Therapeutic Uses of Urolithin Derivatives

Abstract

Methods for treating neuromuscular disorders, muscle disorders, heart disease, pulmonary fibrosis, liver disease, inflammatory bowel disease, or cancer are disclosed. Methods for improving cancer immunotherapy are also disclosed.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application Nos. 63 / 412,078, filed September 30, 2022, and 63 / 392,606, filed July 27, 2022. [Background technology]

[0002] Urolithins have potential benefits in improving numerous health conditions and have been shown to be highly biologically active in vitro and in vivo. Urolithins have been proposed as treatments for a variety of conditions, including conditions associated with insufficient mitochondrial activity, including obesity, poor memory, reduced metabolic rate, metabolic syndrome, diabetes mellitus, cardiovascular disease, hyperlipidemia, neurodegenerative diseases, cognitive impairment, mood disorders, stress, anxiety disorders, and fatty liver disease; as well as for improving liver function and weight management. In particular, urolithins have been shown to have beneficial effects in improving muscle function. Summary of the Invention [Means for solving the problem]

[0003] One aspect of the present invention provides methods useful for treating a neuromuscular disorder (e.g., Charcot-Marie-Tooth disease), a muscle disorder (e.g., hereditary inclusion body myositis, oculopharyngeal muscular dystrophy, inclusion body myopathy, Paget's disease of bone, frontotemporal hereditary disease, or Duchenne myopathy), a cardiac disease (e.g., heart failure), a pulmonary fibrosis (e.g., idiopathic alveolar fibrosis), a liver disease (e.g., non-alcoholic steatohepatitis), an inflammatory bowel disease (e.g., ulcerative colitis or Crohn's disease), a cancer (e.g., bladder cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head and neck cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, prostate cancer, or skin cancer), or a cognitive disorder.

[0004] Thus, the present invention provides a method for treating a subject in need thereof with a neuromuscular disorder (e.g., Charcot-Marie-Tooth disease), a muscle disorder (e.g., hereditary inclusion body myositis, oculopharyngeal muscular dystrophy, inclusion body myopathy, Paget's disease of bone, frontotemporal hereditary disease, or Duchenne myopathy), a cardiac disease (e.g., heart failure), a pulmonary fibrosis (e.g., idiopathic alveolar fibrosis), a liver disease (e.g., non-alcoholic steatohepatitis), an inflammatory bowel disease (e.g., ulcerative colitis), or a combination thereof. or Crohn's disease), cancer (e.g., bladder cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head and neck cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, prostate cancer, or skin cancer), or cognitive disorder, the method comprising administering to the subject an effective amount of a compound of Formula (IA), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ih), Formula (Ij), or Formula (Ik).

[0005] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. Additionally, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0006] Other features, objects, and advantages of the invention will become apparent from the detailed description and claims. [Brief explanation of the drawings]

[0007] [Figure 1A] Schematic representation of the AOM model and treatment regimen. [Figure 1B] Figure 1 shows the tumor incidence of AOM-induced tumors receiving a UA-containing diet or a control diet. Data are mean ± SD, n=4 / 5, *p<0.05 by two-tailed t-test. One of two independent experiments is shown. [Figure 1C]The mean lesion size of AOM-induced tumors receiving a UA-containing diet or a control diet is shown. Data are mean ± SD, n=4 / 5, *p<0.05 by two-tailed t-test. One of two independent experiments is shown. [Figure 1D] Representative images of Swiss roll sections from AOM-induced colon tumors. Scale bar = 2 mm. [Figure 1E] Representative images of CD3+ T cell staining of colons from AOM-treated mice shown in (A, D). Scale bar = 100 μm. [Figure 1F] Relative numbers of CD45+CD3+ T cells in the colon of AOM-treated mice at 24 weeks are shown; data are mean±SD, n=7 / 8, **p<0.01 by two-tailed t-test. [Figure 1G] Organoid treatment scheme is shown. ATPK-organoids were incubated in the presence of UA or DMSO for the indicated time points before flow cytometry analysis. [Figure 1H] Quantification of lysosome formation, as assessed by LysoTracker MFI by flow cytometry, after 24 hours of incubation in the presence of various UA concentrations is shown. Data are mean ± SD, n = 5 / 4 / 4, **p < 0.01 by one-way ANOVA followed by Tukey's multiple comparison test. Representative results from one of two independent experiments are shown. [Figure 1I] Mitotracker signal of APTK organoids incubated in vitro in the presence of UA for 24 hours (n=4 / 4 / 4). [Figure 1J] Antigen presentation by MHC-I molecules 48 hours after treatment is shown (n=5 / 4 / 4). Data for Figures 1I and 1J are mean ± SD, **p<0.01 by one-way ANOVA followed by Tukey's multiple comparison test. Results of one of two independent experiments are shown. [Figure 1K] 1 shows the experimental setup for oral UA administration in mice with established APTK-sc tumors. Treatment feeding began 11 days after tumor injection and was maintained until the end of the experiment. [Figure 1L]Growth curves of mice subcutaneously implanted with APTK tumors receiving either a UA-containing or control diet are shown. Data are mean ± SD, n=7, ***p<0.05 by two-tailed t-test. One of two independent experiments is shown. [Figure 1M] Endpoint tumor weights are shown. [Figure 1N] Figure 1 shows CD8+ T cell infiltration in APTK-sc tumors examined by flow cytometry. Total CD8+ T cell counts are normalized to tumor weight. Data are mean ± SD, n=7, *p<0.05, ***p<0.05 by Mann-Whitney test. [Figure 1O] Figure 1 shows the size of subcutaneous APTK tumors in Rag1- / - mice receiving UA-containing or control diets. Treatment was initiated as indicated in Figure 1K. Data are mean ± SD, n = 7, and represent one of two independent experiments. [Figure 1P] CD8+ T cell depletion or isotype control antibodies were applied every 2 days starting 3 days after sc injection of APTK organoids into C57BL / 6 mice. [Figure 1Q] Figure 1 shows the effect of CD8+ T cell depletion on the size of subcutaneous APTK tumors in C57BL / 6 mice receiving UA-containing or control diets. Data are mean ± SEM, n=5 for isotype, n=9 for UA diet + α-CD8, n=10 for other groups, ****p<0.0001 by one-way ANOVA followed by Tukey's multiple comparison test. Data shown represent pooled data from two experiments with comparable results. [Figure 1R] C57BL / 6 mice were injected with α-PD-1 or isotype antibody every 3 days, starting 5 days after sc injection of APTK organoids. [Figure 1S]Figure 1 shows the effect of α-PD-1 treatment on the size of subcutaneous APTK tumors in C57BL / 6 mice receiving UA-containing or control diets. Data are mean ± SEM, n=5 for isotype, n=9 for control diet + α-PD-1, n=10 for other groups. *p<0.05, **p<0.01, ****p<0.0001 by one-way ANOVA followed by Tukey's multiple comparison test. Data shown represent pooled data from two experiments with comparable results. [Figure 2A] 1 shows a scheme for CD3+ T cell activation, treatment and analysis. [Figure 2B] Figure 1 shows the expression of granzyme B in αCD3 / αCD28-stimulated CD3+ T cells in the presence of UA or DMSO after 48 hours. Data are mean ± SD, n = 4, **p < 0.01 and ****p < 0.0001 by one-way ANOVA followed by Tukey's multiple comparison test. [Figure 2C] Figure 1 shows IFNγ expression in αCD3 / αCD28-stimulated CD3+ T cells in the presence of UA or DMSO after 48 hours. Data are mean ± SD, n = 4, **p < 0.01 and ****p < 0.0001 by one-way ANOVA followed by Tukey's multiple comparison test. [Figure 2D] Quantification of CD44-CD62L+Sca1Hi TSCM after 24, 48, and 72 hours of αCD3 / αCD28 stimulation is shown. Data are mean ± SD, n=4 from four independent experiments, **p<0.01 and ****p<0.001 by two-way ANOVA followed by Tukey's multiple comparison test. [Figure 2E] The frequency of CD62L+CD44-CD8+ T cells with low mitochondrial membrane potential (TMRMLo) after 48 hours is shown in the presence or absence of UA (25 μM). Data are means ± SD, n = 5, ****p < 0.0001 by two-tailed t-test. [Figure 2F]Frequency of CD95HiCD62L+CD44-CD8+ T cells after 48 hours in αCD3 / αCD28 in the presence or absence of UA (25 μM). Data are mean ± SD; n = 5, ****p < 0.0001 by two-tailed t-test. [Figure 2G] Frequency of TSCM (n=7) among CD8+ TILs from APTK-induced tumors receiving control or UA-containing diet. [Figure 2I] Frequency of PD1Hi (n=6) among CD8+ TILs from APTK-induced tumors receiving control or UA-containing diet. [Figure 2H] Frequency of TCF1 (n=7) within CD8+ TILs from APTK-induced tumors receiving control or UA-containing diet. [Figure 2J] Frequency of Tim3Hi (n=6) among CD8+ TILs from APTK-induced tumors receiving control or UA-containing diet. [Figure 2K] Frequency of CTLA4Hi (n=6) among CD8+ TILs from APTK-induced tumors receiving control or UA-containing diet. Data are mean ± SD; *p<0.05; **p<0.01; ***p<0.001 by two-tailed t-test. [Figure 2L] Figure 1 shows the expression of TNFα in CD8+ TILs from control or UA-containing fed APTK-induced tumors upon restimulation with PMA / ionomycin. [Figure 2M] Figure 1 shows IFNγ expression in CD8+ TILs from APTK-induced tumors receiving control or UA-containing diet upon restimulation with PMA / ionomycin. Data are mean ± SD, n = 7 per group; *p < 0.01 and ***p < 0.001 by two-tailed t-test. [Figure 3A] Figure 1 shows the experimental setup for adoptive cell transfer into Rag1- / - mice. CD3+ T cells from OT-1 donor mice were stimulated with αCD3 / αCD28 in the presence of UA (25 μM; TUA) or DMSO (TDMSO) for 48 h before transfer. [Figure 3B]Figure 1 shows the number of splenic CD8+ T cells in Rag1- / - mice 1 week after adoptive transfer of either UA-naive or control T cells. Data are mean ± SD, n = 7 per group, *p < 0.05 by two-tailed t-test. [Figure 3C] Figure 3 shows the experimental setup for adoptive cell transfer of OT-1 CD3+ T cells in APTK-OVA sc tumor-bearing mice. Ex vivo stimulation was performed before transfer as shown in Figure 3A. [Figure 3D] Growth curves of sc APTK-OVA tumors treated as indicated in (C), UA: n=6, DMSO: n=7, data are mean ± SD, ***p<0.001 by two-tailed t-test. [Figure 3E] Figure 1 shows the final tumor weight of sc-implanted APTK-OVA tumors in Rag1- / - mice implanted with TUA or TDMSO. Data are mean ± SD, **p<0.01 by two-tailed t-test. TIL analysis of ACT-treated Rag1- / - mice bearing APTK-OVA tumors. [Figure 3F] CD44 expression is shown in CD8+ TILs derived from APTK-OVA-induced tumors receiving UA-treated OT-I T cells (n=6) or DMSO-treated OT-I T cells (n=7). [Figure 3G] Expression of TCF1 in CD8+ TILs from APTK-OVA-induced tumors receiving UA-treated OT-I T cells (n=6) or DMSO-treated OT-I T cells (n=7) is shown. [Figure 3H] Figure 1 shows CD62L expression in CD8+ TILs derived from APTK-OVA-induced tumors receiving UA-treated OT-I T cells (n=6) or DMSO-treated OT-I T cells (n=7). Data are mean ± SD, *p<0.05 by two-tailed t-test, ns is not significant. [Figure 3I] Figure 1 shows the frequency of exhausted Tim3HiPD-1Hi CD8+ TILs from APTKOVA-induced tumors receiving UA-treated OT-I T cells (n=6) or DMSO-treated OT-I T cells (n=7). Data are mean ± SD, *p<0.05 by two-tailed t-test. [Figure 4A] 1 shows a scheme for CD3+ T cell activation, treatment and analysis. [Figure 4B] The frequency of CD8+ T cells with low mitochondrial membrane potential (TMRMLo) after 6 hours of stimulation with αCD3 / αCD28 in the absence or presence of UA (50 μM) is shown. Data are mean ± SD, n = 4; *p < 0.05 by two-tailed t-test. Data shown represent one of two independent experiments. [Figure 4C] Quantification of lysosome formation in CD8+ T cells after 6 hours of stimulation with αCD3 / αCD28 in the absence or presence of UA (50 μM) is shown. Data are mean ± SD, n=4; **p<0.01 by two-tailed t-test. Data shown represent one of two independent experiments. [Figure 4D] The frequency of MitoTracker Red staining of CD8+ T cells after 24 hours of stimulation with αCD3 / αCD28 in the absence or presence of UA is shown. Data are mean ± SD, n = 6 (UA) or n = 4 (DMSO), **p < 0.01, ***p < 0.001, and ****p < 0.0001 by one-way ANOVA followed by Tukey's multiple comparison test. [Figure 4E] Figure 1 shows MitoTracker expression in T cells 24 hours after stimulation with αCD3 / αCD28 in the absence or presence of UA. Data are mean ± SD, n=5, **p<0.01, ***p<0.001, and ****p<0.0001 by one-way ANOVA followed by Tukey's multiple comparison test. [Figure 4F] Figure 1 shows qPCR analysis of various autophagy / mitophagy-related genes in T cells 24 hours after stimulation with αCD3 / αCD28 in the absence or presence of UA (50 μM). Data ± SEM, n = 3, *p < 0.05, **p < 0.01 by two-tailed t-test. [Figure 4G] Immunoblot analysis of the indicated proteins in T cells 24 hours after stimulation with αCD3 / αCD28 in the absence or presence of UA (50 μM) is shown. [Figure 4H] Quantification of lysosome formation in Pink1- / - CD8+ T cells after 6 hours of stimulation with αCD3 / αCD28 in the absence or presence of UA (50 μM) is shown. Data are mean ± SD, n=4; ns, not significant by two-tailed t-test. Data shown represent one of two independent experiments. [Figure 4I] Frequency of MitotrackerHi Pink1- / - CD8+ T cells after 48 hours of stimulation with αCD3 / αCD28 in the absence or presence of UA (50 μM). Data are mean ± SD, n=4; ns, not significant by two-tailed t-test. Data shown are from one of two independent experiments. [Figure 4J] Frequency of TSCM in Pink1- / - CD8+ T cells after 48 hours of stimulation with αCD3 / αCD28 in the absence or presence of UA (25 and 50 μM). Data are mean ± SD, n = 4; ***p < 0.0001 by two-tailed t-test. [Figure 4K] Figure 1 shows TCF1 expression in CD62L+CD44-CD8+ cells from Pink1- / - mice after 48 hours of stimulation with αCD3 / αCD28 in the absence or presence of UA (50 μM). Data are mean ± SD, n = 4; ***p < 0.0001 by two-tailed t-test. [Figure 4L] Figure 1 shows the growth curves of Pink1 mice injected sc with APTK-organoids and fed the UA-containing or control diet shown in Figure 1K. All data are mean ± SD, n = 4 / group. [Figure 4M] 1 shows the frequency of TCFHi CD8+ TILs in APTK-induced tumors in Pink1− / − mice fed either UA or a control diet. [Figure 4N] 1 shows the frequency of PDHi CD8+ TILs in APTK-induced tumors in Pink1− / − mice fed either UA or a control diet. [Figure 4O]Figure 1 shows the frequency of Tim3Hi CD8+ TILs in APTK-induced tumors in Pink1- / - mice fed either UA or a control diet. All data are mean ± SD, n=4 / group. [Figure 4P] Figure 1 shows IFNγ expression in CD8+ TILs from Pink1- / - mice restimulated ex vivo with PMA / ionomycin for 3 hours in the presence of brefeldin A. All data are mean ± SD, n = 1. [Figure 4Q] Figure 1 shows TNFα expression in CD8+ TILs from Pink1- / - mice restimulated ex vivo with PMA / ionomycin for 3 hours in the presence of brefeldin A. All data are mean ± SD, n = 1. [Figure 5A] Expanded volcano plots of RNAseq data are shown for T cells stimulated with αCD3 / αCD28 for 48 hours in the absence or presence of UA (50 μM). A log2 fold change of 1 and a p-value of p<0.05 were considered significant (red, significantly upregulated in UA-treated cells; green, significantly upregulated in DMSO-treated cells). [Figure 5B] A heatmap of differentially expressed genes associated with genes encoding immune checkpoints, effector molecules, and leukocyte migration is shown. [Figure 5C] Heatmap of differentially expressed genes associated with T cell memory vs. effector fate decisions. Data were z-score normalized for presentation (n=3 per group). [Figure 5D] The frequency of TCF1Hi-expressing CD8+ T cells in the presence of UA (50 μM) or the TCF1 inhibitor ICG001 (10 μM) compared to DMSO control is shown. Data are mean ± SD, n = 4, ***p < 0.001 and ****p < 0.0001 by one-way ANOVA followed by Tukey's multiple comparison test. [Figure 5E]The frequency of TSCMs in the presence of UA (50 μM) and the TCF1 inhibitor ICG001 (10 μM) is shown compared to DMSO controls. All data are mean ± SD, n = 4: DMSO, UA, ICG001; n = 3: UA + ICG001. *p<0.05, p***<0.001; ns not significant by one-way ANOVA followed by Tukey's multiple comparison test. One of two independent experiments is shown. [Figure 5F] Immunoblot analysis of phospho-β-catenin in T cells stimulated with αCD3 / αCD28 for 6 h in the absence or presence of UA (50 μM) is shown. [Figure 5G] Immunoblot analysis of fractionated T cells in T cells stimulated with αCD3 / αCD28 for 6 hours in the absence or presence of UA (50 μM); c = cytosol, m = mitochondrial fraction. Experiments were repeated twice. [Figure 5H] Immunofluorescence of PGAM5 (green) in T cells stimulated with αCD3 / αCD28 for 6 h in the absence or presence of UA (50 μM). Cells were stained with MitoTracker Red to visualize mitochondria (m, mitochondrial localization; c, cytoplasmic localization). Scale bar = 5 μm. [Figure 5I] The frequency of Pgam5 − / − CD8 + T cells expressing TSCM after 48 hours of stimulation with αCD3 / αCD28 in the absence or presence of UA is shown. [Figure 5J] The frequency of Pgam5- / - CD8+ T cells expressing CD95+ after 48 hours of stimulation with αCD3 / αCD28 in the absence or presence of UA is shown. [Figure 5K] Figure 1 shows the frequency of Pgam5- / - CD8+ T cells expressing TCF1 after 48 hours of stimulation with αCD3 / αCD28 in the absence or presence of UA. Data are mean ± SD, n = 4 / group, *p < 0.05; ns not significant by one-way ANOVA followed by Tukey's multiple comparison test. [Figure 5L]Figure 1 shows PGC-1 expression in CD8+ T cells after 48 hours of stimulation with αCD3 / αCD28 in the absence or presence of UA (50 μM). Data are mean ± SD, n = 3, p** < 0.01 by two-tailed t-test. One of two independent experiments is shown. [Figure 5M] Figure 1 shows the mitochondrial content of CD8+ TILs from APTK-induced tumors derived from wt mice fed UA or a control diet as shown in Figure 1K. Data are mean ± SD, n = 6 / group, *p < 0.05 by two-tailed t-test. [Figure 5N] Figure 1 shows PGC-1α expression in CD8+ T cells from Pink1- / - KO mice after 48 hours of stimulation with αCD3 / αCD28 in the absence or presence of UA (50 μM). [Figure 5O] Figure 1 shows PGC-1α expression in CD8+ T cells from Pgam− / − mice after 48 hours of stimulation with αCD3 / αCD28 in the absence or presence of UA (50 μM). All data are mean ± SD, n = . [Figure 5P] The frequency of TSCM after 48 hours of stimulation with αCD3 / αCD28 in the presence of UA (50 μM) or PGC-1 inhibitor (PGC-1i, 10 μM) is shown. Data are mean ± SD, n = 4, **p < 0.01, ***p < 0.001, ****p < 0.0001, ns not significant by one-way ANOVA followed by Tukey's multiple comparison test. [Figure 6A] Human PBMCs were isolated from healthy donors, and T cells were purified and stimulated ex vivo with αCD3 / αCD28 in the presence of UA (50 μM) or DMSO control. [Figure 6B] The frequency of human TSCM 48 hours after stimulation is shown in Figure 6A. Data are means ± SD, one-way ANOVA followed by Tukey's multiple comparison test, p****0.0001. [Figure 6C] Quantification of human TMRMlo CD8+ T cells 48 hours after stimulation in the presence of UA or DMSO control is shown. Data are mean ± SD, p**0.01 by two-tailed t-test. [Figure 6D] Figure 6b shows TCF1 expression in human CD8+ T cells 48 hours after stimulation in the presence of UA or DMSO control. Data are mean ± SD, p*0.05 by two-tailed t-test. Figure 6b shows representative data from one of five donors with comparable outcomes. [Figure 6E] Figure 1 shows the experimental layout for the generation and expansion of CD19-CAR T cells. PBMCs from a healthy donor were expanded for 3 days in the presence of IL-7 / IL-15 before VSV-LV transduction. After 3 days of incubation, Nalm-6 cells were examined during 24 hours of co-culture. [Figure 6F] Figure 6B shows the frequency of TSCM within CD19-CAR+CD8+ cells after generation as shown in Figure 6E. Data are mean ± SD, p****0.0001 by two-tailed t-test. Data pooled from three independent experiments. [Figure 6G] Figure 1 shows the killing capacity of CD19-CAR-CAR-T cells. Percentage of NALM-6 cells that died upon 24-hour co-culture with untransduced or CAR-transduced T cells ± UA / DMSO is shown. Data are mean ± SD, n=5 / 3 (transduced / untransduced); p*0.05, p**<0.01, p****0.0001 by two-way ANOVA followed by Sidak's multiple comparison test. [Figure 6H] Figure 1 shows the experimental layout of the CEA-CAR T cell experiment. After CAR gene transduction (top panel), the CAR T cells were frozen for subsequent experiments after thawing (bottom panel). [Figure 6I] Figure 1 shows the frequency of TSCM in CAR+CD8+ cells specific for CEA. Data are mean ± SD, n=4, p****0.0001 by two-tailed t-test. Data were pooled from two independent experiments. [Figure 6J]Figure 1 shows the killing capacity of CEA-specific CAR-T cells. Percentages of CEA-expressing human CRC organoids that died upon 72-hour coculture with untransduced or CAR-transduced T cells ± UA / DMSO are shown. Data are mean ± SD, n=3; ***p<0.001, p****0.0001, ns not significant by two-way ANOVA followed by Sidak's multiple comparison test. [Figure 7A] Representative histograms are shown for Figures 1H-I. The right panel shows lysosome formation examined by flow cytometry and Lysotracker MFI after 24 h. The left panel shows Mitotracker signal of APTK organoids incubated in vitro in the presence of UA for 24 h, followed by 24 h incubation in the presence of various UA concentrations. [Figure 7B] Representative gating strategies are shown to identify naive T cells (TN; CD44-CD62L+), effector memory cells (TEM; CD44-CD62L-), central memory cells (TCM; CD44+CD62L+), and memory stem cells (TSCM; CD44+CD62L+Sca1+) subsets within stimulated CD8+ or CD4+ T cells. [Figure 7C] Quantification of TN in CD8+ T cells stimulated with αCD3 / αCD28 for 48 hours in the presence of various doses of UA is shown. [Figure 7D] Quantification of TCM in CD8+ T cells stimulated with αCD3 / αCD28 for 48 hours in the presence of various doses of UA is shown. [Figure 7E] Quantification of TEM in CD8+ T cells stimulated with αCD3 / αCD28 for 48 hours in the presence of various doses of UA. Data are mean ± SD, n=4, p*<0.05, p**<0.01, ***p<0.001, ns not significant by two-way ANOVA followed by Tukey's multiple comparison test. [Figure 7F] A complete subset analysis of CD4+ cells showing quantification of TN in CD4+ T cells stimulated with αCD3 / αCD28 in the presence of various doses of UA for 48 hours is shown. [Figure 7G] Figure 1 shows a complete subset analysis of CD4+ cells showing quantification of TCMs in CD4+ T cells stimulated with αCD3 / αCD28 in the presence of various doses of UA for 48 hours. [Figure 7H] Figure 1 shows a complete subset analysis of CD4+ cells showing quantification of TEM in CD4+ T cells stimulated with αCD3 / αCD28 in the presence of various doses of UA for 48 hours. [Figure 7I] A complete subset analysis of CD4+ cells is shown, showing quantification of TSCM in CD4+ T cells stimulated with αCD3 / αCD28 for 48 hours in the presence of various doses of UA. Data are mean ± SD, n=4, p*<0.05, p**<0.01, ns not significant by two-way ANOVA followed by Tukey's multiple comparison test. [Figure 8A] A representative gating strategy for identifying dead cells within mouse T cells is shown. [Figure 8B] Analysis of mouse T cells upon stimulation with various concentrations of UA at the indicated time points is shown. Data are mean ± SD, n = 8–11, ****p < 0.0001, ns not significant by two-way ANOVA followed by Tukey's multiple comparison test. [Figure 8C] Figure 1 shows that UA limits T cell proliferation. Representative analysis of T cell proliferation in response to UA over 72 hours. [Figure 8D] Quantification of proliferation data from Figure 8 is shown. The percentage of proliferative generation as assessed by FlowJo software is shown (Undiv are undivided cells, Gen1 have divided once). Data are mean ± SD, n = 3, p** < 0.01; ****p < 0.0001, ns not significant by two-way ANOVA followed by Tukey's multiple comparison test. One of two independent experiments is shown. [Figure 8E] A representative analysis of cyclin D1 expression after 48 hours of αCD3 / αCD28 stimulation in the absence or presence of UA (50 μM) is shown. Data are mean ± SD, n = 4, p<0.05 by two-tailed t-test. One of two independent experiments is shown. [Figure 8F]The frequency of TSCM 48 hours after αCD3 / αCD28 stimulation in the absence or presence of UA (50 μM) is shown. Data are mean ± SD, n = 5 per group, ***p < 0.001, ****p < 0.0001 by one-way ANOVA followed by Tukey's multiple comparison test. [Figure 8G] Immunoblot analysis of T cells stimulated with αCD3 / αCD28 for 6 hours in the absence or presence of UA (50 μM) is shown. [Figure 8H] A representative gating method is shown. [Figure 8I] Quantification of TAMs in APTK tumors from mice receiving control or UA-containing diets (treatment regimens in FIG. 1K) is shown. [Figure 8J] Quantification of M-MDSCs in APTK tumors from mice receiving control or UA-containing diet (treatment regimen in FIG. 1K) is shown. [Figure 8K] Quantification of PMN-MDSCs in APTK tumors from mice receiving control or UA-containing diet (treatment regimen in FIG. 1K) is shown. [Figure 8L] Quantification of DCs in APTK tumors from mice receiving control or UA-containing diets (treatment regimens in FIG. 1K) is shown. Data are mean ± SD, n=7 / group. Statistical analysis was performed by two-way t-test. [Figure 8M] Figure 1 shows the frequency of TSCM among CD4+ TILs from APTK-induced tumors receiving control or UA-containing diets. Data are mean ± SD, n=7, ns, not significant by two-tailed t-test. [Figure 9A] 1 shows a scheme for activation, treatment and analysis of OT-1 CD3+ T cells. [Figure 9B] Quantification of OT-1 CD44-CD62L+Sca1Hi TSCM 48 hours after αCD3 / αCD28 stimulation is shown. Data are mean ± SD, n=4; *p<0.05 by two-tailed t-test. Data from one of two independent experiments are shown. [Figure 9C]Quantification and gating of CD95 expression on OT-1 CD8+ cells 48 hours after αCD3 / αCD28 stimulation. Data are mean ± SD, n=4; ****p<0.0001 by two-tailed t-test. Data from one of two independent experiments are shown. [Figure 10A] Figure 1 shows an analysis (IPA) of upstream regulators of the subtle pathway in UA-treated T cells, as identified from RNA-seq data. Relevant upregulation is indicated by z-score, and significance is shown in overlapping dot plots. Genes with a log2 fold change of 1 and p<0.05 were first considered. [Figure 10B] qPCR analysis of selected Wnt target genes 24 hours after stimulation. Data are mean ± SEM, n=4, *p<0.05, **p<0.01, ***p<0.001 by two-tailed t-test. [Figure 10C] A representative histogram of the data shown in Figure 5K is shown. [Figure 10D] Flow cytometry analysis of lysosome formation in Pgam5- / - CD8+ T cells after 6 hours of stimulation with αCD3 / αCD28 in the absence or presence of UA (50 μM). Data are mean ± SD, *p<0.05 by two-tailed t-test. [Figure 10E] Mitotracker Red staining of Pgam5 T cells after 24 hours of stimulation with αCD3 / αCD28 in the absence or presence of UA (50 μM) is shown. Data are mean ± SD, n = 4, p*** < 0.001 by two-tailed t-test. [Figure 10F] Immunoblot analysis of cellular fractions of Pink1- / - T cells stimulated with αCD3 / αCD28 for 6 hours in the absence or presence of UA (50 μM). One of two independent experiments is shown (c = cytosolic fraction, m = mitochondrial fraction). [Figure 10G] A representative histogram of the data shown in Figure 5N is shown. [Figure 10H] A representative histogram of the data shown in Figure 5M is shown. [Figure 11A]A representative gating strategy for identifying human TSCM (CD45RA+CCR7HiCD62L+CD95+CD8+) is shown. [Figure 11B] Representative flow cytograms are shown demonstrating a dose-dependent increase in CD95hiCD62L+ cells within the CD45RA+CCR7hiCD8+ population. [Figure 12A] A representative gating strategy for investigating CAR expression and identification of human TSCM in CAR T cell experiments is shown. [Figure 12B] Quantification of CD19 CAR expression in CD8+ cells after VSV-LV-assisted gene transduction in the presence of DMSO or UA (25 μM) for 72 hours. Data are mean ± SD, n=5, ns, not significant by two-tailed t-test. [Figure 12C] Figure 6E shows the frequency of exhausted Tim3HiPD-1Hi CD8+CAR+ cells after activation and CD19 CAR transduction. Data were acquired 3 days after transduction. Data are mean ± SD, n=6, ns, not significant by two-tailed t-test. [Figure 13A] 1 is a graph showing the effect of oral administration of 66 on the myocardium in a rat model of heart failure. Ejection fraction expressed as the difference between 2 months of treatment and day 0 is shown. [Figure 13B] Figure 1 shows the effect of oral administration of 66 to the myocardium in a rat model of heart failure. Fractional shortening, expressed as the difference between the second month of treatment and day 0, is shown. Differences in mean delta LV function were examined between Sham / Vehicle and MI / Vehicle using an unpaired t-test followed by Welch's correction. Differences were then examined between the MI / Vehicle group and MI / 66 using an unpaired t-test followed by Welch's correction. n = 10-19 per group. A value of p < 0.05 was considered statistically significant. Sham / Vehicle vs MI / Vehicle: **p < 0.01; ***p < 0.001. MI / Vehicle vs MI / 66: #p < 0.05. [Figure 14]1 is a graph showing the effect of 66, 77, and 77A in inducing mitophagy in human T lymphocytes. Results are presented as a bar graph. [Figure 15] 1 is a graph showing the effect of 66 on the percentage of T memory (Tscm). The results are presented as a bar graph. [Figure 16A] 1 is a graph showing the effect of 33 treatments on injured cortical neurons with chronic application of Aβ1-42. Cortical neuron survival, as measured by immunostaining for MAP-2, is shown. [Figure 16B] 1 is a graph showing the effect of 33 treatments on chronically applied injured cortical neurons on Aβ1-42 neurite networks of cortical neurons as measured by MAP-2 immunostaining. [Figure 16C] Graph showing the effect of 33 treatments on injured cortical neurons following chronic application of Aβ-42 on microglial activity, as measured by OX-1 immunostaining. Results are expressed as a percentage of the control condition (n=4-6). BNDF: brain-derived neurotrophic factor. *p<0.05 after one-way ANOVA followed by Fisher's LSD test. [Figure 17A] 1 is a graph showing the effect of 117A treatment on injured cortical neurons following chronic application of Aβ1-42. Cortical neuron survival as measured by immunostaining for MAP-2 is shown. [Figure 17B] 1 is a graph showing the effect of 117A treatment on injured cortical neurons following chronic application of Aβ1-42. The neurite network of cortical neurons is shown, as measured by immunostaining for MAP-2. [Figure 17C] Graph showing the effect of 117A treatment on injured cortical neurons chronically treated with Aβ1-42. Microglial activation, measured by OX-1 immunostaining, is shown. Results are expressed as a percentage of the control condition (n=4-6). BNDF: brain-derived neurotrophic factor. *p<0.05 after one-way ANOVA followed by Fisher's LSD test. [Figure 18A]1 shows the effect of oral administration of 33 on short-term spatial memory induced by intrahippocampal injection of Aβ1-42 (Y-maze test) in aged mice. A graph showing the total distance traveled during the Y-maze test. [Figure 18B] The effect of oral administration of 33 on short-term spatial memory induced by intrahippocampal injection of Aβ1-42 (Y-maze test) in aged mice. The graph shows the time elapsed in the new group (test session). The results are presented as box-and-whisker plots (n=8-11 / group). *p<0.05 after one-way anova followed by Fisher's test. [Figure 19A] Figure 1 shows the effect of oral administration of 33 on neurodegeneration and neuroinflammation induced by intrahippocampal injection of Aβ1-42 in aged mice. Figure 2 shows a graph showing neuronal survival. Results are presented as box-and-whisker plots (n=5 / group). *p<0.05 after one-way ANOVA followed by Fisher's test for the Aβ1-42 group. [Figure 19B] Figure 1 shows the effect of oral administration of 33 on neurodegeneration and neuroinflammation induced by intrahippocampal injection of Aβ1-42 in aged mice. Figure 2 shows a graph showing Tau hyperphosphorylation. Results are presented as box-and-whisker plots (n=5 / group). *p<0.05 after one-way ANOVA followed by Fisher's test for the Aβ1-42 group. [Figure 19C] Figure 1 shows the effect of oral administration of 33 on neurodegeneration and neuroinflammation induced by intrahippocampal injection of Aβ1-42 in aged mice. Figure 2 shows a graph depicting neuronal activation. Results are presented as box-and-whisker plots (n=5 / group). *p<0.05 after one-way ANOVA followed by Fisher's test for the Aβ1-42 group. [Figure 20A] Figure 1 shows the effect of oral administration of 66 on the myocardium in a rat model of heart failure. Ejection fraction expressed as the difference between day 0 and month 2 of treatment is shown. [Figure 20B]Figure 1 shows the effect of oral administration of 66 on the myocardium in a rat model of heart failure. Fractional shortening, expressed as the difference between the second month of treatment and day 0, is shown. Differences in mean delta LV function were examined between Sham / Vehicle and MI / Vehicle using an unpaired t-test followed by Welch's correction. Differences were then examined between the MI / Vehicle group and MI / 66 using an unpaired t-test followed by Welch's correction. n = 10-19 per group. A value of p < 0.05 was considered statistically significant. Sham / Vehicle vs. MI / Vehicle: **p < 0.01; ***p < 0.001. MI / Vehicle vs. MI / VNA-052: #p < 0.05. [Figure 21] 1 is a graph showing the mitochondrial content of activated mouse T lymphocytes 72 hours after treatment with either DMSO or NCE at 2 μM. Results are presented as a bar graph. [Figure 22] 1 is a graph showing the percentage of mouse T memory stem cells (Tscm) among CD8+ T lymphocytes 72 hours after treatment with either DMSO or NCE at 2 μM. Results are presented as a bar graph. [Figure 23] Graph showing the percentage of human T memory stem cells (Tscm) among CD8+ T lymphocytes 72 hours after treatment with either DMSO or NCE at 400 nM. Results are presented as bar graphs with mean ± SEM. ***P<0.001 after unpaired one-tailed t-test. DETAILED DESCRIPTION OF THE INVENTION

