hz, 2H), 6.88 (d, J = 9.2 Hz, 2H), 5.73 (dd, J = 4.4, 3.6 Hz, 2H), 5.15 (s, 2H), 3.68 (s, 3H), 3.35 (m, 2H), 3.03 (m, 2H), 1.05 (m, 2H), 0.24-0.14 (m, 2H); 13 C NMR (100 MHz, CDCl3 / CD3OD) δ 193.1, 178.3 (2C), 157.9, 154.3, 144.2, 129.5 (2C), 128.6, 127.8 (2C), 127.7 (2C), 125.1, 117.7 (2C), 115.2 (2C), 70.5, 52.3, 45.2 (2C), 33.7 (2C), 9.8 (2C), 4.5; ES-API MS: m / z calcd for C 27 H 25 N2O6473.2, found 473.2 [M+H] + .

[0103] Methyl 4-(2-(4-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-ethenocyclopropa[f]isoindol-2(1H)-yl)phenoxy)acetyl)benzoate (45a) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0% to 50% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 45a (27 mg, 0.060 mmol, 33%) as a yellow solid. IR (cm -1 ) 1705, 1513, 1282, 1218, 1186, 1110, 734; 1 H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.4 Hz, 2H), 8.04 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 5.84 (dd, J = 4.8, 3.6 Hz, 2H), 5.24 (s, 2H), 3.96 (s, 3H), 3.48 (m, 2H), 3.12 (m, 2H), 1.15 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 194.1, 178.0 (2C), 166.2, 157.8, 137.8, 134.8, 130.2 (2C), 128.4 (2C), 128.1 (2C), 128.0 (2C), 125.8, 115.5 (2C), 71.4, 52.8, 45.5 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 27 H 23 NO6Na 480.1, found 480.1 [M+Na] + .

[0104] (4R,4aR,5aS,6S,6aS)-2-(5-(2-(6-methoxypyridin-3-yl)-2-oxoethoxy)pyridin-2-yl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (46a) Method C Purification by silica gel flash chromatography (0→45% EtOAc in hexanes) and recrystallization in CH 2 Cl 2 / hexanes afforded the title compound 46a as a white solid (63 mg, 0.15 mmol, 42%). 1 H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 8.4 Hz, 2H), 7.81 (dd, J = 8.4, 1.2 Hz, 2H), 7.63 (dddd, J = 7.2, 7.6, 1.2, 1.2 Hz, 1H), 7.51 (dd, J = 7.6, 7.6 Hz, 2H), 7.10 (d, J = 9.2 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 5.84 (dd, J = 4.8, 3.6 Hz, 2H), 5.27 (s, 2H), 3.48 (m, 2H), 3.12 (dd, J = 1.6, 1.6 Hz, 2H), 1.15 (m, 2H), 0.35-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 196.0, 194.2, 178.0 (2C), 157.8, 142.3, 137.1, 136.9, 133.3, 130.4 (2C), 130.3 (2C), 128.7 (2C), 128.4 (2C), 128.1 (2C), 128.0 (2C), 125.8, 115.5 (2C), 71.5, 45.5 (2C), 34.0 (2C), 10.1 (2C), 4.9.

[0105] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(naphthalen-2-yl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (47a) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0 to 45% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 47a (33 mg, 0.076 mmol, 43%) as a white solid. IR (cm -1 ) 3410, 2964, 1710, 1261, 1029, 801; 1 H NMR (400 MHz, CDCl3) δ 7.97 (dd, J = 2.0, 1.6 Hz, 1H), 7.86 (ddd, J = 7.6, 1.6, 1.2 Hz, 1H), 7.59 (ddd, J = 8.0, 1.2, 1.2 Hz, 1H), 7.44 (dd, J = 8.0, 8.0 Hz, 1H), 7.09 (d, J = 9.2 Hz, 2H), 6.97 (d, J = 9.2 Hz, 2H), 5.84 (dd, J = 4.8, 3.2 Hz, 2H), 5.20 (s, 2H), 3.48 (m, 2H), 3.12 (dd, J = 1.6, 1.2 Hz, 2H), 1.14 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 193.3, 178.0 (2C), 157.8, 136.1, 135.4, 134.1, 130.4, 128.6, 128.1 (2C), 128.0 (2C), 126.5, 125.8, 115.5 (2C), 71.3, 45.5 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 25 H 21ClNO4434.1, found 434.1 [M+H] + .

[0106] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(2,3-dichlorophenyl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (48a) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0% to 40% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 48a (140 mg, 0.30 mmol, 42%) as a white solid. IR (cm -1 ) 3056, 3010, 2955, 1705, 1512, 1187, 735; 1 H NMR (400 MHz, CDCl3) δ 7.60 (dd, J = 8.0, 2.0 Hz, 1H), 7.37 (dd, J = 7.6, 1.6 Hz, 1H), 7.30 (dd, J = 8.0, 7.6 Hz, 1H), 7.09 (d, J = 9.2 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 5.84 (dd, J = 4.8, 3.6 Hz, 2H), 5.10 (s, 2H), 3.48 (m, 2H), 3.12 (dd, J = 1.6, 1.6 Hz, 2H), 1.14 (m, 2H), 0.35-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 197.8, 178.0 (2C), 157.7, 138.9, 134.4, 133.3, 128.06, 128.04 (2C), 127.99 (2C), 127.7, 125.9, 115.5 (2C), 73.0, 45.5 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C25 H 20 Cl2NO4468.1, found 468.1 [M+H] + .

[0107] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(2,5-dichlorophenyl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (49a) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0% to 40% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 49a (37 mg, 0.080 mmol, 17%) as a white solid. IR (cm -1 ) 2962, 1710, 1261, 1048, 803; 1 H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 2.4 Hz, 1H), 7.42 (d, J = 8.8, 2.4 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 5.84 (dd, J = 4.8, 3.6 Hz, 2H), 5.13 (s, 2H), 3.48 (m, 2H), 3.12 (dd, J = 1.6, 1.6 Hz, 2H), 1.14 (m, 2H), 0.35-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 196.6, 178.0 (2C), 157.7, 137.6, 133.6, 132.9, 132.9, 131.9, 130.1, 128.1 (2C), 128.0 (2C), 125.9, 115.5 (2C), 73.1, 45.5 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 25 H 20 Cl2NO4468.1, found 468.1 [M+H] + .

[0108] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(2,6-dichlorophenyl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (50a) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0% to 40% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 50a (155 mg, 0.33 mmol, 47%) as a white solid. IR (cm -1 ) 2961, 1709, 1513, 1184, 1045, 785; 1 H NMR (400 MHz, CDCl3) δ 7.35 (m, 3H), 7.10 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 9.2 Hz, 2H), 5.85 (dd, J = 4.8, 3.6 Hz, 2H), 5.02 (s, 2H), 3.48 (m, 2H), 3.12 (dd, J = 1.6, 2.0 Hz, 2H), 1.14 (m, 2H), 0.35-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 197.2, 178.0 (2C), 157.8, 136.7, 131.7, 131.6, 128.4 (2C), 128.0 (5C), 125.9, 115.7 (2C), 73.1, 45.5 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 25 H 20 Cl2NO4468.1, found 468.1 [M+H] + .

[0109] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-oxo-2-(2,3,4-trichlorophenyl)ethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (51a) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0% to 40% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 51a (133 mg, 0.26 mmol, 41%) as a white solid. IR (cm -1 ) 2964, 1709, 1512, 1261, 1026, 801; 1 H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 9.2 Hz, 2H), 6.90 (d, J = 9.2 Hz, 2H), 5.84 (dd, J = 4.8, 3.6 Hz, 2H), 5.08 (s, 2H), 3.48 (m, 2H), 3.12 (dd, J = 1.6, 2.0 Hz, 2H), 1.14 (m, 2H), 0.35-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 197.1, 178.0 (2C), 157.6, 137.8, 136.9, 133.3, 131.8, 129.1, 128.08 (2C), 127.99 (2C), 127.7, 126.0, 115.4 (2C), 73.0, 45.5 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 25 H 19 Cl3NO4502.0, found 502.1 [M+H] + .

[0110] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(3,5-dichlorophenyl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (52a) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0% to 40% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 52a (142 mg, 0.30 mmol, 43%) as a white solid. IR (cm -1 ) 2960, 1708, 1513, 1214, 801; 1 H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 2.0 Hz, 2H), 7.60 (t, J = 2.0 Hz, 1H), 7.10 (d, J = 9.2 Hz, 2H), 6.97 (d, J = 9.2 Hz, 2H), 5.84 (dd, J = 4.8, 3.2 Hz, 2H), 5.17 (s, 2H), 3.48 (m, 2H), 3.12 (dd, J = 1.6, 1.6 Hz, 2H), 1.14 (m, 2H), 0.35-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 192.4, 178.0 (2C), 157.6, 136.9, 136.1, 133.9, 128.1 (2C), 128.0 (3C), 127.0 (2C), 126.0, 115.5 (2C), 71.3, 45.5 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 25 H 20 Cl2NO4468.1, found 468.1 [M+H] + .

[0111] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(3,5-dichlorophenyl)-2-oxoethoxy)-2-fluorophenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (52b) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0% to 30% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes afforded the title compound 52b (133 mg, 0.27 mmol, 32%) as a pale yellow solid. IR (cm -1 ) 3085, 3005, 1716, 1516, 1221, 1171, 734; 1 H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 1.6 Hz, 2H), 7.61 (m, 1H), 7.02 (br, 1H), 6.76 (s, 1H), 6.74 (s, 1H), 5.85 (dd, J = 4.0, 3.6 Hz, 2H), 5.16 (s, 2H), 3.47 (m, 2H), 3.15 (m, 2H), 1.14 (m, 2H), 0.35-0.26 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 191.7 (2C), 177.2, 159.4 (d, J = 4.8 Hz, 1C), 158.1 (d, J = 237.1 Hz, 1C), 136.7, 136.2 (2C), 134.0 (2C), 130.1 (d, J = 11.3 Hz, 1C), 127.9 (d, J = 15.4 Hz, 1C), 126.9 (2C), 113.7 (d, J = 13.9 Hz, 1C), 111.0 (d, J = 17.3 Hz, 1C), 104.0 (d, J = 26.0 Hz, 1C), 71.3, 45.9, 45.6, 33.9 (2C), 10.0 (2C), 4.9; ES-API MS: m / z calcd for C 25 H 19 Cl2FNO4486.1, found 486.1 [M+H] + .

[0112] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(3-chloro-5-fluorophenyl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (53a) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0 to 35% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 53a (37 mg, 0.082 mmol, 22%) as a white solid. IR (cm -1 ) 2964, 1711, 1261, 1029, 802; 1H NMR (400 MHz, CDCl3) δ 7.77 (dd, J = 1.2, 1.2 Hz, 1H), 7.59 (ddd, J = 8.4, 1.2, 1.2 Hz, 1H), 7.34 (ddd, J = 8.0, 2.0, 2.0 Hz, 1H), 7.10 (d, J = 9.2 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 5.84 (dd, J = 4.8, 3.2 Hz, 2H), 5.16 (s, 2H), 3.48 (m, 2H), 3.12 (dd, J = 1.6, 2.0 Hz, 2H), 1.14 (m, 2H), 0.35-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 192.4, 178.0 (2C), 162.9 (d, J = 251.2 Hz, 1C), 157.6, 137.2 (d, J = 7.1 Hz, 1C), 136.3 (d, J = 9.5 Hz, 1C), 128.1 (2C), 128.0 (2C), 126.0, 124.7 (d, J = 3.3 Hz, 1C), 121.7 (d, J = 24.7 Hz, 1C), 115.5 (2C), 114.0 (d, J = 22.6 Hz, 1C), 71.4, 45.5 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 25 H 20 FClNO4452.1, found 452.1 [M+H] + .

[0113] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(3-クロロ-5-(トリフルオロメチル)フェニル)-2-オキソエトキシ)フェニル)-4,4a,5,5a,6,6a-ヘキサヒドロ-4,6-エテノシクロプロパ[f]イソインドール-1,3(2H,3aH)-ジオン(54a)

change

[0114] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(3,4-dimethoxyphenyl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (55a) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0% to 60% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 55a (100 mg, 0.22 mmol, 61%) as a white solid. IR (cm -1 ) 3056, 3008, 2957, 1705, 1513, 1267, 1169, 1021, 734; 1 H NMR (400 MHz, CDCl3) δ 7.63 (dd, J = 8.4, 2.0 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.4 Hz, 1H), 5.84 (dd, J = 4.8, 3.2 Hz, 2H), 5.20 (s, 2H), 3.96 (s, 3H), 3.94 (s, 3H), 3.48 (m, 2H), 3.11 (dd, J = 1.6, 1.6 Hz, 2H), 1.14 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 192.9, 178.0 (2C), 158.1, 154.2, 149.5, 127.99 (2C), 127.97 (2C), 127.8, 125.6, 123.1, 115.5 (2C), 110.5, 110.3, 71.1, 56.4, 56.3, 45.5 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 27 H 26 NO6460.2, found 460.1 [M+H] + .

[0115] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(3,4-dimethoxyphenyl)-2-oxoethoxy)-2-fluorophenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (55b) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0 to 65% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 55b (130 mg, 0.27 mmol, 82%) as an orange solid. IR (cm -1 ) 3009, 2957, 1715, 1595, 1515, 1265, 1165, 733; 1 H NMR (400 MHz, CDCl3) δ 7.61 (dd, J = 8.4, 2.0 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.00 (m, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.77 (m, 1H), 6.75 (m, 1H), 5.84 (dd, J = 4.0, 4.0 Hz, 2H), 5.20 (s, 2H), 3.97 (s, 3H), 3.94 (s, 3H), 3.47 (m, 2H), 3.15 (m, 2H), 1.14 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 192.2, 177.3 (2C), 159.9 (d, J = 10.4 Hz, 1C), 158.1 (d, J = 251.8 Hz, 1C), 154.3, 149.6, 129.9 (d, J = 19.1 Hz, 1C), 127.9 (d, J = 19.5 Hz, 1C), 127.6, 123.1, 113.2 (d, J = 13.0 Hz, 1C), 111.1 (d, J = 10.3 Hz, 1C), 110.5, 110.4, 110.2, 104.0, 71.1, 56.4, 56.3, 45.9, 45.6, 33.9 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 27 H 25 FNO6478.2, found 478.1 [M+H] + .

[0116] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(benzo[d][1,3]dioxol-5-yl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (56a) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0% to 50% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 56a (95 mg, 0.21 mmol, 61%) as a white solid. IR (cm -1 ) 3009, 2955, 2909, 1704, 1512, 1252, 1037, 734; 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J = 8.4, 1.6 Hz, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.4 Hz, 1H), 6.06 (s, 2H), 5.84 (dd, J = 4.8, 3.6 Hz, 2H), 5.15 (s, 2H), 3.48 (m, 2H), 3.11 (dd, J = 1.6, 1.6 Hz, 2H), 1.14 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 192.4, 178.0 (2C), 158.0, 152.7, 148.6, 129.4, 127.99 (2C), 127.98 (2C), 125.6, 124.9, 115.5 (2C), 108.4, 108.2, 102.2, 71.1, 45.5 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 26 H 22 NO6444.1, found 444.1 [M+H] + .

[0117] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(benzo[d][1,3]dioxol-5-yl)-2-oxoethoxy)-2-fluorophenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (56b) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0 to 45% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 56b (88 mg, 0.19 mmol, 58%) as an off-white solid. IR (cm -1) 3010, 2955, 2913, 1715, 1516, 1254, 1170, 1038, 733; 1 H NMR (400 MHz, CDCl3) δ 7.58 (dd, J = 8.4, 1.6 Hz, 1H), 7.45 (d, J = 1.6 Hz, 1H), 7.01 (m, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.76 (m, 1H), 6.74 (m, 1H), 6.07 (s, 2H), 5.84 (dd, J = 4.0, 4.0 Hz, 2H), 5.15 (s, 2H), 3.47 (m, 2H), 3.14 (m, 2H), 1.14 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 191.7, 177.3 (2C), 159.8 (d, J = 10.3 Hz, 1C), 158.1 (d, J = 251.7 Hz, 1C), 152.8, 148.7, 129.9 (d, J = 18.3 Hz, 1C), 129.1, 127.9 (d, J = 12.3 Hz, 1C), 124.8, 113.3, 113.2, 111.1 (d, J = 18.2 Hz, 1C), 108.4, 108.2, 104.0 (d, J = 28.3 Hz, 1C), 102.3, 71.2, 45.9, 45.6, 33.9 (2C), 10.0 (2C), 4.9; ES-API MS: m / z calcd for C 26 H 21 FNO6462.1, found 462.1 [M+H] + .