[0008] definition For convenience, before further description of the present invention, certain terms employed in the specification, examples, and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and should be understood by one of ordinary skill in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0009] In order to more readily understand the present invention, certain terms and phrases are defined below and throughout the specification.

[0010] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0011] As used herein in the specification and claims, the term "and / or" should be understood to mean "either or both" of conjunctive elements, i.e., elements that are sometimes conjunctively present and other times disjunctively present. Multiple elements listed with "and / or" must be arranged in the same manner, i.e., "one or more" of the conjunctive elements. Other elements, whether related or unrelated to those elements specifically identified, may optionally be present other than the elements specifically identified in the "and / or" clause. Thus, as a non-limiting example, when used in conjunction with open-ended language such as "comprising," a reference to "A and / or B" can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); and so forth.

[0012] In the specification and claims, when used herein, "or" should be understood to have the same meaning as "and / or," as defined above. For example, when separating items in a list, "or" or "and / or" should be interpreted as being inclusive, i.e., including at least one, but also including two or more of a number or series of elements, and optionally including additional unlisted items. Clearly indicated terms, such as "only one of," or "exactly one of," or, when used in the claims, "consisting of," only mean the inclusion of exactly one element of a number or series of elements. Generally, when used herein, the term "or" should only be interpreted as indicating exclusive alternatives (i.e., "one or the other, but not both") when preceded by terms of exclusivity, such as "either," "one of," "only one of," or "exactly one of." When used in the claims, "consisting essentially of" should have its ordinary meaning as used in the field of patent law.

[0013] As used herein in the specification and claims, the phrase "at least one" in reference to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but not necessarily including at least one of each and every element specifically listed in the list of elements, and not excluding any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than those specifically identified in the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently, "at least one of A and / or B") can refer in one embodiment to at least one, optionally including two or more As, and no B (and optionally including elements other than B); in another embodiment to at least one, optionally including two or more Bs, and no A (and optionally including elements other than A); in yet another embodiment to at least one, optionally including two or more As, and at least one, optionally including two or more Bs (and optionally including other elements); and so forth.

[0014] It should also be understood that, unless expressly indicated otherwise, in any method claimed herein that includes more than one step or action, the order of the method steps or actions is not necessarily limited to the order in which the method steps or actions are recited.

[0015] In the claims, as in the foregoing specification, transitional phrases such as "comprising / including," "carrying / having," "containing," "involving," "holding," "consisting of," and the like, shall be construed as open-ended, i.e., meaning including but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively, as explained in Section 2111.03 of the United States Patent Office Manual of Patent Examining Procedures.

[0016] Certain compounds contained in the compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, the polymers of the present invention may also be optically active. The present invention contemplates all such compounds, including cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are intended to be included in the present invention.

[0017] "Geometric isomer" refers to isomers that differ in the orientation of substituent atoms relative to a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic system. Atoms (other than H) on each side of a carbon-carbon double bond can be in the E configuration (substituents on opposite sides of the carbon-carbon double bond) or the Z configuration (substituents on the same side). "R," "S," "S*," "R*," "E," "Z," "cis," and "trans" refer to structures relative to the core molecule. Certain disclosed compounds can exist in "atropisomeric" forms or as "atropisomers." Atropisomers are stereoisomers resulting from hindrance of rotation about a single bond, where the steric strain hindrance to rotation is sufficiently high to allow for separation of conformers. The compounds of the present invention can be prepared as individual isomers either by isomer-specific synthesis or by resolution from a mixture of isomers. Classical separation techniques include forming a salt of the free base of each isomer of the isomeric pair with an optically active acid (followed by fractional crystallization and regeneration of the free base), forming a salt of the acid form of each isomer of the isomeric pair with an optically active amine (followed by fractional crystallization and regeneration of the free base), forming an ester or amide of each isomer of the isomer pair with an optically pure acid, amine, or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving the isomeric mixture of either the starting materials or the final product using a variety of well-known chromatographic methods.

[0018] For example, if a particular enantiomer of a compound of the present invention is desired, that enantiomer can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, separating the resulting mixture of diastereomers, and cleaving the auxiliary to obtain the desired pure enantiomer. Alternatively, if the molecule contains a basic functional group such as amino, or an acidic functional group such as carboxyl, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by separation of the diastereomers so formed by fractional crystallization or chromatographic methods well known in the art, followed by recovery of the pure enantiomers.

[0019] A mole fraction purity percentage is the mole ratio of an enantiomer (or diastereomer), or the ratio of moles of an enantiomer (or diastereomer) to moles of its optical isomer. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% pure by mole fraction relative to other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% pure by mole fraction. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% pure by mole fraction.

[0020] When a disclosed compound is named or depicted by structure without indicating stereochemistry, and the compound has at least one chiral center, the name or structure should be understood to encompass any enantiomer of the compound, free of the corresponding optical isomer, a racemic mixture of the compound, or a mixture enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating stereochemistry, and the compound has two or more chiral centers, the name or structure should be understood to encompass a diastereomer free of the other diastereomer, multiple diastereomers free of other diastereomeric pairs, a mixture of diastereomers, a mixture of diastereomeric pairs, a mixture of diastereomers enriched in one diastereomer relative to the other diastereomer(s), or a mixture of diastereomers enriched in one or more diastereomers relative to the other diastereomers. The present invention encompasses all of these forms.

[0021] Structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms, for example, replacing a hydrogen with a deuterium or tritium atom, or replacing a carbon with a 13 C or 14 Compounds produced by substituting C-enriched carbons are within the scope of the present invention.

[0022] The term "prodrug," as used herein, encompasses compounds that are converted into therapeutically active agents under physiological conditions. A common method for making a prodrug is to include selected moieties that hydrolyze under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by enzymatic activity in the host animal.

[0023] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting the subject chemical entity from one organ or body part to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially non-pyrogenic. Some examples of materials that can function as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and These include soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer; and (21) other non-toxic, compatible substances employed in pharmaceutical formulations. In certain embodiments, the pharmaceutical compositions of the present invention are non-pyrogenic, i.e., do not cause a significant temperature increase when administered to a patient.

[0024] The term "pharmaceutically acceptable salt" refers to relatively non-toxic inorganic and organic acid addition salts of a compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and lauryl sulfate. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts," J. Pharm. Sci. 66:1-19.)

[0025] In other cases, compounds useful in the methods of the present invention may contain one or more acidic functional groups and, therefore, can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these instances, the term "pharmaceutically acceptable salts" refers to the relatively non-toxic, inorganic and organic base addition salts of the compound(s). These salts can also be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in their free acid form with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, e.g., Berge et al., supra).

[0026] The term "pharmaceutically acceptable cocrystal" refers to a solid coformer that does not form formal ionic interactions with the small molecule.

[0027] A "therapeutically effective amount" (or "effective amount") of a compound, in terms of therapeutic use, means the quantity of the compound(s) that, when administered as part of a desired dosing regimen (to a mammal, preferably a human), reduces the symptoms, ameliorates the condition, or delays the onset of a disease or condition, e.g., in a preparation, at a reasonable benefit / risk ratio applicable to any medical treatment, or according to clinically acceptable standards for cosmetic purposes.

[0028] The term "prophylactic or therapeutic" treatment is art-recognized and includes administration of one or more of the subject compositions to a host. A treatment is prophylactic (i.e., it protects the host against the onset of the undesirable condition) if it is administered prior to clinical manifestation of an undesirable condition (e.g., a disease or other undesirable condition in a host animal), and is therapeutic (i.e., it is intended to reduce, ameliorate, or stabilize an existing undesirable condition or its side effects) if it is administered after the onset of the undesirable condition.

[0029] The term "patient" or "subject" means a mammal in need of a particular treatment. In certain embodiments, the patient is a primate, dog, cat, or horse. In certain embodiments, the patient is human.

[0030] Aliphatic chains include the classes alkyl, alkenyl, and alkynyl, as defined below. Straight-chain aliphatic chains are limited to unbranched carbon chain moieties. As used herein, the term "aliphatic group" refers to a straight-chain, branched-chain, or cyclic aliphatic hydrocarbon group, and includes saturated and unsaturated aliphatic groups, such as alkyl, alkenyl, or alkynyl groups.

[0031] "Alkyl" refers to a fully saturated, cyclic or acyclic, branched or unbranched carbon chain moiety having the specified number of carbon atoms, or, if not specified, up to 30 carbon atoms. For example, alkyl of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, as well as moieties that are positional isomers of these moieties. Alkyl of 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, and tetracosyl. In certain embodiments, a straight-chain or branched-chain alkyl has up to 30, and more preferably up to 20, carbon atoms in its backbone (e.g., C1-C6 for a straight chain). 30 , C3-C for branched chains 30 The alkyl group may be substituted or unsubstituted.

[0032] As used herein, the term "heteroalkyl" means an alkyl moiety, as defined above, that contains one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of a carbon atom.

[0033] As used herein, the term "haloalkyl" means an alkyl group, as defined above, substituted with at least one halogen.

[0034] As used herein, the term "hydroxyalkyl" means an alkyl group, as defined above, substituted with at least one hydroxyl.

[0035] As used herein, the term "alkylene" refers to an alkyl group having a specified number of carbons, e.g., 2 to 12 carbon atoms, and containing two points of attachment to the remainder of the compound on the longest carbon chain. Non-limiting examples of alkylene groups include methylene-(CH)-, ethylene-(CHCH)-, n-propylene-(CHCHCH)-, isopropylene-(CHCH(CH))-, and the like. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moieties, and can be optionally substituted with one or more substituents.

[0036] "Cycloalkyl" means a monocyclic, bicyclic, bridged, spirocyclic, or polycyclic saturated carbocyclic ring, each of which has from 3 to 12 carbon atoms. Preferred cycloalkyls have from 3 to 10 carbon atoms in their ring structure, and more preferably have from 3 to 6 carbons in the ring structure. Cycloalkyl groups can be substituted or unsubstituted.

[0037] As used herein, the term "halocycloalkyl" means a cycloalkyl group, as defined above, that is substituted with at least one halogen.

[0038] "Cycloheteroalkyl" or "heterocycloalkyl" means a cycloalkyl moiety, as defined above, that contains one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of a carbon atom. Preferred cycloheteroalkyls have from 4 to 8 carbon atoms and heteroatoms in their ring structure, and more preferably 4 to 6 carbon atoms and heteroatoms in the ring structure. A cycloheteroalkyl or heterocycloalkyl group can be substituted or unsubstituted.

[0039] Unless the number of carbon atoms is otherwise specified, as used herein, "lower alkyl" refers to an alkyl group, as defined above, having 1 to 10 carbons in its backbone structure, more preferably 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Similarly, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Throughout this application, preferred alkyl groups are lower alkyls. In certain embodiments, a substituent described herein as alkyl is a lower alkyl.

[0040] "Alkenyl" refers to any cyclic or acyclic, branched or unbranched, unsaturated carbon chain moiety having a specified number of carbon atoms, or up to 26 carbon atoms if no carbon atom limit is specified, and having one or more double bonds in the moiety. Alkenyls having 6 to 26 carbon atoms are exemplified by hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosoenyl, docosenyl, tricosenyl, and tetracosenyl in their various isomeric forms, where the unsaturated bond(s) can be located anywhere in the moiety and can have either the (Z) or (E) configuration about the double bond(s).

[0041] "Alkynyl" refers to a hydrocarbyl moiety within the scope of alkenyl, but having one or more triple bonds within the moiety.

[0042] The term "aryl," as used herein, includes 3- to 12-membered substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or one or more atoms is a heteroatom (i.e., heteroaryl). Preferably, the aryl group includes a 5- to 12-membered ring, more preferably a 6- to 10-membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of which is aromatic; for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, and aniline. Heteroaryl groups include substituted or unsubstituted aromatic 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, and more preferably 5- to 10-membered rings, in which the ring structure contains 1 to 4 heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, etc. Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic.

[0043] The terms "halo," "halide," or "halogen," as used herein, mean halogens, including, but not limited to, fluoro, chloro, bromo, iodo, and the like, in both radioactive and non-radioactive forms. In preferred embodiments, halo is selected from the group consisting of fluoro, chloro, and bromo.

[0044] The terms "heterocyclyl" or "heterocyclic group" refer to 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, and more preferably 5- to 10-membered rings, which include one to four heteroatoms in the ring structure. The heterocycle can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathine, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring can be substituted at one or more positions with the substituents described above, such as, for example, halogen, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, -CF3, -CN, etc.

[0045] The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more backbone carbons. It is understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is subject to the permissible valences of the substituted atom and substituent, and that the substitution results in a stable compound (e.g., one that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, etc.). As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituent of organic compounds described herein that satisfy the valence of the heteroatom. The substituents may include any of the substituents described herein, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, arylalkyl, or aromatic or heteroaromatic moieties. In a preferred embodiment, the substituted alkyl substituent is C 1-6 Alkyl, C 3-6 In a preferred embodiment, the substituent on the substituted alkyl is selected from fluoro, carbonyl, cyano, or hydroxyl. Those skilled in the art will understand that, where appropriate, the substituents themselves may be substituted. Unless specifically stated as "unsubstituted," reference to a chemical moiety herein is understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0046] As used herein, each expression, e.g., alkyl, m, n, etc., when it occurs more than once in any structure, means that it is independent of its definition elsewhere in the same structure.

[0047] As used herein, "small molecule" means a small organic or inorganic molecule having a molecular weight of less than about 3,000 Daltons. Generally, small molecules useful in the present invention have a molecular weight of less than 3,000 Daltons (Da). A small molecule can be, for example, at least about 100 Da to about 3,000 Da (e.g., about 100 to about 3,000 Da, about 100 to about 2,500 Da, about 100 to about 2,000 Da, about 100 to about 1,750 Da, about 100 to about 1,500 Da, about 100 to about 1,250 Da, about 100 to about 1,000 Da, about 100 to about 750 Da, about 100 to about 500 Da, about 200 to about 1,500, about 500 to about 1,000, about 300 to about 1,000 Da, or about 100 to about 250 Da).

[0048] In some embodiments, "small molecule" refers to an organic, inorganic, or organometallic compound, typically having a molecular weight of less than about 1000. In some embodiments, small molecules are organic compounds having sizes on the order of 1 nm. In some embodiments, small molecule drugs of the present invention include oligopeptides and other biomolecules having a molecular weight of less than about 1000.

[0049] An "effective amount" is an amount sufficient to achieve a beneficial or desired result. For example, a therapeutic amount is an amount that achieves a desired therapeutic effect. This amount can be the same as or different from a prophylactically effective amount, which is the amount necessary to prevent the onset of a disease or disease symptoms. An effective amount can be administered in one or more administrations, applications, or dosages. The therapeutically effective amount of a composition will vary depending on the composition selected. The composition can be administered once or more times daily to once or more times weekly (including once every other day). One of skill in the art will understand that certain factors, including, but not limited to, the severity of the disease or disorder, previous treatments, the subject's general health and / or age, and other diseases present, can affect the dosage and timing required to effectively treat a subject. Furthermore, treatment of a subject with a therapeutically effective amount of a composition described herein can include a single treatment or a series of treatments.

[0050] The terms "reduce," "lower," "reduced," "reduce," "reduce," and "inhibit" are all generally used herein to refer to a statistically significant amount of reduction compared to a reference. However, for the avoidance of doubt, "reduce," "reduce," or "reduce," or "inhibit" typically refers to a reduction of at least 10% compared to a reference level, and can include, for example, a reduction of at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, including any reduction between 10% and 99% compared to the complete absence of a given element or parameter compared to a reference level, or compared to the absence of a given treatment.

[0051] The terms "increased," "increase," or "improve," or "activate" are all used herein to generally mean an increase by a statistically significant amount, and for the avoidance of doubt, the terms "increased," "increase," or "improve," or "activate" mean an increase of at least 10% compared to a reference level, for example, at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or up to and including a 100% increase compared to a reference level, or any increase between 10-100% compared to a reference level, or at least about 2-fold, or at least about 3-fold, or at least about 4-fold, or at least about 5-fold, or at least about 10-fold, or any increase between 2-fold and 10-fold or more compared to a reference level.

[0052] As used herein, the term "modulate" includes upregulation and downregulation, eg, enhancing or inhibiting a response.

[0053] As defined herein, a "radiopharmaceutical agent" refers to a pharmaceutical agent containing at least one radiation-emitting radioisotope. Radiopharmaceutical agents are routinely used in nuclear medicine for the diagnosis and / or treatment of various diseases. Radiolabeled pharmaceutical agents, such as radiolabeled antibodies, contain a radioisotope (RI) that functions as a radiation source. As contemplated herein, the term "radioisotope" includes metallic and non-metallic radioisotopes. The radioisotope is selected based on the medical use of the radiolabeled pharmaceutical agent. When the radioisotope is a metallic radioisotope, a chelating agent is typically used to bind the metallic radioisotope to the remainder of the molecule. When the radioisotope is a non-metallic radioisotope, the non-metallic radioisotope is typically bound to the remainder of the molecule directly or via a linker.

[0054] For purposes of this invention, the chemical elements are identified according to the Periodic Table of the Elements, CAS version, inside pages of Handbook of Chemistry and Physics, 67th Ed., 1986-87.

[0055] Treatment method One aspect of the present invention is a method for treating a neuromuscular disorder, a muscle disorder, a cardiac disease, pulmonary fibrosis, a liver disease, an inflammatory bowel disease, cancer, or a cognitive disorder, comprising administering to a subject in need of such treatment an effective amount of a compound of formula (Ia) [ka] [In the formula, A is [ka] and X1 is selected from O and S; Y1 is O, R1, R4, R5, and R8 are independently selected from H and halogen; R3 and R6 are independently selected from H, CN, OH, CF3, halogen, and alkyl; One of R2 and R7 is H, OH, or OAc, and the other of R2 and R7 is halogen, CN, CF3, CO2H, NO2, NHAc, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, alkyl-R9, alkenyl-R9, alkynyl-R9, OR 10 , NHR 10 , N.R. 11 C(O)R 12 , C(O)NR 11 R 12 , and NR 11 SO2R 12 and each occurrence of R is independently selected from OH, NH, O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH)C(O)-alkyl, NHSO-alkyl, N(CH)SO-alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; R 10 is C2-C 12 selected from alkyl, C(O)-alkyl, hydroxyalkyl, aminoalkyl, alkyl-O-alkyl, alkyl-O-alkyl-OH, alkyl-O-alkyl-O-alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, alkyl-heterocycloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, SO3H, SO2-alkyl, and SO2-haloalkyl; Each existing R 11 is selected from H and alkyl; Each existing R 12 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, and alkyl-heterocycloalkyl. or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments, the compound has the proviso that when X1 and Y1 are each O, R2 is OH, and R1, R3, R4, R5, R6, and R8 are each H, then R7 is not OBn, and when X1 and Y1 are each O, R7 is OH, and R1, R3, R4, R5, R6, and R8 are each H, then R2 is not OCH2C(O)NH2.

[0057] In some embodiments, A is [ka] is.

[0058] In some embodiments, R2 is H. In other embodiments, R2 is OH. In other embodiments, R2 is OAc.

[0059] In some embodiments, R2 is haloalkyl, substituted cycloalkyl, alkynyl-R9, OR 10 , and C(O)NR 11 R 12 R9 is selected from OH, substituted cycloalkyl, and heterocycloalkyl; R 10 is selected from alkyl, substituted cycloalkyl, heterocycloalkyl, and alkyl-heterocycloalkyl; and R 11 is H and R 12 is alkyl-heterocycloalkyl.

[0060] In some embodiments, R7 is H. In other embodiments, R7 is OH. In other embodiments, R7 is OAc.

[0061] In some embodiments, R7 is haloalkyl, substituted cycloalkyl, alkynyl-R9, OR 10 , and C(O)NR 11 R 12 R9 is selected from OH, substituted cycloalkyl, and heterocycloalkyl; R 10 is selected from alkyl, substituted cycloalkyl, heterocycloalkyl, and alkyl-heterocycloalkyl; and R 11 is H and R 12 is alkyl-heterocycloalkyl.

[0062] In some embodiments, each occurrence of substituted cycloalkyl is independently substituted with OH, halogen, or hydroxyalkyl.

[0063] In some embodiments, R1, R3, R4, R5, R6, and R8 are each H. In other embodiments, one of R1, R3, R4, R5, R6, and R8 is not H. In other embodiments, two of R1, R3, R4, R5, R6, and R8 are not H.

[0064] In some embodiments, one of R1, R3, R4, R5, R6, and R8 is alkyl or halogen. In other embodiments, two of R1, R3, R4, R5, R6, and R8 are independently alkyl or halogen.

[0065] In some embodiments, the compound of Formula (Ia) is selected from: [ka]

[0066] In some embodiments, the compound of Formula (Ia) is selected from: [ka] [ka] [ka] [ka] [ka] [ka]

[0067] In some embodiments, the compound of Formula (Ia) is selected from: [ka]

[0068] In some embodiments, the compound of Formula (Ia) is selected from: [ka]

[0069] In some embodiments, the compound of Formula (Ia) is selected from: [ka]

[0070] In some embodiments, the compound of Formula (Ia) is selected from: [ka]

[0071] Another aspect of the present invention is a method for treating a neuromuscular disorder, a muscle disorder, a heart disease, a pulmonary fibrosis, a liver disease, an inflammatory bowel disease, a cancer, or a cognitive disorder, comprising administering to a subject in need of such treatment an effective amount of a compound of formula (Ic) [ka] [In the formula, A is [ka] and one of n and m is 0 and the other of n and m is 1; X1 and Y1 are each O; R1, R2, R3, R6, R7, and R8 are H, OH, OCH3, OAc, NH2, halogen, CN, CF3, CO2H, NO2, NHAc, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, alkyl-R9, alkenyl-R9, alkynyl-R9, OR 10 , NHR 10 , N.R. 11 C(O)R 12 , C(O)NR 11 R 12, and NR 11 SO2R 12 are independently selected from R4 and R5 are independently selected from H, halogen, and alkyl; each occurrence of R is independently selected from OH, NH, O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH)C(O)-alkyl, NHSO-alkyl, N(CH)SO-alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; R 10 is C2-C 12 selected from alkyl, hydroxyalkyl, aminoalkyl, alkyl-O-alkyl, alkyl-O-alkyl-OH, alkyl-O-alkyl-O-alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, alkyl-heterocycloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, SO3H, SO2-alkyl, and SO2-haloalkyl; Each existing R 11 is selected from H and alkyl; Each existing R 12 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, and alkyl-heterocycloalkyl. or a pharmaceutically acceptable salt thereof.

[0072] In some embodiments, A is [ka] is selected from.

[0073] In some embodiments, R2 and R7 are each OH. In other embodiments, R2 and R7 are each O-alkyl. In other embodiments, R2 is OH and R7 is H or O-alkyl. In other embodiments, R2 is H or O-alkyl and R7 is OH.

[0074] In some embodiments, R1, R3, R4, R5, R6, and R8 are each H. In other embodiments, one of R1, R3, R4, R5, R6, and R8 is not H. In other embodiments, two of R1, R3, R4, R5, R6, and R8 are not H. In other embodiments, one of R1, R3, R4, R5, R6, and R8 is alkyl or halogen. In other embodiments, two of R1, R3, R4, R5, R6, and R8 are alkyl or halogen.

[0075] In some embodiments, the compound of Compound (Ic) is selected from: [ka]

[0076] In some embodiments, the compound of Formula (Ic) is selected from: [ka]

[0077] In some embodiments, the compound of Compound (Ic) is selected from: [ka]

[0078] Another aspect of the present invention is a method for treating a neuromuscular disorder, a muscle disorder, a cardiac disease, pulmonary fibrosis, a liver disease, an inflammatory bowel disease, cancer, or a cognitive disorder, comprising administering to a subject in need of such treatment an effective amount of a compound of formula (Id) [ka] [In the formula, A is [ka] and Y2 is O, Y and Y are independently selected from H, halogen, and alkyl, or combined with the carbon to which they are attached to form a cycloalkyl or heterocycloalkyl; R1, R4, R5, and R8 are independently selected from H and halogen; R2, R3, R6, and R7 are H, OH, OCH3, OAc, NH2, halogen, CN, CF3, CO2H, NO2, NHAc, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, alkyl-R9, alkenyl-R9, alkynyl-R9, OR 10 , NHR 10 , N.R. 11 C(O)R 12 , C(O)NR 11 R 12 , and NR 11 SO2R 12 are independently selected from each occurrence of R is independently selected from OH, NH, O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH)C(O)-alkyl, NHSO-alkyl, N(CH)SO-alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; R 10 is C2-C 12 selected from alkyl, hydroxyalkyl, aminoalkyl, alkyl-O-alkyl, alkyl-O-alkyl-OH, alkyl-O-alkyl-O-alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, alkyl-heterocycloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, SO3H, SO2-alkyl, and SO2-haloalkyl; Each existing R 11is selected from H and alkyl; Each existing R 12 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, and alkyl-heterocycloalkyl. or a pharmaceutically acceptable salt thereof.

[0079] In some embodiments, the compound has the proviso that when Y2 is O, R2 and R7 are each OH, and R1, R3, R4, R5, R6, and R8 are each H, then X3 and X4 are not both halogens.

[0080] In some embodiments, A is [ka] is selected from.

[0081] In some embodiments, R2 and R7 are each OH. In other embodiments, one of R2 and R7 is OH and the other of R2 and R7 is O-alkyl. In other embodiments, one of R1, R3, R4, R5, R6, and R8 is alkyl or halogen. In other embodiments, two of R1, R3, R4, R5, R6, and R8 are alkyl or halogen.

[0082] In some embodiments, the compound of formula (Id) is selected from: [ka]

[0083] In some embodiments, the compound of formula (Id) is selected from: [ka] [ka]

[0084] In some embodiments, the compound of formula (Id) is selected from: [ka]

[0085] In some embodiments, the compound of formula (Id) is selected from: [ka]

[0086] Another aspect of the present invention is a method for treating a neuromuscular disorder, a muscle disorder, a heart disease, pulmonary fibrosis, a liver disease, an inflammatory bowel disease, cancer, or a cognitive disorder, comprising administering to a subject in need of such treatment an effective amount of a compound of formula (Ie) [ka] [In the formula, A is [ka] and n and m are both 0, or one of n and m is 0 and the other of n and m is 1; X1 is O, Y1 is selected from NH, N-CH3, Nt-Bu, N-cycloalkyl, and N-heterocycloalkyl; R1, R2, R3, R6, R7, and R8 are H, OH, OCH3, OAc, NH2, halogen, CN, CF3, CO2H, NO2, NHAc, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, alkyl-R9, alkenyl-R9, alkynyl-R9, OR 10 , NHR 10 , N.R. 11 C(O)R 12 , C(O)NR 11 R 12 , and NR11 SO2R 12 are independently selected from R4 and R5 are independently selected from H, alkyl, and halogen; each occurrence of R is independently selected from OH, NH, O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH)C(O)-alkyl, NHSO-alkyl, N(CH)SO-alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; R 10 is C2-C 12 selected from alkyl, hydroxyalkyl, aminoalkyl, alkyl-O-alkyl, alkyl-O-alkyl-OH, alkyl-O-alkyl-O-alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, alkyl-heterocycloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, SO3H, SO2-alkyl, and SO2-haloalkyl; Each existing R 11 is selected from H and alkyl; Each existing R 12 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, and alkyl-heterocycloalkyl. or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments, the compound has the proviso that no more than two of R1, R2, R3, R6, R7, and R8 are OH or OCH3; A is [ka] and when R1, R3, R4, R5, R6, and R8 are each H, R2 and R7 are not both OH, not both OCH3, or both OR 10 Instead, A is [ka] and when R1, R3, R4, R5, R6, and R8 are each H, R2 and R7 are both OR 10 isn't it.

[0088] In some embodiments, n and m are both 0. In other embodiments, one of n and m is 0 and the other of n and m is 1.

[0089] In some embodiments, A is [ka] In other embodiments, A is selected from: [ka] is selected from.

[0090] In some embodiments, R2 and R7 are each OH.

[0091] In some embodiments, one of R2 and R7 is OH and the other of R2 and R7 is OH but not OH. In other embodiments, R2 and R7 are each O-alkyl. In other embodiments, R2 is OH and R7 is O-alkyl, or R2 is O-alkyl and R7 is OH.

[0092] In some embodiments, R1, R3, R4, R5, R6, and R8 are each H. In other embodiments, one of R1, R3, R4, R5, R6, and R8 is not H. In other embodiments, two of R1, R3, R4, R5, R6, and R8 in the compound are not H. In other embodiments, one of R1, R3, R4, R5, R6, and R8 is alkyl or halogen. In other embodiments, two of R1, R3, R4, R5, R6, and R8 are alkyl or halogen.

[0093] In some embodiments, the compound of Formula (Ie) is selected from: [ka]

[0094] In some embodiments, the compound of Formula (Ie) is selected from: [ka] [ka]

[0095] In some embodiments, the compound of Formula (Ie) is selected from: [ka]

[0096] In one embodiment, the compound of formula (Ie) is selected from: [ka]

[0097] Another aspect of the present invention is a method for treating a neuromuscular disorder, a muscle disorder, a heart disease, pulmonary fibrosis, a liver disease, an inflammatory bowel disease, cancer, or a cognitive disorder, comprising administering to a subject in need of such treatment an effective amount of a compound of formula (If) [ka] During the ceremony, A is, [ka] is selected from n and m are both 0, or one of n and m is 0 and the other of n and m is 1; o and p are both 0, or one of o and p is 0 and the other of o and p is 1; q is 0 or 1, r and s are both 0, or one of r and s is 0 and the other of r and s is 1; X1 and X2 are each O; X3 is O or N(alkyl); Y1 is S, Y2 is selected from O, CH2, NH, N-alkyl, S, S(O), and SO2; Y and Y are independently selected from H, halogen, OH, and alkyl, or combined with the carbon to which they are attached to form a cycloalkyl or cycloheteroalkyl; Y5 is selected from CH2, NH, N-alkyl, N-aralkyl, N-cycloalkyl, and N-heterocycloalkyl; each occurrence of Y6 is independently selected from O, S, S(O), SO2, NH, N-alkyl, N-alkylaryl, and N-cycloalkyl; Y7 is selected from O, NH, and N-alkyl; Y8 is selected from O and S; R1, R2, R3, R6, R7, and R8 are H, OH, OCH3, OAc, NH2, halogen, CN, CF3, CO2H, NO2, NHAc, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, alkyl-R9, alkenyl-R9, alkynyl-R9, OR 10 , NHR 10 , N.R. 11 C(O)R 12 , C(O)NR 11 R 12 , and NR 11 SO2R 12 are independently selected from R4 and R5 are independently selected from H, alkyl, and halogen; each occurrence of R is independently selected from OH, NH, O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH)C(O)-alkyl, NHSO-alkyl, N(CH)SO-alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; R 10 is C2-C 12 selected from alkyl, hydroxyalkyl, aminoalkyl, alkyl-O-alkyl, alkyl-O-alkyl-OH, alkyl-O-alkyl-O-alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, alkyl-heterocycloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, SO3H, SO2-alkyl, and SO2-haloalkyl; Each existing R 11 is selected from H and alkyl; Each existing R 12 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, and alkyl-heterocycloalkyl. or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments, the compound has the proviso that when Y2 is CH2, one of Y3 or Y4 is not H, or Y3 or Y4, together with the carbon to which they are attached, combine to form a cycloalkyl or heterocycloalkyl; and when Y2 is O, one of r and s is 0 and the other of r and s is 1.

[0099] In some embodiments, A is [ka] and n and m are both 0. In other embodiments, A is [ka] is.

[0100] In some embodiments, A is [ka] In other embodiments, A is [ka] is selected from.

[0101] In some embodiments, A is [ka] is.

[0102] In other embodiments, A is [ka] is selected from.

[0103] In some embodiments, A is [ka] is selected from.

[0104] In some embodiments, A is [ka] is selected from.

[0105] In some embodiments, R2 and R7 are each OH. In other embodiments, one of R2 and R7 is OH and the other of R2 and R7 is OH, but not OH. In other embodiments, R2 and R7 are each O-alkyl. In other embodiments, R2 is OH and R7 is O-alkyl, or R2 is O-alkyl and R7 is OH.

[0106] In some embodiments, R1, R3, R4, R5, R6, and R8 are each H. In other embodiments, one of R1, R3, R4, R5, R6, and R8 is not H. In other embodiments, two of R1, R3, R4, R5, R6, and R8 are not H. In other embodiments, one of R1, R3, R4, R5, R6, and R8 is alkyl or halogen. In other embodiments, two of R1, R3, R4, R5, R6, and R8 are alkyl or halogen.

[0107] In some embodiments, the compound of formula (If) is selected from: [ka]

[0108] In some embodiments, the compound of formula (If) is selected from: [ka] [ka] [ka]

[0109] In some embodiments, the compound of formula (If) is selected from: [ka]

[0110] Another aspect of the present invention is a method for treating a neuromuscular disorder, a muscle disorder, a heart disease, pulmonary fibrosis, a liver disease, an inflammatory bowel disease, cancer, or a cognitive disorder, comprising administering to a subject in need of such treatment an effective amount of a compound of formula (Ih). [ka] [In the formula, A is, [ka] is selected from n and m are both 0, or one of n and m is 0 and the other of n and m is 1; r and s are both 0, or one of r and s is 0 and the other of r and s is 1; X1 is O, Y1 is selected from O, NH, N-alkyl, and N-cycloalkyl; Y2 is O, Y and Y are independently selected from H, halogen, and alkyl, or combined with the carbon to which they are attached to form a cycloalkyl or cycloheteroalkyl; R1, R4, R5, and R8 are independently selected from H and halogen; R3 and R6 are independently selected from H, CN, OH, CF3, halogen, and alkyl; One of R2 and R7 is NH2, NHCH3, or N(CH3)2, and the other of R2 and R7 is H, halogen, OCH3, CN, CF3, CO2H, NO2, NHAc, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, alkyl-R9, alkenyl-R9, alkynyl-R9, OR 10 , NHR 10 , N.R. 11 C(O)R 12 , C(O)NR 11 R 12 , and NR 11 SO2R 12 and each occurrence of R is independently selected from OH, NH, O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH)C(O)-alkyl, NHSO-alkyl, N(CH)SO-alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; R 10 is C2-C 12selected from alkyl, hydroxyalkyl, aminoalkyl, alkyl-O-alkyl, alkyl-O-alkyl-OH, alkyl-O-alkyl-O-alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, alkyl-heterocycloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, SO3H, SO2-alkyl, and SO2-haloalkyl; Each existing R 11 is selected from H and alkyl; Each existing R 12 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, and alkyl-heterocycloalkyl. or a pharmaceutically acceptable salt thereof.

[0111] In some embodiments, the compound has the proviso that A is [ka] and when R1, R3, R4, R5, R6, and R8 are each H, and R7 is NH2, then R2 is not OH.

[0112] In some embodiments, Y 1 is selected from O, NH, and N-alkyl.

[0113] In some embodiments, A is [ka] and n and m are both 0. In other embodiments, A is [ka] In other embodiments, A is [ka] is.

[0114] In some embodiments, A is [ka] wherein one of n or m is 0 and the other of n or m is 1. In other embodiments, A is [ka] In other embodiments, A is [ka] is selected from.

[0115] In some embodiments, A is [ka] and r and s are both 0. In other embodiments, A is [ka] In other embodiments, A is selected from [ka] is selected from.

[0116] In some embodiments, R2 is selected from NH2, NHCH3, and N(CH3)2.

[0117] In some embodiments, R7 is selected from H, OH, halogen, O-alkyl, and haloalkyl.

[0118] In some embodiments, R7 is alkynyl-R9 and OR 10 R9 is OH and R 10 is alkyl-heterocycloalkyl.

[0119] In some embodiments, R1, R3, R4, R5, R6, and R8 are each H. In other embodiments, one of R1, R3, R4, R5, R6, and R8 is not H. In other embodiments, two of R1, R3, R4, R5, R6, and R8 are not H. In other embodiments, one of R1, R3, R4, R5, R6, and R8 is alkyl or halogen. In other embodiments, two of R1, R3, R4, R5, R6, and R8 are independently alkyl or halogen.

[0120] In some embodiments, the compound of Formula (Ih) is selected from: [ka]

[0121] In some embodiments, the compound of Formula (Ih) is selected from: [ka] [ka] [ka]

[0122] In some embodiments, the compound of Formula (Ih) is selected from: [ka] [ka]

[0123] In some embodiments, the compound of Formula (Ih) is selected from: [ka] [ka]

[0124] In some embodiments, the compound of Formula (Ih) is selected from: [ka]

[0125] Another aspect of the invention relates to a method for treating a neuromuscular disorder, a muscle disorder, a heart disease, a pulmonary fibrosis, a liver disease, an inflammatory bowel disease, a cancer, or a cognitive disorder, comprising administering to a subject in need of such treatment an effective amount of a compound having the structure: [ka] [ka]

[0126] In some embodiments of any of the disclosed methods, the compound has R2 and R7 each being OH. In other embodiments, R2 is OH and R7 is not OH. In other embodiments, R2 is OH and R7 is not OCH3. In other embodiments, R2 is OH and R7 is not H.

[0127] In some embodiments of any of the disclosed compounds, R2 is OH and R7 is OCH3. In other embodiments, R2 is OH and R7 is H. In other embodiments, R2 is OH and R7 is alkynyl-R9. In other embodiments, R2 is OH and R7 is OR 10 In other embodiments, R2 is OH and R7 is OR 10 is.

[0128] In some embodiments of any of the disclosed methods, the compound is [ka] is.

[0129] In some embodiments of any of the disclosed compounds, the compound is selected from Table 1. [Table 1-1] [Table 1-2]

[0130] In some embodiments of any of the disclosed methods, the compounds are atropisomers. Furthermore, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, replacing a hydrogen with a deuterium or tritium, or replacing a carbon with a 13 C or 14 Compounds produced by replacing the variable R with C-enriched carbon are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents according to the present invention. For example, 1 In the case of -C1-C4 alkyl, or -O-(C1-C4) alkyl, the alkyl may be suitably deuterated (e.g., -CD3, -OCD3).

[0131] Any of the compounds of the present invention may also be radiolabeled for the preparation of radiopharmaceuticals.

[0132] In one embodiment of any one of the above methods, a neuromuscular disorder, a muscle disorder, a heart disease, pulmonary fibrosis, a liver disease, an inflammatory bowel disease, or a cancer is treated. In one embodiment of any one of the above methods, a neuromuscular disorder is treated.

[0133] In one embodiment of any one of the above methods, a muscle disorder is treated.

[0134] In one embodiment of any one of the above methods, cardiac disease is treated.

[0135] In one embodiment of any one of the above methods, pulmonary fibrosis is treated.

[0136] In one embodiment of any one of the above methods, liver disease is treated.

[0137] In one embodiment of any one of the above methods, inflammatory bowel disease is treated.

[0138] In one embodiment of any one of the above methods, cancer is treated.

[0139] In one embodiment of any one of the above methods, a cognitive disorder is treated.

[0140] In one embodiment of any one of the above methods, the neuromuscular disorder is Charcot-Marie-Tooth disease.

[0141] In one embodiment of any one of the above methods, the muscle disorder is hereditary inclusion body myositis, oculopharyngeal muscular dystrophy, inclusion body myopathy, Paget's disease of bone, frontotemporal hereditary disease, or Duchenne myopathy.

[0142] In one embodiment of any one of the above methods, the cardiac disease is heart failure.

[0143] In one embodiment, the compound reduces heart failure following a myocardial infarction in a subject.

[0144] In one embodiment, the compound reduces heart failure when administered to a subject following a myocardial infarction in the subject.

[0145] In one embodiment, the compound reduces left ventricular systolic dysfunction following myocardial infarction in a subject.

[0146] In one embodiment, the compound reduces left ventricular systolic dysfunction when administered to a subject following a myocardial infarction in the subject.

[0147] In one embodiment, the subject's ejection fraction, ie, the percentage of the total volume of blood in the heart that is ejected with each heartbeat, is increased.

[0148] In one embodiment, the subject's fractional shortening, ie, the percentage decrease in size of the left ventricle during systole, is increased.

[0149] In one embodiment of any one of the above methods, the cardiac disease is myocardial infarction, coronary artery disease (CAD), congestive heart failure (CHF), angina, stroke, arrhythmia, fibrillation, peripheral arterial disease (PAD), or a cardiac or arterial disorder.

[0150] In one embodiment of any one of the above methods, the liver disease is non-alcoholic steatohepatitis.

[0151] In one embodiment of any one of the above methods, the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

[0152] In one embodiment of any one of the above methods, the cancer is responsive to immunotherapy.

[0153] In one embodiment of any one of the above methods, the compound inhibits tumor growth.

[0154] In one embodiment of any one of the above methods, the subject is concurrently being treated with cancer immunotherapy.

[0155] In one embodiment of any one of the above methods, the compound improves the efficacy of cancer immunotherapy.

[0156] In one embodiment of any one of the above methods, the compound enhances the anti-tumor response of cancer immunotherapy in the subject.

[0157] In one embodiment of any one of the above methods, the compound enhances an immune response in the subject against tumor cells.

[0158] In one embodiment of any one of the above methods, the compound is a T memory stem cell (T SCM ) formation.

[0159] In one embodiment of any one of the above methods, the compound is a chimeric antigen receptor (CAR) T memory stem cell (T SCM ) formation.

[0160] In one embodiment of any one of the above methods, the compound promotes anti-tumor CD8+ T cell immunity.

[0161] In one embodiment of any one of the above methods, the compound promotes anti-tumorigenesis upon adoptive cell transfer. In one embodiment of any one of the above methods, the cancer is bladder cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head and neck cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, prostate cancer, or skin cancer.

[0162] In one embodiment of any one of the above methods, the subject is concurrently being treated with an immune checkpoint inhibitor.

[0163] In one embodiment of any one of the above methods, the cancer is colorectal cancer.

[0164] In one embodiment of any one of the above methods, the subject is concurrently being treated with pembrolizumab, nivolumab, or ipilimumab.

[0165] Also provided herein is a method for enhancing the effectiveness of cancer immunotherapy in need thereof, the method comprising administering a compound of Formula (Ia), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ih), Formula (Ij), or Formula (Ik).

[0166] Also provided herein is a method for enhancing the effectiveness of cancer immunotherapy in a subject in need thereof, the method comprising administering a compound of Formula (Ia), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ih), Formula (Ij), or Formula (Ik) to a subject already being treated with cancer immunotherapy.

[0167] Pharmaceutical Compositions, Routes of Administration, and Dosage In certain embodiments, the present invention relates to a method for treating a neuromuscular disorder, a muscle disorder, a heart disease, a pulmonary fibrosis, a liver disease, an inflammatory bowel disease, or a cancer, comprising administering to a subject in need of such treatment a pharmaceutical composition comprising an effective amount of a compound of Formula (Ia), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), or Formula (Ih) and a pharmaceutically acceptable carrier.

[0168] In one embodiment of the above method, a neuromuscular disorder is treated.

[0169] In one embodiment of the above method, a muscle disorder is treated.

[0170] In one embodiment of the above method, a cardiac disease is treated.