[0118] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(3,4-ジメチルフェニル)-2-オキソエトキシ)フェニル)-4 ,4a,5,5a,6,6a-ヘキサヒドロ-4,6-エテノシクロプロパ[f]イソインドール-1,3(2H,3aH)-ジオン(57a)

change

[0119] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(3,4-dimethylphenyl)-2-oxoethoxy)-2-fluorophenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (57b) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0 to 45% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes afforded the title compound 57b (105 mg, 0.24 mmol, 71%) as a pale pink solid. IR (cm -1 ) 3014, 2952, 1715, 1516, 1166, 1124, 733; 1 H NMR (400 MHz, CDCl3) δ 7.74 (m, 1H), 7.70 (dd, J = 7.6, 1.2 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.00 (m, 1H), 6.77 (m, 1H), 6.74 (m, 1H), 5.84 (dd, J = 4.0, 3.6 Hz, 2H), 5.22 (s, 2H), 3.47 (m, 2H), 3.14 (m, 2H), 2.33 (s, 3H), 2.32 (s, 3H), 1.14 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 193.3, 177.3 (2C), 159.9 (d, J = 10.3 Hz, 1C), 158.1 (d, J = 251.5 Hz, 1C), 144.1, 137.6, 132.3, 130.3, 129.9 (d, J = 14.0 Hz, 1C), 129.3, 127.9 (d, J = 16.3 Hz, 1C), 126.0, 113.2, 113.1, 111.2 (d, J = 17.2 Hz, 1C), 103.9 (d, J = 33.2 Hz, 1C), 71.1, 45.9, 45.6, 33.9 (2C), 20.4, 20.0, 10.0 (2C), 4.9; ES-API MS: m / z calcd for C 27 H 25 FNO4446.2, found 446.1 [M+H] + .

[0120] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(3,4-dichlorophenyl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (58a) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0 to 50% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 58a (33 mg, 0.070 mmol, 40%) as a white solid. IR (cm -1 ) 2955, 1704, 1512, 1393, 1212, 1185, 995, 734; 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 8.4, 2.0 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.8 Hz, 2H), 6.96 (d, 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 192.7, 178.0 (2C), 157.7, 138.9, 134.1, 133.9, 131.2, 130.6, 128.1 (2C), 128.0 (2C), 127.6, 125.9, 115.5 (2C), 71.4, 45.5 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 25 H 19 Cl2NO4Na 490.1 found 490.5 [M+Na] + .

[0121] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(3,4-dichlorophenyl)-2-oxoethoxy)-2-fluorophenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (58b) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0 to 35% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 58b (122 mg, 0.25 mmol, 75%) as a light brown solid. IR (cm -1) 2956, 1716, 1517, 1396, 1170, 735; 1 H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 2.0 Hz, 1H), 7.81 (dd, J = 8.4, 2.0 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.02 (br, 1H), 6.76 (m, 1H), 6.74 (m, 1H), 5.85 (dd, J = 4.0, 3.6 Hz, 2H), 5.16 (s, 2H), 3.47 (m, 2H), 3.15 (m, 2H), 1.13 (m, 2H), 0.35-0.26 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 192.0 (2C), 177.3, 159.4 (d, J = 2.4 Hz, 1C), 158.1 (d, J = 244.4 Hz, 1C), 139.1, 134.0, 133.9, 131.3, 130.5, 130.1, (d, J = 15.8 Hz, 1C), 127.9 (d, J = 15.1 Hz, 1C), 127.5 (2C), 113.6 (d, J = 13.8 Hz, 1C), 111.0 (d, J = 11.6 Hz, 1C), 104.0 (d, J = 25.8 Hz, 1C), 71.3, 45.9, 45.6, 33.9 (2C), 10.0 (2C), 4.9; ES-API MS: m / z calcd for C 25 H 19 Cl2FNO4486.1 found 486.1 [M+H] + .

[0122] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(3-fluoro-4-methoxyphenyl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (59a) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0 to 65% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 59a (32 mg, 0.072 mmol, 62%) as a pale yellow solid. IR (cm -1 ) 3010, 2956, 1705, 1613, 1513, 1434, 1392, 1286, 1227, 1186, 734; 1 H NMR (400 MHz, CDCl3) δ 7.80 (ddd, J = 8.4, 2.0, 0.8 Hz, 1H), 7.75 (dd, J = 11.6, 2.0 Hz, 1H), 7.08 (d, J = 9.2 Hz, 2H), 7.01 (dd, J = 8.4, 8.4 Hz, 1H), 6.97 (d, J = 9.2 Hz, 2H), 5.84 (dd, J = 4.8, 3.6 Hz, 2H), 5.15 (s, 2H), 3.97 (s, 3H), 3.48 (m, 2H), 3.11 (dd, J = 1.6, 1.6 Hz, 2H), 1.14 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 192.3 (d, J = 1.8, 1C), 178.0 (2C), 157.9, 153.1 (d, J = 75.5, 1C), 152.0 (d, J = 182.6, 1C), 128.03 (2C), 127.98 (2C), 127.8 (d, J = 5.2, 1C), 126.0 (d, J = 3.3, 1C), 125.7, 116.2 (d, J = 19.1, 1C), 115.5 (2C), 112.7 (d, J = 1.9, 1C), 71.2, 56.6, 45.5 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 26 H 22 FNO5Na 470.1, found 470.1 [M+Na] + .

[0123] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(3-chloro-4-methoxyphenyl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (60a) [ka] Method C After purification by silica gel flash chromatography (gradient elution, 0 to 65% EtOAc in hexanes) and recrystallization in CH2Cl2 / hexanes, the title compound 60a (57 mg, 0.12 mmol, 57%) was obtained as a pale yellow solid. IR (cm -1 ) 1705, 1594, 1508, 1207, 1061, 734; 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 2.0 Hz, 1H), 7.92 (dd, J = 8.8, 2.4 Hz, 1H), 7.08 (d, J = 9.2 Hz, 2H), 6.99 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 8.8 Hz, 2H), 5.84 (dd, J = 4.4, 3.6 Hz, 2H), 5.15 (s, 2H), 3.98 (s, 3H), 3.48 (m, 2H), 3.11 (dd, J = 1.2, 1.6 Hz, 2H), 1.13 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 192.2, 178.0 (2C), 159.6, 157.9, 130.8, 129.1, 128.1, 128.03 (2C), 127.97 (2C), 125.7, 123.4, 115.5 (2C), 111.7, 71.2, 56.7, 45.5 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 26 H 22 ClNO5Na 486.1, found 486.1 [M+Na]+ .

[0124] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(3-chloro-4-methoxyphenyl)-2-oxoethoxy)-2-fluorophenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (60b) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0 to 55% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 60b (94 mg, 0.20 mmol, 58%) as a white solid. IR (cm -1 ) 3057, 3011, 2954, 1716, 1595, 1516, 1260, 1169, 1061, 1008, 735; 1 H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 2.4 Hz, 1H), 7.91 (dd, J = 8.8, 2.0 Hz, 1H), 7.01 (br, 1H), 6.99 (d, J = 8.8 Hz, 1H), 6.77 (m, 1H), 6.74 (m, 1H), 5.84 (dd, J = 4.0, 4.0 Hz, 2H), 5.15 (s, 2H), 3.99 (s, 3H), 3.47 (m, 2H), 3.14 (m, 2H), 1.13 (m, 2H), 0.34-0.26 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 191.5 (2C), 177.3, 159.7, 159.6 (d, J = 10.3 Hz, 1C), 158.1 (d, J = 251.7 Hz, 1C), 130.7, 130.0 (d, J = 12.8 Hz, 1C), 129.1, 127.9 (d, J = 14.3 Hz, 1C), 127.9, 123.5, 113.4 (d, J = 13.8 Hz, 1C), 111.7 (2C), 111.1 (d, J = 14.3 Hz, 1C), 103.9 (d, J = 23.2 Hz, 1C), 71.2, 56.7, 45.9, 45.6, 33.9 (2C), 10.0 (2C), 4.9; ES-API MS: m / z calcd for C 26 H 22 ClFNO5482.1, found 482.1 [M+H] + .

[0125] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(4-chloro-3-methylphenyl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (61a) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0% to 40% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 61a (42 mg, 0.094 mmol, 53%) as a white solid. IR (cm -1 ) 2964, 1710, 1261, 1046, 801; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 1.6 Hz, 1H), 7.75 (dd, J = 8.4, 2.0 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 9.2 Hz, 2H), 5.84 (dd, J = 4.8, 3.6 Hz, 2H), 5.19 (s, 2H), 3.48 (m, 2H), 3.12 (dd, J = 2.0, 1.6 Hz, 2H), 2.44 (s, 3H), 1.14 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 193.6, 178.0 (2C), 157.9, 140.9, 137.3, 133.0, 130.8, 129.8, 128.04 (2C), 127.98 (2C), 127.2, 125.7, 115.5 (2C), 71.2, 45.5 (2C), 34.0 (2C), 20.4, 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 26 H 23 ClNO4482.1, found 448.1 [M+H] + .

[0126] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(4-chloro-3-methylphenyl)-2-oxoethoxy)-2-fluorophenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (61b) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0 to 35% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes afforded the title compound 61b (80 mg, 0.17 mmol, 52%) as a pale pink solid. IR (cm -1) 1716, 1519, 1508, 1168, 1049, 734; 1 H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 1.6 Hz, 1H), 7.75 (ddd, J = 8.4, 8.4, 1.6 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.02 (br, 1H), 6.77 (m, 1H), 6.74 (m, 1H), 5.85 (dd, J = 4.0, 3.6 Hz, 2H), 5.19 (s, 2H), 3.47 (m, 2H), 3.15 (m, 2H), 1.13 (m, 2H), 0.35-0.26 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 192.9 (2C), 177.3, 159.6 (d, J = 10.3 Hz, 1C), 158.1 (d, J = 251.9 Hz, 1C), 143.3, 141.1, 137.4, 132.8, 131.6, 130.8, 129.9 (2C), 129.1, 127.9 (d, J = 13.8 Hz, 1C), 127.1, 126.5, 71.2, 45.9, 45.6, 33.9 (2C), 20.4, 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 26 H 22 ClFNO4466.1, found 466.1 [M+H] + .

[0127] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(3-chloro-4-fluorophenyl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (62a) [ka] Method CPurification by silica gel flash chromatography (gradient elution, 0 to 45% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 62a (25 mg, 0.055 mmol, 31%) as a white solid. IR (cm -1 ) 2964, 1710, 1261, 1045, 802; 1 H NMR (400 MHz, CDCl3) δ 8.09 (dd, J = 7.2, 2.0 Hz, 1H), 7.92 (ddd, J = 8.4, 4.4, 2.0 Hz, 1H), 7.26 (dd, J = 8.4, 8.4 Hz, 1H), 7.09 (d, J = 9.2 Hz, 2H), 6.96 (d, J = 9.2 Hz, 2H), 5.84 (dd, J = 4.8, 3.6 Hz, 2H), 5.15 (s, 2H), 3.48 (m, 2H), 3.12 (dd, J = 1.6, 1.6 Hz, 2H), 1.14 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 192.3, 178.0 (2C), 161.7 (d, J = 257.1 Hz, 1C), 157.7, 131.8 (d, J = 3.7 Hz, 1C), 131.6 (d, J = 1.2 Hz, 1C), 129.1 (d, J = 8.6 Hz, 1C), 128.1 (2C), 128.0 (2C), 125.9, 122.5 (d, J = 18.3 Hz, 1C), 117.4 (d, J = 21.8 Hz, 1C), 115.5 (2C), 71.3, 45.5 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 25 H 20 FClNO4452.1, found 452.1 [M+H] + .

[0128] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(3-chloro-4-fluorophenyl)-2-oxoethoxy)-2-fluorophenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (62b) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0 to 45% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 62b (86 mg, 0.18 mmol, 55%) as a pale yellow solid. IR (cm -1 ) 2956, 1716, 1517, 1253, 1170, 734; 1 H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.8 Hz, 1H), 7.90 (m, 1H), 7.27 (dd, J = 8.4, 8.4 Hz, 1H), 7.02 (br, 1H), 6.76 (m, 1H), 6.74 (m, 1H), 5.84 (dd, J = 4.0, 3.6 Hz, 2H), 5.16 (s, 2H), 3.47 (m, 2H), 3.15 (m, 2H), 1.14 (m, 2H), 0.34-0.27 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 191.3 (2C), 177.0, 161.6 (d, J = 257.6 Hz, 1C), 159.2 (d, J = 11.0 Hz, 1C), 157.9 (d, J = 252.0 Hz, 1C), 131.4 (2C), 131.4 (d, J = 1.2 Hz, 1C), 129.9 (d, J = 20.6 Hz, 1C), 128.8 (d, J = 8.6 Hz, 1C), 127.7 (d, J = 12.9 Hz, 1C), 122.5, 117.2 (d, J = 21.7 Hz, 1C), 113.4 (d, J = ES-API MS: m / z calcd for C 25 H 19 ClF2NO4470.1, found 470.1 [M+H] + .

[0129] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(4-chloro-3-(trifluoromethyl)phenyl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (63a) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0 to 35% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 63a (97 mg, 0.19 mmol, 34%) as a white solid. IR (cm -1 ) 2961, 1710, 1604, 1513, 1261, 1180, 1036, 803, 735; 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 2.0 Hz, 1H), 8.10 (d, J = 8.4, 2.0 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 5.83 (dd, J = 4.8, 3.6 Hz, 2H), 5.17 (s, 2H), 3.47 (m, 2H), 3.11 (dd, J = 1.6, 1.6 Hz, 2H), 1.14 (m, 2H), 0.35-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 192.9, 178.0 (2C), 157.5, 138.5 (d, J = 1.6 Hz, 1C), 133.0, 132.8, 123.4, 129.4 (d, J = 3.2 Hz, 1C), 128.1 (2C), 128.0 (2C), 127.9, 127.8 (d, J = 3.0 Hz, 1C), 126.0, 122.5 (d, J = 272.4 Hz, 1C), 115.4 (2C), 71.5, 45.5 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 26 H 20 F3ClNO4502.1, found 502.1 [M+H] + .

[0130] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(4-chloro-3-(trifluoromethyl)phenyl)-2-oxoethoxy)-2-fluorophenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (63b) [ka] Method CPurification by silica gel flash chromatography (gradient elution, 0 to 45% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 63b (31 mg, 0.06 mmol, 18%) as a pale yellow solid. IR (cm -1 ) 2957, 1716, 1519, 1319, 1172, 1141, 1114, 1036, 735; 1 H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 1.6 Hz, 1H), 8.09 (dd, J = 8.4, 2.0 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.03 (br, 1H), 6.77 (m, 1H), 6.74 (m, 1H), 5.85 (dd, J = 4.0, 3.6 Hz, 2H), 5.18 (s, 2H), 3.47 (m, 2H), 3.15 (m, 2H), 1.14 (m, 2H), 0.35-0.26 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 191.9 (2C), 177.0, 157.9 (d, J = 252.3 Hz, 1C), 159.0 (d, J = 10.3 Hz, 1C), 138.5 (d, J = 1.7 Hz, 1C), 132.6, 132.5, 132.3, 129.9 (d, J = 12.1 Hz, 1C), 129.4 (d, J = 32.0 Hz, 1C), 127.8, 127.6 (q, J = 5.2 Hz, 1C), 123.6, 120.9, 113.6 (d, J = 13.8 Hz, 1C), 110.7, 103.7 (d, J = 23.0 Hz, 1C), 71.3, 45.7, 45.4, 33.7 (2C), 9.8 (2C), 4.7; ES-API MS: m / z calcd for C 26 H 19 ClF4NO4520.1, found 520.1 [M+H] + .

[0131] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(naphthalen-2-yl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (64a) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0% to 40% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 64a (116 mg, 0.25 mmol, 73%) as a pale yellow solid. IR (cm -1 ) 3055, 3010, 2954, 1704, 1512, 1188, 734; 1 H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.03 (dd, J = 8.8, 1.6 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.64 (dd, J = 6.8, 7.2 Hz, 1H), 7.58 (dd, J = 7.2, 7.2 Hz, 1H), 7.10 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 5.84 (dd, J = 4.4, 3.6 Hz, 1H), 5.38 (s, 2H), 3.48 (m, 2H), 3.12 (m, 2H), 1.14 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 194.2, 178.0 (2C), 158.1, 136.2, 132.6, 132.0, 130.3, 129.9, 129.2, 129.0, 128.1, 128.03 (2C), 127.98 (2C), 127.3, 125.6, 123.8, 115.6 (2C), 71.3, 45.5 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 29 H 34 NO4460.2, found 460.1 [M+H] + .

[0132] (3aR,4R,4aR,5aS,6S,6aS)-2-(5-(2-(4-methoxyphenyl)-2-oxoethoxy)pyridin-2-yl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (71) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0% to 70% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 71 (86 mg, 0.20 mmol, 57%) as a pale yellow solid. IR (cm -1 ) 3063, 2940, 2840, 1710, 1601, 1401, 1232, 1173, 972; 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 2.8 Hz, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.32 (dd, J = 8.8, 3.2 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 8.8 Hz, 2H), 5.88 (dd, J = 4.8, 3.2 Hz, 2H), 5.27 (s, 2H), 3.89 (s, 3H), 3.49 (m, 2H), 3.14 (dd, J = 1.6, 1.6 Hz, 2H), 1.14 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 191.8, 177.5 (2C), 164.5, 154.6, 139.6, 137.9, 130.7 (2C), 128.0 (2C), 127.3, 123.8, 122.7, 114.4 (2C), 71.1, 55.8, 45.8 (2C), 33.9 (2C), 10.1 (2C), 5.0; ES-API MS: m / z calcd for C 25 H 23 N2O5431.2, found 431.2 [M+H] + .

[0133] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(6-methoxypyridin-3-yl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (72) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0% to 50% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 72 (40 mg, 0.093 mmol, 26%) as a white solid. IR (cm -1) 3053, 3009, 2953, 1705, 1602, 1513, 1377, 1298, 1226, 1186, 735; 1 H NMR (400 MHz, CDCl3) δ 8.86 (d, J = 2.4 Hz, 1H), 8.16 (dd, J = 8.4, 2.4 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 9.2 Hz, 2H), 6.81 (d, J = 8.8 Hz, 1H), 5.83 (dd, J = 3.6, 4.4 Hz, 2H), 5.13 (s, 2H), 4.01 (s, 3H), 3.47 (m, 2H), 3.11 (m, 2H), 1.13 (m, 2H), 0.33-0.24 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 192.8, 178.0 (2C), 167.3, 157.8, 149.6, 138.6, 128.0 (2C), 127.9 (2C), 125.7, 124.7, 115.4 (2C), 111.8, 71.3, 54.4, 45.4 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 25 H 23 N2O5431.2, found 431.2 [M+H] + .

[0134] (3aR,4R,4aR,5aS,6S,6aS)-2-(5-(2-(6-methoxypyridin-3-yl)-2-oxoethoxy)pyridin-2-yl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (73) [ka] Method CPurification by silica gel flash chromatography (gradient elution, 0% to 70% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 73 (63 mg, 0.15 mmol, 42%) as a pale yellow solid. IR (cm -1 ) 3054, 3011, 2953, 1710, 1602, 1490, 1376, 1298, 1231, 969, 730; 1 H NMR (400 MHz, CDCl3) δ 8.84 (d, J = 2.4 Hz, 1H), 8.32 (d, J = 2.8 Hz, 1H), 8.15 (dd, J = 8.8, 2.4 Hz, 1H), 7.33 (dd, J = 8.8, 2.8 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 5.88 (dd, J = 4.4, 3.6 Hz, 2H), 5.22 (s, 2H), 4.02 (s, 3H), 3.49 (m, 2H), 3.14 (dd, J = 1.6, 1.6 Hz, 2H), 1.13 (m, 2H), 0.35-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 191.6, 177.5 (2C), 167.5, 154.4, 149.5, 139.8, 138.5, 137.8, 128.1 (2C), 124.4, 123.9, 122.8, 112.0, 71.2, 54.5, 45.8 (2C), 33.9 (2C), 10.1 (2C), 5.0; ES-API MS: m / z calcd for C 24 H 22 N3O5432.2, found 432.2 [M+H] + .

[0135] (3aR,4R,4aR,5aS,6S,6aS)-2-(5-(2-(4-methoxyphenyl)-2-oxoethoxy)pyrimidin-2-yl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (74) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0 to 25% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 74 (58 mg, 0.13 mmol, 79%) as a white solid. IR (cm -1 ) 2975, 1714, 1601, 1428, 1237, 1177, 973, 730; 1 H NMR (400 MHz, CDCl3) δ 8.45 (s, 2H), 7.93 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 5.91 (dd, J = 4.4, 3.6 Hz, 2H), 5.36 (s, 2H), 3.90 (s, 3H), 3.50 (m, 2H), 3.17 (dd, J = 1.6, 1.6 Hz, 2H), 1.13 (m, 2H), 0.35-0.26 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 190.7, 176.8 (2C), 164.7, 152.1, 146.7, 146.1 (2C), 130.6 (2C), 128.0 (2C), 126.9, 114.5 (2C), 71.0, 55.8, 46.0 (2C), 33.9 (2C), 10.1 (2C), 5.0; ES-API MS: m / z calcd for C 24 H 22 N3O5432.2, found 432.2 [M+H] + .

[0136] (3aR,4R,4aR,5aS,6S,6aS)-2-(5-(2-(3-chloro-4-methoxyphenyl)-2-oxoethoxy)pyridin-2-yl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (75) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0% to 40% EtOAc in CH2Cl2) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 75 (86 mg, 0.18 mmol, 52%) as a yellow solid. IR (cm -1 ) 3055, 3009, 2954, 2846, 1775, 1711, 1595, 1478, 1400, 1263, 1209, 1061, 730; 1 H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 3.2 Hz, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.90 (dd, J = 8.4, 2.4 Hz, 1H), 7.32 (dd, J = 8.8, 2.8 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 5.88 (dd, J = 4.8, 3.6 Hz, 2H), 5.24 (s, 2H), 3.99 (s, 3H), 3.49 (m, 2H), 3.14 (dd, J = 2.0, 2.0 Hz, 2H), 1.14 (m, 2H), 0.35-0.26 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 191.1, 177.5 (2C), 159.8, 154.4, 139.7, 137.8, 130.7, 129.0, 128.1 (2C), 127.8, 123.8, 123.6, 122.8, 111.8, 71.1, 56.7, 45.8 (2C), 33.9 (2C), 10.1 (2C), 5.0; ES-API MS: m / z calcd for C25 H 22 ClN2O5465.1, found 465.1 [M+H] + .

[0137] (3aR,4R,4aR,5aS,6S,6aS)-2-(5-(2-(4-chloro-3-methylphenyl)-2-oxoethoxy)pyridin-2-yl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (76) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0 to 65% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 76 (94 mg, 0.21 mmol, 59%) as a yellow solid. IR (cm -1 ) 2956, 1710, 1580, 1478, 1400, 1291, 1232, 1186, 1050, 912, 730; 1 H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 2.8 Hz, 1H), 7.83 (d, J = 1.6 Hz, 1H), 7.72 (dd, J = 8.4, 2.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.31 (dd, J = 8.8, 3.2 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H), 5.88 (dd, J = 4.8, 3.6 Hz, 2H), 5.27 (s, 2H), 3.49 (m, 2H), 3.14 (dd, J = 2.0, 2.0 Hz, 2H), 2.45 (s, 3H), 1.14 (m, 2H), 0.35-0.26 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 192.6, 177.5 (2C), 154.4, 141.2, 139.8, 137.8, 132.7, 131.7, 130.7, 129.9, 128.1 (2C), 127.0, 123.9, 122.8, 71.2, 45.8 (2C), 33.9 (2C), 20.4, 10.1 (2C), 5.0; ES-API MS: m / z calcd for C 25 H 22 ClN2O4449.1, found 449.1 [M+H] + .

[0138] (3aR,4R,4aR,5aS,6S,6aS)-2-(5-(2-(3-chloro-4-fluorophenyl)-2-oxoethoxy)pyridin-2-yl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (77) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0 to 65% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 77 (71 mg, 0.16 mmol, 71%) as a yellow solid. IR (cm -1 ) 3055, 3010, 2957, 1776, 1714, 1581, 1488, 1402, 1292, 1253, 1206, 1059, 831, 731; 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 2.8 Hz, 1H), 8.07 (dd, J = 6.8, 2.4 Hz, 1H), 7.90 (ddd, J = 8.4, 4.4, 2.0 Hz, 1H), 7.32 (dd, J = 8.8, 3.2 Hz, 1H), 7.28 (d, J = 9.2 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 5.88 (dd, J = 4.8, 3.6 Hz, 2H), 5.25 (s, 2H), 3.49 (m, 2H), 3.15 (dd, J = 1.6, 1.6Hz, 2H), 1.14 (m, 2H), 0.35-0.26 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 191.2, 177.5 (2C), 161.9 (d, J = 257.9 Hz, 1C), 154.2, 140.0, 137.7, 131.5, 131.4 (d, J = 3.8 Hz, 1C), 128.9 (d, J = 8.6 Hz, 1C), 128.1 (2C), 123.4 (d, J = 110.2 Hz, 1C), 122.7 (d, J = 18.7 Hz, 1C), 117.5 (d, J = 21.7 Hz, 1C), 71.2, 45.8 (2C), 33.9 (2C), 10.1 (2C), 5.0; ES-API MS: m / z calculation for C 24 H 19 ClFN2O4453.1, found 453.1 [M+H] + .

[0139] (3aR,4R,4aR,5aS,6S,6aS)-2-(5-(2-(4-chloro-3-(trifluoromethyl)phenyl)-2-oxoethoxy)pyridin-2-yl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (78) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0 to 65% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 78 (37 mg, 0.074 mmol, 44%) as a white solid. IR (cm -1 ) 3055, 3012, 2957, 1774, 1710, 1604, 1478, 1401, 1320, 1209, 1181, 1141, 730; 1 H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 3.6 Hz, 1H), 8.31 (d, J = 2.4 Hz, 1H), 8.09 (dd, J = 8.4, 2.0 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.33 (dd, J = 8.8, 2.8 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 5.88 (dd, J = 4.8, 3.6 Hz, 2H), 5.28 (s, 2H), 3.50 (m, 2H), 3.15 (dd, J = 2.0, 2.0 Hz, 2H), 1.14 (m, 2H), 0.35-0.26 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 191.7, 177.5 (2C), 154.1, 140.1, 138.9 (q, J = 2.0 Hz, 1C), 137.7, 132.7, 132.6, 129.9, 129.5, 128.1 (2C), 127.8 (q, J = 5.0 Hz, 1C), 124.0, 122.9, 122.4 (q, J = 273.0 Hz, 1C), 71.5, 45.8 (2C), 33.9 (2C), 10.1 (2C), 5.0; ES-API MS: m / z calcd for C 25 H 19 ClF3N2O4503.1, found 503.1 [M+H] + .

[0140] (3aR,4R,4aR,5aS,6S,6aS)-2-(5-(2-(3,4-dichlorophenyl)-2-oxoethoxy)pyridin-2-yl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (79) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0% to 60% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 79 (133 mg, 0.28 mmol, 80%) as a yellow solid. IR (cm -1 ) 3060, 3038, 3010, 2956, 1776, 1709, 1582, 1479, 1399, 1211, 1187, 1032, 730; 1 H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 2.8 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.80 (dd, J = 8.4, 2.0 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.32 (dd, J = 8.8, 3.2 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 5.88 (dd, J = 4.8, 3.6 Hz, 2H), 5.25 (s, 2H), 3.49 (m, 2H), 3.15 (dd, J = 1.6, 1.6 Hz, 2H), 1.14 (m, 2H), 0.35-0.26 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 191.6, 177.5 (2C), 154.2, 140.0, 139.2, 137.7, 134.1, 133.7, 131.4, 130.4, 128.1 (2C), 127.4, 123.9, 122.8, 71.3, 45.8 (2C), 33.9 (2C), 10.1 (2C), 5.0; ES-API MS: m / z calcd for C 24 H 19Cl2N2O4469.1, found 469.1 [M+H] + .

[0141] (3aR,4R,4aR,5aS,6S,6aS)-2-(5-(2-(3,5-dichlorophenyl)-2-oxoethoxy)pyridin-2-yl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (80) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0 to 55% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 80 (44 mg, 0.094 mmol, 27%) as a white solid. IR (cm -1 ) 3076, 2955, 1710, 1568, 1488, 1399, 1291, 1216, 1187, 730; 1 H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 2.8 Hz, 1H), 7.83 (d, J = 2.0 Hz, 2H), 7.62 (t, J = 2.0 Hz, 1H), 7.32 (dd, J = 8.4, 3.2 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 5.88 (dd, J = 4.4, 3.6 Hz, 2H), 5.25 (s, 2H), 3.49 (m, 2H), 3.15 (dd, J = 1.5, 1.5 Hz, 2H), 1.14 (m, 2H), 0.35-0.26 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 191.3, 177.5 (2C), 154.1, 140.0, 137.8, 136.5, 136.3, 134.1 (2C), 128.1 (2C), 126.8 (2C), 123.9, 122.8, 71.3, 45.8 (2C), 33.9 (2C), 10.1 (2C), 5.0; ES-API MS: m / z calcd for C 24 H 19 Cl2N2O4469.1, found 469.1 [M+H] + .

[0142] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(5,6-dichloropyridin-3-yl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (81) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0 to 45% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 81 (50 mg, 0.10 mmol, 30%) as a pale yellow solid. IR (cm -1 ) 3009, 1704, 1512, 1187, 734; 1 H NMR (400 MHz, CDCl3) δ 8.91 (d, J = 2.0 Hz, 1H), 8.35 (d, J = 2.0 Hz, 1H), 7.11 (d, J = 9.2 Hz, 2H), 6.96 (d, J = 9.2 Hz, 2H), 5.84 (dd, J = 4.8, 3.6 Hz, 2H), 5.13 (s, 2H), 3.48 (m, 2H), 3.12 (dd, J = 1.6, 1.6 Hz, 2H), 1.14 (m, 2H), 0.35-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 192.6, 178.0 (2C), 157.3, 154.2, 147.4, 138.5, 137.7, 131.8, 130.1, 128.3 (2C), 128.0 (2C), 126.2, 115.4 (2C), 71.8, 45.5 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 24 H 19 Cl2N2O4469.1, found 469.1 [M+H] + .

[0143] (3aR,4R,4aR,5aS,6S,6aS)-2-(5-(2-(3-chloro-4-methoxyphenyl)-2-oxoethoxy)pyrimidin-2-yl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (82) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0% to 30% EtOAc in CH2Cl2) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 82 (106 mg, 0.23 mmol, 65%) as a pale yellow solid. IR (cm -1 ) 2952, 1714, 1595, 1428, 1263, 1212, 731; 1 H NMR (400 MHz, CDCl3) δ 8.49 (s, 2H), 7.99 (d, J = 2.0 Hz, 1H), 7.88 (dd, J = 8.8, 2.0 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 5.91 (dd, J = 4.4, 3.6 Hz, 2H), 5.33 (s, 2H), 4.08 (s, 3H), 3.50 (m, 2H), 3.17 (dd, J = 1.6, 1.6 Hz, 2H), 1.14 (m, 2H), 0.36-0.27 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 190.0, 176.8 (2C), 160.0, 152.0, 146.9, 146.1 (2C), 130.5, 128.9, 128.0 (2C), 127.4, 123.8, 111.9, 110.2, 71.0, 56.8, 46.0 (2C), 33.9 (2C), 10.1 (2C), 5.0; ES-API MS: m / z calcd for C 24 H 21 ClN3O5466.1, found 466.1 [M+H] + .

[0144] (3aR,4R,4aR,5aS,6S,6aS)-2-(5-(2-(4-chloro-3-methylphenyl)-2-oxoethoxy)pyrimidin-2-yl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (83) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0% to 15% EtOAc in CH2Cl2) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 83 (67 mg, 0.15 mmol, 43%) as a white solid. IR (cm -1 ) 2953, 1714, 1428, 1290, 1236, 1050, 731; 1 H NMR (400 MHz, CDCl3) δ 8.48 (s, 2H), 7.82 (d, J = 2.0 Hz, 1H), 7.70 (dd, J = 8.4, 2.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 5.91 (dd, J = 4.8, 3.6 Hz, 2H), 5.36 (s, 2H), 3.50 (m, 2H), 3.17 (dd, J = 1.6, 1.6 Hz, 2H), 2.46 (s, 3H), 1.14 (m, 2H), 0.36-0.27 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 191.5, 176.8 (2C), 152.0, 146.9, 146.1 (2C), 141.5, 137.7, 132.3, 130.6, 130.1, 128.0 (2C), 126.8, 71.1, 46.0 (2C), 33.9 (2C), 20.4, 10.1 (2C), 5.0; ES-API MS: m / z calcd for C 24 H 21 ClN3O4450.1, found 450.1 [M+H] + .

[0145] (3aR,4R,4aR,5aS,6S,6aS)-2-(5-(2-(3-chloro-4-fluorophenyl)-2-oxoethoxy)pyrimidin-2-yl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (84) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0% to 25% EtOAc in CH2Cl2) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 84 (35 mg, 0.077 mmol, 45%) as a pale yellow solid. IR (cm -1 ) 3010, 1713, 1428, 1251, 1187, 731; 1 H NMR (400 MHz, CDCl3) δ 8.49 (s, 2H), 8.05 (dd, J = 6.8, 2.0 Hz, 1H), 7.89 (ddd, J = 8.8, 4.4, 2.0 Hz, 1H), 7.30 (dd, J = 8.4, 8.4 Hz, 1H), 5.91 (dd, J = 4.8, 3.6 Hz, 2H), 5.35 (s, 2H), 3.50 (m, 2H), 3.17 (dd, J = 1.6, 1.6 Hz, 2H), 1.14 (m, 2H), 0.35-0.27 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 190.1, 176.8 (2C), 162.0 (d, J = 258.3 Hz, 1C), 151.8, 147.1, 146.1 (2C), 131.4 (d, J = 1.3 Hz, 1C), 131.1 (d, J = 3.7 Hz, 1C), 128.8 (d, J = 8.6 Hz, 1C), 128.1 (2C), 117.7 (d, J = 21.7 Hz, 1C), 110.2, 71.1, 46.0 (2C), 33.9 (2C), 10.1 (2C), 5.0; ES-API MS: m / z calcd for C 23 H 17 ClFN3O4453.1 found 453.1 [M] + .