[0171] In one embodiment of the above method, pulmonary fibrosis is treated.

[0172] In one embodiment of the above method, liver disease is treated.

[0173] In one embodiment of the above method, inflammatory bowel disease is treated.

[0174] In one embodiment of the above method, cancer is treated.

[0175] In one embodiment of the above method, the neuromuscular disorder is Charcot-Marie-Tooth disease.

[0176] In one embodiment of the above method, the muscle disorder is hereditary inclusion body myositis, oculopharyngeal muscular dystrophy, inclusion body myopathy, Paget's disease of bone, frontotemporal hereditary disease, or Duchenne myopathy.

[0177] In one embodiment of the above method, the heart disease is heart failure.

[0178] In one embodiment of the above method, the liver disease is non-alcoholic steatohepatitis.

[0179] In one embodiment of the above method, the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

[0180] In one embodiment of the above method, the cancer is bladder cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head and neck cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, prostate cancer, or skin cancer.

[0181] In certain embodiments, a pharmaceutical composition comprises a plurality of compounds of the invention and a pharmaceutically acceptable carrier.

[0182] In certain embodiments, the pharmaceutical compositions of the present invention further comprise at least one additional pharmaceutically active agent other than the compound of the present invention. The at least one additional pharmaceutically active agent can be an agent useful in the treatment of ischemia-reperfusion injury.

[0183] Pharmaceutical compositions of the present invention can be prepared by combining one or more compounds of the present invention with a pharmaceutically acceptable carrier and, optionally, one or more additional pharmaceutically active agents.

[0184] As stated above, "effective amount" refers to any amount sufficient to achieve a desired biological effect. By combining the teachings provided herein and selecting from among various active compounds, and by weighing factors such as potency, relative bioavailability, patient weight, severity of adverse side effects, and method of administration, an effective prophylactic or therapeutic treatment regimen can be designed that is effective in treating a particular subject without causing substantial undesirable toxicity. The effective amount for any particular application may vary depending on factors such as the disease or condition being treated, the particular compound of the present invention being administered, the size of the subject, or the severity of the disease or condition. Those of ordinary skill in the art can empirically determine the effective amount of a particular compound of the present invention and / or other therapeutic agent without necessitating undue experimentation. A maximum dosage, i.e., the highest safe dose according to some medical judgment, can be used. Multiple daily administrations may be contemplated to achieve an appropriate systemic dose of the compound. For example, an appropriate systemic dose can be determined by measuring a patient's peak or sustained plasma concentration of the drug. "Dose" and "administration" are used interchangeably herein.

[0185] The formulations of the present invention can be administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salts, buffers, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.

[0186] The pharmaceutical compositions of the present invention contain an effective amount of a compound described herein and, optionally, a therapeutic agent contained in a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers, diluents, or encapsulating substances suitable for administration to humans or other vertebrates. The term "carrier" refers to a natural or synthetic, organic or inorganic component that combines with an active ingredient to facilitate application. The components of the pharmaceutical compositions can also be mixed with the compounds of the present invention and with each other without any interaction that would substantially impair the desired pharmaceutical efficiency.

[0187] It will be appreciated by those skilled in the art that other suitable modifications and adaptations to the compositions and methods described herein will be readily apparent from the description of the invention contained herein, in light of the information known to those skilled in the art, and can be made without departing from the scope of the invention, or any embodiment thereof. Having now described the invention in detail, the invention will be more clearly understood by reference to the following examples. The examples are included herein for illustrative purposes only and are not intended to limit the invention. [Example]

[0188] The invention is described in more detail in the following examples, which do not limit the scope of the invention described in the claims.

[0189] Example 1: Synthesis of exemplary compounds for use in the methods of the present invention All reactions were carried out under an inert atmosphere (nitrogen) using oven-dried glassware unless otherwise noted. All solvents were used as purchased unless otherwise noted. Commercially available reagents were used as purchased without further purification. Organic solutions were concentrated under reduced pressure on a Buchi rotary evaporator.

[0190] Thin-layer chromatography was performed using Merck Kieselgel 60 F254 (230-400 mesh) fluorescent-treated silica and visualized under ultraviolet light (254 and 366 nm) and / or by staining with aqueous potassium permanganate. H NMR spectra were recorded in deuterated solvents at 400 MHz on a Bruker spectrometer or at 60 MHz on a Nanalysis NMReady-60PRO spectrometer, using the remaining protic solvent as the internal standard. C NMR spectra were recorded in deuterated solvents at 100 MHz on a Bruker spectrometer, with the central peak of the deuterated solvent used as the internal standard. Chemical shifts (δ) are given in parts per million (ppm), and coupling constants (J) are given in hertz (Hz), rounded to the nearest 0.1 Hz. 1H NMR spectra are reported as δ / ppm downfield from tetramethylsilane (multiplicity, number of protons, coupling constant J / Hz). 13 C NMR spectra are reported as δ / ppm. TLC-MS data were obtained on an Advion Expression CMS equipped with a Plate Express TLC-plate reader. Medium-pressure liquid chromatography (MPLC) was performed on a Biotage Isolera Four equipped with a UV detector and a fraction collector equipped with an Interchim silica gel column.

[0191] Synthesis of 1.6-membered urolithin A analogues A) Analogues of the ester "A" group via Hartley reaction

[0192] General Procedure 1A (GP1a) As a general example, the synthesis of 3-hydroxy-8-methoxy-6H-benzo[c]chromen-6-one (1) is used as a general procedure for cyclization using NaOH and CuSO4 (GP1a). [ka]

[0193] A mixture of 2-bromo-5-methoxybenzoic acid (0.500 g, 2.16 mmol, 1.0 equiv.), resorcinol (0.477 g, 4.33 mmol, 2.0 equiv.), and sodium hydroxide (0.2 g, 4.98 mmol, 2.4 equiv.) in water (10 mL) was heated under reflux for 30 min. After adding copper sulfate (5% aqueous solution, 2.5 mL), the mixture was refluxed again overnight. The precipitate formed was filtered, washed with 1 M HCl, and then dried under vacuum to give 3-hydroxy-8-methoxy-6H-benzo[c]chromen-6-one (300 mg, 1.24 mmol, 57%). 1 H NMR(400MHz,DMSO)δ8.27(d,J=8.9Hz,1H),8.14(d,J=8.8Hz,1H),7.67(d,J=2.8Hz,1H),7. 56(dd,J=8.8,2.9Hz,1H),6.88(dd,J=8.7,2.4Hz,1H),6.80(d,J=2.4Hz,1H),3.95(s,3H).

[0194] General Procedure 1B (GP1b) As a general example, the synthesis of 3-hydroxy-6-oxo-6H-benzo[c]chromene-8-carboxylic acid (2) is used as a general procedure for cyclization using Na2CO3 and CuI (GP1b). [ka]

[0195] Resorcinol (8.9 g, 81.6 mmol, 2.0 equiv.) was dissolved in water, sodium carbonate (8.60 g, 81.6 mmol, 2.0 equiv.) was added, and the mixture was heated to 50 °C until everything dissolved. Acid (10.00 g, 40.8 mmol, 1.0 equiv.) was then added, and stirring at 50 °C was continued for 1 h. CuI (0.77 g, 4.08 mmol) was then added in one portion, and the reaction was stirred overnight. The precipitate formed was filtered and washed twice with 1 M HCl to give 3-hydroxy-6-oxo-6H-benzo[c]chromene-8-carboxylic acid (4.45 g, 17.4 mmol, 43%) as a beige solid. 1H NMR(400MHz,DMSO)δ13.31(s,1H),10.52(s,1H),8.65(s,1H),8.35(d,J=5.9Hz,1H),8 .29(s,1H),8.18(d,J=8.7Hz,1H),6.85(dd,J=8.7,2.3Hz,1H),6.75(d,J=2.2Hz,1H).

[0196] Synthesis of 8-bromo-3-hydroxy-6H-benzo[c]chromen-6-one (3) [ka]

[0197] The compound was prepared according to GP1a starting from resorcinol (3.93 g, 35.7 mmol) and 2,5-dibromobenzoic acid (5.00 g, 17.9 mmol) to give 8-bromo-3-hydroxy-6H-benzo[c]chromen-6-one (2.14 g, 42%) as a brownish solid. 1 H NMR(400MHz,DMSO)δ10.44(s,1H),8.21(d,J=2.2Hz,1H),8.18(d,J=8.8Hz,1H),8.12(d,J= 8.8Hz,1H), 8.01(dd,J=8.7,2.2Hz,1H),6.84(dd,J=8.7,2.4Hz,1H),6.74(d,J=2.4Hz,1H).

[0198] Synthesis of N-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)acetamide (4) [ka]

[0199] The compound was prepared according to GP1b starting from resorcinol (1.40, 12.8 mmol) and 5-acetamido-2-bromobenzoic acid (1.00 g, 3.87 mmol) to give N-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)acetamide (620 mg, 29%) as a beige solid. 1H NMR(400MHz,DMSO)δ10.32(s,1H),10.27(s,1H),8.50(d,J=2.2Hz,1H),8.20(d,J=8.8Hz,1H),8.07(d,J= 8.7Hz,1H), 7.99(dd,J=8.8,2.3Hz,1H),6.83(dd,J=8.7,2.4Hz,1H),6.74(d,J=2.3Hz,1H),2.10(s,3H).

[0200] Deprotection of 4 gave 8-amino-3-hydroxy-6H-benzo[c]chromen-6-one (5). [ka]

[0201] Synthesis of 8-fluoro-3-hydroxy-6H-benzo[c]chromen-6-one (6) [ka]

[0202] The compound was prepared according to GP1a starting from resorcinol (2.01 g, 18.3 mmol) and 2-bromo-5-fluorobenzoic acid (2.00 g, 9.13 mmol) to give 8-fluoro-3-hydroxy-6H-benzo[c]chromen-6-one (1.00 g, 48%) as a brownish solid. 1 H NMR(400MHz,DMSO)δ10.54(s,1H),8.31(d,J=2.2Hz,1H),8.28(d,J=8.8Hz,1H),8.32(d,J= 8.8Hz,1H), 8.21(dd,J=8.7,2.2Hz,1H),7.04(dd,J=8.7,2.4Hz,1H),6.94(d,J=2.4Hz,1H).

[0203] B) Analogues of the "A" group of amides Synthesis of 3,8-dihydroxyphenanthridin-6(5H)-one (18) [ka]

[0204] Step 1: Synthesis of 3,8-dimethoxyphenanthridin-6(5H)-one [ka]

[0205] To cold sulfuric acid (10 mL) at 0 °C, 2,7-dimethoxy-9H-fluoren-9-one (1.10 g, 4.57 mmol) was added, followed by careful addition of sodium azide (387 mg, 5.95 mmol). The reaction mixture was stirred at 0 °C for 3 h. EtOAc (10 mL) was added, and the mixture was poured into ice water and stirred for 1 h. The brownish precipitate was filtered, and the aqueous phase was extracted three times with EtOAc. The organic phase was dried over sodium sulfate and evaporated under vacuum. The crude product was purified by MPLC (SiO2, EtOAc / cyclohexane, 0% to 80%) to give 3,8-dimethoxyphenanthridin-6(5H)-one (150 mg, 13%) as a brown solid. R f =0.4 (50% EtOAc / hexane). 1 H NMR(400MHz,DMSO)δ11.60(s,1H),8.32(d,J=8.9Hz,1H),8.20(d,J=8.7Hz,1H),7.70(d, J=2.8Hz,1H),7.40(dd,J=8.9,2.9Hz,1H),6.91-6.81(m,2H),3.89(s,3H),3.81(s,3H).

[0206] Step 2: Synthesis of 3,8-dihydroxyphenanthridin-6(5H)-one [ka]

[0207] 18 was prepared from 3,8-dimethoxyphenanthridin-6(5H)-one (90 mg, 0.35 mmol) and BBr3 (1 m in THF, 2.10 mL, 2.10 mmol) according to GP2, which gave 3,8-dihydroxyphenanthridin-6(5H)-one (70 mg, 87%) as a brownish solid after purification by MPLC (SiO2, MeOH / DCM, 0%-10%). f =0.2 (10% MeOH in DCM). 1 H NMR (400MHz, DMSO) δ11.91-11.20(m,1H),10.34-9.57(m,2H),8.08(d,J=49.2Hz,2H),7.82-7.48(m,1H),7.23(s,1H),6.70(d,J=27.5Hz,2H).

[0208] Synthesis of 3,8-dihydroxy-5-methylphenanthridin-6(5H)-one (20) [ka]

[0209] Step 1: Synthesis of 3,8-dimethoxy-5-methylphenanthridin-6(5H)-one (19) [ka]

[0210] NaH (60% mineral oil dispersion, 59 mg, 1.5 mmol) was added to a solution of 3,8-dimethoxyphenanthridin-6(5H)-one (250 mg, 0.98 mmol) in DMF (10 mL) at 0 °C, and the mixture was stirred for 30 min at 0 °C. Then, MeI (0.122 mL, 1.96 mmol) was added, and stirring was continued at room temperature for 2 h. The reaction mixture was poured into a saturated aqueous solution of NH4Cl and extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by MPLC (SiO2, EtOAc / cyclohexane, 0% to 40%) to give 3,8-dimethoxy-5-methylphenanthridin-6(5H)-one (176 mg, 67%). R f=0.3 eluent (EtOAc / hexane 50%). 1 H NMR(400MHz,CDCl3)δ8.10(dd,J=9.2,8.0Hz,2H),7.93(d,J=2.8Hz,1H),7.32(d d,J=8.9,2.9Hz,1H),6.93-6.86(m,2H),3.95(s,3H),3.93(s,3H),3.80(s,3H).

[0211] Step 2: Synthesis of 3,8-dihydroxy-5-methylphenanthridin-6(5H)-one (20) [ka]

[0212] Starting from 3,8-dimethoxy-5-methylphenanthridin-6(5H)-one (150 mg, 0.550 mmol), 20 was prepared according to GP2 to give 3,8-dihydroxy-5-methylphenanthridin-6(5H)-one (120 mg, 89%) as a beige solid after purification by MPLC (SiO, MeOH / DCM, 0%–10%). f =0.8 (MeOH / DCM 10 / 90). 1 H NMR(400MHz,DMSO)δ9.92(s,2H),8.18(d,J=8.9Hz,1H),8.13(d,J=8.8Hz,1H),7.64(d,J=2.7Hz, 1H),7.22(dd,J=8.8,2.7Hz,1H),6.85(d,J=2.3Hz,1H),6.77(dd,J=8.7,2.3Hz,1H),3.63(s,3H).

[0213] Synthesis of 5-cyclopropyl-3,8-dihydroxyphenanthridin-6(5H)-one (21) [ka]

[0214] Step 1: Synthesis of 5-cyclopropyl-3,8-dimethoxyphenanthridin-6(5H)-one [ka]

[0215] A microwave vial was charged with 3,8-dimethoxyphenanthridin-6(5H)-one (120 mg, 0.470 mmol, 1.0 equiv.), cyclopropylboronic acid (121 mg, 1.41 mmol, 3.0 equiv.), pyridine (355 mg, 4.23 mmol, 9.0 equiv.), triethylamine (285 mg, 2.82 mmol, 6.0 equiv.), and THF (2.0 mL). The resulting mixture was degassed with a N balloon for 10 min at room temperature. Cu(OAc) (171 mg, 0.940 mmol, 2.0 equiv.) was then added in one portion, and the vial was closed and placed in a preheated oil bath at 130 °C for 2 h. Upon complete consumption of the starting material, the reaction was cooled to room temperature and subsequently quenched with water, extracted with EtOAc, dried over NaSO, and concentrated in vacuo. The crude product was purified by MPLC (SiO2, 25 g, EtOAc in hexanes, 0-50%) to give 5-cyclopropyl-3,8-dimethoxyphenanthridin-6(5H)-one (50 mg, 36%) as a brown solid. 1 HNMR(400MHz,CDCl3)δ8.02(dd,J=8.9,2.1Hz,2H),7.87(d,J=2.8Hz,1H),7.39(d,J=2.5Hz,1H),7.29(dd,J=8.9,2.8 Hz,1H),6.87(dd,J=8.8,2.5Hz,1H),3.93(d,J=3.2Hz,6H),3.05-2.99(m,1H),1.45-1.36(m,2H),0.97-0.90(m,2H).

[0216] Step 2: Synthesis of 5-cyclopropyl-3,8-dihydroxyphenanthridin-6(5H)-one [ka]

[0217] 5-Cyclopropyl-3,8-dimethoxyphenanthridin-6(5H)-one (20 mg, 0.070 mmol, 1.0 equiv) was dissolved in DCM (1 mL) and cooled to 0 °C in an ice bath, and stirring was continued for 5 min. BBr3 (0.20 mL, 1 M in DCM, 0.020 mmol, 3.0 equiv) was then added dropwise to the reaction mixture. Upon complete addition, the mixture was left in the ice bath and allowed to warm to room temperature over 2 h. Once no more starting material was observed (TLC), the reaction mixture was added dropwise to 0 °C-chilled methanol (10 mL) and stirred for an additional 10 min. The mixture was then concentrated, loaded onto silica, and purified by MPLC (SiO2, 12 g, MeOH in DCM, 0-5%) to give 5-cyclopropyl-3,8-dihydroxyphenanthridin-6(5H)-one (13 mg, 0.050 mmol, 71%) as a white solid. MS (ESI+): m / z = 268. 1 H NMR(400MHz,DMSO)δ9.86(d,J=9.3Hz,2H),8.12(d,J=8.9Hz,1H),8.06(d,J=8.8Hz,1H),7.57(d,J=2.7Hz,1H),7.27(d,J=2.3Hz,1H) ,7.18(dd,J=8.7,2.8Hz,1H),6.73(dd,J=8.7,2.3Hz,1H),2.94(dt,J=7.0,3.1Hz,1H),1.35-1.18(m,2H),0.74(p,J=5.4,5.0Hz,2H).

[0218] C) Sulfonamide "A" Group Analogues Synthesis of 3,8-dihydroxy-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (22) [ka]

[0219] Step 1: Synthesis of N-(2-bromo-5-methoxyphenyl)-3-methoxybenzenesulfonamide [ka]

[0220] 3-Methoxybenzenesulfonyl chloride (2.00 g, 9.68 mmol, 1.3 equiv) was slowly added to a solution of 2-bromo-5-methoxyaniline (1.79 g, 8.81 mmol, 1.0 equiv) and pyridine (2.79 g, 35.2 mmol, 4.0 equiv) in DCM (20 mL) at 0 °C. Upon warming to room temperature, no more starting material was observed by TLC, and the reaction mixture was concentrated under reduced pressure. The reaction mixture was diluted with EtOAc and washed with 1 N aqueous hydrochloric acid. The organic phase was dried over Na SO and concentrated under reduced pressure to give N-(2-bromo-5-methoxyphenyl)-3-methoxybenzenesulfonamide (3.28 g, 99%) as a brown oil. 1 H NMR (400MHz, CDCl3) δ7.41-7.21(m,4H),7.07(ddd,J=7.7,2.5,1.5Hz,1H),6.94(s,1H),6.55(dd,J=8.9,3.0Hz,1H),3.78(s,3H),3.77(s,3H).

[0221] Step 2: Synthesis of N-benzyl-N-(2-bromo-5-methoxyphenyl)-3-methoxybenzenesulfonamide [ka]

[0222] N-(2-Bromo-5-methoxyphenyl)-3-methoxybenzenesulfonamide (5.90 g, 18.9 mmol, 1.0 equiv.) was dissolved in MeCN (53 mL) and KCO (6.57 g, 47.6 mmol, 3.0 equiv.) was added in one portion. Benzyl bromide (2.98 g, 17.4 mmol, 1.1 equiv.) was added dropwise at room temperature. Upon complete addition, the reaction mixture was heated to 60 °C in an oil bath for 3 h. Upon complete consumption of the starting material (as indicated by TLC), the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, loaded onto silica, and purified by MPLC (SiO, 240 g, 0–10% EtOAc in hexanes) to give N-benzyl-N-(2-bromo-5-methoxyphenyl)-3-methoxybenzenesulfonamide (6.83 g, 93%) as a light brown solid. 1 H NMR(400MHz,CDCl3)δ7.42-7.34(m,3H),7.28-7.18(m,6H),7.15-7.10(m,1H),6.69(dd,J=8.9,3.0Hz ,1H),6.48(d,J=3.0Hz,1H),4.89(d,J=14.4Hz,1H),4.66(d,J=14.3Hz,1H),3.79(s,3H),3.59(s,3H).

[0223] Step 3: Synthesis of 6-benzyl-3,8-dimethoxy-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide [ka]

[0224] N-benzyl-N-(2-bromo-5-methoxyphenyl)-3-methoxybenzenesulfonamide (2.00 g, 4.33 mmol, 1.0 equiv.) was dissolved in a mixture of DMA (20 mL) and water (5 mL), and Pd(OAc) (291 mg, 1.30 mmol, 0.3 equiv.) and KOAc (1.69 g, 17.3 mmol, 4.0 equiv.) were added. After complete dissolution of the reagents, the flask was placed in an oil bath at 140 °C and stirred for 48 h. The reaction mixture was then concentrated to complete dryness using a rotary evaporator at 90 °C. The reaction mixture was loaded onto silica and purified by MPLC (SiO, 80 g, EtOAc in hexanes, 0–15%) to give 6-benzyl-3,8-dimethoxy-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (560 mg, 34%) as a white solid. 1 H NMR(400MHz,DMSO)δ8.00(t,J=8.5Hz,2H),7.39(d,J=2.7Hz,1H),7.34(dd,J=8.8,2.7Hz,1H),7.25-7 .09(m,5H),6.95(d,J=2.5Hz,1H),6.91(dd,J=8.8,2.5Hz,1H),5.16(s,2H),3.91(s,3H),3.75(s,3H).

[0225] Step 4: Synthesis of 6-benzyl-3,8-dihydroxy-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide [ka]

[0226] 6-Benzyl-3,8-dimethoxy-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (180 mg, 0.470 mmol, 1.0 equiv) was dissolved in DCM (2 mL) and cooled to 0 °C in an ice bath, and stirring was continued for 5 min. BBr3 (1.89 mL, 1 M in DCM, 1.88 mmol, 4.0 equiv) was then added dropwise to the reaction mixture. Upon complete addition, the mixture was left in the ice bath and allowed to warm to room temperature over 2 h. When no more starting material was observed (TLC), the reaction mixture was added to methanol (20 mL) cooled to 0 °C and stirred for an additional 10 min. The mixture was then concentrated, loaded onto silica, and purified by MPLC (SiO, 20 g, MeOH in DCM, 0–3%) to give 6-benzyl-3,8-dihydroxy-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (100 mg, 60%) as a pale yellow solid. 1 H NMR (400MHz, DMSO) δ10.33(s,1H),9.94(s,1H),7.90-7.80(m,2H),7.39-7.09(m,7H),6.83-6.62(m,2H),5.04(s,2H).

[0227] Step 5: Synthesis of 3,8-dihydroxy-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide [ka]

[0228] 6-Benzyl-3,8-dihydroxy-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (100 mg, 0.370 mmol, 1.0 equiv) was dissolved in MeOH (10 mL) and Pd(OH)2 / C (26 mg) was added in one portion. The reaction mixture was then degassed and filled with N2 three times before being placed under a hydrogen atmosphere (balloon). The reaction mixture was stirred for 4 h, and upon complete consumption of the starting material (as indicated by TLC), it was filtered through silica and concentrated under reduced pressure. The crude product was loaded onto silica and purified by MPLC (SiO2, 12 g, EtOAc in hexanes, 0–50%) to give 3,8-dihydroxy-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (65 mg, 67%) as a white solid. 1 H NMR(400MHz,DMSO)δ10.24(s,1H),9.87(s,1H),7.88(d,J=8.8Hz,1H),7.83(d,J=8.5Hz,1H),7.17 (d,J=2.6Hz,1H),7.11(dd,J=8.7,2.6Hz,1H),6.64(dd,J=8.7,2.5Hz,1H),6.55(d,J=2.5Hz,1H).

[0229] D) Analogues of the ether "A" group Synthesis of 6H-benzo[c]chromene-3,8-diol (23) [ka]

[0230] Step 1: Synthesis of 3,8-bis((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one [ka]

[0231] Urolithin A (12 g, 53 mmol) was added to a solution of imidazole (9.0 g, 0.13 mol) in DCM (100 mL) and stirred for 1 h. When no reaction occurred, DMF (20 mL) was added and stirring continued overnight. DCM was removed under reduced pressure. Water was added, and the mixture was extracted with EtO (3*). The organic layer was washed successively with water twice and brine, dried over NaSO, filtered through silica, and concentrated. The crude product was purified by MPLC (SiO, EtOAc / cyclohexane, 0–20%) to give 3,8-bis((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one (20 g, 96%) as a white solid. 1 H NMR(400MHz,CDCl3)δ7.89(d,J=8.8Hz,1H),7.85-7.80(m,1H),7.76(d,J=2.6Hz,1H),7.29(d d,J=8.7,2.7Hz,1H),6.86-6.80(m,2H),1.02(s,9H),0.98(s,9H),0.26(s,6H),0.24(s,6H).

[0232] Step 2: Synthesis of ((6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane) [ka]

[0233] InBr (142 mg, 0.400 mmol) was added to a solution of 3,8-bis((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one (1.8 g, 4.0 mmol) in toluene (20 mL), and the reaction mixture was heated at 70 °C for 1 h. The reaction mixture was cooled to room temperature and filtered. The solvent was evaporated in vacuo, and the crude product was purified by MPLC (SiO, cyclohexane / dichloromethane, 0%–10%) to give ((6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane) (81 mg, 88%) as a white solid. 1H NMR(400MHz,CDCl3)δ7.48(t,J=8.5Hz,2H),6.81(dd,J=8.4,2.5Hz,1H),6.60(d,J=2.4Hz,1H),6.53(dd,J =8.4,2.5Hz,1H),6.47(d,J=2.4Hz,1H),5.02(s,2H),1.00(s,9H),0.98(s,9H),0.22(s,6H),0.20(s,6H).