[0146] (3aR,4R,4aR,5aS,6S,6aS)-2-(5-(2-(3,4-dichlorophenyl)-2-oxoethoxy)pyrimidin-2-yl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (85) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0% to 35% EtOAc in CH2Cl2) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 85 (65 mg, 0.14 mmol, 40%) as a white solid. IR (cm -1 ) 3009, 1712, 1429, 1397, 1216, 1184, 732; 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 2H), 8.04 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 8.4, 2.0 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 5.92 (dd, J = 4.8, 3.2 Hz, 2H), 5.35 (s, 2H), 3.50 (m, 2H), 3.18 (dd, J = 1.6, 2.0 Hz, 2H), 1.14 (m, 2H), 0.35-0.27 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 190.5, 176.8 (2C), 151.8, 147.1, 146.1 (2C), 139.6, 134.2, 133.4, 131.5, 130.3, 128.1 (2C), 127.2, 71.1, 46.0 (2C), 33.9 (2C), 10.1 (2C), 5.0; ES-API MS: m / z calcd for C 23 H 18 Cl2N3O4470.1, found 470.1 [M+H] + .

[0147] (3aR,4R,4aR,5aS,6S,6aS)-2-(5-(2-(3,5-dichlorophenyl)-2-oxoethoxy)pyrimidin-2-yl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (86) [ka] Method C Purification by silica gel flash chromatography (gradient elution, 0 to 20% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 86 (33 mg, 0.07 mmol, 42%) as a pale yellow solid. IR (cm -1 ) 3008, 1712, 1428, 1220, 731; 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 2H), 7.81 (d, J = 2.0 Hz, 2H), 7.65 (t, J = 2.0 Hz, 1H), 5.92 (dd, J = 4.8, 3.6 Hz, 2H), 5.34 (s, 2H), 3.51 (m, 2H), 3.18 (dd, J = 1.6, 1.6 Hz, 2H), 1.14 (m, 2H), 0.36-0.27 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 190.3, 176.8 (2C), 151.8, 147.1, 146.1 (2C), 136.5, 136.2, 134.4 (2C), 128.1 (2C), 126.7 (2C), 71.1, 46.0 (2C), 33.9 (2C), 10.1 (2C), 5.0; ES-API MS: m / z calcd for C 23 H 18 Cl2N3O4470.1, found 470.1 [M+H] + .

[0148] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(hydroxymethyl)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (105) [ka] Method A Purification by silica gel flash chromatography (gradient elution, 0% to 80% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 105 (80 mg, 0.27 mmol, 52%) as a pale yellow solid. IR (cm -1 ) 3504, 3052, 3033, 2963, 2886, 1696, 1508, 1395, 1191, 1175, 1006; 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 5.86 (dd, J = 4.8, 3.6 Hz, 2H), 4.69 (s, 2H), 3.49 (m, 2H), 3.13 (dd, J = 2.0, 1.6 Hz, 2H), 1.79 (br, 1H), 1.15 (m, 2H), 0.30 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 177.7 (2C), 141.4, 131.1, 127.8 (2C), 127.4 (2C), 126.6 (2C), 64.8, 45.3 (2C), 33.8 (2C), 9.9 (2C), 4.7; ES-API MS: m / z calcd for C 18 H 18 NO3296.1, found 296.1 [M+H] + .

[0149] 4-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-ethenocyclopropa[f]isoindol-2(1H)-yl)-3-fluorobenzonitrile (106) [ka] Method B (Microwave) Crystallization in CH2Cl2 / Et2O / hexane gave the title benzonitrile 106 as yellow crystals (2.55 g, 8.27 mmol, 80%). IR (cm -1 ) 3067, 2989, 2360, 1722, 1421, 1266, 1254, 1169, 1045, 899, 728; 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.30 (br, 1H), 5.87 (dd, J = 4.4, 4.0 Hz, 2H), 3.50 (m, 2H), 3.21 (m, 2H), 1.16 (m, 2H), 0.38-0.27 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 177.9 (2C), 176.2 (2C), 157.2 (d, J = 256.6 Hz, 1C), 130.7, 128.7 (d, J = 4.2 Hz, 1C), 128.0 (2C), 124.7 (d, J = 13.3 Hz, 1C), 120.8 (d, J = 23.1 Hz, 1C), 117.0 (d, J = 2.6 Hz, 1C), 114.5 (d, J = 9.1 Hz, 1C), 46.00, 45.96, 34.0 (2C), 10.0 (2C), 5.0; ES-API MS: m / z calcd for C 18 H 14 FN2O2309.1, found 309.1 [M+H] + .

[0150] 4-((3aR,4R,4aR,5aS,6S,6aS)-1,3-ジオキソ-3,3a,4,4a,5,5a,6,6 a-オクタヒドロ-4,6-エテノシクロプロパ[f]イソインドール-2(1H)-イル)ベンズアルデヒド(107)

change

[0151] 4-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-ethenocyclopropa[f]isoindol-2(1H)-yl)-3-fluorobenzaldehyde (108) [ka] In a pressure sealed tube, benzonitrile 106 (2.46 g, 7.98 mmol) was dissolved in formic acid (16 mL, 80% deionized water). Raney nickel (1.2 g) was added in one portion to the reaction. The resulting mixture was sealed and refluxed at 110 °C for 4 h, cooled to room temperature, filtered through a pad of Celite, and washed with EtOAc. The eluate was neutralized with saturated NaHCO, washed with brine, dried over anhydrous NaSO, and filtered. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (gradient elution, 0 to 45% EtOAc in hexanes) and recrystallized in CHCl / hexanes to give the desired title benzaldehyde 108 (1.95 g, 6.26 mmol, 79%) as a colorless solid. IR (cm -1 ) 3069, 3045, 3015, 1780, 1698, 1588, 1512, 1391, 1253, 1181, 816, 736, 718; 1 H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 9.6 Hz, 1H), 7.35 (br, 1H), 5.88 (dd, J = 4.4, 3.6 Hz, 2H), 3.50 (m, 2H), 3.21 (m, 2H), 1.17 (m, 2H), 0.37-0.28 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 190.1 (d, J = 1.8 Hz, 1C), 176.4 (2C), 157.9 (d, J = 255.7 Hz, 1C), 138.4 (d, J = 6.0 Hz, 1C), 130.4, 128.0 (2C), 126.2 (d, J = 3.5 Hz, 1C), 125.4 (d, J = 14.0 Hz, 1C), 116.9 (d, J = 20.3 Hz, 1C), 46.04, 45.99, 34.0 (2C), 10.1 (2C), 5.0; ES-API MS: m / z calcd for C 18 H 15 FNO3312.1, found 312.1 [M+H]+ .

[0152] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(aminomethyl)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (109) [ka] Step 1: (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(azidomethyl)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione To a solution of benzyl alcohol 105 (50 mg, 0.17 mmol) and PPh3 (67 mg, 0.25 mmol) in anhydrous DMF (0.85 mL) was added tetrabromomethane (84 mg, 0.25 mmol) at 0 °C. The resulting yellow mixture was stirred at 0 °C until TLC showed complete conversion of the benzyl alcohol. NaN3 (33 mg, 0.51 mmol) was then added in one portion, and stirring was continued at room temperature for an additional 2 h. The reaction was diluted with H2O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and filtered. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography (gradient elution, 0 → 35% EtOAc in hexanes) to give the title azide (49 mg, 0.15 mmol, 91%) as a white solid. IR (cm -1 ) 3078, 3052, 3009, 2979, 2949, 2099, 1706, 1516, 1387, 1190, 734, 714; 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 5.84 (dd, J = 4.4, 3.2 Hz, 2H), 4.33 (s, 2H), 3.47 (m, 2H), 3.12 (dd, J = 1.6, 1.6 Hz, 2H), 1.15-1.11(m, 2H), 0.33-0.24 (m, 2H); 13 C NMR (100MHz, CDCl3) δ 177.5 (2C), 135.9, 131.7, 128.6 (2C), 127.8 (2C), 126.8 (2C), 54.2, 45.3 (2C), 33.8 (2C), 9.9 (2C), 4.7; ES-API MS: m / z calcd for C 18 H 18 N2O2K 333.1, found 333.1 [M+K-N2] + .

[0153] Step 2: To a solution of the above azide (Step 1) (1.31 g, 4.09 mmol) in THF / HO (10:1 (v:v), 40 mL) was added PMe3 solution (8.2 mL, 1.0 M in THF). The resulting mixture was stirred at room temperature for 1 h. The reaction was then diluted with HO (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and filtered. The solvent was removed under reduced pressure, and the residue was recrystallized in CHCl / hexane to give the title amine 109 (1.15 g, 0.15 mmol, 91%) as a yellow solid. IR (cm -1 ) 3461, 3372, 3008, 2954, 2867, 1772, 1713, 1704, 1514, 1385, 1186, 734; 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 5.83 (dd, J = 4.8, 3.2 Hz, 2H), 3.85 (m, 2H), 1.76 (m, 2H), 1.14-1.10 (m, 2H), 0.32-0.23 (m, 2H); 13 C NMR ES-API MS: m / z calcd for C 18 H 19 N2O2Na 318.1, found 318.1 [M+Na+H] + .

[0154] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-((E)-3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (110) [ka] Method E Purification by silica gel flash chromatography (gradient elution, 0 to 50% EtOAc in hexanes) afforded the title enone 110 (70 mg, 0.16 mmol, 85%) as an amorphous yellow solid. IR (cm -1 ) 3465, 3010, 2957, 2841, 1707, 1660, 1604, 1512, 1378, 1335, 1261, 1222, 1172, 1022, 819, 733; 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 9.2 Hz, 2H), 7.77 (d, J = 15.6 Hz, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 15.6 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 5.87 (dd, J = 4.8, 3.2 Hz, 2H), 3.89 (s, 3H), 3.51 (m, 2H), 3.16 (dd, J = 1.6, 1.6 Hz, 2H), 1.16 (m, 2H), 0.36-0.27 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 188.4, 177.4 (2C), 163.5, 142.6, 135.2, 133.3, 130.9, 130.8 (2C), 128.8 (2C), 127.8 (2C), 126.8 (2C), 122.9, 113.9 (2C), 55.5, 45.4 (2C), 33.8 (2C), 9.9 (2C), 4.7; ES-API MS: m / z calcd for C 27 H 24 NO4426.2, found 426.0 [M+H] + .

[0155] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-((E)-3-(3-chloro-4-methoxyphenyl)-3-oxoprop-1-en-1-yl)-2-fluorophenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (111a) [ka] Method E Purification by silica gel flash chromatography (gradient elution, 0 to 50% EtOAc in hexanes) afforded the title enone 111a (263 mg, 0.55 mmol, 86%) as a pale yellow solid. IR (cm -1) 3056, 3010, 2954, 1722, 1662, 1607, 1593, 1392, 1276, 734; 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 1.6 Hz, 1H), 7.91 (dd, J = 8.4, 2.0 Hz, 1H), 7.66 (d, J = 15.6 Hz, 1H), 7.44 (d, J = 15.6 Hz, 1H), 7.40 (m, 1H), 7.38 (m, 1H), 7.12 (br, 1H), 6.96 (d, J = 8.8 Hz, 1H), 5.84 (dd, J = 4.0, 3.6 Hz, 2H), 3.93 (s, 3H), 3.45 (m, 2H), 3.16 (m, 2H), 1.12 (m, 2H), 0.32-0.24 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 186.9, 176.6 (2C), 158.8, 157.4 (d, J = 252.9 Hz, 1C), 142.0 (d, J = 2.0 Hz, 1C), 137.7 (d, J = 7.6 Hz, 1C), 131.1, 130.8, 129.6, 129.1, 127.7, 124.7 (d, J = 2.1 Hz, 1C), 123.3, 123.0, 121.2 (d, J = 13.9 Hz, 1C), 115.6 (d, J = 20.2 Hz, 1C), 111.4, 56.4, 45.7 (2C), 33.8 (2C), 9.9 (2C), 4.8; ES-API MS: m / z calcd for C 27 H 22 ClFNO4478.1, found 478.1 [M+H] + .

[0156] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-((E)-3-(4-chloro-3-methylphenyl)-3-oxoprop-1-en-1-yl)-2-fluorophenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (111b) [ka] Method E Purification by silica gel flash chromatography (gradient elution, 0 to 40% EtOAc in hexanes) afforded the title enone 111b (228 mg, 0.49 mmol, 77%) as a pale yellow solid. IR (cm -1 ) 3055, 2947, 3007, 1716, 1666, 1609, 1517, 1391, 1181, 1050, 734; 1 H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 1.2 Hz, 1H), 7.77 (dd, J = 8.4, 2.4 Hz, 1H), 7.72 (d, J = 15.6 Hz, 1H), 7.48 (d, J = 2.4 Hz, 1H), 7.46-7.43 (m, 3H), 7.18 (br, 1H), 5.88 (dd, J = 4.0, 4.0 Hz, 2H), 3.50 (m, 2H), 3.20 (m, 2H), 2.46 (s, 3H), 1.16 (m, 2H), 0.37-0.28 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 189.0, 176.8 (2C), 157.7 (d, J = 253.2 Hz, 1C), 142.6 (d, J = 2.3 Hz, 1C), 140.0, 137.9 (d, J = 7.5 Hz, 1C), 137.0, 136.3, 131.2, 129.9, 129.7, 128.0, 127.5, 124.9 (d, J = 2.9 Hz, 1C), 124.0, 123.8, 121.5 (d, J = 13.9 Hz, 1C), 115.9 (d, J = 20.0Hz, 1C), 46.0, 45.9, 34.0 (2C), 20.4, 10.1 (2C), 5.0; ES-API MS: m / z calcd for C 27 H 22 ClFNO3462.1, found 462.1 [M+H] + .

[0157] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-((E)-3-(3-chloro-4-fluorophenyl)-3-oxoprop-1-en-1-yl)-2-fluorophenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (111c) [ka] Method E Purification by silica gel flash chromatography (gradient elution, 0 to 40% EtOAc in hexanes) afforded the title enone 111c (189 mg, 0.41 mmol, 63%) as a pale yellow solid. IR (cm -1 ) 3008, 1713, 1609, 1516, 1391, 1250, 1205, 814, 740; 1H NMR (400 MHz, CDCl3) δ 8.08 (dd, J = 7.2, 2.0 Hz, 1H), 7.92 (m, 1H), 7.73 (d, J = 15.6 Hz, 1H), 7.44 (m, 1H), 7.42 (m, 1H), 7.42 (d, J = 15.6 Hz, 1H), 7.26 (dd, J = 8.8, 8.4 Hz, 1H), 7.17 (br, 1H), 5.87 (dd, J = 3.6, 4.0 Hz, 2H), 3.49 (m, 2H), 3.19 (m, 2H), 1.15 (m, 2H), 0.36-0.27 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 187.2, 176.7 (2C), 161.2 (d, J = 255.9 Hz, 1C), 157.6 (d, J = 253.2 Hz, 1C), 143.3 (d, J = 2.4 Hz, 1C), 137.6 (d, J = 7.5 Hz, 1C), 135.0 (d, J = 3.6 Hz, 1C), 131.6 (d, J = 0.8 Hz, 1C), 130.0, 129.1 (d, J = 8.4 Hz, 1C), 127.9, 125.0 (d, J = 3.1 Hz, 1C), 123.2 (2C), 122.2 (d, J = 18.1 Hz, 1C), 121.7 (d, J = 17.8 Hz, 1C), 117.1 (d, J = 21.6 Hz, 1C), 115.9 (d, J = 20.2 Hz, 1C), 45.96, 45.93, 34.0 (2C), 10.0 (2C), 5.0; ES-API MS: m / z calcd for C 26 H 19 ClF2NO3466.1, found 466.1 [M+H] + .

[0158] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-((E)-3-(4-chloro-3-(trifluoromethyl)phenyl)-3-oxoprop-1-en-1-yl)-2-fluorophenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (111d) [ka] Method E Purification by silica gel flash chromatography (gradient elution, 0 to 40% EtOAc in hexanes) afforded the title enone 111d (192 mg, 0.37 mmol, 58%) as a pale yellow solid. IR (cm -1 ) 3009, 2997, 1713, 1610, 1515, 1311, 1206, 1175, 737; 1 H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.10 (dd, J = 8.4, 1.2 Hz, 1H), 7.75 (d, J = 15.6 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 15.6 Hz, 1H), 7.45 (m, 1H), 7.43 (m, 1H), 7.18 (br, 1H), 5.87 (dd, J = 4.0, 3.6 Hz, 2H), 3.49 (m, 2H), 3.19 (m, 2H), 1.15 (m, 2H), 0.37-0.27 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 187.4, 176.7 (2C), 157.6 (d, J = 253.4 Hz, 1C), 143.8 (d, J = 2.2 Hz, 1C), 137.5 (q, J = 1.5 Hz, 1C), 137.4 (d, J = 7.5 Hz, 1C), 136.3, 132.7, 132.2, 130.0, 129.2 (q, J = 31.8 Hz, 1C), 127.9, 127.8 (q, J = 5.3 Hz, 1C), 125.1 (d, J = 2.0 Hz, 1C), 122.9 (2C), 122.6 (q, J = ES-API MS: m / z calcd for C 27 H 19 ClF4NO3516.1, found 516.1 [M+H] + .

[0159] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-((E)-3-(3,4-dichlorophenyl)-3-oxoprop-1-en-1-yl)-2-fluorophenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (111e) [ka] Method E Purification by silica gel flash chromatography (gradient elution, 0 to 40% EtOAc in hexanes) afforded the title enone 111e (175 mg, 0.36 mmol, 57%) as a pale yellow solid. IR (cm -1 ) 2957, 1714, 1607, 1516, 1391, 1210, 1031, 739; 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 1.6 Hz, 1H), 7.82 (dd, J = 8.4, 1.6 Hz, 1H), 7.73 (d, J = 16.0 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.44 (m, 1H), 7.42 (m, 1H), 7.41 (d, J = 16.0 Hz, 1H), 7.17 (br, 1H), 5.87 (dd, J = 4.0, 4.0 Hz, 2H), 3.49 (m, 2H), 3.19 (m, 2H), 1.15 (m, 2H), 0.36-0.27 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 187.6, 176.7 (2C), 157.6 (d, J = 253.3 Hz, 1C), 143.5 (d, J = 2.2 Hz, 1C), 137.9, 137.5 (d, J = 7.5 Hz, 1C), 137.4, 133.6, 131.0, 130.7, 129.9, 128.0, 127.7, 125.0 (d, J = 2.8 Hz, 1C), 123.2 (2C), 121.8 (d, J = 13.8 Hz, 1C), 115.9 (d, J = 20.3 Hz, 1C), 45.94, 45.90, 34.0 (2C), 10.0 (2C), 5.0; ES-API MS: m / z calcd for C 26 H 19 Cl2FNO3482.1, found 482.1 [M+H] + .

[0160] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-((E)-3-(3,5-dichlorophenyl)-3-oxoprop-1-en-1-yl)-2-fluorophenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (111f) [ka] Method E Purification by silica gel flash chromatography (gradient elution, 0 to 40% EtOAc in hexanes) afforded the title enone 111f (271 mg, 0.56 mmol, 88%) as a pale yellow solid. IR (cm -1 ) 3077, 3009, 2957, 1714, 1564, 1516, 1391, 1214, 1178, 738, 700; 1 H NMR (400 MHz, CDCl3) δ 7.81 (s, 2H), 7.66 (d, J = 15.6 Hz, 1H), 7.51 (m, 1H), 7.41 (m, 1H), 7.38 (m, 1H), 7.38 (d, J = 15.6 Hz, 1H), 7.13 (br, 1H), 5.83 (m, 2H), 3.45 (m, 2H), 3.16 (m, 2H), 1.12 (m, 2H), 0.32-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 187.1, 176.6 (2C), 157.4 (d, J = 253.2 Hz, 1C), 143.6 (d, J = 1.8 Hz, 1C), 140.2, 137.2 (d, J = 7.5 Hz, 1C), 135.7 (2C), 132.7, 129.8, 127.8, 127.0 (2C), 125.1, 122.9 (2C), 121.7 (d, J = 13.9 Hz, 1C), 115.8 (d, J = 20.4 Hz, 1C), 45.8 (2C), 33.8 (2C), 9.9 (2C), 4.9; ES-API MS: m / z calcd for C 26 H 19 Cl2FNO3482.1, found 482.0 [M+H] + .

[0161] 4-Methoxybenzoate 4-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-ethenocyclopropa[f]isoindol-2(1H)-yl)benzyl (12) [ka] To a mixture of benzyl alcohol 105 (50 mg, 0.17 mmol), p-anisic acid (39 mg, 0.25 mmol), and PPh3 (67 mg, 0.25 mmol) in anhydrous THF (1.7 mL) was added dropwise DIAD (51 mg, 0.25 mmol) at 0 °C. The resulting mixture was stirred and allowed to warm slowly to room temperature over 3 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography (gradient elution, 0% to 45% EtOAc in hexanes) and recrystallized in CHCl / hexanes to give the title ester 12 (52 mg, 0.12 mmol, 71%) as a yellow solid. IR (cm -1 ) 3450, 3056, 3008, 1707, 1606, 1512, 1377, 1274, 1257, 1169, 736; 1 H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 5.86 (dd, J = 4.8, 3.6 Hz, 2H), 5.33 (s, 2H), 3.86 (s, 3H), 3.50 (m, 2H), 3.14 (dd, J = 1.2, 1.2 Hz, 2H), 1.15 (m, 2H), 0.35-0.26 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 177.6 (2C), 166.0, 163.5, 136.7, 131.7 (2C), 131.6, 128.82 (2C), 127.79 (2C), 126.6 (2C), 122.3, 113.6 (2C), 65.7, 55.4, 45.3 (2C), 33.8 (2C), 9.9 (2C), 4.7; ES-API MS: m / z calcd for C 26 H 24 NO5430.2, found 430.1 [M+H] + .

[0162] N-(4-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-ethenocyclopropa[f]isoindol-2(1H)-yl)benzyl)-4-methoxybenzamide (17) [ka] To a solution of benzylamine 109 (45 mg, 0.15 mmol) in anhydrous CHCl (0.5 mL) was added EtN (18.6 mg, 0.18 mmol) and p-methoxybenzoyl chloride (27.5 mg, 0.16 mmol). The resulting mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography (gradient elution, 0% to 90% EtOAc in hexanes) and recrystallized in CHCl / hexanes to give the title amide 17 (54 mg, 0.13 mmol, 83%) as a pale yellow solid. IR (cm -1 ) 3338, 3010, 2956, 1704, 1607, 1505, 1387, 1255, 1181, 732; 1 H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 6.35 (t, J = 5.6 Hz, 1H), 5.85 (dd, J = 4.8, 3.2 Hz, 2H), 4.62 (d, J = 5.6 Hz, 2H), 3.84 (s, 3H), 3.49 (m, 2H), 3.13 (dd, J = 2.0, 2.0 Hz, 2H), 1.14 (m, 2H), 0.35-0.26 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 177.6 (2C), 166.8, 162.3, 138.9, 131.1, 128.77 (2C), 128.76 (2C), 127.8 (2C), 126.8 (2C), 126.4, 113.8 (2C), 55.4, 45.3 (2C), 43.6, 33.8 (2C), 9.9 (2C), 4.7; ES-API MS: m / z calcd for C 26 H 25 N2O4429.2, found 429.2 [M+H] + .

[0163] N-(4-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-ethenocyclopropa[f]isoindol-2(1H)-yl)benzyl)-4-methoxybenzenesulfonamide (18) [ka] To a solution of p-methoxybenzenesulfonyl chloride (1.0 equiv.) in anhydrous CHCl (0.2 M) was added benzylamine 109 (1.15 equiv.) at 0 °C, followed by EtN (2.0 equiv.). The resulting yellow mixture was allowed to warm to room temperature and stirred at this temperature for 2 h. The reaction was quenched with aqueous HCl (1 N) and extracted with EtOAc. The combined organic layers were washed with saturated NaHCO solution, then brine, dried over anhydrous NaSO, and filtered. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (gradient elution, 0% to 50% EtOAc in hexanes) and recrystallized in CHCl / hexanes to give the title sulfonamide 18 (156 mg, 0.34 mmol, 58%) as a colorless solid. IR (cm -1 ) 3278, 3007, 2952, 1703, 1597, 1389, 1260, 1184, 1157, 734; 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 9.2 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 5.83 (dd, J = 4.4, 3.2 Hz, 2H), 4.64 (t, J = 6.4 Hz, 1H), 4.11 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 3.46 (m, 2H), 3.11 (dd, J = 2.0, 1.6 Hz, 2H), 1.15-1.11 (m, 2H), 0.33-0.24 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 177.5 (2C), 163.0, 136.7, 131.4, 131.3, 129.3 (2C), 128.5 (2C), 127.8 (2C), 126.8 (2C), 114.3 (2C), 55.6, 46.7, 45.3 (2C), 33.8 (2C), 9.9 (2C), 4.7; ES-API MS: m / z calcd for C 25 H 24 N2O5SNa 487.1, found 487.1 [M+Na] + .

[0164] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(3-(4-methoxyphenyl)-3-oxopropyl)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (19) [ka] To a solution of enone 110 (53 mg, 0.12 mmol) and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (also known as Hantzsch ester) (63 mg, 0.25 mmol) in anhydrous THF (1.2 mL) was added TiCl4 solution (0.18 mL, 0.18 mmol, 1 M CHCl2 solution) dropwise. The resulting heterogeneous mixture gradually turned into a brown homogeneous solution. After 20 min, the reaction mixture was poured into a separatory funnel containing a biphasic layer of 10 mL EtOAc and a saturated NaHCO3 solution (10 mL). The aqueous layer was extracted with 2 × 10 mL EtOAc, and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography (gradient elution, 0% to 45% EtOAc in hexanes) and recrystallized in CH2Cl2 / hexanes to give the desired title compound 19 (44 mg, 0.10 mmol, 86%) as a white solid. IR (cm -1 ) 3010, 2956, 1706, 1674, 1601, 1515, 1384, 1259, 1176; 1 H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 9.2 Hz, 2H), 5.85 (dd, J = 4.8, 3.6 Hz, 2H), 3.86 (s, 3H), 3.49 (m, 2H), 3.23 (dd, J = 7.6, 8.4 Hz, 2H), 3.13 (dd, J = 2.0, 1.6 Hz, 2H), 3.06 (dd, J = 8.0, 7.2 Hz, 2H), 1.14 (m, 2H), 0.35-0.26 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 197.4, 177.7 (2C), 163.5, 142.1, 130.2 (2C), 129.82, 129.79, 129.2 (2C), 127.8 (2C), 126.5 (2C), 113.7 (2C), 55.5, 45.3 (2C), 39.9, 33.8 (2C), 29.9, 9.9 (2C), 4.7; ES-API MS: m / z calculation for C 27 H 26 NO4428.2, found 428.1 [M+H] + .

[0165] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(4-methoxybenzoyl)cyclopropyl)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (24) [ka] Method F Purification by silica gel flash chromatography (gradient elution, 0 to 45% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 24 (70 mg, 0.16 mmol, 85%) as a pale yellow solid. IR (cm -1 ) 3007, 2956, 1707, 1599, 1393, 1232, 1178, 1029, 734; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 5.86 (dd, J = 4.8, 3.6 Hz, 2H), 3.87 (s, 3H), 3.50 (m, 2H), 3.14 (dd, J = 1.6, 1.6 Hz, 2H), 2.83 (m, 1H), 2.65 (m, 1H), 1.90 (m, 1H), 1.49 (m, 1H), 1.15 (m, 2H), 0.35-0.26 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 196.5, 177.7 (2C), 163.5, 141.3, 130.6, 130.4 (2C), 130.1, 127.78, 127.76, 126.9 (2C), 126.6 (2C), 113.7 (2C), 55.5, 45.3 (2C), 33.8 (2C), 29.0, 18.7, 14.1, 9.9 (2C), 4.7; ES-API MS: m / z calcd for C 28 H 26 NO4440.2, found 440.2 [M+H] + .

[0166] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(3-(4-methoxybenzoyl)oxiran-2-yl)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (25) [ka] To a solution of enone 110 (220 mg, 0.52 mmol) in MeOH / CHCl (5 mL, 1:1 (v:v)), HO (234 mg, 2.07 mmol, 30 wt% solution) and NaOH (114 mg, 2.84 mmol, 0.5 M aqueous solution) were added dropwise at 0 °C. The resulting heterogeneous yellow mixture gradually turned colorless. The reaction mixture was allowed to warm slowly to room temperature and stirred for 2 days. After that, it was poured into a separatory funnel containing 15 mL of EtOAc and 15 mL of saturated aqueous NaHCO. The aqueous phase was extracted with 2 × 10 mL of EtOAc, dried over anhydrous NaSO, and filtered. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography (gradient elution, 0% to 60% EtOAc in hexanes) and recrystallized in CHCl / hexanes to give the desired title epoxide 25 (200 mg, 0.45 mmol, 89%) as an amorphous white solid. IR (cm -1 ) 3464, 3010, 2957, 1708, 1600, 1517, 1382, 1242, 1174, 734; 1 H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 5.87 (dd, J = 4.0, 4.0 Hz, 2H), 4.20 (d, J = 2.0 Hz, 1H), 4.08 (d, J = 1.6 Hz, 1H), 3.88 (s, 3H), 3.50 (m, 2H), 3.16 (dd, J = 1.6, 1.6 Hz, 2H), 1.16 (m, 2H), 0.36-0.27 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 190.8, 177.5 (2C), 164.3, 136.2, 132.3, 130.7 (2C), 128.5, 127.83, 127.79, 126.8 (2C), 126.4 (2C), 114.1 (2C), 60.8, 58.6, 55.6, 45.4 (2C), 33.8 (2C), 9.9 (2C), 4.7; ES-API MS: m / z calcd for C 27 H 24 NO5442.2, found 442.1 [M+H] + .

[0167] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(3-chloro-4-methoxybenzoyl)cyclopropyl)-2-fluorophenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (65) [ka] Method F Purification by silica gel flash chromatography (gradient elution, 0 to 45% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 65 (43 mg, 0.087 mmol, 84%) as a pale yellow solid. IR (cm -1 ) 3055, 3009, 2954, 1714, 1663, 1594, 1395, 1259, 1211, 1183, 1063, 1014, 736, 698; 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 2.4 Hz, 1H), 7.89 (dd, J = 8.4, 2.4 Hz, 1H), 7.11 (br, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 8.8 Hz, 1H), 6.96 (d, J = 10.8 Hz, 1H), 5.86 (dd, J = 4.0, 4.0 Hz, 2H), 3.98 (s, 3H), 3.49 (m, 2H), 3.17 (m, 2H), 2.79 (m, 1H), 2.67 (m, 1H), 1.90 (m, 1H), 1.51 (m, 1H), 1.14 (m, 2H), 0.35-0.27 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 195.5, 177.1 (2C), 159.1, 157.6 (d, J = 251.9 Hz, 1C), 144.5 (d, J = 7.5 Hz, 1C), 131.1, 130.6, 129.4, 128.8, 128.0, 123.3, 122.8 (d, J = 2.3 Hz, 1C), 118.1 (d, J = 14.3 Hz, 1C), 114.4 (d, J = 20.2 Hz, 1C), 111.5 (2C), 110.2, 56.6, 53.7, 46.0, 34.0 (2C), 29.1 (2C), 19.4, 10.1 (2C), 5.0; ES-API MS: m / z calcd for C 28 H 24 ClFNO4492.1, found 492.2 [M+H] + .

[0168] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(4-chloro-3-methylbenzoyl)cyclopropyl)-2-fluorophenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (66) [ka] Method F Purification by silica gel flash chromatography (gradient elution, 0% to 40% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 66 (40 mg, 0.084 mmol, 78%) as a yellow solid. IR (cm -1 ) 3054, 3009, 2956, 1716, 1666, 1521, 1395, 1180, 1049, 912, 735; 1 H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 1.6 Hz, 1H), 7.73 (dd, J = 8.4, 2.0 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.11 (br, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 10.4 Hz, 1H), 5.86 (dd, J = 4.0, 4.0 Hz, 2H), 3.49 (m, 2H), 3.17 (m, 2H), 2.82 (m, 1H), 2.68 (m, 1H), 2.44 (s, 3H), 1.92 (m, 1H), 1.53 (m, 1H), 1.15 (m, 2H), 0.36-0.27 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 197.1, 177.1 (2C), 157.6 (d, J = 251.9 Hz, 1C), 144.4, 140.0, 136.4 (d, J = 96.8 Hz, 1C), 130.7, 129.6, 127.9, 127.1, 122.8, 118.1 (d, J = 13.6 Hz, 1C), 114.4 (d, J = 19.3 Hz, 1C), 46.0, 45.7, 34.0 (2C), 31.8, 29.5, 29.4, 22.9, 20.3, 19.6, 14.4, 10.1 (2C), 5.0; ES-API MS: m / z calcd for C 28 H 24 ClFNO3476.1, found 476.2 [M+H] + .

[0169] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(3-chloro-4-fluorobenzoyl)cyclopropyl)-2-fluorophenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (67) [ka] Method F Purification by silica gel flash chromatography (gradient elution, 0% to 40% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 67 (18 mg, 0.038 mmol, 35%) as a white solid. IR (cm -1 ) 3056, 3010, 2957, 1722, 1668, 1520, 1394, 1250, 1182, 1065, 736; 1 H NMR (400 MHz, CDCl3) δ 8.05 (dd, J = 6.8, 2.4 Hz, 1H), 7.88 (ddd, J = 8.4, 4.4, 2.0 Hz, 1H), 7.24 (dd, J = 8.8, 8.8 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.96 (d, J = 10.8 Hz, 1H), 5.86 (m, 2H), 3.49 (m, 2H), 3.17 (m, 2H), 2.79 (m, 1H), 2.70 (m, 1H), 1.93 (m, 1H), 1.56 (m, 1H), 1.15 (m, 2H), 0.36-0.27 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 195.5, 177.1 (2C), 161.3 (d, J = 256.0 Hz, 1C), 157.6 (d, J = 252.3 Hz, 1C), 144.0 (d, J = 7.5 Hz, 1C), 134.7 (d, J = 3.6 Hz, 1C), 131.3 (d, J = 0.5 Hz, 1C), 129.5 (d, J = 15.3 Hz, 1C), 128.7 (d, J = 8.4 Hz, 1C), 128.2, 127.9 (d, J = 14.9 Hz, 1C), 126.2 (d, J = 7.3 Hz, 1C), 122.5 (d, J = 39.7 Hz, 1C), 118.3 (d, J = 13.7 Hz, 1C), 117.1 (d, J = 21.6 Hz, 1C), 114.4 (d, J = 20.0 Hz, 1C), 46.0, 45.7, 34.0, 31.8, 29.4, 22.9, 19.9, 14.4, 10.1, 5.0; ES-API MS: m / z calcd for C 27 H 21 ClF2NO3480.1, found 480.1 [M+H] + .