[0234] Step 3: Synthesis of 6H-benzo[c]chromene-3,8-diol [ka]

[0235] Acetyl chloride (0.105 mL, 1.40 mmol) was added to a solution of ((6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane) (421 mg, 0.950 mmol) in methanol (10 mL) at room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure and purified by MPLC (SiO, EtOAc in hexanes, 0–100%) to give 6H-benzo[c]chromene-3,8-diol (203 mg, 0.950 mmol, 99%) as a white solid. 1 H NMR(400MHz,DMSO)δ9.50(s,1H),9.48(s,1H),7.49(dd,J=12.5,8.4Hz,2H),6.74(dd,J=8.4,2. 6Hz,1H),6.60(d,J=2.5Hz,1H),6.45(dd,J=8.4,2.4Hz,1H),6.32(d,J=2.4Hz,1H),4.96(s,2H).

[0236] Synthesis of 6-methyl-6H-benzo[c]chromene-3,8-diol (24) [ka]

[0237] Step 1: Synthesis of 3,8-bis((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-ol [ka]

[0238] DIBAL-H (2.10 mL, 2.10 mmol) was added slowly down the side of the flask to a solution of 3,8-bis((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one (912 mg, 2.00 mmol) in toluene (20 mL) at −78° C. under nitrogen. The reaction was monitored by TLC elution (cyclohexane / DCM, 1:1). The reaction was complete within 1 hour of stirring. After Fieser workup, the product was used in the next step without further purification. 1 H NMR(400MHz,CDCl3)δ7.60(dd,J=8.9,6.9Hz,2H),6.93(dd,J=8.5,2.5Hz,1H),6.83(d,J= 2.6Hz, 1H), 6.62-6.58 (m, 2H), 6.26 (s, 1H), 1.00 (s, 9H), 0.98 (s, 9H), 0.25-0.18 (m, 12H).

[0239] Step 2: Synthesis of 4,4'-bis((tert-butyldimethylsilyl)oxy)-2'-(1-hydroxyethyl)-[1,1'-biphenyl]-2-ol [ka]

[0240] To a solution of 3,8-bis((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-ol (456 mg, 1.00 mmol, 1.0 equiv) in anhydrous THF (10 mL) was slowly added MeMgr (3 M in EtO, 1.0 mL, 3.0 mmol, 3.0 equiv) under a nitrogen atmosphere at 0 °C. The reaction was complete within 1 h. The reaction mixture was diluted with ether, filtered through a silica pad with ether washes, and concentrated to afford the title product as a viscous, colorless, 60:40 mixture of rotatory / diastereomeric oil (474 mg, quantitative), which was used in the next step without further purification. 1H NMR(400MHz,CDCl3)δ7.15(d,J=2.6Hz,0.4H),7.12(d,J=2.6Hz,0.6H),7.07(s,0.4H),7 .04(s,0.6H),6.96(d,J=8.1Hz,0.4H),6.90(d,J=8.5Hz,0.6H),6.86-6.78(m,1H),6.52 -6.43(m,2H),4.79(q,J=6.4Hz,0.4H),4.73(q,J=6.5Hz,0.6H),1.36(d,J=6.4Hz,1.2H) ,1.30(d,J=6.4Hz,1.8H),1.01(s,7.2H),1.00(s,10.8H),0.25(s,4.8H),0.24(s,7.2H).

[0241] Step 3: ((6-methyl-((6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane) [ka]

[0242] A solution of 4-methylbenzenesulfonic acid hydrate (19 mg, 0.19 mmol) and 4,4'-bis((tert-butyldimethylsilyl)oxy)-2'-(1-hydroxyethyl)-[1,1'-biphenyl]-2-ol (474 mg, 1.00 mmol) in toluene (10 mL) was heated at 80 °C overnight. TLC (cyclohexane / dichloromethane 9:1) showed no more starting material. The reaction mixture was concentrated under reduced pressure and purified by column (SiO, CyH / DCM) to give ((6-methyl-((6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane)) (411 mg, 90%) as a white solid. 1H NMR(400MHz,CDCl3)δ7.48(dd,J=8.5,4.1Hz,2H),6.80(dd,J=8.4,2.5Hz,1H),6.61(dd,J=2.4,0.8Hz,1H),6.52(dd,J=8.4,2 .4Hz,1H),6.47(d,J=2.4Hz,1H),5.17(q,J=6.5Hz,1H),1.00(s,9H),0.98(s,9H)0.92-0.84(m,3H),0.21(s,6H),0.20(s,6H).

[0243] Step 4: 6-methyl-6H-benzo[c]chromene-3,8-diol [ka]

[0244] Acetyl chloride (0.100 mL, 1.40 mmol) was added to a solution of ((6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane) (411 mg, 0.900 mmol) in methanol (10 mL) at room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure and purified by MPLC (SiO, EtOAc in hexanes, 0–100%) to give 6-methyl-6H-benzo[c]chromene-3,8-diol (202 mg, 98%) as a white solid. 1 H NMR(400MHz,DMSO)δ9.47(s,1H),9.45(s,1H),7.49(t,J=8.7Hz,2H),6.73(dd,J=8.4,2.5Hz,1H),6.60(d,J= 2.4Hz,1H),6.43(dd,J=8.4,2.4Hz,1H),6.30(d,J=2.4Hz,1H),5.14(q,J=6.5Hz,1H),1.44(d,J=6.5Hz,3H).

[0245] Synthesis of 6,6-dimethyl-6H-benzo[c]chromene-3,8-diol (25) [ka]

[0246] Step 1: Synthesis of 4,4'-bis((tert-butyldimethylsilyl)oxy)-2'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-2-ol [ka]

[0247] To a solution of 3,8-bis((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one (456 mg, 1.00 mmol, 1.0 equiv.) in anhydrous THF (10 mL) was slowly added MeMgBr (3 M in EtO, 1.0 mL, 3.00 mmol, 3.0 equiv.) under a nitrogen atmosphere at 0 °C. The reaction was complete within 1 h. The reaction mixture was diluted with ether, filtered through a silica pad with ether washes, and concentrated to afford 4,4'-bis((tert-butyldimethylsilyl)oxy)-2'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-2-ol as a viscous, colorless oil (489 mg, quantitative), which was used in the next step without further purification. 1 H NMR (400MHz,CDCl3)δ7.13(d,J=2.5Hz,1H),6.96(d,J=1.0Hz,1H),6.94(d,J=1.1Hz,1H),6.76(dd,J=8.2,2.6Hz,1H),6.49(d ,J=2.4Hz,1H),6.45(dd,J=8.2,2.4Hz,1H),1.52(s,3H),1.40(s,3H),1.01(s,9H),1.00(s,9H),0.25(s,6H),0.23(s,6H).

[0248] Step 2: Synthesis of ((6,6-dimethyl-((6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane) [ka]

[0249] A solution of 4-methylbenzenesulfonic acid hydrate (19 mg, 0.19 mmol) and 4,4'-bis((tert-butyldimethylsilyl)oxy)-2'-(1-hydroxyethyl)-[1,1'-biphenyl]-2-ol (489 mg, 1.00 mmol) in toluene (10 mL) was heated at 80 °C overnight. TLC (cyclohexane / dichloromethane 9:1) showed no more starting material. The reaction mixture was concentrated under reduced pressure and purified by MPLC (SiO, CyH / DCM) to give ((6-methyl-((6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane) (446 mg, 95%) as a white solid. 1 H NMR(400MHz,CDCl3)δ7.49(dd,J=8.5,3.4Hz,2H),6.79(dd,J=8.4,2.4Hz,1H),6.69(d,J=2.4Hz,1H),6.50(d d,J=8.4,2.4Hz,1H),6.45(d,J=2.4Hz,1H),1.58(s,6H),1.00(s,9H),0.99(s,9H),0.22(s,6H),0.21(s,6H).

[0250] Step 3: Synthesis of 6,6-dimethyl-6H-benzo[c]chromene-3,8-diol [ka]

[0251] Acetyl chloride (0.100 mL, 1.40 mmol) was added to a solution of 4,4'-bis((tert-butyldimethylsilyl)oxy)-2'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-2-ol (446 mg, 0.900 mmol) in methanol (10 mL) at room temperature, and the solution was stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by MPLC (SiO2, EtOAc in hexanes, 0-100%) to give 6,6-dimethyl-6H-benzo[c]chromene-3,8-diol (228 mg, 98%) as a white solid. MS (ESI+): m / z = 243. 1H NMR(400MHz,DMSO)δ9.44(s,1H),9.42(s,1H),7.49(dd,J=8.5,4.2Hz,2H),6.72(dd,J=8.4,2.5 Hz,1H),6.67(d,J=2.4Hz,1H),6.40(dd,J=8.4,2.4Hz,1H),6.26(d,J=2.4Hz,1H),1.49(s,6H).

[0252] E) Analogues of the ester "A" group containing a pyridine ring Synthesis of 3,8-dihydroxy-6H-isochromeno[4,3-b]pyridin-6-one (27) [ka]

[0253] Step 1: Synthesis of 3,8-dimethoxy-6H-isochromeno[4,3-b]pyridin-6-one (26) [ka]

[0254] Sodium nitrite (130 mg, 1.88 mmol) was added to a solution of methyl 2-amino-5-methoxybenzoate (341 mg, 1.88 mmol) in water (1 mL) and HCl (3N, 1 mL) at 0 °C. The reaction mixture was stirred for 15 min at 0 °C, and this solution was added dropwise to a solution of 5-methoxypyridin-3-ol (1.18 g, 9.42 mmol) in water (1 mL) and HCl (3N, 1 mL) with TiCl (0.25 mL, 1.88 mmol) at 0 °C, and stirring was continued overnight at room temperature. A saturated solution of Na CO was added. After extraction three times with EtOAc, the combined organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by MPLC (SiO, EtOAc / cyclohexane, 0% to 30%) to give 3,8-dimethoxy-6H-isochromeno[4,3-b]pyridin-6-one (85 mg, 18%) as a white solid. f =0.25 (20% EtOAc / hexane). 1H NMR(400MHz,CDCl3)δ8.47(d,J=8.8Hz,1H),8.33(d,J=2.6Hz,1H),7.74(d,J=2.7Hz ,1H),7.45(dd,J=8.8,2.7Hz,1H),7.14(d,J=2.6Hz,1H),3.95(s,3H),3.93(s,3H).

[0255] Step 2: Synthesis of 3,8-dihydroxy-6H-isochromeno[4,3-b]pyridin-6-one (27) [ka]

[0256] Starting from 3,8-dimethoxy-6H-isochromeno[4,3-b]pyridin-6-one (26) (120 mg, 0.460 mmol), 27 was prepared according to GP2 to give 3,8-dihydroxy-6H-isochromeno[4,3-b]pyridin-6-one (20 mg, 19%) as a white solid after purification by MPLC (SiO, EtOAc / cyclohexane, 5% to 90%). f =0.1 (EtOAc / hexane 80%). 1 H NMR(400MHz,DMSO)δ10.60(s,1H),10.39(s,1H),8.30(d,J=8.7Hz,1H),8.19(d,J=2 .4Hz,1H),7.50(d,J=2.6Hz,1H),7.38(dd,J=8.7,2.6Hz,1H),7.15(d,J=2.4Hz,1H).

[0257] Synthesis of 3,8-dihydroxy-5H-chromeno[4,3-b]pyridin-5-one (28) [ka]

[0258] Step 1: Synthesis of methyl 2-(2-chloro-4-methoxyphenyl)-5-methoxynicotinate [ka]

[0259] Water (1 mL) was added to a mixture of (2-hydroxy-4-methoxyphenyl)boronic acid (144 mg, 0.774 mmol), methyl 2-chloro-5-methoxynicotinate (120 mg, 0.595 mmol), cesium carbonate (170 mg, 1.61 mmol), and palladium tetrakis(triphenylphosphine)palladium (35 mg, 0.029 mmol) in DME (5 mL), and the mixture was refluxed for 3 h. TLC showed complete conversion of the starting material. A saturated solution of NH4Cl was added, and the aqueous phase was extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by MPLC (SiO2, EtOAc / hexane, 0% to 60%) to give methyl 2-(2-chloro-4-methoxyphenyl)-5-methoxynicotinate (160 mg, 87%) as a colorless oil. R f =0.3 (50% EtOAc / hexane). 1 H NMR (400MHz,CDCl3)δ8.49(d,J=3.0Hz,1H),7.77(d,J=3.0Hz,1H),7.33(d,J=8.5Hz,1H),6. 96(d,J=2.5Hz,1H),6.90(dd,J=8.5,2.5Hz,1H),3.95(s,3H),3.84(s,3H),3.74(s,3H).

[0260] Step 2: Synthesis of 3,8-dimethoxy-5H-chromeno[4,3-b]pyridin-5-one [ka]

[0261] To a mixture of methyl 2-(2-chloro-4-methoxyphenyl)-5-methoxynicotinate (900 mg, 2.92 mmol, 1.0 equiv.), copper(I) thiophene-2-carboxylic acid (278 mg, 1.46 mmol, 0.5 equiv.), and CsCO (476 mg, 1.46 mmol, 0.5 equiv.) in deionized water (10 mL) was added TMEDA (339 mg, 2.92 mmol, 1.0 equiv.) via a microsyringe in a microwave oven. The mixture was stirred at room temperature for 15 minutes and then refluxed at 130 °C overnight. The reaction mixture was cooled to room temperature and extracted with EtOAc and a saturated solution of NH4Cl. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by MPLC (SiO, EtOAc / cyclohexane, 0% to 30%) to give 3,8-dimethoxy-5H-chromeno[4,3-b]pyridin-5-one (120 mg, 16%) as a white solid. f =0.4 (EtOAc / hexane 80%). 1 H NMR(400MHz,CDCl3)δ8.69(d,J=3.1Hz,1H),8.37(d,J=8.8Hz,1H),7.93(d,J=3.1Hz ,1H),6.96(dd,J=8.8,2.5Hz,1H),6.87(d,J=2.4Hz,1H),3.96(s,3H),3.89(s,3H).

[0262] Step 3: Synthesis of 3,8-dihydroxy-5H-chromeno[4,3-b]pyridin-5-one [ka]

[0263] Starting from 3,8-dimethoxy-5H-chromeno[4,3-b]pyridin-5-one (120 mg, 0.460 mmol), 28 was prepared according to GP2 to give 3,8-dihydroxy-5H-chromeno[4,3-b]pyridin-5-one (26 mg, 56%) as a white solid after purification by MPLC (SiO, MeOH / DCM, 0%-10%). f =0.1 (EtOAc / hexane 80%). 1H NMR(400MHz,DMSO)δ10.55(s,1H),10.50(s,1H),8.62(d,J=2.9Hz,1H),8.19(dd,J=8.6 ,1.5Hz,1H),7.74(d,J=2.9Hz,1H),6.86(dd,J=8.7,2.3Hz,1H),6.76(d,J=2.3Hz,1H).

[0264] F) Analogs of the ester "A" ring with ether substitutions prepared by the Mitsunobu reaction The Mitsunobu target was achieved starting from two common intermediates (CI1 and CI2) described below.

[0265] Synthesis of CI1 [ka]

[0266] Step 1: Synthesis of 3-(benzyloxy)-8-bromo-6H-benzo[c]chromen-6-one [ka]

[0267] To a suspension of 3 (synthesized as above) (500 mg, 1.72 mmol, 1.0 equiv.) in DMF (5 mL) was added KCO (522 mg, 3.78 mmol, 2.2 equiv.) in one portion. The suspension was then cooled to 0 °C in an ice bath and stirred for 5 min. Benzyl bromide (323 mg, 1.89 mmol, 1.2 equiv.) was added dropwise over 1 min. Upon complete addition, the reaction mixture was stirred at 0 °C for 10 min and then warmed to room temperature overnight. Upon complete consumption of the starting material (as indicated by TLC), the reaction mixture was quenched with a half-saturated aqueous solution of sodium bicarbonate. The precipitate was filtered through a Buchner funnel, washed with hexane, and dried to give 3-(benzyloxy)-8-bromo-6H-benzo[c]chromen-6-one (400 mg, 61%) as a light brown solid. 1H NMR(400MHz,CDCl3)δ10.27(s,1H),8.18(d,J=8.8Hz,1H),8.14(d,J=8.9Hz,1H),7.53(d,J=2.7Hz,1H),7.51-7. 47(m,2H),7.44-7.39(m,2H),7.37-7.32(m,1H),7.07(d,J=2.5Hz,1H),7.04(dd,J=8.7,2.5Hz,1H),5.21(s,2H).

[0268] Step 2: Synthesis of 3-(benzyloxy)-8-hydroxy-6H-benzo[c]chromen-6-one (CI1) [ka]

[0269] 3-(Benzyloxy)-8-bromo-6H-benzo[c]chromen-6-one (700 mg, 1.84 mmol, 1.0 equiv) was suspended in 1,4-dioxane (7 mL) in a 20 mL Biotage MW vial. To this suspension, Pd2dba3 (43 mg, 0.18 mmol, 0.1 equiv) was added, followed by tBuXPhos (175 mg, 0.370 mmol, 0.2 equiv). The MW vial was then sealed and degassed with nitrogen for 10 minutes. Next, a solution of KOH (412 mg, 7.34 mmol, 4.4 equiv) in HO (3 mL) was slowly added to the reaction mixture, which was then stirred at 90 °C in a preheated oil bath for 3 hours. Upon complete consumption of the starting material (as indicated by TLC), the reaction mixture was cooled to 0 °C and the pH was adjusted to 1 with 6 M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (3 × 10 mL), and the combined organic phase was dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by MPLC (SiO, 40 g, EtOAc in hexanes, 0–30%) to give 3-(benzyloxy)-8-hydroxy-6H-benzo[c]chromen-6-one (390 mg, 67%) as a pale yellow solid. 1H NMR(400MHz,DMSO)δ10.27(s,1H),8.18(d,J=8.8Hz,1H),8.14(d,J=8.9Hz,1H),7.53(d,J=2.7Hz,1H),7.51-7.4 7(m,2H),7.44-7.39(m,2H),7.37-7.32(m,2H),7.07(d,J=2.5Hz,1H),7.04(dd,J=8.7,2.5Hz,1H),5.21(s,2H).

[0270] Synthesis of CI2 [ka]

[0271] Step 1: Synthesis of 8-(benzyloxy)-3-((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one [ka]

[0272] 8-(Benzyloxy)-3-hydroxy-6H-benzo[c]chromen-6-one (1.46 g, 4.59 mmol) was dissolved in dry THF (12 mL). Triethylamine (1.92 mL, 13.8 mmol) was added dropwise at room temperature and stirred for 15 minutes. Then, tert-butylchlorodimethylsilane (832 mg, 5.51 mmol) was added and stirring was continued for 3 hours at room temperature. TLC showed no more starting material. The reaction mixture was extracted twice with EtOAc and 1 M HCl. The organic phase was washed successively with water and brine, then dried over sodium sulfate to give 8-(benzyloxy)-3-((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one (1.83 g, 92%) as a brownish solid. 1 H NMR(400MHz,CDCl3)δ7.94(d,J=8.9Hz,1H),7.88(d,J=2.8Hz,1H),7.86-7.81(m, 1H), 7.50-7.34 (m, 6H), 6.86-6.80 (m, 2H), 5.18 (s, 2H), 1.00 (s, 9H), 0.25 (s, 6H).

[0273] Step 2: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-hydroxy-6H-benzo[c]chromen-6-one (C2) [ka]

[0274] 8-(Benzyloxy)-3-((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one (1.83 g, 4.23 mmol, 1.0 equiv.) was dissolved in methanol (20 mL), dichloromethane (10 mL), and Pd(OH) / C (368 mg, 0.5 mmol, 0.12 equiv.) were added, and the reaction mixture was hydrogenated overnight under atmospheric pressure. The mixture was filtered through a pad of Celite, and the solvent was evaporated in vacuo to give 3-((tert-butyldimethylsilyl)oxy)-8-hydroxy-6H-benzo[c]chromen-6-one (1.3 g, 3.8 mmol, 90%) as a beige solid. 1 H NMR(400MHz,CDCl3)δ7.95(d,J=8.8Hz,1H),7.91(d,J=2.7Hz,1H),7.89-7.83(m,1H), 7.39(dd,J=8.7,2.8Hz,1H),6.92-6.83(m,2H),6.21(s,1H),1.03(s,9H),0.28(s,6H).

[0275] Synthesis of 3-hydroxy-8-(oxetan-3-ylmethoxy)-6H-benzo[c]chromen-6-one (29) [ka]

[0276] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-(oxetan-3-ylmethoxy)-6H-benzo[c]chromen-6-one [ka]

[0277] In a sealed tube, DIAD (0.187 mL, 0.960 mmol) was added to a solution of 3-((tert-butyldimethylsilyl)oxy)-8-hydroxy-6H-benzo[c]chromen-6-one (150 mg, 0.430 mmol) and oxetan-3-ylmethanol (58 mg, 0.65 mmol) in THF (2 mL) at 0 °C, and stirring was continued at room temperature overnight. TLC showed complete conversion of the starting material. The reaction mixture was loaded onto silica gel and purified by MPLC (SiO, EtOAc / cyclohexane, 0% to 30%) to give a mixture of 3-((tert-butyldimethylsilyl)oxy)-8-(oxetan-3-ylmethoxy)-6H-benzo[c]chromen-6-one and reduced DIAD (280 mg). f =0.3 (20 / 80 EtOAc / hexanes). After purification, a significant amount of reduced DIAD was present in the NMR. Therefore, this was used crude in the next step and will not be described further.

[0278] Step 2: Synthesis of 3-hydroxy-8-(oxetan-3-ylmethoxy)-6H-benzo[c]chromen-6-one [ka]

[0279] KHF (108 mg, 1.38 mmol) was added in one portion to a solution of 3-((tert-butyldimethylsilyl)oxy)-8-(oxetan-3-ylmethoxy)-6H-benzo[c]chromen-6-one (285 mg, 0.690 mmol) (crude mixture of PPhO and reduced DIAD) in MeOH (5 mL) at room temperature and stirred for 4 h. The white precipitate that formed was filtered and dried under vacuum to give 3-hydroxy-8-(oxetan-3-ylmethoxy)-6H-benzo[c]chromen-6-one (65 mg, 32%) as a white solid. 1H NMR(400MHz,DMSO)δ10.27(s,1H),8.26-8.06(m,2H),7.64-7.52(m,1H),7.52-7.27(m,1H),7.08-6.96(m,1H),6.85-6.71(m,1 H),4.73(ddd,J=7.6,6.0,1.4Hz,2H),4.46(dt,J=11.9,6.1Hz,2H),4.33(dd,J=18.2,6.7Hz,2H),3.43(tt,J=6.8,6.8Hz,1H).

[0280] Synthesis of 3-hydroxy-8-(2-(4-methylpiperazin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one (30) [ka]

[0281] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-(2-(4-methylpiperazin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one) [ka]

[0282] 3-((tert-butyldimethylsilyl)oxy)-8-(2-(4-methylpiperazin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one) was prepared from 3-((tert-butyldimethylsilyl)oxy)-8-hydroxy-6H-benzo[c]chromen-6-one (80 mg, 0.23 mmol) and 2-(4-methyl-piperazin-1-yl)-ethanol (34 mg, 0.23 mmol) (according to the synthesis of 29). After MPLC purification (SiO, MeOH / DCM, 0% to 20%), 3-((tert-butyldimethylsilyl)oxy)-8-(2-(4-methylpiperazin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one) (60 mg, 55%) was obtained as a yellowish oil. NMR still showed a significant amount of reduced DIAD, but the impure / crude material was carried on to the next step. f=0.4 (20% MeOH / DCM).

[0283] Step 2: Synthesis of 3-hydroxy-8-(2-(4-methylpiperazin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one [ka]

[0284] Acetyl chloride (0.046 mL, 0.64 mmol, 5.0 equiv.) was added to a solution of 3-((tert-butyldimethylsilyl)oxy)-8-(2-(4-methylpiperazin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one (60 mg, 0.13 mmol, 1.0 equiv.) in MeOH (2 mL) at room temperature, and the reaction mixture was stirred overnight. Methanol was evaporated in vacuo, and the crude product was diluted with EtOAc and washed with a saturated solution of sodium carbonate. The aqueous layer was extracted with EtOAc, and the combined organic phases were dried over sodium sulfate. The crude product was purified by MPLC (SiO2, MeOH / DCM, 0%–30%) to give 3-hydroxy-8-(2-(4-methylpiperazin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one (17 mg, 0.048 mmol, 37%). 1 H NMR(400MHz,DMSO)δ10.23(br,1H),8.25-8.06(m,2H),7.53(d,J=2.7Hz,1H),7.50(dd,J=8.8,2.9Hz,1H),7.02- 6.94(m,1H),6.86-6.71(m,1H),4.18(dt,J=18.4,5.7Hz,3H),2.76-2.65(m,6H),2.34-2.32(m,3H),2.14(s,3H).

[0285] Synthesis of (S)-3-hydroxy-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one (31) [ka]

[0286] Step 1: Synthesis of (S)-3-((tert-butyldimethylsilyl)oxy)-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one [ka]

[0287] Starting from C2 (80 mg, 0.23 mmol) and (R)-tetrahydrofuran-3-ol (31 mg, 0.35 mmol), (S)-3-((tert-butyldimethylsilyl)oxy)-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one was prepared (according to the synthesis of 29) to give (S)-3-((tert-butyldimethylsilyl)oxy)-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one (45 mg, 47%) as a yellowish oil. f =0.6 (EtOAc / hexane 1 / 1). 1 H NMR(400MHz,CDCl3)δ8.00-7.80(m,2H),7.74(dd,J=23.0,2.7Hz,1H),7.33(ddd,J=26.5,8.8,2.7Hz,1H),6.90-6.8 0(m,2H),5.09-4.95(m,1H),4.13-3.88(m,4H),2.43-2.07(m,2H),1.02(s,J=3.8Hz,9H),0.27(s,3H),0.25(s,3H).

[0288] Step 2: Synthesis of (S)-3-hydroxy-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one [ka]

[0289] Starting from (S)-3-((tert-butyldimethylsilyl)oxy)-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one (40 mg, 0.097 mmol) and KHF (27 mg, 0.34 mmol), 31 was prepared according to the synthesis of 29 to give (S)-3-hydroxy-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one (22 mg, 76%) as a white solid. 1 H NMR(400MHz,CDCl3)δ7.92-7.76(m,2H),7.69(s,1H),7.29(ddd,J=11.3,8.8,2.8H z,1H),6.88-6.70(m,2H),5.41-5.35(m,1H),4.01-3.82(m,4H),2.36-2.04(m,2H).

[0290] Synthesis of 3-hydroxy-8-(2-(2-methoxyethoxy)ethoxy)-6H-benzo[c]chromen-6-one (32) [ka]

[0291] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-(2-(2-methoxyethoxy)ethoxy)-6H-benzo[c]chromen-6-one [ka]

[0292] Starting with C2 (100 mg, 0.29 mmol) and 2-(2-methoxyethoxy)ethan-1-ol (42 mg, 0.35 mmol), 3-((tert-butyldimethylsilyl)oxy)-8-(2-(2-methoxyethoxy)ethoxy)-6H-benzo[c]chromen-6-one was prepared (according to the synthesis of 29) to give 3-((tert-butyldimethylsilyl)oxy)-8-(2-(2-methoxyethoxy)ethoxy)-6H-benzo[c]chromen-6-one (125 mg, 47%) contaminated with reduced DIAD as a yellowish oil.f =0.5 (EtOAc / hexane 1 / 1). 1 H NMR(400MHz,CDCl3)δ7.91-7.66(m,3H),7.32-7.24(m,1H),6.88-6.74(m,2H),4.22-4.11(m,2H),3. 87-3.81(m,2H),3.74-3.63(m,2H),3.59-3.49(m,2H),3.33(s,3H),0.95-0.93(m,9H),0.20(s,3H).

[0293] Step 2: Synthesis of 3-hydroxy-8-(2-(2-methoxyethoxy)ethoxy)-6H-benzo[c]chromen-6-one [ka]

[0294] Starting from 32 (100 mg, 0.220 mmol) and KHF (70 mg, 0.90 mmol), 32 was prepared according to the synthesis of 29. After purification by MPLC (SiO, EtAOc / hexane, 0%–30%), a mixture of two compounds was obtained, giving 3-hydroxy-8-(2-(2-methoxyethoxy)ethoxy)-6H-benzo[c]chromen-6-one (24 mg, 32%) as a white solid. 1 H NMR(400MHz,CDCl3)δ7.75-7.56(m,2H),7.34(dd,J=42.4,2.8Hz,1H),7.21-6.48(m,3H),4.05(dt,J=14.8,4.4H z,2H),3.92-3.85(m,2H),3.80(dt,J=6.1,2.5Hz,2H),3.70(ddd,J=4.4,3.5,1.5Hz,2H),3.46(d,J=1.4Hz,3H).

[0295] Synthesis of 3-hydroxy-8-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one (33) [ka]

[0296] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one [ka]

[0297] Starting from C2 (100 mg, 0.29 mmol) and tetrahydro-2H-pyran-4-ol (36 mg, 0.35 mmol), the compound was prepared according to the synthesis of 29 to give 3-((tert-butyldimethylsilyl)oxy)-8-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one (64 mg, 51%) as a yellowish oil. f =0.67 (EtOAc / hexane 4 / 6). 1 H NMR(400MHz,CDCl3)δ7.98-7.81(m,2H),7.77(dd,J=7.3,2.7Hz,1H),7.42-7.2 7(m,1H),6.96-6.80(m,2H),4.61(dtt,J=44.2,7.8,3.9Hz,1H),4.01(ddd,J=1 0.4,5.9,3.9Hz,2H),3.62(ddt,J=11.9,7.8,3.7Hz,2H),2.06(d,J=12.6Hz,2H ),1.83(dtd,J=12.5,8.2,3.9Hz,2H),1.01(d,J=3.7Hz,9H),0.32-0.20(m,6H).

[0298] Step 2: Synthesis of 3-hydroxy-8-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one [ka]

[0299] Preparation of 33 was initiated from 3-((tert-butyldimethylsilyl)oxy)-8-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one (60 mg, 0.14 mmol) and KHF (38 mg, 0.49 mmol) to give 3-hydroxy-8-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one (29 mg, 66%) as a white solid. MS (ESI+): m / z = 313. 1 H NMR(400MHz,DMSO)δ10.30-10.11(m,1H),8.23-7.98(m,2H),7.66-7.28(m,2H),7.09-6.68(m,2H),4.74(dtt,J=25.7,8.6,4.0Hz,1H ),3.86(dt,J=10.3,4.2Hz,2H),3.52(tdd,J=11.6,8.9,2.7Hz,2H),2.01(dd,J=13.2,3.5Hz,2H),1.62(dtt,J=14.1,9.1,4.6Hz,2H).

[0300] Synthesis of 3-hydroxy-8-((tetrahydro-2H-pyran-3-yl)oxy)-6H-benzo[c]chromen-6-one (34) [ka]

[0301] Step 1: Synthesis of 3-(benzyloxy)-8-((tetrahydro-2H-pyran-3-yl)oxy)-6H-benzo[c]chromen-6-one [ka]

[0302] 3-(Benzyloxy)-8-hydroxy-6H-benzo[c]chromen-6-one (64 mg, 0.20 mmol, 1.0 equiv.) was dissolved in THF (0.7 mL) in a 10 mL Biotage MW vial. PPh3 (79 mg, 0.30 mmol, 1.5 equiv.) and tetrahydro-2H-pyran-3-ol (31 mg, 0.30 mmol, 1.5 equiv.) were then added, and the reaction mixture was cooled to 0 °C in an ice bath and stirred for 5 min. Next, a solution of di-tert-butyl-diazene-1,2-dicarboxylate (69 mg, 0.30 mmol, 1.5 equiv.) (DTAD) in THF (0.1 mL) was added dropwise to the reaction mixture. Upon completion of the addition, the reaction mixture turned pale yellow and was allowed to stir at room temperature overnight. After stirring overnight, starting material was still present. Therefore, PPh3 (79 mg, 0.30 mmol, 1.5 equiv.), tetrahydro-2H-pyran-3-ol (31 mg, 0.30 mmol, 1.5 equiv.), and a solution of di-tert-butyl-diazene-1,2-dicarboxylate (DTAD) in THF (0.1 mL) were added to the reaction mixture to drive the reaction to completion. After stirring at room temperature for an additional 2 h, the reaction mixture was concentrated under reduced pressure, loaded onto silica, and purified by MPLC (SiO2, 12 g, EtOAc in hexanes, 0-35%) to give 3-(benzyloxy)-8-((tetrahydro-2H-pyran-3-yl)oxy)-6H-benzo[c]chromen-6-one (50 mg, 62%) as a pale yellow solid. 1 H NMR(400MHz,CDCl3)δ7.92(d,J=8.9Hz,1H),7.86(d,J=8.9Hz,1H),7.77(d,J=2.8Hz,1H),7.46- 7.31(m,5H),6.97(dd,J=8.8,2.6Hz,1H),6.92(d,J=2.5Hz,1H),5.12(s,2H),4.47(tt,J=6.8,3. 5Hz,1H),3.95(ddd,J=11.6,3.2,1.2Hz,1H),3.75(ddd,J=10.6,6.2,3.9Hz,1H),3.70-3.60(m, 2H),2.12(tt,J=11.8,6.0Hz,1H),1.89(dddt,J=31.0,17.3,8.0,3.9Hz,3H),1.70-1.59(m,1H).

[0303] Step 2: Synthesis of 3-hydroxy-8-((tetrahydro-2H-pyran-3-yl)oxy)-6H-benzo[c]chromen-6-one [ka]

[0304] 3-(Benzyloxy)-8-((tetrahydro-2H-pyran-3-yl)oxy)-6H-benzo[c]chromen-6-one (50 mg, 0.12 mmol, 1.0 equiv) was dissolved in MeOH / DCM (5 mL, 10 / 1) and Pd(OH)2 / C (20 mg) was added in one portion. The reaction mixture was then degassed and filled with N2 three times before being placed under a hydrogen atmosphere (balloon). The reaction mixture was stirred for 2 h, and upon complete consumption of the starting material (as indicated by TLC), it was filtered through silica and concentrated under reduced pressure to give the crude product, which was loaded onto silica and purified by MPLC (SiO2, 12 g, EtOAc in hexanes, 0–50%) to give 3-hydroxy-8-((tetrahydro-2H-pyran-3-yl)oxy)-6H-benzo[c]chromen-6-one (33 mg, 0.11 mmol, 89%) as a white solid. 1 H NMR(400MHz,DMSO)δ10.21(s,1H),8.20(d,J=9.0Hz,1H),8.09(d,J=8.8Hz,1H),7.61(d,J=2. 8Hz,1H),7.53(dd,J=8.9,2.8Hz,1H),6.82(dd,J=8.7,2.4Hz,1H),6.74(d,J=2.4Hz,1H),4.5 7(dt,J=6.2,3.2Hz,1H),3.84(dd,J=11.6,2.1Hz,1H),3.64(ddd,J=10.8,6.5,3.7Hz,1H),3. 56(dd,J=11.7,5.6Hz,2H),2.05(dd,J=8.9,4.9Hz,1H),1.87-1.68(m,2H),1.63-1.48(m,1H).

[0305] Synthesis of 3-hydroxy-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one (35) [ka]

[0306] Step 1: Synthesis of 3-(benzyloxy)-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one [ka]

[0307] 3-(Benzyloxy)-8-hydroxy-6H-benzo[c]chromen-6-one (100 mg, 0.31 mmol, 1.0 equiv.) was dissolved in THF (1.1 mL). PPh3 (124 mg, 0.470 mmol, 1.5 equiv.) and tetrahydrofuran-3-ol (42 mg, 0.47 mmol, 1.5 equiv.) were then added, and the reaction mixture was cooled to 0 °C in an ice bath and stirred for 5 min. Next, a solution of di-tert-butyl-diazene-1,2-dicarboxylate (109 mg, 0.470 mmol, 1.5 equiv.) (DTAD) in THF (0.2 mL) was added dropwise to the reaction mixture. Upon completion of the addition, the reaction mixture turned pale yellow and was continued stirring at room temperature overnight. After stirring overnight, starting material was still present, so a solution of PPh3 (124 mg, 0.470 mmol, 1.5 equiv.), tetrahydrofuran-3-ol (42 mg, 0.47 mmol, 1.5 equiv.), and di-tert-butyl-diazene-1,2-dicarboxylate (109 mg, 0.470 mmol, 1.5 equiv.) (DTAD) in THF (0.2 mL) was added to the reaction mixture to drive the reaction to completion. After stirring at room temperature for an additional 2 h, the reaction mixture was concentrated under reduced pressure, loaded onto silica, and purified by MPLC (SiO2, 12 g, EtOAc in hexanes, 0–35%) to give 3-(benzyloxy)-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one (100 mg, 82%) as a pale yellow solid. NMR after purification still showed a significant amount of reduced DTAD, but the reaction was carried on crude to the next step and so the NMR is not reported here.

[0308] Step 2: Synthesis of 3-hydroxy-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one [ka]

[0309] 3-(Benzyloxy)-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one (100 mg, 0.260 mmol, 1.0 equiv) was dissolved in MeOH / DCM (7 mL, 10 / 1) and Pd(OH)2 / C (60 mg) was added in one portion. The reaction mixture was then degassed and filled with N2 three times before being placed under a hydrogen atmosphere using a balloon. The reaction mixture was stirred for 2 h, and upon complete consumption of the starting material (as indicated by TLC), it was filtered through silica and concentrated under reduced pressure to give the crude product, which was loaded onto silica and purified by flash column chromatography (SiO2, 12 g, EtOAc in hexanes, 0–50%) to give 3-hydroxy-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one (65 mg, 72%) as a white solid. 1 H NMR(400MHz,DMSO)δ10.21(s,1H),8.22(d,J=8.8Hz,1H),8.09(d,J=8.8Hz,1H),7 .57(d,J=2.7Hz,1H),7.49(dd,J=8.9,2.8Hz,1H),6.83(dd,J=8.7,2.4Hz,1H),6.7 5(d,J=2.4Hz,1H),5.25-5.19(m,1H),3.92(dd,J=10.2,4.4Hz,1H),3.88-3.83(m, 2H),3.78(td,J=8.4,4.6Hz,1H),2.36-2.20(m,1H),2.02(dd,J=14.2,7.5Hz,1H).

[0310] Synthesis of 3-hydroxy-8-(oxetan-3-yloxy)-6H-benzo[c]chromen-6-one (36) [ka]

[0311] Step 1: Synthesis of 3-(benzyloxy)-8-(oxetan-3-yloxy)-6H-benzo[c]chromen-6-one [ka]

[0312] Cyanomethylenetributylphosphorane (150 mg, 0.630 mmol, 2.5 equiv.) was added in one portion to a solution of 3-(benzyloxy)-8-hydroxy-6H-benzo[c]chromen-6-one (80 mg, 0.25 mmol, 1 equiv.) and oxetan-3-ol (56 mg, 0.75 mmol, 3.0 equiv.) in toluene (1.3 mL) at room temperature, and the reaction mixture was heated to 120 °C for 2 h in a sealed vial. After complete conversion of the starting material, the reaction mixture was cooled to room temperature, concentrated, loaded onto silica, and purified by MPLC (SiO, 12 g, EtOAc in hexanes, 0–30%) to give 3-(benzyloxy)-8-(oxetan-3-yloxy)-6H-benzo[c]chromen-6-one (74 mg, 79%) as a pale yellow foam. 1 H NMR (400 MHz, CDCl 3 )δ7.96(d,J=8.8Hz,1H),7.88(d,J=8.9Hz,1H),7.48-7.34(m,7H),6.99(dd,J=8.8,2.6Hz,1H),6.94(d,J=2.5 Hz,1H),5.39-5.29(m,1H),5.14(s,2H),5.07(ddd,J=7.1,6.0,0.9Hz,2H),4.79(ddd,J=7.4,5.0,1.0Hz,2H).

[0313] Step 2: Synthesis of 3-hydroxy-8-(oxetan-3-yloxy)-6H-benzo[c]chromen-6-one [ka]

[0314] 3-(Benzyloxy)-8-(oxetan-3-yloxy)-6H-benzo[c]chromen-6-one (70 mg, 0.19 mmol, 1.0 equiv) was dissolved in MeOH / DCM (5 mL, 10 / 1) and Pd(OH)2 / C (15 mg) was added in one portion. The reaction mixture was then degassed and filled with N2 three times, then placed under a hydrogen atmosphere using a balloon. The reaction mixture was stirred for 4 h, and upon complete consumption of the starting material (as indicated by TLC), it was filtered through silica and concentrated under reduced pressure to give the crude product, which was loaded onto silica and purified by flash column chromatography (SiO2, 12 g, EtOAc in hexanes, 0–50%) to give 3-hydroxy-8-(oxetan-3-yloxy)-6H-benzo[c]chromen-6-one (25 mg, 0.09 mmol, 47%) as a white solid. 1 H NMR(400MHz,DMSO)δ10.24(s,1H),8.24(d,J=8.9Hz,1H),8.10(d,J=8.8Hz,1H),7.45(dd,J=8.8,2.8Hz,1H),7.35(d,J=2.8Hz,1H) ,6.83(dd,J=8.7,2.4Hz,1H),6.75(d,J=2.4Hz,1H),5.47(q,J=5.4,4.8Hz,1H),4.98(t,J=7.0Hz,2H),4.59(dd,J=7.7,5.1Hz,2H).

[0315] Synthesis of 8-((2-oxaspiro[3.3]heptan-6-yl)oxy)-3-hydroxy-6H-benzo[c]chromen-6-one (37) [ka]

[0316] Step 1: Synthesis of 8-((2-oxaspiro[3.3]heptan-6-yl)oxy)-3-(benzyloxy)-6H-benzo[c]chromen-6-one [ka]

[0317] Cyanomethylenetributylphosphorane (95 mg, 0.39 mmol, 2.5 equiv) was added in one portion to a solution of 3-(benzyloxy)-8-hydroxy-6H-benzo[c]chromen-6-one (50 mg, 0.16 mmol, 1.0 equiv) and 2-oxaspiro[3.3]heptan-6-ol (39 mg, 0.35 mmol, 2.2 equiv) in toluene (3.0 mL) at room temperature, and the reaction mixture was heated to 120° C. for 2 h in a sealed vial. After complete conversion of the starting material, the reaction mixture was cooled to room temperature, concentrated, loaded onto silica, and purified by flash column chromatography (SiO, 12 g, EtOAc in hexanes, 0–30%) to give 8-((2-oxaspiro[3.3]heptan-6-yl)oxy)-3-(benzyloxy)-6H-benzo[c]chromen-6-one (40 mg, 0.10 mmol, 61%) as a pale yellow solid. 1 H NMR(400MHz,DMSO)δ8.26(d,J=8.9Hz,1H),8.20(d,J=8.9Hz,1H),7.54-7.32(m,7H),7.09(d,J=2.5Hz,1H),7.06(dd,J =8.7,2.6Hz,1H),5.22(s,2H),4.77(p,J=6.8Hz,1H),4.66(s,2H),4.55(s,2H),2.88-2.78(m,2H),2.33-2.24(m,2H).

[0318] Step 2: Synthesis of 8-((2-oxaspiro[3.3]heptan-6-yl)oxy)-3-hydroxy-6H-benzo[c]chromen-6-one [ka]

[0319] 8-((2-oxaspiro[3.3]heptan-6-yl)oxy)-3-(benzyloxy)-6H-benzo[c]chromen-6-one (40 mg, 0.10 mmol, 1.0 equiv) was dissolved in MeOH / DCM (5 mL, 10 / 1) and Pd(OH) / C (14 mg) was added in one portion. The reaction mixture was then degassed and filled with N three times before being placed under a hydrogen atmosphere using a balloon. The reaction mixture was stirred for 4 h and upon complete consumption of starting material (as indicated by TLC), it was filtered through silica and concentrated under reduced pressure to give the crude product, which was loaded onto silica and purified by flash column chromatography (SiO, 12 g, EtOAc in hexanes, 0–50%) to give 8-((2-oxaspiro[3.3]heptan-6-yl)oxy)-3-hydroxy-6H-benzo[c]chromen-6-one (26 mg, 0.08 mmol, 83%) as a white solid. MS (ESI+): m / z = 325. 1 H NMR(400MHz,DMSO)δ10.23(s,1H),8.19(d,J=8.9Hz,1H),8.08(d,J=8.8Hz,1H),7.46(d,J=2.8Hz,1H),7.41(dd,J=8.8,2.8Hz,1H),6.8 2(dd,J=8.7,2.4Hz,1H),6.74(d,J=2.4Hz,1H),4.76(q,J=6.8Hz,1H),4.66(s,2H),4.55(s,2H),2.87-2.76(m,2H),2.32-2.18(m,2H).

[0320] Similarly, the 9-substituted analog 38 was prepared according to the following scheme:

[0321] Synthesis of 3-hydroxy-9-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one (38) [ka]

[0322] Step 1: Synthesis of 9-bromo-3-hydroxy-6H-benzo[c]chromen-6-one [ka]

[0323] A mixture of 2,4-dibromobenzoic acid (5.00 g, 17.9 mmol, 1.0 equiv.), resorcinol (3.93 g, 35.7 mmol, 2.0 equiv.), and sodium hydroxide (1.71 g, 42.9 mmol, 2.4 equiv.) in water (15 mL) was heated under reflux for 60 min. After adding copper sulfate (5% aqueous solution, 10 mL), the mixture was refluxed again overnight. A precipitate formed, which was filtered off, washed with HCl (1 M), and then dried under vacuum to give 9-bromo-3-hydroxy-6H-benzo[c]chromen-6-one (2.91 g, 56%) as an ochre solid. 1 H NMR (400MHz, DMSO) δ10.44(s,1H),8.47(s,1H),8.19(d,J=8.7Hz,1H),8.04(d,J=8.4Hz,1H),7.69(d,J=8.4Hz,1H),6.86-6.78(m,1H),6.73(s,1H).

[0324] Step 2: Synthesis of 3-(benzyloxy)-9-bromo-6H-benzo[c]chromen-6-one [ka]

[0325] To a suspension of 9-bromo-3-hydroxy-6H-benzo[c]chromen-6-one (2.00 mg, 6.87 mmol, 1.0 equiv) in DMF (35 mL) was added KCO (2.09 g, 15.1 mmol, 2.2 equiv) in one portion. The suspension was cooled to 0 °C and stirred for 5 min. Benzyl bromide (1.41 g, 8.24 mmol, 1.2 equiv) was added dropwise over 5 min. Upon complete addition, the reaction mixture was stirred at 0 °C for 10 min and then warmed to room temperature for 2 h. Upon complete consumption of the starting material (as indicated by TLC), the reaction mixture was quenched with a half-saturated aqueous solution of sodium bicarbonate. The precipitate was filtered through a Buchner funnel, washed with hexane and dried to give 3-(benzyloxy)-9-bromo-6H-benzo[c]chromen-6-one (1.49 g, 61%) as a light brown solid. 1 H NMR (400MHz, CDCl3) δ8.20(d,J=8.7Hz,1H),7.78(d,J=8.9Hz,1H),7.41-7.28(m,6H),6.91-6.88(m,2H),6.85(d,J=2.5Hz,1H),5.07(s,2H).

[0326] Step 3: Synthesis of 3-(benzyloxy)-9-hydroxy-6H-benzo[c]chromen-6-one [ka]

[0327] 3-(Benzyloxy)-9-bromo-6H-benzo[c]chromen-6-one (800 mg, 2.10 mmol, 1.0 equiv) was suspended in 1,4-dioxane (7 mL) in a 20 mL Biotage MW vial. To this suspension was added Pd2dba3 (49 mg, 0.21 mmol, 0.1 equiv), followed by tBuXPhos (200 mg, 0.42 mmol, 0.2 equiv). The MW vial was then sealed and degassed with nitrogen for 10 minutes. Next, a solution of KOH (471 mg, 8.39 mmol, 4.4 equiv) in HO (3 mL) was slowly added to the reaction mixture, which was then placed in a preheated oil bath at 90 °C and stirred for 3 hours. Upon complete consumption of the starting material (as indicated by TLC), the reaction mixture was cooled to 0 °C and the pH was adjusted to 1 with 6 M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (3 × 10 mL), and the combined organic phase was dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by MPLC (SiO, 40 g, EtOAc in hexanes, 0–30%) to give 3-(benzyloxy)-9-hydroxy-6H-benzo[c]chromen-6-one (225 mg, 37%) as a pale yellow solid. 1 H NMR (400MHz, CDCl3) δ8.20(d,J=8.7Hz,1H),7.78(d,J=8.9Hz,1H),7.41-7.28(m,6H),6.91-6.88(m,2H),6.85(d,J=2.5Hz,1H),5.07(s,2H).

[0328] Step 4: Synthesis of 3-(benzyloxy)-9-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one [ka]

[0329] Cyanomethylenetributylphosphorane (227 mg, 0.940 mmol, 2.5 equiv) was added in one portion to a solution of 3-(benzyloxy)-9-hydroxy-6H-benzo[c]chromen-6-one (120 mg, 0.380 mmol, 1.0 equiv) and tetrahydro-2H-pyran-4-ol (77 mg, 0.71 mmol, 2.0 equiv) in toluene (3.8 mL) at room temperature, and the reaction mixture was heated to 120 °C for 2 h in a sealed vial. After complete conversion of the starting material, the reaction mixture was cooled to room temperature, concentrated, loaded onto silica, and purified by MPLC (SiO, 12 g, EtOAc in hexanes, 0–30%) to give 3-(benzyloxy)-9-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one (135 mg, 89%) as a pale yellow foam. 1 H NMR(400MHz,CDCl3)δ8.28(d,J=8.8Hz,1H),7.86(d,J=8.9Hz,1H),7.51-7.32( m,6H),7.03(dd,J=8.9,2.4Hz,1H),6.97(dd,J=8.8,2.6Hz,1H),6.91(d,J=2.5H z,1H),5.13(s,2H),4.73(tt,J=7.7,3.8Hz,1H),4.02(ddd,J=11.8,6.3,3.8Hz ,2H),3.65(ddd,J=11.5,8.1,3.3Hz,2H),2.17-2.05(m,2H),1.94-1.82(m,2H).

[0330] Step 5: Synthesis of 3-hydroxy-9-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one [ka]

[0331] 3-(Benzyloxy)-9-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one (135 mg, 0.340 mmol, 1.0 equiv) was dissolved in MeOH / DCM (10 mL, 10 / 1) and Pd(OH)2 / C (70 mg) was added in one portion. The reaction mixture was then degassed and filled with N2 three times before being placed under a hydrogen atmosphere (balloon). The reaction mixture was stirred for 4 h, and upon complete consumption of the starting material (as indicated by TLC), it was filtered through silica and concentrated under reduced pressure to give the crude product, which was loaded onto silica and purified by MPLC (SiO2, 12 g, EtOAc in hexanes, 0–50%) to give 3-hydroxy-9-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one (40 mg, 34%) as a white solid. 1 H NMR(400MHz,DMSO)δ10.33(s,1H),8.25(d,J=8.9Hz,1H),8.11(d,J=8.9Hz,1H),7.72 (d,J=2.4Hz,1H),7.17(dd,J=8.9,2.4Hz,1H),6.83(dd,J=8.7,2.4Hz,1H),6.73(d,J= 2.4Hz,1H),4.97(tt,J=8.6,4.1Hz,1H),3.90(dt,J=11.7,4.3Hz,2H),3.56(ddd,J=11 .8,9.6,2.7Hz,2H),2.07(dd,J=11.3,7.7Hz,2H),1.66(ddt,J=13.7,9.1,4.6Hz,2H).

[0332] G) Analogs of the ester "A" ring with alkynyl substitution prepared by the Sonogashira reaction Synthesis of 3-hydroxy-8-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (39) [ka]

[0333] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one [ka]

[0334] To a solution of S-bromo-3-((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one (1.45 g, 3.58 mmol, 1.0 equiv.) in THF (50 mL) in a 250 mL flask was added propargyl alcohol (501 mg, 8.94 mmol, 2.5 equiv.), Pd(PPh3)2Cl2 (251 mg, 0.360 mmol, 0.1 equiv.), and CuI (68 mg, 0.36 mmol, 0.1 equiv.), and the reaction was degassed with N2 at room temperature for 10 min. Triethylamine (724 mg, 7.15 mmol, 2.0 equiv.) was added in one portion, and the reaction mixture was placed in a preheated oil bath at 90 °C. Upon complete conversion of the starting material (as indicated by TLC), the reaction mixture was cooled to room temperature, quenched with water, and extracted with EtOAc (2 × 100 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by MPLC (SiO, 80 g, EtOAc in hexanes, 0–40%) to give 3-((tert-butyldimethylsilyl)oxy)-8-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (490 mg, 36%) as a brownish solid. 1 H NMR (400MHz,CDCl3)δ8.41(d,J=1.8Hz,1H),7.94(d,J=8.4Hz,1H),7.88(d,J=8.5Hz,1H),7.79 (dd,J=8.3,1.8Hz,1H),6.94-6.80(m,2H),4.54(d,J=6.1Hz,2H),1.00(s,9H),0.26(s,6H).