[0170] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(4-chloro-3-(trifluoromethyl)benzoyl)cyclopropyl)-2-fluorophenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (68) [ka] Method F Purification by silica gel flash chromatography (gradient elution, 0% to 40% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 68 (48 mg, 0.091 mmol, 78%) as a white solid. IR (cm -1) 3055, 3010, 2957, 1715, 1674, 1603, 1520, 1394, 1315, 1036, 737; 1 H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 1.6 Hz, 1H), 8.06 (dd, J = 8.4, 2.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.12 (m, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.96 (d, J = 10.4 Hz, 1H), 5.86 (dd, J = 3.6, 3.6 Hz, 2H), 3.49 (m, 2H), 3.17 (m, 2H), 2.81 (m, 1H), 2.74 (m, 1H), 1.95 (m, 1H), 1.61 (m, 1H), 1.15 (m, 2H), 0.36-0.29 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 195.8, 177.1 (2C), 157.6 (d, J = 252.3 Hz, 1C), 145.7, 143.8, 137.7, 135.9, 132.4, 132.2, 131.8, 129.4, ES-API MS: m / z calcd for C 28 H 21 ClF4NO3530.1, found 530.1 [M+H] + .

[0171] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(3,4-dichlorobenzoyl)cyclopropyl)-2-fluorophenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (69) [ka] Method F Purification by silica gel flash chromatography (gradient elution, 0% to 40% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 69 (44 mg, 0.088 mmol, 86%) as a white solid. IR (cm -1 ) 3009, 2919, 1715, 1668, 1520, 1393, 1181, 736; 1 H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 8.4, 2.0 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.12 (m, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.96 (d, J = 10.8 Hz, 1H), 5.86 (dd, J = 3.6, 3.6 Hz, 2H), 3.49 (m, 2H), 3.17 (m, 2H), 2.79 (m, 1H), 2.71 (m, 1H), 1.93 (m, 1H), 1.57 (m, 1H), 1.15 (m, 2H), 0.35-0.27 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 195.9, 177.1 (2C), 158.9, 143.9, 138.0, 137.0, 133.7, 131.0, 130.7 (d, J = 4.0 Hz, 1C), 130.3, 127.9, 127.4, 125.7, 122.7, 122.3, 46.0, 45.7, 34.0, 31.8, 29.8, 29.5, 22.9, 19.9, 14.4, 10.1, 5.0; ES-API MS: m / z calculation 27 H 21 Cl2FNO3496.1, found 496.1 [M+H] + .

[0172] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-(3,5-dichlorobenzoyl)cyclopropyl)-2-fluorophenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (70) [ka] Method F Purification by silica gel flash chromatography (gradient elution, 0% to 40% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title compound 70 (44 mg, 0.088 mmol, 86%) as a yellow solid. IR (cm -1 ) 3077, 3009, 2956, 1715, 1566, 1520, 1397, 1217, 1182, 736; 1 H NMR (400 MHz, CDCl3) δ 7.80 (s, 2H), 7.53 (s, 1H), 7.09 (m, 1H), 6.99 (d, J = 6.8 Hz, 1H), 6.94 (d, J = 10.4 Hz, 1H), 5.84 (dd, J = 3.6, 3.6 Hz, 2H), 3.46 (m, 2H), 3.15 (m, 2H), 2.77 (m, 1H), 2.70 (m, 1H), 1.89 (m, 1H), 1.55 (m, 1H), 1.13 (m, 2H), 0.33-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 195.6, 177.0 (2C), 157.5 (d, J = 252.3 Hz, 1C), 143.7 (d, J = 7.4 Hz, 1C), 139.8, 135.8 (2C), 132.8 (2C), 129.4 (d, J = 17.0 Hz, 1C), 127.8 (d, J = 7.5 Hz, 1C), 126.7 (2C), 122.6, 118.2 (d, J = 13.7 Hz, 1C), 114.3 (d, J = 20.8 Hz, 1C), 45.9, 45.6, 33.8 (2C), 29.8, 29.4, 20.2, 10.0 (2C), 4.9; ES-API MS: m / z calcd for C 27 H 21 Cl2FNO3496.1, found 496.1 [M+H] + .

[0173] 2-(4-Methoxyphenyl)acetic acid 4-((3aR,4R,4aR,5aS,6S,6aS)-1,3-dioxo-3,3a,4,4a,5,5a,6,6a-octahydro-4,6-ethenocyclopropa[f]isoindol-2(1H)-yl)phenyl (13) [ka] To a solution of phenol 102 (50 mg, 0.18 mmol) in anhydrous THF (1.8 mL), NaH (17 mg, 0.71 mmol, 60% mineral oil dispersion) was added and heated to 60 °C for 20 min. After the mixture was cooled to room temperature, pure 2-(4'-methoxyphenyl)-acetyl chloride (66 mg, 0.36 mmol) was added. The cloudy mixture turned clear, and the reaction was complete in 30 min. The reaction was quenched with HO (5 mL) and extracted with EtOAc (2 × 10 mL). The combined organic phases were washed with brine, dried over anhydrous NaSO, and filtered. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography (gradient elution, 0 → 50% EtOAc in hexanes) to give the title ester 13 (65 mg, 0.15 mmol, 86%) as a white solid. IR (cm -1) 3006, 2959, 1748, 1713, 1506, 1393, 1204, 1124, 1038, 812, 735; 1 H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 9.2 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 5.84 (dd, J = 4.8, 3.2 Hz, 2H), 3.80 (s, 3H), 3.78 (s, 2H), 3.47 (m, 2H), 3.11 (dd, J = 1.6, 1.6 Hz, 2H), 1.13 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 177.6 (2C), 170.0, 159.0, 150.5, 130.5 (2C), 129.4, 127.9 (2C), 127.6 (2C), 125.4, 122.2 (2C), 114.3 (2C), 55.4, 45.4 (2C), 40.6, 34.0 (2C), 10.0 (2C), 4.8; ES-API MS: m / z calcd for C 26 H 23 NO5Na 452.1, found 452.1 [M+Na] + .

[0174] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-((E)-2-(methoxyimino)-2-(4-methoxyphenyl)ethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (26) [ka] A mixture of ketone 1 (50 mg, 0.12 mmol), methoxyamine hydrochloride (26.3 mg, 0.31 mmol), and sodium acetate (42 mg, 0.51 mmol) was dissolved in a mixture of EtOH (0.4 mL) and HO (1.2 mmol). The resulting suspension was heated to 70 °C and stirred for 2 h. The reaction mixture was cooled to room temperature and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO, and filtered. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (gradient elution, 0% to 40% EtOAc in hexanes) and recrystallized in CHCl / hexanes to give the title compound 26 (27 mg, 0.059 mmol, 49%) as a white solid. IR (cm -1 ) 2938, 1707, 1608, 1512, 1250, 1180, 1048, 1030, 830, 734; 1 H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 9.2 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 5.84 (dd, J = 4.4, 3.6 Hz, 2H), 5.16 (s, 2H), 4.02 (s, 3H), 3.81 (s, 3H), 3.48 (m, 2H), 3.11 (m, 2H), 1.13 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 178.0 (2C), 160.8, 158.2, 153.7, 128.6 (2C), 128.0 (2C), 127.9 (2C), 126.1, 125.2, 115.3 (2C), 114.0 (2C), 62.6, 60.3, 55.5, 45.5 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 27 H 27 N2O5459.2, found 459.2 [M+H] + .

[0175] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-((E)-2-(hydroxyimino)-2-(4-methoxyphenyl)ethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (27) [ka] A mixture of ketone 1 (48 mg, 0.11 mmol), aminohydroxide hydrochloride (31 mg, 0.44 mmol), and sodium acetate (55 mg, 0.67 mmol) was dissolved in a mixture of EtOH (0.55 mL) and HO (0.55 mmol). The resulting suspension was heated to 70 °C and stirred for 2 h. The reaction mixture was cooled to room temperature and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO, and filtered. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (gradient elution, 0% to 40% EtOAc in hexanes) and recrystallized in CHCl / hexanes to give the title compound 27 (38 mg, 0.085 mmol, 78%) as a white solid. IR (cm -1 ) 3370, 2838, 1704, 1513, 1250, 1181, 1029, 830, 734; 1 H NMR (400 MHz, CDCl3) δ 8.77 (br, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 5.84 (dd, J = 4.4, 3.6 Hz, 2H), 5.24 (s, 2H), 3.81 (s, 3H), 3.48 (m, 2H), 3.11 (m, 2H), 1.13 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 178.2 (2C), 160.9, 158.2, 155.0, 128.6 (2C), 128.0 (2C), 127.9 (2C), 125.9, 125.2, 115.3 (2C), 114.1 (2C), 59.8, 55.5, 45.4 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 26 H 24 NO5430.2, found 430.1 [M+H2O-NHOH] + .

[0176] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(2-hydroxy-2-(4-methoxyphenyl)ethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (28) [ka] To a solution of ketone 1 (50 mg, 0.12 mmol) in MeOH / CHCl (1:1 (v:v), 2.30 mL) was added NaBH (5.7 mg, 0.15 mmol) at 0 °C. The resulting mixture was stirred at the same temperature for 2 h. The reaction was quenched with cold H0 (1 mL) and extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO, and filtered. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography (gradient elution, 0 → 65% EtOAc in hexanes) to give the title benzyl alcohol 28 (33 mg, 0.076 mmol, 66%) as a white solid. IR (cm -1 ) 3462, 2955, 1704, 1513, 1247, 1182, 734; 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 9.2 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 5.85 (dd, J = 4.4, 3.6 Hz, 2H), 5.05 (ddd, J = 8.4, 2.8, 2.8 Hz, 1H), 4.05 (dd, J = 9.6, 3.2 Hz, 1H), 3.99 (dd, J = 8.8, 9.2 Hz, 1H), 3.81 (s, 3H), 3.48 (m, 2H), 3.11 (dd, J = 2.0, 2.0 Hz, 2H), 2.71 (d, J = 2.8 Hz, 1H), 1.14 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 178.1 (2C), 159.8, 158.5, 131.8, 128.00 (2C), 127.97 (2C), 127.8 (2C), 125.2, 115.3 (2C), 114.2 (2C), 73.7, 72.2, 55.5, 45.5 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 26 H 24 NO4414.2, found 414.2 [M-OH] + .

[0177] (1R,2R,4S,5S,6S,7R)-トリシクロ[3.2.2.02,4]ノナ-8-エン-6,7-ジジカボン acid (112)

change

[0178] (1R,3aS,4S,5S,5aS,6aR,6bR,7R)-4-Bromo-2-oxooctahydro-2H-1,5-methanocyclopropa[e]benzofuran-7-carboxylic acid (113) [ka] To a mixture of dicarboxylic acid 112 (500 mg, 2.40 mmol) and NaHCO3 (504 mg, 6.00 mmol) was added HO (24 mL). Gas effervescence occurred immediately. The mixture was stirred and heated to 50 °C for 10 min to allow complete consumption of the starting material and formation of the dicarboxylate salt. The mixture was cooled to 0 °C, and a solution of bromine (575 mg, 3.6 mmol) was added dropwise until no further discoloration was observed. The resulting mixture was allowed to warm to room temperature and stirred for an additional 6 h. The mixture was extracted with CHCl3 (3 times). The combined organic layers were washed with 15% aqueous Na2S2O5, then brine, dried over anhydrous MgSO4, and filtered. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography (gradient elution, 0% to 5% MeOH in CH2Cl2) and recrystallized in EtOAc / hexanes to give the title bromolactone 113 (380 mg, 1.32 mmol, 55%) as a colorless solid. IR (cm -1 ) 3022, 1773, 1717, 1164, 981; 1 H NMR (400 MHz, CDCl3 / CD3OD) δ 4.58 (ddd, J = 3.2, 1.2, 0.8 Hz, 1H), 4.49 (ddd, J = 4.8, 1.2, 0.8 Hz, 1H), 3.09 (ddd, J = 9.2, 4.8, 4.8 Hz, 1H), 3.00 (dd, J = 10.0, 1.2 Hz, 1H), 2.82-2.77 (m, 2H), 1.15 (ddd, J = 6.8, 4.0, 3.6 Hz, 1H), 1.12-1.03 (m, 2H), 0.68 (ddd, J = 8.0, 8.0, 6.8 Hz, 1H); 13 C NMR (100 MHz, CDCl3 / CD3OD) δ 177.5, 173.5, 84.3, 46.4, 46.1, 41.9, 39.6, 35.7, 11.5, 8.0, 6.2; ES-API MS: m / z calcd for C 11 H 12 BrO4287.0 ( 79 Br isotope), found 286.9 [M+H] + .

[0179] (1R,3aS,4S,5S,5aS,6aR,6bR,7R)-4-Bromo-N-(4-(2-(4-methoxyphenyl)-2-oxoethoxy)phenyl)-2-oxooctahydro-2H-1,5-methanocyclopropa[e]benzofuran-7-carboxamide (114) [ka] To a solution of bromolactone 113 (30 mg, 0.10 mmol) and HATU (40 mg, 0.10 mmol) in anhydrous DMF (0.2 mL) was added DIPEA (13.5 mg, 0.10 mmol). The reaction mixture was stirred at room temperature for 15 min until homogeneous. A solution of 2-(4-aminophenoxy)-1-(4-methoxyphenyl)ethan-1-one (26 mg, 0.10 mmol) in anhydrous DMF (0.2 mL) was added via syringe to the reaction mixture, and the mixture was stirred at room temperature until TLC showed complete consumption of the aniline. The mixture was quenched with aqueous HCl (1 N, 5 mL) and extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography (gradient elution, 0 to 55% EtOAc in hexanes) to give the title amide 114 (33 mg, 0.062 mmol, 63%) as a white amorphous solid. IR (cm -1 ) 3446, 2934, 1704, 1694, 1601, 1513, 1234, 1172, 834, 729; 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 9.2 Hz, 2H), 6.96 (d, J = 9.2 Hz, 2H), 5.20 (s, 2H), 4.06 (dd, J = 6.4, 3.2 Hz, 1H), 3.88 (s, 3H), 3.76 (m, 1H), 3.26 (dd, J = 9.6, 4.0 Hz, 1H), 3.13 (dd, J = 6.4, 3.2 Hz, 1H), 3.01 (dd, J = 10.0, 3.2Hz, 1H), 2.90 (dd, J = 6.8, 3.2 Hz, 1H), 2.68 (d, J = 2.8 Hz, 1H), 1.39 (m, 1H), 1.19-1.09 (m, 2H), 0.74 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ 192.9, 178.5, 177.2, 164.3, 158.3, 130.8 (2C), 128.2 (2C), 127.7, 125.5, 115.6 (2C), 114.3 (2C), 76.3, 71.1, 55.8, 51.7, 47.4, 41.2, 38.0, 37.4, 13.7, 11.2, 8.6; ES-API MS: m / z calcd for C 26 H 26 BrNO7527.1 ( 81 Br isotope), found 527.1 [M] + .

[0180] (3aR,4R,4aR,5aS,6S,6aS,7S,8S)-7,8-dihydroxy-2-(4-(2-(4-methoxyphenyl)-2-oxoethoxy)phenyl)hexahydro-4,6-ethanocyclopropa[f]isoindole-1,3(2H,3aH)-dione (6) [ka] To a solution of lactone 114 (31 mg, 0.060 mmol) in anhydrous DMF (0.6 mL) was added NaH (2.6 mg, 0.065 mmol, 60% oil dispersion). The resulting mixture was sealed in a pressure sealed tube and heated to 100 °C for 3 h. The mixture was cooled to room temperature, quenched with HO (5 mL), and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, and filtered. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC (70% EtOAc in hexanes) to give the title diol 6 (18 mg, 0.038 mmol, 67%) as a white solid. IR (cm -1 ) 3343, 2921, 2851, 1714, 1694, 1682, 1506, 1259, 1221, 1171, 802; 1 H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 9.2 Hz, 2H), 7.18 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 5.19 (s, 2H), 4.16 (m, 1H), 3.88 (s, 3H), 3.14 (m, 1H), 3.00 (d, J = 4.8 Hz, 1H), 2.84 (ddd, J = 8.8, 3.2, 1.6 Hz, 1H), 1.89 (dd, J = 8.8, 1.2 Hz, 1H), 1.80 (d, J = 1.6 Hz, 1H), 1.58 (br, 2H), 1.18 (m, 2H), 0.58 (m, 1H), 0.49 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ 193.0, 176.2, 175.5, 164.3, 157.9, 130.8 (2C), 128.3 (2C), 127.7, 126.2, 115.5 (2C), 114.3 (2C), 71.9, 71.2, 55.8, 50.2, 40.6, 38.7, 36.1, 27.8, 14.9, 9.6, 8.0; ES-API MS: m / z calcd for C 26 H 25NO7463.2, found 463.2 [M] + .