[0335] Step 2: Synthesis of 3-hydroxy-8-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one [ka]

[0336] 3-((tert-Butyldimethylsilyl)oxy)-8-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (160 mg, 0.420 mmol, 1.0 equiv.) was dissolved in MeOH (2 mL) and cooled to room temperature in an ice bath. The resulting yellow solution was stirred for 10 min. KHF (66 mg, 0.82 mmol, 2.0 equiv.) was then added in one portion, and the reaction was stirred at room temperature overnight. Upon complete consumption of the starting material (as indicated by TLC), the reaction mixture was filtered through a glass frit (Por. 4). The filter cake was washed with MeOH and dried under vacuum to give 3-hydroxy-8-(3-methoxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (112 mg, 0.420 mmol, 99%) as a light brown solid. 1 H NMR(400MHz,DMSO)δ10.45(s,1H),8.26(d,J=8.4Hz,1H),8.15(d,J=8.8Hz,1H),8.12(d,J=1.8Hz,1H),7 .87(dd,J=8.4,1.9Hz,1H),6.85(dd,J=8.7,2.4Hz,1H),6.75(d,J=2.4Hz,1H),5.41(s,1H),4.35(s,2H).

[0337] Further hydrogenation of the above compound was carried out as follows:

[0338] Step 3: Synthesis of 3-hydroxy-8-(3-hydroxypropyl)-6H-benzo[c]chromen-6-one (40) [ka]

[0339] A mixture of 3-hydroxy-8-(3-methoxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (86 mg, 0.32 mmol, 1.0 equiv.) and Pd(OH)2 / C (9 mg, 0.07 mmol, 0.2 equiv.) in MeOH (5 mL) was hydrogenated overnight at atmospheric pressure. The reaction mixture was filtered through a pad of Celite, and the solvent was evaporated in vacuo to give 3-hydroxy-8-(3-hydroxypropyl)-6H-benzo[c]chromen-6-one (70 mg, 80%) as a white solid. MS (ESI+): m / z = 271. 1 H NMR(400MHz,DMSO)δ8.13(d,J=8.3Hz,1H),8.04(dd,J=8.8,2.2Hz,1H),7.97(d,J=1.9Hz,1H),7.70(dd,J=8.3,2.0Hz,1H),6 .76(dd,J=8.7,2.4Hz,1H),6.64(d,J=2.5Hz,1H),4.52(s,1H),3.43(t,J=6.4Hz,2H),2.81-2.71(m,2H),1.86-1.73(m,2H).

[0340] Synthesis of 3-hydroxy-8-(3-methoxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (41) [ka]

[0341] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-(3-methoxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one [ka]

[0342] To a solution of 8-bromo-3-((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one (370 mg, 0.910 mmol, 1.0 equiv.) in THF (3.04 mL) in a 20 mL Biotage MW vial, 3-methoxyprop-1-yne (224 mg, 3.19 mmol, 3.5 equiv.), Pd(PPh3)2Cl2 (64 mg, 0.09 mmol, 0.1 equiv.), and CuI (17 mg, 0.09 mmol, 0.1 equiv.) were added, and the reaction was degassed with N2 at room temperature for 10 min. Triethylamine (277 mg, 2.74 mmol, 3.0 equiv.) was added in one portion, and the reaction mixture was placed in a preheated oil bath at 90 °C. Upon complete conversion of the starting material (as indicated by TLC), the reaction mixture was cooled to room temperature, quenched with water, and extracted with EtOAc (2 × 25 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by MPLC (SiO, 40 g, EtOAc in hexanes, 0–40%) to give 3-((tert-butyldimethylsilyl)oxy)-8-(3-methoxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (160 mg, 44%) as a brownish solid. 1 H NMR(400MHz,CDCl3)δ8.42(d,J=1.8Hz,1H),7.94(d,J=8.4Hz,1H),7.87(d,J=8.4Hz,1H),7.80 (dd,J=8.4,1.8Hz,1H),6.86-6.81(m,2H),4.35(s,2H),3.48(s,3H),1.00(s,9H),0.26(s,6H).

[0343] Step 2: Synthesis of 3-hydroxy-8-(3-methoxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one [ka]

[0344] 3-((tert-Butyldimethylsilyl)oxy)-8-(3-methoxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (160 mg, 0.410 mmol, 1.0 equiv.) was dissolved in MeOH (2 mL), cooled to room temperature in an ice bath, and the resulting yellow solution was stirred for 10 min. KHF (63 mg, 0.81 mmol, 2.0 equiv.) was then added in one portion, and the reaction was stirred overnight. Upon complete consumption of the starting material (as indicated by TLC), the reaction mixture was filtered through a glass frit (Por. 4), and the filter cake was washed with MeOH and dried under vacuum to give 3-hydroxy-8-(3-methoxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (85 mg, 75%) as a light brown solid. 1 H NMR(400MHz,DMSO)δ10.45(s,1H),8.28(d,J=8.5Hz,1H),8.20-8.13(m,2H),7.91(dd,J=8. 4,1.9Hz,1H),6.86(dd,J=8.7,2.4Hz,1H),6.76(d,J=2.4Hz,1H),4.38(s,2H),3.36(s,3H).

[0345] Synthesis of 3-hydroxy-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-6H-benzo[c]chromen-6-one (42) [ka]

[0346] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-6H-benzo[c]chromen-6-one [ka]

[0347] To a solution of 8-bromo-3-((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one (370 mg, 0.910 mmol, 1.0 equiv.) in THF (3.0 mL) in a 20 mL Biotage MW vial was added 2-methylbut-3-yn-2-ol (269 mg, 3.19 mmol, 3.5 equiv.), Pd(PPh3)2Cl2 (64 mg, 0.090 mmol, 0.1 equiv.), and CuI (17 mg, 0.090 mmol, 0.1 equiv.), followed by degassing with N2 for 10 min at room temperature. Triethylamine (277 mg, 2.74 mmol, 3.0 equiv.) was added in one portion, and the reaction mixture was placed in a preheated oil bath at 90 °C. Upon complete conversion of the starting material (as indicated by TLC), the reaction mixture was cooled to room temperature, quenched with water, and extracted with EtOAc (2 × 25 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by MPLC (SiO, 40 g, EtOAc in hexanes, 0–40%) to give 3-((tert-butyldimethylsilyl)oxy)-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-6H-benzo[c]chromen-6-one (233 mg, 0.570 mmol, 63%) as a yellowish solid. 1 H NMR(400MHz,CDCl3)δ8.41(d,J=1.8Hz,1H),7.94(d,J=8.4Hz,1H),7.88(d,J=8.3Hz,1H) ,7.78(dd,J=8.4,1.9Hz,1H),6.88-6.82(m,2H),1.65(s,6H),1.00(s,9H),0.26(s,6H).

[0348] Step 2: Synthesis of 3-hydroxy-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-6H-benzo[c]chromen-6-one [ka]

[0349] 3-((tert-Butyldimethylsilyl)oxy)-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-6H-benzo[c]chromen-6-one (233 mg, 0.570 mmol, 1.0 equiv.) was dissolved in MeOH (3 mL), cooled to room temperature in an ice bath, and the resulting yellow solution was stirred for 10 min. KHF (89 mg, 1.1 mmol, 2.0 equiv.) was then added in one portion, and the reaction was stirred overnight. Upon complete consumption of the starting material (as indicated by TLC), the reaction mixture was filtered through a glass frit (Por. 4), and the filter cake was washed with MeOH and dried under vacuum to give 3-hydroxy-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-6H-benzo[c]chromen-6-one (120 mg, 0.410 mmol, 72%) as a light brown solid. 1 H NMR(400MHz,DMSO)δ10.44(s,1H),8.25(d,J=8.5Hz,1H),8.16(d,J=8.9Hz,1H),8.10(d,J=1.8Hz,1H),7 .83(dd,J=8.4,1.9Hz,1H),6.86(dd,J=8.8,2.4Hz,1H),6.76(d,J=2.4Hz,1H),5.54(s,1H),3.32(s,6H).

[0350] Synthesis of 3-hydroxy-8-((1-hydroxycyclobutyl)ethynyl)-6H-benzo[c]chromen-6-one (43) [ka]

[0351] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-((1-hydroxycyclobutyl)ethynyl)-6H-benzo[c]chromen-6-one [ka]

[0352] To a solution of 8-bromo-3-((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one (250 mg, 0.620 mmol, 1.0 equiv.) in THF (2.06 mL) in a 20 mL Biotage MW vial was added 1-ethynylcyclobutan-1-ol (208 mg, 2.16 mmol, 3.5 equiv.), Pd(PPh3)2Cl2 (43 mg, 0.060 mmol, 0.1 equiv.), and CuI (12 mg, 0.060 mmol, 0.1 equiv.), and the reaction was degassed with N2 at room temperature for 10 min. Triethylamine (187 mg, 1.85 mmol, 3.00 equiv.) was added in one portion, and the reaction mixture was placed in a preheated oil bath at 90 °C. Upon complete conversion of the starting material (as indicated by TLC), the reaction mixture was cooled to room temperature, quenched with water, and extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by MPLC (SiO, 40 g, EtOAc in hexanes, 0–40%) to give 3-((tert-butyldimethylsilyl)oxy)-8-((1-hydroxycyclobutyl)ethynyl)-6H-benzo[c]chromen-6-one (195 mg, 75%) as a yellowish solid. 1 H NMR(400MHz,CDCl3)δ8.38(d,J=1.8Hz,1H),7.90(d,J=8.4Hz,1H),7.85(d,J=8.6Hz,1H),7.76(dd,J=8.4,1.9Hz,1 H),6.86-6.78(m,2H),2.61-2.52(m,2H),2.36(td,J=9.3,2.8Hz,2H),2.06-1.79(m,2H),1.00(s,9H),0.25(s,6H).

[0353] Step 2: Synthesis of 3-hydroxy-8-((1-hydroxycyclobutyl)ethynyl)-6H-benzo[c]chromen-6-one [ka]

[0354] 3-((tert-Butyldimethylsilyl)oxy)-8-((1-hydroxycyclobutyl)ethynyl)-6H-benzo[c]chromen-6-one (195 mg, 0.460 mmol, 1.0 equiv.) was dissolved in MeOH (2 mL), cooled to room temperature in an ice bath, and the resulting yellow solution was stirred for 10 min. KHF (72 mg, 0.93 mmol, 2.0 equiv.) was then added in one portion, and the reaction was stirred overnight. Upon complete consumption of the starting material (as indicated by TLC), the reaction mixture was filtered through a glass frit (Por. 4), and the filter cake was washed with MeOH and dried under vacuum to give 3-hydroxy-8-((1-hydroxycyclobutyl)ethynyl)-6H-benzo[c]chromen-6-one (100 mg, 70%) as a white solid. 1 H NMR(400MHz,DMSO)δ10.44(s,1H),8.26(d,J=8.4Hz,1H),8.17(d,J=8.9Hz,1H),8.13(d,J=1.8Hz,1H),7.87(dd,J=8.4,1.9Hz,1H),6.86(d d,J=8.7,2.4Hz,1H),6.76(d,J=2.4Hz,1H),5.95(s,1H),2.41(ddd,J=9.2,7.6,4.4Hz,2H),2.25(td,J=9.3,2.7Hz,2H),1.84-1.76(m,2H).

[0355] Synthesis of 3-hydroxy-9-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (44) [ka]

[0356] Step 1: Synthesis of 9-bromo-3-((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one [ka]

[0357] 9-Bromo-3-hydroxy-6H-benzo[c]chromen-6-one (610 mg, 2.10 mmol, 1.0 equiv) was suspended in DMF (10 mL) and triethylamine (636 mg, 6.29 mmol, 3.0 equiv) was added in one portion. The reaction mixture was cooled to 0 °C in an ice bath and stirred at this temperature for 10 min. Subsequently, TBSCl (411 mg, 2.72 mmol, 1.3 equiv) was added in one portion, and the reaction mixture was warmed to room temperature and stirred for an additional 2 h. Upon complete conversion of the starting material (as indicated by TLC), the reaction mixture was quenched with a half-saturated aqueous solution of sodium bicarbonate, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous Na2SO4. The crude product was purified by MPLC (SiO, 80 g, EtOAc in hexanes, 0–15%) to give 9-bromo-3-((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one (566 mg, 67%) as a light brown solid. 1 H NMR(400MHz,CDCl3)δ8.10(d,J=8.4Hz,1H),8.04(d,J=1.8Hz,1H),7.75(d,J=8.5 Hz, 1H), 7.52 (dd, J=8.5, 1.8Hz, 1H), 6.84-6.67 (m, 2H), 0.90 (s, 9H), 0.17 (s, 6H).

[0358] Step 2: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-9-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one [ka]

[0359] To a solution of 9-bromo-3-((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one (250 mg, 0.620 mmol, 1.0 equiv.) in THF (2.0 mL) in a 20 mL Biotage MW vial was added propargyl alcohol (208 mg, 2.16 mmol, 3.5 equiv.), Pd(PPh3)2Cl2 (43 mg, 0.060 mmol, 0.1 equiv.), and CuI (12 mg, 0.060 mmol, 0.1 equiv.), followed by sparging with N2 for 10 min at room temperature. Triethylamine (187 mg, 1.85 mmol, 3.0 equiv.) was added in one portion, and the reaction mixture was placed in a preheated oil bath at 90 °C. Upon complete conversion of the starting material (as indicated by TLC), the reaction mixture was cooled to room temperature, quenched with water, and extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by MPLC (SiO, 40 g, EtOAc in hexanes, 0–40%) to give 3-((tert-butyldimethylsilyl)oxy)-9-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (176 mg, 75%) as a yellowish solid. 1 H NMR(500MHz,DMSO)δ11.36(s,1H),8.28(s,1H),8.19(dd,J=8.8,1.6Hz,1H),8.13(d,J=8.2Hz,1H),7.51(d,J=8.2Hz,1 H),6.80(dd,J=8.8,2.4Hz,1H),6.71(d,J=2.4Hz,1H),5.63(d,J=124.9Hz,1H),4.39(s,2H),0.90(s,9H),0.17(s,6H).

[0360] Step 2: Synthesis of 3-hydroxy-9-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one [ka]

[0361] 3-((tert-Butyldimethylsilyl)oxy)-9-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (176 mg, 0.460 mmol, 1.0 equiv.) was dissolved in MeOH (2 mL), and the resulting yellow solution was stirred for 10 min. KHF (72 mg, 0.93 mmol, 2.0 equiv.) was then added in one portion, and the reaction was stirred overnight. Upon complete consumption of the starting material (as indicated by TLC), the reaction mixture was filtered through a glass frit (Por. 4), and the filter cake was washed with MeOH and dried under vacuum to give 3-hydroxy-8-((1-hydroxycyclobutyl)ethynyl)-6H-benzo[c]chromen-6-one (90 mg, 0.34 mmol, 73%) as a white solid. MS (ESI+): m / z = 267. 1 H NMR(500MHz,DMSO)δ11.36(s,1H),8.28(s,1H),8.19(dd,J=8.8,1.6Hz,1H),8.13(d,J=8.2Hz,1H),7.51( d,J=8.2Hz,1H),6.80(dd,J=8.8,2.4Hz,1H),6.71(d,J=2.4Hz,1H),5.63(d,J=124.9Hz,1H),4.39(s,2H).

[0362] Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-(3-(4-methylpiperazin-1-yl)prop-1-yn-1-yl)-6H-benzo[c]chromen-6-one [ka]

[0363] Mesyl chloride (0.037 mL, 0.47 mmol) was added to a solution of 3-((tert-butyldimethylsilyl)oxy)-8-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (140 mg, 0.360 mmol) and NEt (0.150 mL, 1.10 mmol) in THF (5 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. TLC showed complete conversion of the starting material. N-Methylpiperazine (111 mg, 1.10 mmol) was added, and the mixture was heated at 60 °C overnight. A saturated solution of ammonium chloride was added, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by MPLC (SiO, MeOH / DCM, 0% to 20%) to give 3-((tert-butyldimethylsilyl)oxy)-8-(3-(4-methylpiperazin-1-yl)prop-1-yn-1-yl)-6H-benzo[c]chromen-6-one, which was used in the next step without further purification.

[0364] Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-(3-(4-methylpiperazin-1-yl)propyl)-6H-benzo[c]chromen-6-one [ka]

[0365] A suspension of 3-((tert-butyldimethylsilyl)oxy)-8-(3-(4-methylpiperazin-1-yl)prop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (10) (67 mg, 0.14 mmol) and Pd(OH) / C (20 mg, 0.030 mmol) in MeOH (5 mL) was hydrogenated overnight at atmospheric pressure. The reaction mixture was filtered through a pad of Celite, and the solvent was evaporated in vacuo to give 3-((tert-butyldimethylsilyl)oxy)-8-(3-(4-methylpiperazin-1-yl)propyl)-6H-benzo[c]chromen-6-one (64 mg, 95%) as a yellowish oil, which was used in the next step without further purification.

[0366] Synthesis of 3-hydroxy-8-(3-(4-methylpiperazin-1-yl)propyl)-6H-benzo[c]chromen-6-one (45) [ka]

[0367] 45 was prepared starting from 3-((tert-butyldimethylsilyl)oxy)-8-(3-(4-methylpiperazin-1-yl)propyl)-6H-benzo[c]chromen-6-one (65 mg, 0.14 mmol) and KHF (22 mg, 0.28 mmol), which after purification by MPLC (SiO, MeOH / DCM, 5% to 30%) gave 3-hydroxy-8-(3-(4-methylpiperazin-1-yl)propyl)-6H-benzo[c]chromen-6-one (36 mg, 73%) as a yellowish solid. f =0.4 (MeOH / DCM 30 / 70). 1 H NMR(400MHz,CDCl3)δ8.04(s,1H),7.73(d,J=8.5Hz,1H),7.66(d,J=8.8Hz,1H),7.51(d,J=6 .5Hz,1H),6.61(d,J=9.1Hz,1H),6.53(s,1H),2.86-2.48(m,12H),2.39(s,3H),1.99(s,2H).

[0368] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-(3-morpholinoprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one [ka]

[0369] Mesyl chloride (0.04 mL, 0.51 mmol) was added to a solution of 3-((tert-butyldimethylsilyl)oxy)-8-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (150 mg, 0.039 mmol) and NEt (0.160 mL, 1.18 mmol) in THF (5 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. TLC showed complete conversion of the starting material. Morpholine (0.100 mL, 1.18 mmol) was added, and the mixture was heated at 60 °C overnight. A saturated solution of ammonium chloride was added, and the reaction mixture was extracted three times with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by MPLC (SiO, MeOH / DCM, 0% to 20%) to give 3-((tert-butyldimethylsilyl)oxy)-8-(3-morpholinoprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (101 mg, 57%), which was used in the next step without further purification.

[0370] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-(3-morpholinopropyl)-6H-benzo[c]chromen-6-one [ka]

[0371] A mixture of 3-(3-((tert-butyldimethylsilyl)oxy)-6-oxo-6H-benzo[c]chromen-8-yl)prop-2-yn-1-yl methanesulfonate OTBS-morpholine (100 mg, 0.220 mmol) and Pd(OH) / C (31 mg, 0.22 mmol) in MeOH (5 mL) was hydrogenated overnight under atmospheric pressure. The reaction mixture was filtered through a pad of Celite, and the solvent was concentrated under reduced pressure to give 3-((tert-butyldimethylsilyl)oxy)-8-(3-morpholinopropyl)-6H-benzo[c]chromen-6-one (70 mg, 69%) as a yellowish oil. 1H NMR(400MHz,CDCl3)δ8.16(d,J=1.9Hz,1H),7.91(d,J=8.3Hz,1H),7.87(d,J=9.4Hz,1H),7.61(dd,J=8.2,2.0Hz,1H),6.82(h,J=2.4Hz,2H),3.71 (t,J=4.7Hz,4H),2.76(d,J=7.8Hz,2H),2.43(t,J=4.6Hz,4H),2.36(dd,J=8.4,6.4Hz,2H),1.87(h,J=7.4,6.8Hz,2H),0.99(s,9H),0.24(s,6H).

[0372] Synthesis of 3-hydroxy-8-(3-morpholinopropyl)-6H-benzo[c]chromen-6-one (46) [ka]

[0373] Starting from 3-((tert-butyldimethylsilyl)oxy)-8-(3-morpholinopropyl)-6H-benzo[c]chromen-6-one (70 mg, 0.15 mmol) and KHF (24 mg, 0.31 mmol), 46 was prepared, which after purification by MPLC (SiO, MeOH / DCM, 5% to 30%) gave 3-hydroxy-8-(3-morpholinopropyl)-6H-benzo[c]chromen-6-one (70 mg, 69%) as a yellowish solid. f =0.4 (MeOH / DCM 30 / 70). 1 H NMR(400MHz,DMSO)δ10.31(s,1H),8.18(d,J=8.3Hz,1H),8.13(d,J=8.9Hz,1H),8.01(d,J=1.9Hz,1H),7.75(dd,J=8.3,2.0Hz,1H),6.83(dd,J=8. 7,2.4Hz,1H),6.74(d,J=2.4Hz,1H),3.57(t,J=4.7Hz,4H),2.74(t,J=7. 6Hz, 2H), 2.35-2.31 (m, 4H), 2.28 (t, J=7.2Hz, 2H), 1.78 (p, J=7.4Hz, 2H).

[0374] Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-(3-(piperidin-1-yl)prop-1-yn-1-yl)-6H-benzo[c]chromen-6-one [ka]

[0375] Mesyl chloride (0.0980 mL, 1.26 mmol) was added to a solution of 3-((tert-butyldimethylsilyl)oxy)-8-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (240 mg, 0.630 mmol) and NEt (0.260 mL, 1.89 mmol) in THF (10 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. TLC showed complete conversion of the starting material. Piperidine (0.081 mL, 0.82 mmol) was added, and the mixture was heated at 60 °C overnight. A saturated solution of ammonium chloride was added, and the reaction mixture was extracted three times with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by MPLC (SiO, MeOH / DCM, 0% to 20%) to give 3-((tert-butyldimethylsilyl)oxy)-8-(3-(piperidin-1-yl)prop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (66 mg, 23%). 1 H NMR(400MHz,CDCl3)δ8.41(d,J=1.8Hz,1H),7.93(d,J=8.4Hz,1H),7.88(d,J=8.3Hz,1H),7.79(dd,J=8.3, 1.8Hz, 1H), 6.85 (d, J=8.2Hz, 2H), 3.53 (s, 2H), 2.61 (s, 4H), 1.70-1.45 (m, 6H), 1.00 (s, 9H), 0.26 (s, 6H).

[0376] Synthesis of 3-hydroxy-8-(3-(piperidin-1-yl)prop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (47) [ka]

[0377] Starting from 3-((tert-butyldimethylsilyl)oxy)-8-(3-(piperidin-1-yl)prop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (60 mg, 0.13 mmol) and KHF (21 mg, 0.27 mmol), 47 was prepared to give, after purification by MPLC (SiO, EtOAc / cyclohexane 0% to 80%), 3-hydroxy-8-(3-(piperidin-1-yl)prop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (37 mg, 83%) as a yellowish solid. f =0.4 (40% EtOAc / hexane). 1 H NMR(400MHz,CDCl3)δ7.70-7.62(m,2H),7.59(d,J=1.7Hz,1H),7.54(dd,J=8.4,1.8Hz,1H),6.82(dd,J =8.7,2.4Hz,1H),6.55(d,J=2.4Hz,1H),3.36(s,2H),2.77(s,4H),1.80(q,J=5.7Hz,4H),1.58(b,2H).

[0378] Synthesis of tert-butyl (3-(3-((tert-butyldimethylsilyl)oxy)-6-oxo-6H-benzo[c]chromen-8-yl)prop-2-yn-1-yl)carbamate [ka]

[0379] To a thoroughly degassed solution of Pd(PPh)Cl (41.8 mg, 0.059 mmol, 0.1 equiv.) and CuI (11.3 mg, 0.059 mmol, 0.1 equiv.) in THF (10 mL), 8-bromo-3-((dimethyl(tert-butyl)silyl)oxy)-6H-benzo[c]chromen-6-one (250 mg, 0.590 mmol) and prop-2-ynyl-carbamic acid tert-butyl ester (277 mg, 1.79 mmol, 3.0 equiv.) was added NEt (0.330 mL, 2.38 mmol, 4.0 equiv.), and the mixture was heated at 70 °C overnight. The reaction mixture was diluted with saturated NH Cl and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by MPLC (SiO, EtOAc / hexanes, 0% to 20%) to give tert-butyl (3-(3-((tert-butyldimethylsilyl)oxy)-6-oxo-6H-benzo[c]chromen-8-yl)prop-2-yn-1-yl)carbamate (190 mg, 0.39 mmol, 66%) as a yellowish foam. f =0.4 (20% EtOAc / hexane). 1 H NMR(400MHz,CDCl3)δ8.39(d,J=1.7Hz,1H),7.93(d,J=8.4Hz,1H),7.87(dd,J=8.5,0.8Hz,1H),7.77(dd,J=8 .3,1.8Hz,1H),6.89-6.81(m,2H),4.79(s,1H),4.19(d,J=5.6Hz,2H),1.48(s,9H),1.00(s,9H),0.26(s,6H).

[0380] Synthesis of tert-butyl (3-(3-((tert-butyldimethylsilyl)oxy)-6-oxo-6H-benzo[c]chromen-8-yl)prop-2-yn-1-yl)carbamate

[0381] Synthesis of tert-butyl (3-(3-((tert-butyldimethylsilyl)oxy)-6-oxo-6H-benzo[c]chromen-8-yl)propyl)carbamate A suspension of tert-butyl (3-(3-((tert-butyldimethylsilyl)oxy)-6-oxo-6H-benzo[c]chromen-8-yl)prop-2-yn-1-yl)carbamate (190 mg, 0.390 mmol) and Pd(OH)2 / C 20% (56 mg, 0.79 mmol) was hydrogenated in methanol under atmospheric pressure and stirred overnight. The reaction mixture was filtered through a pad of Celite, and the solvent was evaporated in vacuo. The crude product was purified by MPLC (SiO2, EtOAc / cyclohexane, 0% to 20%) to give tert-butyl (3-(3-((tert-butyldimethylsilyl)oxy)-6-oxo-6H-benzo[c]chromen-8-yl)propyl)carbamate (175 mg, 91%) as a yellowish oil. R f =0.4 (20% EtOAc / hexane). 1 H NMR(400MHz,CDCl3)δ8.17(d,J=1.9Hz,1H),7.93(d,J=8.3Hz,1H),7.88(d,J=9.3Hz,1H),7.62(dd,J=8.2,2.0Hz,1H),6.84(dq,J=4 .5,2.4Hz,2H),4.57(s,1H),3.18(d,J=7.0Hz,2H),2.89-2.71(m,2H),1.88(p,J=7.3Hz,2H),1.45(s,9H),1.00(s,9H),0.26(s,6H).