[0181] (4aS)-2-(4-(hydroxy(4-methoxyphenyl)methyl)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (14) To a solution of aldehyde 107 (67 mg, 0.23 mmol) in anhydrous THF (0.77 mL) was added 4-methoxyphenylmagnesium bromide (0.7 mL, 0.34 mmol, 0.5 M THF solution) at 0 °C. The mixture was slowly warmed to room temperature and stirred overnight. An additional 1.5 equiv. of 4-methoxyphenylmagnesium bromide was added, and the mixture was heated to 65 °C. After cooling to room temperature, the reaction mixture was poured into a separatory funnel containing EtOAc and saturated aqueous NH4Cl. The aqueous phase was removed, and the organic layer was neutralized with saturated aqueous NaHCO3 and dried over Na2SO4. The crude product was collected by filtration, concentrated under reduced pressure, and purified by flash chromatography (gradient elution, 0–50% EtOAc / hexanes) to give the title compound 14 (45 mg, 0.11 mmol, 49%) as an amorphous yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 5.84 (dd, J = 4.4, 3.6 Hz, 2H), 5.80 (br, 1H), 3.79 (s, 3H), 3.48 (m, 2H), 3.12 (dd, J = 1.6, 1.6 Hz, 2H), 2.21 (d, J = 2.8 Hz, 1H), 1.14 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 177.7(2C), 159.2, 144.3, 135.6, 130.8, 128.0(2C), 127.8(2C), 127.0(2C), 126.4(2C), 113.9(2C), 75.4, 55.3, 45.3(2C), 33.8(2C), 9.9(2C), 4.7; ES-API MS: m / z calcd for C 25 H 22 NO3384.2 found 384.1 [M-OH] + .

[0182] (4aS)-2-(4-(1-hydroxy-2-phenylethyl)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (21) Benzylmagnesium chloride (0.17 mL, 0.25 mmol, 2 M THF solution) was added to a solution of aldehyde 107 (50 mg, 0.17 mmol) in anhydrous THF (0.6 mL) at 0 °C. The mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was poured into a separatory funnel containing EtOAc and saturated aqueous NH4Cl. The aqueous phase was removed, and the organic layer was neutralized with saturated aqueous NaHCO3 and dried over Na2SO4. The crude product was collected by filtration, concentrated under reduced pressure, and purified by flash chromatography (gradient elution, 0–45% EtOAc / hexanes) to give the title compound 21 (40 mg, 0.10 mmol, 62%) as an amorphous yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.8 Hz, 2H), 7.32 (dd, J = 7.6, 6.8 Hz, 2H), 7.23 (m, 3H), 7.16 (d, J = 8.4 Hz, 2H), 5.87 (dd, J = 4.4, 3.6 Hz, 2H), 4.92 (m, 1H), 3.50 (m, 2H), 3.14 (dd, J = 1.6, 1.6 Hz, 2H), 3.03 (dd, J = 13.6, 4.4 Hz, 1H), 2.93 (dd, J = 13.6, 8.8 Hz, 1H), 1.95 (d, J = 2.8 Hz, 1H), 1.15 (m, 2H), 0.36-0.27 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 177.7(2C), 144.3, 137.8, 131.0, 129.5(2C), 128.6(2C), 127.8(2C), 126.7, 126.50(2C), 126.46(2C), 74.8, 46.1, 45.3(2C), 33.8(2C), 9.9(2C), 4.7; ES-API MS: m / z calcd for C 25 H 24 NO3386.2 found 386.1 [M+H] + .

[0183] (4aS)-2-(4-(1-hydroxy-3-phenylpropyl)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (22) Phenethylmagnesium chloride (0.34 mL, 0.34 mmol, 1 M THF solution) was added to a solution of aldehyde 107 (50 mg, 0.17 mmol) in anhydrous THF (0.6 mL) at 0 °C. The mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was poured into a separatory funnel containing EtOAc and saturated aqueous NH4Cl. The aqueous phase was removed, and the organic layer was neutralized with saturated aqueous NaHCO3 and dried over Na2SO4. The crude product was collected by filtration, concentrated under reduced pressure, and purified by flash chromatography (gradient elution, 0–50% EtOAc / hexanes) to give the title compound 22 (48 mg, 0.12 mmol, 71%) as an amorphous yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 7.20-7.15 (m, 5H), 5.86 (dd, J = 4.8, 3.6 Hz, 2H), 4.70 (m, 1H), 3.49(m, 2H), 3.14 (dd, J = 1.6, 1.6 Hz, 2H), 2.73 (m, 2H), 2.10 (m, 1H), 2.00 (m, 1H), 1.89 (d, J = 3.2 Hz, 1H), 1.15 (m, 2H), 0.35-0.26 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 177.7(2C), 145.0, 141.5, 131.0, 128.42(2C), 128.40(2C), 127.8(2C), 126.6(2C), 126.5(2C), 125.9, 73.3, 45.3(2C), 40.3, 33.8(2C), 31.9, 9.9(2C), 4.7; ES-API MS: m / z calcd for C 26 H 24 NO2382.2, found 382.2 [M-OH] + .

[0184] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-ethynylphenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (115) [ka] Method A Purification by silica gel flash chromatography (gradient elution, 0 to 35% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title alkyne 115 (1.42 g, 4.9 mmol, 47%) as an orange solid. IR (cm -1 ) 3278, 1703, 1509, 1391, 1194; 1 H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H), 5.83 (dd, J = 4.8, 3.2 Hz, 2H), 3.47 (m, 2H), 3.12 (dd, J = 1.6, 1.6 Hz, 2H), 3.08 (s, 1H), 1.13 (m, 2H), 0.33-0.24 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 177.3 (2C), 132.7 (2C), 132.0, 127.8 (2C), 126.3 (2C), 122.3, 82.7, 78.2, 45.3 (2C), 33.8 (2C), 9.9 (2C), 4.7; ES-API MS: m / z calcd for C 19 H 16 NO2290.1, found 290.1 ​​[M+H] + .

[0185] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(3-(4-methoxyphenyl)-3-oxoprop-1-yn-1-yl)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (23) [ka] A flame-dried round-bottom flask was charged with PdCl2(PPh3)2 (2.4 mg, 0.003 mmol), CuI (1.3 mg, 0.007 mmol), and anhydrous THF (0.6 mL). The mixture was degassed and purged with argon (3 times). A degassed solution of Et3N (0.025 mL, 0.18 mmol) was added to the reaction mixture, followed by the addition of 4-methoxybenzoyl chloride (31 mg, 0.18 mmol) and a solution of alkyne 115 (50 mg, 0.17 mmol) in anhydrous THF (0.5 mL) via syringe. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture changed from a yellow / orange color to a greenish precipitate. The mixture was poured into a separatory funnel containing saturated aqueous NaHCO3 (5 mL) and EtOAc (10 mL). The organic phase was separated, washed with brine, dried over anhydrous NaSO, and filtered. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography (gradient elution, 0% to 30% EtOAc in hexanes) and recrystallized in CHCl / hexanes to give the title ynone 23 (52 g, 0.12 mmol, 71%) as a yellow solid. IR (cm -1 ) 2201, 1711, 1633, 1597, 1509, 1377, 1292, 1261, 1163, 736; 1 H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 9.2 Hz, 2H), 5.87 (dd, J = 4.8, 3.6 Hz, 2H), 3.90 (s, 3H), 3.51 (m, 2H), 3.16 (dd, J = 1.6, 1.6 Hz, 2H), 1.16 (m, 2H), 0.37-0.27 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 177.1 (2C), 176.5, 164.6, 133.6, 133.5 (2C), 132.0 (2C), 130.2, 127.8 (2C), 126.5 (2C), 120.4, 113.9 (2C), 91.0, 87.4, 55.6, 45.4 (2C), 33.9 (2C), 9.9 (2C), 4.7; ES-API MS: m / z calcd for C 27 H 22 NO4424.2, found 424.1 [M+H] + .

[0186] (1aS,2S,2aS,9aR,10R,10aR)-5-Methoxy-1a,2,2a,9a,10,10a-hexahydro-2,10-ethenobenzo[4,5]imidazo[2,1-a]cyclopropa[f]isoindol-9(1H)-one (116) [ka] Method B Purification by flash chromatography on silica gel (gradient elution, 0% to 70% EtOAc in hexanes) (conventional heating) afforded an inseparable mixture of regioisomers (2:1 ratio; the desired isomer 116 predominates) (131 mg, 0.45 mmol, 85%) as a pale yellow solid. IR (cm -1 ) 3458, 3364, 3007, 2955, 1768, 1630, 1515, 1212, 1188, 735; 1H NMR (400 MHz, CDCl3) 116: δ 6.83 (d, J = 8.4 Hz, 1H), 6.37 (dd, J = 8.4, 2.8 Hz, 1H), 6.29 (d, J = 2.8 Hz, 1H), 5.94 (dd, J = 4.4, 3.6 Hz, 2H), 3.75 (s, 3H), 3.50 (m, 2H), 3.16 (m, 2H), 1.15 (m, 2H), 0.37-0.23 (m, 2H); Positional isomer: δ 6.71 (d, J = 8.8 Hz, 1H), 6.37 (dd, J = 8.8, 2.4 Hz, 1H), 6.33 (d, J = 2.4 Hz, 1H), 5.87 (dd, J = 4.0, 3.6 Hz, 2H), 3.62 (m, 2H), 3.53 (s, 3H), 3.13 (m, 2H), 1.15 (m, 2H), 0.37-0.23 (m, 2H); 13 C NMR (100 MHz, CDCl3) 116: δ 177.7, 161.1, 143.8, 129.6, 128.6 (2C), 127.8, 110.8, 104.9, 102.78, 101.91, 55.3, 45.7, 33.9, 9.8, 4.8; Positional isomer: δ 178.0, 161.1, 143.6, 129.2, 128.7, 127.8, 111.8, 110.0, 105.3, 102.80, 101.91, 55.30, 45.2, 33.8, 9.9, 4.6; ES-API MS: m / z calcd for C 18 H 17 N2O2 293.1, found 293.1 [M+H] + .

[0187] (1aR,2R,2aR,9aS,10S,10aS)-5-ヒドロキシ-1a,2,2a,9a,10,10a-ヘキサヒドロ-2,10-エテノベンゾ[4,5]イミダゾ[2,1-a]シクロプロパ[f]イソインドール-9(1H)-オン(117)

change

[0188] (1aR,2R,2aR,9aS,10S,10aS)-5-(2-(4-methoxyphenyl)-2-oxoethoxy)-1a,2,2a,9a,10,10a-hexahydro-2,10-ethenobenzo[4,5]imidazo[2,1-a]cyclopropa[f]isoindol-9(1H)-one (87) [ka] To a solution of the above regioisomeric mixture of phenol 117 (50 mg, 0.18 mmol) in ethanol (1.8 mL) was added CsCO (176 mg, 0.54 mmol) and 2-bromo-4'-OMe-acetophenone (82 mg, 0.36 mmol). The resulting mixture was heated to 50 °C and allowed to react for 4 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography (gradient elution, 0% to 45% EtOAc in hexanes), followed by HPLC (reverse-phase, MeCN / H2O / 0.1% TFA) and recrystallization in CHCl2 / hexanes to give the desired title product 87 as a single regioisomer (23 mg, 0.05 mmol, 30%) as a white solid. IR (cm -1 ) 3460, 3365, 3051, 3009, 2956, 1704, 1601, 1514, 1393, 1308, 1241, 1173, 735; 1 H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.4 Hz, 1H), 6.39 (d, J = 1.6 Hz, 1H), 6.36 (dd, J = 6.8, 2.4 Hz, 1H), 5.94-5.85 (m, 2H), 5.11 (s, 2H), 3.88 (s, 3H), 3.50 (m, 2H), 3.16-3.13 (m, 2H), 1.15 (m, 2H), 0.36-0.23 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 193.0, 177.6, 164.0, 159.5, 144.0, 130.7 (2C), 129.7, 128.6 (2C), 127.8, 127.6, 114.0 (2C), 111.6, 105.4, 102.9, 71.0, 55.5, 45.7, 45.2, 33.8, 9.9, 9.8, 4.8, 4.6; ES-API MS: m / z calcd for C 26 H 23 N2O4427.2, found 427.1 [M+H]+ .

[0189] (5-Aminobenzofuran-2-yl)(4-methoxyphenyl)methanone (118) [ka] A mixture of N-(3-formyl-4-hydroxyphenyl)acetamide (200 mg, 1.12 mmol), K2CO3 (308 mg, 2.23 mmol), and 4'-MeO-2-bromoacetophenone (511 mg, 2.23 mmol) was dissolved in anhydrous DMF (3.72 mL). The resulting mixture was heated to 90 °C and stirred for 4 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography (gradient elution, 0% to 55% EtOAc in CHCl2) to give the acetamide intermediate (200 mg, 0.65 mmol, 58%) as a pale yellow solid. Next, this acetamide intermediate (200 mg, 0.65 mmol) was dissolved in EtOH (6.5 mL), aqueous HCl (3 N, 3.2 mL) was added, and the resulting mixture was refluxed overnight. The solvent was removed under reduced pressure, and the residue was diluted with EtOAc and neutralized with saturated aqueous NaHCO3. The organic layer was washed with brine, dried over anhydrous MgSO4, and filtered. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography (100% EtOAc) to give the title free aniline 118 (168 mg, 0.63 mmol, 97%) as a bright yellow solid. IR (cm -1 ) 3445, 3360, 1634, 1601, 1573, 1548, 1510, 1329, 1261, 1164, 975, 765; 1 H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.8 Hz, 1H), 7.35 (s, 1H), 7.00 (d, J = 9.2 Hz, 2H), 6.91 (d, J = 2.0 Hz, 1H), 6.87 (dd, J = 8.4, 2.4 Hz, 1H), 3.89 (s, 3H), 3.71 (br, 2H); 13 C NMR (100 MHz, CDCl3) δ 183.0, 163.6, 153.3, 150.7, 143.2, 132.1 (2C), 130.1, 128.1, 118.3, 115.3, 113.9 (2C), 113.0, 106.5, 55.7; ES-API MS: m / z calcd for C 16 H 14 NO3268.1, found 268.1 [M+H] + .

[0190] (3aR,4R,4aR,5aS,6S,6aS)-2-(2-(4-methoxybenzoyl)benzofuran-5-yl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (88) [ka] A mixture of aniline 118 (175 mg, 0.92 mmol) and maleic anhydride 97 (175 mg, 0.92 mmol) was dissolved in acetic acid (3.0 mL) and heated to 100 °C with stirring for 3 h. The mixture was cooled to room temperature, diluted with EtOAc, and quenched with saturated aqueous NaHCO3. The organic layer was washed with brine, dried over anhydrous MgSO4, and filtered. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (gradient elution, 0% to 60% EtOAc in hexanes) and recrystallized in CHCl2 / hexanes to give the title product 88 (227 mg, 0.52 mmol, 56%) as an orange-yellow solid. IR (cm -1 ) 2952, 1714, 1644, 1601, 1558, 1392, 1281, 1259, 1175, 884, 735; 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.50 (s, 1H), 7.26 (dd, J = 8.8, 2.0 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 5.90 (dd, J = 4.8, 3.6 Hz, 2H), 3.91 (s, 3H), 3.52 (m, 2H), 3.18 (dd, J = 1.6, 1.6 Hz, 2H), 1.17 (m, 2H), 0.37-0.28 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 182.8, 178.0 (2C), 164.0, 155.2, 153.9, 132.2 (2C), 129.8, 128.1 (2C), 128.0, 127.7, 126.7, 121.7, 115.3, 114.1 (2C), 113.4, 55.8, 45.5 (2C), 34.1 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 27 H 22 NO5440.1, found 440.1 [M+H] + .

[0191] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-((E)-3-(2-bromo-4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (119) [ka] Method E Purification by silica gel flash chromatography (gradient elution, 0 to 50% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes afforded the title enone 119 (333 mg, 0.66 mmol, 71%) as a pale yellow solid. IR (cm-1 ) 3008, 2956, 1709, 1599, 1378, 1293, 1233, 1181, 1032, 732; 1 H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 16.0 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 16.0 Hz, 1H), 6.93 (dd, J = 8.4, 2.4 Hz, 1H), 5.86 (dd, J = 4.8, 3.6 Hz, 2H), 3.86 (s, 3H), 3.50 (m, 2H), 3.15 (dd, J = 1.6, 2.0 Hz, 2H), 1.16 (m, 2H), 0.36-0.26 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 193.1, 177.5 (2C), 161.9, 143.6, 135.0, 133.8, 133.4, 131.5, 129.2 (2C), 128.0 (2C), 127.2, 127.0 (2C), 121.4, 119.2, 113.5, 56.0, 45.6 (2C), 34.1 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 27 H 22 BrNO4Na 528.0 ( 81 Br isotope), found 528.0 [M+Na] + .

[0192] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-(5-methoxy-1-oxo-1H-inden-3-yl)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (89) [ka] A mixture of enone 119 (20 mg, 0.040 mmol), PdCl2 (3.5 mg, 0.02 mmol), PPh3 (16 mg, 0.06 mmol), and K2CO3 (14 mg, 0.10 mmol) in DMF (0.5 mL) was heated to 110 °C and stirred for 3 h. The reaction was cooled to room temperature, filtered through a pad of Celite, and washed with EtOAc. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (gradient elution, 0 to 45% EtOAc in hexanes) to give the title benzofuranone 89 (5.0 mg, 0.012 mmol, 31%) as a yellow solid. IR (cm -1 ) 3006, 2925, 2855, 1711, 1601, 1384, 1180, 734; 1 H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 2.0 Hz, 1H), 6.69 (dd, J = 8.0, 1.6 Hz, 1H), 6.01 (s, 1H), 5.89 (dd, J = 4.4, 4.0 Hz, 2H), 3.85 (s, 3H), 3.53 (m, 2H), 3.19 (m, 2H), 1.18 (m, 2H), 0.38-0.28 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 195.6, 177.4, 164.0, 159.5, 146.3, 133.1, 128.0 (2C), 127.9 (2C), 126.9 (2C), 125.3, 124.8, 124.7, 110.9, 110.6, 55.8, 45.4 (2C), 33.9 (2C), 29.7, 9.9 (2C), 4.7; ES-API MS: m / z calcd for C 27 H 22 NO4424.2, found 424.1 [M+H] + .

[0193] (3aR,4R,4aR,5aS,6S,6aS)-2-(4-((6-methoxybenzo[d]isoxazol-3-yl)methoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (90) [ka] A mixture of phenol 102 (45 mg, 0.16 mmol) and K2CO3 (33 mg, 0.24 mmol) in anhydrous DMF (0.30 mL) was heated to 50 °C for 30 min, cooled to room temperature, and 3-(bromomethyl)-6-methoxybenzisoxazole (120) (77 mg, 0.32 mmol) was added. The resulting mixture was heated to 65 °C and stirred overnight. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography (gradient elution, 0% to 40% EtOAc in hexanes) and recrystallized in CHCl2 / hexanes to give the title benzisoxazole analog 90 (55 mg, 0.14 mmol, 77%) as a white solid. IR (cm -1 ) 3054, 3006, 2960, 1705, 1616, 1511, 1140, 831; 1 H NMR (400 MHz, CDCl3) δ 7.65 (dd, J = 8.8, 0.4 Hz, 1H), 7.09 (s, 4H), 7.00 (d, J = 2.0 Hz, 1H), 6.92 (dd, J = 8.8, 2.0 Hz, 1H), 5.84 (dd, J = 4.8, 3.6 Hz, 2H), 5.42 (s, 2H), 3.88 (s, 3H), 3.48 (m, 2H), 3.12 (dd, J = 1.6, 1.6 Hz, 2H), 1.14 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 178.0 (2C), 165.7, 162.7, 158.0, 154.9, 128.1 (2C), 128.0 (2C), 125.6, 122.5, 115.4 (2C), 115.1, 114.2, 92.8, 62.3, 56.0, 45.5 (2C), 34.0 (2C), 10.1 (2C), 4.9; ES-API MS: m / z calcd for C 26 H 23 N2O5443.2, found 443.2 [M+H] + .

[0194] (3aR,4R,4aR,5aS,6S,6aS)-2-(3-hydroxyphenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (121) [ka] Method B Purification by silica gel flash chromatography (gradient elution, 0% to 50% EtOAc in hexanes) followed by recrystallization in CH2Cl2 / hexanes gave the title phenol 121 (90 mg, 0.32 mmol, 61%) as colorless crystals. IR (cm -1 ) 3310, 1773, 1686, 1595, 1389, 1272, 1179, 733, 714; 1 H NMR (400 MHz, CDCl3) δ 7.26 (dd, J = 8.4, 7.6 Hz, 1H), 6.79 (dd, J = 8.4, 2.4 Hz, 1H), 6.72 (dd, J = 7.6, 0.8 Hz, 1H), 6.62 (dd, J = 2.0, 2.0 Hz, 1H), 5.85 (dd, J = 4.8, 3.6 Hz, 2H), 5.63 (br, 1H), 3.49 (m, 2H), 3.14 (dd, J = 2.0, 1.6 Hz, 2H), 1.15 (m, 2H), 0.35-0.26 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 177.9 (2C), 156.2, 132.6, 130.0, 127.8 (2C), 118.6, 116.0, 113.8, 45.3 (2C), 33.8 (2C), 9.9 (2C), 4.6; m / z calcd for C 17 H 16 NO3282.1, found 282.1 [M+H] + .

[0195] (3aR,4R,4aR,5aS,6S,6aS)-2-(3-(2-(4-methoxyphenyl)-2-oxoethoxy)phenyl)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole-1,3(2H,3aH)-dione (91) [ka] To a solution of phenol 121 (37 mg, 0.13 mmol) in reagent-grade acetone (1.3 mL) was added K2CO3 (54 mg, 0.39 mmol), 18-crown-6 (17 mg, 0.07 mmol), tetrabutylammonium iodide (24 mg, 0.07 mmol), and 2-bromo-4'-OMe-acetophenone (60 mg, 0.26 mmol). The resulting mixture was refluxed at 65-70 °C for 48 h (the Rf value of the product was the same as that of the starting material). The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography (gradient elution, 0% to 50% EtOAc in hexanes) and recrystallized in CHCl2 / hexanes to give the title product 91 (40 mg, 0.09 mmol, 71%) as a pale yellow solid. IR (cm -1 ) 3082, 3051, 3007, 2841, 1772, 1709, 1602, 1493, 1384, 1262, 1234, 1181, 971, 839, 733; 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.8 Hz, 2H), 7.32 (dd, J = 8.0, 8.0 Hz, 1H), 6.96 (d, J = 8.8 Hz, 2H), 6.93 (m, 1H), 6.80 (m, 2H), 5.84 (dd, J = 4.8, 3.6 Hz, 2H), 5.17 (s, 2H), 3.88 (s, 3H), 3.48 (m, 2H), 3.12 (dd, J = 1.6, 1.6 Hz, 2H), 1.14 (m, 2H), 0.34-0.25 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 192.6, 177.4 (2C), 164.1, 158.5, 132.9, 130.6 (2C), 129.9, 127.8 (2C), 127.5, 119.7, 114.8, 114.0 (2C), 113.6, 70.9, 55.5, 45.3 (2C), 33.8 (2C), 9.9 (2C), 4.7; ES-API MS: m / z calcd for C 26 H 24 NO5430.2, found 430.1 [M+H] + .

[0196] In vivo studies Each analog listed in Tables 1-9 was administered to mice once daily by oral administration and was well tolerated. ICR SCID mice were treated with 5 mg / kg, 20 mg / kg, or 60 mg / kg of each analog or vehicle by oral administration once daily for 14 consecutive days, and body weight was assessed. n = 5 per group. Complete blood counts, including total hemoglobin (Hb) and platelet counts (PLT), were assessed on day 14. Blood chemistry analysis was also assessed on day 14. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were used as markers of liver injury. Creatinine was used as a marker of renal function. Triglycerides were used as a systemic biomarker of cholesterol synthesis inhibition. Plasma concentrations of each analog were assessed on day 14.

[0197] The results of this in vivo animal study showed that in mice during chronic treatment, each of the analogs listed in Tables 1-9 exhibited bioavailability and brain penetration, did not cause weight loss, and did not cause hematotoxicity, hepatotoxicity, or nephrotoxicity, and reduced, but did not increase, triglyceride levels.

[0198] Scheme 1: [ka]

[0199] Scheme 2: [ka]

[0200] Scheme 3, Part 1: [ka]

[0201] Scheme 3, Part 2: [ka]

[0202] [Table 1]

[0203] Table 2. SAR of the central phenyl ring [ka] [Table 2]

[0204] Table 3. SAR of linkers [ka] [Table 3] JPEG2025510303000144.jpg104137

[0205] Table 4. SAR of the benzoyl moiety [ka] [Table 4] JPEG2025510303000147.jpg143136

[0206] Table 5. SAR of trans-benzoylcyclopropane analogues [ka] [Table 5]

[0207] Table 6. SAR of benzoylcyclopropane analogues [ka] [Table 6]

[0208] Table 7. Series II compounds were synthesized according to the synthetic schemes 1-3 described above. A GBM transgenic mouse model was generated by inducing spontaneous tumor formation in mouse astrocytes through silencing the tumor suppressors Trp53, Pten, and Nf1 via GFAP-Cre. Cell survival screening was performed using the murine GBM stem cell (GSC) line Mut6 derived from this GBM transgenic mouse model, confirming anti-GBM activity at concentrations of 1-200 nM. Furthermore, animal studies demonstrated that these analogs were bioavailable and brain-permeable, did not induce weight loss, or cause hematotoxicity, hepatotoxicity, or nephrotoxicity, and reduced triglyceride levels without elevation in mice during chronic treatment. [ka]

[0209] Table 8. III series compounds were synthesized according to the synthetic schemes 1-3 described above. A GBM transgenic mouse model was generated by inducing spontaneous tumor formation in mouse astrocytes through silencing the tumor suppressors Trp53, Pten, and Nf1 via GFAP-Cre. Cell survival screening was performed using the murine GBM stem cell (GSC) line Mut6 derived from this GBM transgenic mouse model, confirming anti-GBM activity at concentrations of 1-200 nM. Furthermore, animal studies demonstrated that these analogs were bioavailable and brain-permeable, did not induce weight loss, or cause hematotoxicity, hepatotoxicity, or nephrotoxicity, and reduced triglyceride levels without elevation in mice during chronic treatment. [ka]

[0210] Table 9. IV series compounds were synthesized according to the aforementioned synthetic schemes 1-3. A GBM transgenic mouse model was generated by inducing spontaneous tumor formation in mouse astrocytes through silencing the tumor suppressors Trp53, Pten, and Nf1 via GFAP-Cre. Cell survival screening was performed using the murine GBM stem cell (GSC) line Mut6 derived from this GBM transgenic mouse model, confirming anti-GBM activity at concentrations of 1-200 nM. Furthermore, animal studies demonstrated that these analogs were bioavailable and brain-permeable, did not induce weight loss, or cause hematotoxicity, hepatotoxicity, or nephrotoxicity, and reduced triglyceride levels without elevation in mice during chronic treatment. [ka]

[0211] [Table 7]

Claims

1. Formula I: 【Chemistry 1】 (In the formula, Q is cyclopropane-1,2-diyl and (CH 2 ) Selected from 2; X, Y, Z, and W are CR, N, and CH 3 Each is independently selected from; R is H or a halogen; X, Y, Z and W may be fluorinated or deuterated; L is -SCH 2 C(O)-, -CH 2 NHSO 2 -, -O(CH 2 ) n -[n = 2], -OCH 2 CHR-[R = OH, OMe, OCF 3 , OCHF 2 , OCH 2 F], -(CH 2 ) n C(O)-[n = 2], -CHRCH 2 C(O)-[R = OH], -CHORCH 2n -[n = 2; R = H], -(CH 2 ) n CHOR-[n = 2; R = H, Me, CF 3 , CHF 2 , CH 2 F], -CH=CHC(O)-, CH=CHCHR-[R = OH, OMe, OCF 3 , OCHF 2 , OCH 2 F], -C≡CC(O)-, -C≡CCHR[R = OH, OMe, OCF 3 , OCHF 2 , OCH 2 F], -(cyclopropane-1,2-diyl)C(O)-, and -(cyclopropane-1,2-diyl)CHR-[R = OH, OMe, OCF 3 , OCHF 2 , OCH 2 F] is selected from; Ar is a phenyl that is monosubstituted, disubstituted, or trisubstituted at the 2nd, 3rd, or 4th position, and the substituent is preferably selected from halogens, Me, OMe, cyclopropyl, and CN, and each substituent may be fluorinated or deuterated; substituted phenyls and heteroaryls; and selected from monocyclic heteroaryls, condensed bicyclic heteroaryls, heteroaryls, and condensed aryls (naphthyls), each of which may be deuterated, and the substituent may be selected from halogens, Me, OMe, cPr, and CN, each of which may be fluorinated or deuterated. The compound indicated by, or its salt, hydrate, or stereoisomer.

2. The compound according to claim 1, or a salt, hydrate, or stereoisomer thereof, wherein Q is cyclopropane-1,2-diyl.

3. The compound according to claim 1, or a salt, hydrate, or stereoisomer thereof, wherein X is N and Y, Z, and W are each CH; or X, Y, Z, and W are each CH.

4. L is selected from -SCH₂C(O)-, -CH₂NHSO₂-, -(CH₂)₂C(O)-, -O(CH₂)₂-, -OCH₂CHOH-, -CH(OH)(CH₂)₂-, and -(cyclopropane-1,2-diyl)C(O)-. The compound described in claim 1, or a salt, hydrate, or stereoisomer thereof.

5. Ar is a phenyl compound monosubstituted, disubstituted, or trisubstituted at the 2nd, 3rd, or 4th position, and the substituent is selected from halogen, Me, OMe, cyclopropyl, and CN, preferably halogen, Me, or OMe, each of which may be fluorinated or deuterated. The compound described in claim 1, or a salt, hydrate, or stereoisomer thereof.

6. Q is cyclopropane-1,2-diyl; X is N and Y, Z, and W are each CH; or X, Y, Z, and W are each CH; Ar is a phenyl compound monosubstituted, disubstituted, or trisubstituted at the 2nd, 3rd, or 4th position, and the substituent is selected from halogen, Me, OMe, cyclopropyl, and CN, preferably halogen, Me, or OMe, each of which may be fluorinated or deuterated. The compound described in claim 1, or a salt, hydrate, or stereoisomer thereof.

7. Q is cyclopropane-1,2-diyl; X is N and Y, Z, and W are each CH; or X, Y, Z, and W are each CH; L is selected from -SCH₂C(O)-, -CH₂NHSO₂-, -(CH₂)₂C(O)-, -O(CH₂)₂-, -OCH₂CHOH-, -CH(OH)(CH₂)₂-, and -(cyclopropane-1,2-diyl)C(O)-; Ar is a phenyl compound monosubstituted, disubstituted, or trisubstituted at the 2nd, 3rd, or 4th position, and the substituent is selected from halogen, Me, OMe, cyclopropyl, and CN, preferably halogen, Me, or OMe, each of which may be fluorinated or deuterated. The compound described in claim 1, or a salt, hydrate, or stereoisomer thereof.

8. Any structure of (a) to (c) below: (a) 【Chemistry 2】 (In the formula, Linker-Anneal, 【Transformation 3】 (In the formula, Ph is phenyl and PMP is p-methoxyphenyl.) (is); (b) 【Chemistry 4】 (In the formula, R Is it Cl in 3rd place and OMe in 4th place? Is Me in 3rd place and Cl in 4th place? Is it Cl in 3rd place and F in 4th place? In third place is CF 3, and in fourth place is Cl, If it is Cl in 3rd place and Cl in 4th place, (Cl is in 3rd place and Cl is in 5th place) ;or (c) 【Transformation 5】 【Transformation 6】 The compound according to claim 1, or a salt, hydrate, or stereoisomer thereof, having the above characteristics.

9. A compound according to any one of claims 1 to 8, or a salt, hydrate, or stereoisomer thereof, which inhibits lanosterol synthase (LSS).

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or additive.

11. The compound according to any one of claims 1 to 8, which is a small molecule inhibitor of lanosterol synthase for use in any of the methods (i) to (iii) below. (i) A method for inhibiting lanosterol synthase, comprising the step of administering a small molecule inhibitor of lanosterol synthase to a person who requires inhibition of lanosterol synthase; (ii) A method for upregulating 24,25-epoxycholesterol (EPC), comprising the step of administering a low-molecular-weight inhibitor of lanosterol synthase to a person in need of upregulation of 24,25-epoxycholesterol (EPC); or (iii) A method for treating a neurological disease or neurological condition, comprising the step of administering a small molecule inhibitor of lanosterol synthase to a person who is in need of treatment for a neurological disease or neurological condition.

12. The compound according to claim 11(iii), wherein the neurological disease or neurological condition is glioblastoma (GBM) or a neurodegenerative disease, and the neurodegenerative disease is, for example, amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, or Huntington's disease.

13. The compound according to claim 11(iii), further comprising a step of detecting or diagnosing the neurological disease or neurological condition before the administration step, and / or a step of detecting improvement or delay in progression of the neurological disease or neurological condition due to the administration after the administration step.

14. A method for screening candidate therapeutic agents for the treatment of neurological diseases or neurological conditions in vitro, comprising the step of identifying an inhibitor of lanosterol synthase (p75).

Images