[0382] Synthesis of tert-butyl (3-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)propyl)carbamate (48) [ka]

[0383] Starting with tert-butyl (3-(3-((tert-butyldimethylsilyl)oxy)-6-oxo-6H-benzo[c]chromen-8-yl)propyl)carbamate (170 mg, 0.350 mmol) and KHF (55 mg, 0.70 mmol), 48 was prepared, which after purification by MPLC (SiO, EtOAc / cyclohexane, 0% to 20%) gave tert-butyl (3-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)propyl)carbamate (108 mg, 0.290 mmol, 83%) as a white solid. f =0.4 (EtOAc / hexane 20 / 100). 1 H NMR(400MHz,DMSO)δ10.27(s,1H),8.15(dd,J=21.4,8.5Hz,2H),8.00(d,J=1.9Hz,1H),7.73(dd,J=8.3,2.0Hz,1H),6.87(t,J=5.4Hz,1 H),6.82(dd,J=8.7,2.4Hz,1H),6.73(d,J=2.3Hz,1H),2.94(q,J=6.6Hz,2H),2.70(t,J=7.6Hz,2H),1.72(p,J=7.3Hz,2H),1.36(s,9H).

[0384] Synthesis of 8-(3-aminopropyl)-3-hydroxy-6H-benzo[c]chromen-6-one hydrochloride (49) [ka]

[0385] HCl (4 M in dioxane, 1.35 mL, 5.4 mmol) was added to a solution of tert-butyl (3-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)propyl)carbamate (100 mg, 0.270 mmol) in dioxane (0.5 mL) at room temperature, and the reaction mixture was stirred overnight at room temperature, resulting in the formation of a precipitate. The solvent was concentrated under reduced pressure, and the crude product was triturated in EtO, filtered, and dried to give (3-aminopropyl)-3-hydroxy-6H-benzo[c]chromen-6-one hydrochloride (70 mg, 86%) as a white solid. MS (ESI+): m / z = 270. 1 H NMR(400MHz,DMSO)δ10.36(s,1H),8.22(d,J=8.3Hz,1H),8.14(d,J=8.8Hz,1H),8.05(d,J=1.9Hz,1H),7.83(s,3H),7.76(dd ,J=8.3,2.0Hz,1H),6.85(dd,J=8.7,2.4Hz,1H),6.76(dd,J=2.4,1.2Hz,1H),2.81(q,J=7.7,6.4Hz,4H),1.98-1.85(m,2H).

[0386] H) Spirocyclic (Oxetane and Azetidine) "A" Ring Analogues Synthesis of spiro[benzo[c]chromene-6,3'-oxetane]-3,8-diol (50) [ka]

[0387] Step 1: Synthesis of 2-bromo-4'-chloro-2'-fluoro-4-methoxy-1,1'-biphenyl [ka]

[0388] 2-Bromo-1-iodo-4-methoxybenzene (4.00 g, 12.8 mmol) and (4-chloro-2-fluorophenyl)boronic acid (1.01 g, 23.0 mmol) were dissolved in dioxane (80 mL). Tetrakis(triphenylphosphine)palladium(0) (738 mg, 0.640 mmol) was added, followed by a solution of Na2CO3 (2.70 g, 25.6 mmol), and the reaction mixture was heated at 80 °C overnight. The reaction mixture was diluted with a saturated solution of sodium carbonate and extracted twice with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by MPLC (SiO2, 0-8% DCM / cyclohexane) to give 2-bromo-4'-chloro-2'-fluoro-4-methoxy-1,1'-biphenyl (1.80 g, 45%) as a colorless oil. f =0.2 (DCM / cyclohexane 3%). 1 H NMR (400MHz, CDCl3) δ7.24-7.14 (m, 5H), 6.92 (dd, J=8.5, 2.6Hz, 1H), 3.84 (s, 3H).

[0389] Step 2: Synthesis of 2-bromo-4'-chloro-2'-fluoro-[1,1'-biphenyl]-4-ol [ka]

[0390] BBr3 (1 M in DCM, 6.97 mL, 6.97 mmol) was added to a solution of 2-bromo-4'-chloro-2'-fluoro-4-methoxy-1,1'-biphenyl (1.10 g, 3.48 mmol) in DCM (5 mL) at 0 °C, and the reaction mixture was allowed to warm to room temperature overnight. Methanol (10 mL) was added at 0 °C, and the solvent was evaporated in vacuo. The crude product was diluted with a saturated solution of sodium bicarbonate and extracted with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 2-bromo-4'-chloro-2'-fluoro-[1,1'-biphenyl]-4-ol (1.10 g), which was used in the next step without further purification. 1H NMR (400MHz, CDCl3) δ7.23-7.01 (m, 5H), 6.79 (dd, J=8.4, 2.6Hz, 1H).

[0391] Step 3: Synthesis of 4-(benzyloxy)-2-bromo-4'-chloro-2'-fluoro-1,1'-biphenyl [ka]

[0392] Benzyl bromide (0.470 mL, 3.98 mmol) was added to a solution of 2-bromo-4'-chloro-2'-fluoro-[1,1'-biphenyl]-4-ol (1.00 g, 3.31 mmol) and potassium carbonate (0.916 g, 6.63 mmol) in ACN (10 mL), and the mixture was heated at 60 °C overnight. The crude product was cooled to room temperature and extracted with ethyl acetate from a saturated solution of bicarbonate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by MPLC (25 g silica cartridge, EtOAc / cyclohexane, 0% to 10%) to give 4-(benzyloxy)-2-bromo-4'-chloro-2'-fluoro-1,1'-biphenyl (1.10 g, 85%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.48-7.35(m,5H),7.32(d,J=2.6Hz,1H),7.23-7.15(m,4H),6.99(dd,J=8.5,2.6Hz,1H),5.09(s,2H).

[0393] Step 4: Synthesis of 3-(4-(benzyloxy)-4'-chloro-2'-fluoro-[1,1'-biphenyl]-2-yl)oxetan-3-ol [ka]

[0394] nBuLi (1.6 M in hexane, 2.58 ml, 4.13 mmol) was added dropwise to a solution of 4-(benzyloxy)-2-bromo-4'-chloro-2'-fluoro-1,1'-biphenyl (900 mg, 2.29 mmol) in anhydrous THF (8 mL) at -78 °C. The pale red solution was stirred at -78 °C for 45 minutes, after which a solution of oxetan-3-one (662 mg, 9.19 mmol) was added dropwise and the reaction was allowed to warm to room temperature over 5 hours. The reaction mixture was quenched with saturated NH4Cl solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The crude product was purified by MPLC (25 g silica cartridge, EtOAc / cyclohexane 0% to 50%) to give 3-(4-(benzyloxy)-4'-chloro-2'-fluoro-[1,1'-biphenyl]-2-yl)oxetan-3-ol (383 mg, 85%) as a colorless oil. f =0.3 (EtOAc / hexane 50 / 50). 1 H NMR(400MHz,CDCl3)δ7.55-7.28(m,6H),7.19-7.14(m,3H),7.00(dd,J=8.5,2.6H z,1H),6.85(d,J=2.6Hz,1H),5.11(s,2H),4.82(s,2H),4.36(s,2H),2.77(s,1H).

[0395] Step 5: Synthesis of 8-(benzyloxy)-3-chlorospiro[benzo[c]chromene-6,3'-oxetane [ka]

[0396] NaH (70.5 mg, 1.76 mmol, 60% dispersion in mineral oil) was added to a solution of 3-(4-(benzyloxy)-4'-chloro-2'-fluoro-[1,1'-biphenyl]-2-yl)oxetan-3-ol (377 mg, 0.980 mmol) in DMF (4 mL) at 0 °C, and the reaction was allowed to warm to room temperature overnight. The crude product was extracted with a half-saturated solution of bicarbonate and ethyl acetate. The organic phase was dried over sodium sulfate and evaporated under vacuum. The crude product was purified by MPLC (25 g silica cartridge, EtOAc / cyclohexane, 0% to 5%) to give 8-(benzyloxy)-3-chlorospiro[benzo[c]chromene-6,3'-oxetane] (290 mg, 81%) as a yellow solid. R f =0.3 (10% EtOAc / hexane). 1 H NMR(400MHz,CDCl3)δ7.63(d,J=8.7Hz,1H),7.54(d,J=8.3Hz,1H),7.49-7.35(m,5H),7.32(d,J=2.5Hz,1H),7.08(d,J= 2.1Hz,1H),7.04(dd,J=8.7,2.6Hz,1H),7.01(dd,J=8.3,2.1Hz,1H),5.17(s,2H),5.08-5.01(m,2H),4.90-4.78(m,2H).

[0397] Step 6: Synthesis of 8-(benzyloxy)spiro[benzo[c]chromene-6,3'-oxetan]-3-ol [ka]

[0398] t-BuXPhos (9 mg, 0.020 mmol) was added to a suspension of Pd2dba3 (2.3 mg, 0.099 mmol) in dioxane (1 mL), degassed, and stirred for 5 min. 8-(benzyloxy)-3-chlorospiro[benzo[c]chromene-6,3'-oxetane (45 mg, 0.12 mmol) was added, followed by a solution of KOH (15 mg, 0.27 mmol) in water (0.3 mL) at room temperature, and the mixture was heated at 90 °C overnight. Water was added, and the mixture was extracted three times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and evaporated in vacuo. The crude product was purified by MPLC (25 g silica cartridge, EtOAc / cyclohexane, 0% to 30%) to give 8-(benzyloxy)spiro[benzo[c]chromene-6,3′-oxetan]-3-ol (30 mg, 0.87 mmol, 70%) as a white solid. R f =0.3 (20% EtOAc / hexanes). MS(ESI+): m / z=347. 1 H NMR(400MHz,DMSO)δ9.72(s,1H),7.69(d,J=8.7Hz,1H),7.60(d,J=8.3Hz,1H),7.53-7.3 6(m,6H),7.09(dd,J=8.6,2.6Hz,1H),6.56-6.43(m,2H),5.21(s,2H),4.86-4.80(m,4H).

[0399] Step 7: Synthesis of spiro[benzo[c]chromene-6,3'-oxetane]-3,8-diol [ka]

[0400] A suspension of 8-(benzyloxy)spiro[benzo[c]chromene-6,3'-oxetane]-3-ol (40 mg, 0.12 mmol) and Pd(OH) / C (16 mg, 0.23 mmol) in methanol (4 mL) was hydrogenated overnight at atmospheric pressure. The reaction mixture was filtered through a pad of Celite, the solvent was evaporated, and the product was further purified by filtration through a pad of silica using 10% DCM / methanol to give spiro[benzo[c]chromene-6,3'-oxetane]-3,8-diol (23 mg, 0.09 mmol, 78%) as a pale yellow solid. MS (ESI+): m / z = 257. 1 H NMR(400MHz,DMSO)δ9.66(d,J=19.6Hz,2H),7.57(d,J=8.5Hz,1H),7.54(d,J=8.4Hz,1H),7.09(d,J=2. 4Hz,1H),6.84(dd,J=8.4,2.4Hz,1H),6.51-6.44(m,2H),4.83(d,J=7.3Hz,2H),4.74(d,J=7.2Hz,2H).

[0401] Synthesis of spiro[azetidine-3,6'-benzo[c]chromene]-3',8'-diol (51) [ka]

[0402] Step 1: Synthesis of tert-butyl 3-(4'-chloro-2'-fluoro-4-methoxy-[1,1'-biphenyl]-2-yl)-3-hydroxyazetidine-1-carboxylate [ka]

[0403] nBuLi (1.6 M in hexane, 2.69 ml, 4.31 mmol) was added dropwise to a solution of 4-(benzyloxy)-2-bromo-4'-chloro-2'-fluoro-1,1'-biphenyl (900 mg, 2.29 mmol) in anhydrous THF (8 mL) at -78 °C. After stirring the pale red solution at -78 °C for 45 minutes, tert-butyl 3-oxoazetidine-1-carboxylate (1.84 g, 10.8 mmol) in anhydrous THF (5 mL) was added dropwise, and the reaction was allowed to warm to room temperature over 5 hours. The reaction mixture was quenched with saturated NH4Cl solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate. The crude product was purified by MPLC (80 g silica cartridge, EtOAc / cyclohexane, 0% to 50%) to give a mixture of two compounds, tert-butyl 3-(4'-chloro-2'-fluoro-4-methoxy-[1,1'-biphenyl]-2-yl)-3-hydroxyazetidine-1-carboxylate (400 mg, 36%) as a colorless oil. f =0.3 (EtOAc / hexane 50 / 50). 1 H NMR(400MHz,CDCl3)δ7.32(t,J=8.2Hz,1H),7.21-7.12(m,3H),6.93(dd,J=8.5,2.7Hz,1H),6.86(d,J=2.6H z,1H),4.18-3.97(m,1H),3.95-3.87(m,1H),3.86(s,3H),3.73(s,2H),2.70(d,J=14.5Hz,1H),1.39(s,9H).

[0404] Step 2: Synthesis of tert-butyl 3'-chloro-8'-methoxyspiro[azetidine-3,6'-benzo[c]chromene]-1-carboxylate [ka]

[0405] NaH (12 mg, 0.30 mmol) was added to a solution of tert-butyl 3-(4'-chloro-2'-fluoro-4-methoxy-[1,1'-biphenyl]-2-yl)-3-hydroxyazetidine-1-carboxylate (67 mg, 0.16 mmol) in DMF (3 mL) at 0 °C, and the reaction mixture was stirred for 3 h. Saturated NH4Cl solution was added, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by MPLC (EtOAc / cyclohexane, 0% to 8%) to give tert-butyl 3'-chloro-8'-methoxyspiro[azetidine-3,6'-benzo[c]chromene]-1-carboxylate (30 mg, 47%) as a yellowish solid. 1 H NMR (400MHz, CDCl3) δ7.63(d,J=8.5Hz,1H),7.55(d,J=8.3Hz,1H),7.09-6.93(m,4H),4.31(d,J=9.5Hz,2H),4.19(s,2H),3.88(s,3H),1.47(s,9H).

[0406] Step 3: Synthesis of tert-butyl 3'-hydroxy-8'-methoxyspiro[azetidine-3,6'-benzo[c]chromene]-1-carboxylate [ka]

[0407] 3'-Chloro-8'-methoxyspiro[azetidine-3,6'-benzo[c]chromene]-1-carboxylate (155 mg, 0.400 mmol, 1.0 equiv) was dissolved in 1,4-dioxane (1.5 mL), and Pd2dba3 (9 mg, 0.04 mmol, 0.1 equiv) and tBuXPhos (38 mg, 0.080 mmol, 0.2 equiv) were added to the solution. The mixture was then degassed using a N2 balloon for 10 minutes. A solution of KOH (67 mg, 1.2 mmol, 3.0 equiv) in water (0.3 mL) was then added in one portion, and the reaction mixture was then placed in an oil bath preheated to 90 °C. After stirring overnight, the reaction was cooled to room temperature, quenched with water, and the aqueous phase was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by flash column chromatography (SiO2, 20 g, EtOAc in hexanes, 0-30%) to afford tert-butyl 3'-hydroxy-8'-methoxyspiro[azetidine-3,6'-benzo[c]chromene]-1-carboxylate (120 mg, 0.330 mmol, 81%) as a pale yellow solid. f =0.3 (EtOAc / hexane 20%) as a yellowish solid. 1 H NMR(400MHz,DMSO)δ9.70(s,1H),7.68(d,J=8.6Hz,1H),7.61(d,J=8.5Hz,1H),7.05(d,J=2.6Hz,1H),7.00(dd,J=8.6,2.6Hz,1 H),6.51(dd,J=8.5,2.4Hz,1H),6.45(d,J=2.4Hz,1H),4.19(d,J=9.6Hz,2H),4.10(d,J=9.7Hz,2H),3.83(s,3H),1.41(s,9H).

[0408] Step 4: Synthesis of spiro[azetidine-3,6'-benzo[c]chromene]-3',8'-diol hydrobromide [ka]

[0409] BBr3 (0.54 mL, 0.54 mmol, 2.0 equiv) was added to a solution of tert-butyl 3'-hydroxy-8'-methoxyspiro[azetidine-3,6'-benzo[c]chromene]-1-carboxylate (100 mg, 0.270 mmol, 1.0 equiv) in DCM (5 mL) at 0 °C, and the mixture was allowed to warm to room temperature overnight. Methanol was added to the mixture at 0 °C, concentrated under reduced pressure, loaded onto silica, and purified by FC elution with MeOH / DCM (0% to 8%) to give spiro[azetidine-3,6'-benzo[c]chromene]-3',8'-diol (40 mg, 44%) as a white solid. MS (ESI+): m / z = 256. 1 H NMR(400MHz,DMSO)δ9.76(d,J=22.3Hz,2H),9.42(s,1H),8.91(s,1H),7.59(t,J=8.7Hz,2H),7.06(d,J=2.4Hz,1H),6.95-6.8 3(m,1H),6.54(dd,J=8.4,2.4Hz,1H),6.49(d,J=2.3Hz,1H),4.38(dt,J=12.6,6.8Hz,2H),4.24(ddd,J=12.2,7.4,4.0Hz,2H).

[0410] I) Ester "A" Ring Analogs with Peptide Substitutions Synthesis of 3-acetoxy-6-oxo-6H-benzo[c]chromene-8-carboxylic acid as a general intermediate [ka]

[0411] Acetyl chloride (0.36 mL, 5.2 mmol) was added to a suspension of 3-hydroxy-6-oxo-6H-benzo[c]chromene-8-carboxylic acid (2) (600 mg, 2.34 mmol) in THF (8 mL) at 0 °C, and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture remained a suspension (nothing was solubilized). HCl (1 M) was added to the suspension and stirred for 30 min at room temperature. The white suspension was filtered, and the solid was washed with cold water and dried under vacuum to give 17 (400 mg, 57%) as a white solid. 1H NMR(400MHz,CDCl3)δ8.72(d,J=1.8Hz,1H),8.53(d,J=8.5Hz,1H),8.47(d,J=8.8Hz,1H),8 .39(dd,J=8.4,1.9Hz,1H),7.34(d,J=2.2Hz,1H),7.26(dd,J=8.7,2.3Hz,1H),2.33(s,3H).

[0412] General Procedure for Peptide Coupling with FDPP and Deprotection with Potassium Carbonate Synthesis of 8-((2-morpholinoethyl)carbamoyl)-6-oxo-6H-benzo[c]chromen-3-yl acetate (52) [ka]

[0413] Step 1: Synthesis of 8-((2-morpholinoethyl)carbamoyl)-6-oxo-6H-benzo[c]chromen-3-yl acetate [ka]

[0414] DIPEA (0.15 mL, 0.86 mmol) was added to a solution of 3-acetoxy-6-oxo-6H-benzo[c]chromene-8-carboxylic acid (80 mg, 0.21 mmol) in DMF (2 mL), followed by pentafluorophenyl diphenylphosphinate (91 mg, 0.24 mmol). The mixture was stirred for 15 min, after which 2-morpholinoethan-1-amine (28 mg, 0.21 mmol) was added dropwise and stirring was continued for 1 h. The reaction mixture was extracted three times with EtOAc and a half-saturated solution of bicarbonate. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by MPLC (SiO, MeOH / DCM, 0%–10%) to give 8-((2-morpholinoethyl)carbamoyl)-6-oxo-6H-benzo[c]chromen-3-yl acetate (45 mg, 51%). R f =0.3 (10% MeOH / DCM). 1H NMR(400MHz,CDCl3)δ8.69(d,J=1.9Hz,1H),8.39(dd,J=8.4,2.0Hz,1H),8.17(d,J=8.4Hz,1H),8.10(d,J=8.7Hz,1H),7.20(d,J=2.2Hz,1H) ),7.17(dd,J=8.6,2.3Hz,1H),7.00(s,1H),3.78(t,J=4.6Hz,4H),3.63(q,J=5.6Hz,2H),2.68(d,J=4.6Hz,2H),2.57(s,4H),2.36(s,3H).

[0415] Step 2: Synthesis of 3-hydroxy-N-(2-morpholinoethyl)-6-oxo-6H-benzo[c]chromene-8-carboxamide [ka]

[0416] Potassium carbonate (36 mg, 0.26 mmol) was added to a solution of 8-((2-morpholinoethyl)carbamoyl)-6-oxo-6H-benzo[c]chromen-3-yl acetate (36 mg, 0.088 mmol) in MeOH at room temperature, and the reaction mixture was stirred at room temperature for 10 minutes. The mixture was loaded onto silica gel and purified by MPLC (SiO, MeOH / dichloromethane, 0%-10%) to give 3-hydroxy-N-(2-morpholinoethyl)-6-oxo-6H-benzo[c]chromene-8-carboxamide UA0350 (23 mg, 71%). f =0.2 (10% MeOH / DCM). 1 H NMR (400 MHz, DMSO) δ 10.48 (s, 1H), 8.76 (t, J = 5.6 Hz, 1H), 8.68 (d, J = 1.9 Hz, 1H), 8.36 (d, J = 8.6 Hz, 1H), 8.29 (dd, J = 8.5, 1.9 Hz, 1H), 8.24-8.19 (m, 1H), 6.90-6.84 (m, 1H), 6.78 (d, J = 2.4 Hz, 1H), 3.58 (t, J = 4.6 Hz, 4H), 3.43 (q, J = 6.5 Hz, 2H), 2.43 (s, 4H) (the two missing protons are obscured by the solvent).

[0417] Synthesis of 3-hydroxy-6-oxo-N-(2-(piperidin-1-yl)ethyl)-6H-benzo[c]chromene-8-carboxamide (53) [ka]

[0418] Step 1: Synthesis of 6-oxo-8-((2-(piperidin-1-yl)ethyl)carbamoyl)-6H-benzo[c]chromen-3-yl acetate [ka]

[0419] The compound was prepared according to the general procedure starting from 3-acetoxy-6-oxo-6H-benzo[c]chromene-8-carboxylic acid (120 mg, 0.320 mmol), pentafluorophenyl-diphenylphosphinate (136 mg, 0.35 mmol), 2-(piperidin-1-yl)ethan-1-amine (41 mg, 0.32 mmol), and DIPEA (0.224 mL, 1.29 mmol), to give 6-oxo-8-((2-(piperidin-1-yl)ethyl)carbamoyl)-6H-benzo[c]chromen-3-yl acetate 19 (65 mg, 49%) as a white solid after purification by MPLC (SiO, MeOH / DCM, 0% to 10%). f =0.3 (MeOH / DCM 10%). 1 H NMR(400MHz,CDCl3)δ8.74(d,J=1.9Hz,1H),8.40(dd,J=8.4,1.9Hz,1H),8.16(d,J=8.5Hz,1H),8.09(d,J=8.7Hz,1H),7.54-7.36( m,1H),7.22-7.13(m,2H),3.63(q,J=5.5Hz,2H),2.68(t,J=5.8Hz,2H),2.56(s,4H),2.36(s,3H),1.75-1.60(m,4H),1.51(s,2H).

[0420] Step 2: Synthesis of 3-hydroxy-6-oxo-N-(2-(piperidin-1-yl)ethyl)-6H-benzo[c]chromene-8-carboxamide [ka]

[0421] 3-Hydroxy-6-oxo-N-(2-(piperidin-1-yl)ethyl)-6H-benzo[c]chromene-8-carboxamide was prepared according to GP5 starting from 6-oxo-8-((2-(piperidin-1-yl)ethyl)carbamoyl)-6H-benzo[c]chromen-3-yl acetate 19 (49 mg, 0.12 mmol) and potassium carbonate (50 mg, 0.36 mmol), affording, after purification by MPLC (SiO, MeOH / DCM, 5% to 35%), 3-hydroxy-6-oxo-N-(2-(piperidin-1-yl)ethyl)-6H-benzo[c]chromene-8-carboxamide 53 (15 mg, 34%) as a white solid. f =0.3 (MeOH / DCM 20%). 1 H NMR(400MHz,DMSO)δ10.52(s,1H),8.83(s,1H),8.68(d,J=1.9Hz,1H),8.36(d,J=8.6Hz,1H),8.29(dd,J=8.5,1.9Hz,1H ),8.22(d,J=8.8Hz,1H),6.87(dd,J=8.7,2.4Hz,1H),6.78(d,J=2.4Hz,1H),3.47(d,J=21.5Hz,5H),1.65-1.19(m,9H).

[0422] Synthesis of hydroxy-N-(2-(4-methylpiperazin-1-yl)ethyl)-6-oxo-6H-benzo[c]chromene-8-carboxamide (54) [ka]

[0423] Step 1: Synthesis of 8-((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)-6-oxo-6H-benzo[c]chromen-3-yl acetate [ka]

[0424] The compound was prepared according to GP4 starting from 3-acetoxy-6-oxo-6H-benzo[c]chromene-8-carboxylic acid (120 mg, 0.260 mmol), pentafluorophenyl diphenylphosphinate (113 mg, 0.290 mmol), and DIPEA (0.187 mL, 1.070 mmol), and after purification by MPLC (SiO, MeOH / DCM, 0% to 10%), 8-((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)-6-oxo-6H-benzo[c]chromen-3-yl acetate (20) (73 mg, 59%) was obtained as a white solid. f =0.3 eluent (MeOH / DCM 10%). 1 H NMR(400MHz,CDCl3)δ8.68(d,J=1.9Hz,1H),8.39(dd,J=8.4,2.0Hz,1H),8.16(d,J=8.5Hz,1H),8.09(d,J=8.7Hz,1H),7.19( d,J=2.2Hz,1H),7.16(dd,J=8.6,2.3Hz,1H),7.11(s,1H),3.62(q,J=5.6Hz,2H),2.73-2.58(m,10H),2.37(d,J=5.2Hz,6H).

[0425] Step 2: Synthesis of hydroxy-N-(2-(4-methylpiperazin-1-yl)ethyl)-6-oxo-6H-benzo[c]chromene-8-carboxamide [ka]

[0426] Starting from 8-((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)-6-oxo-6H-benzo[c]chromen-3-yl acetate 20 (60 mg, 0.14 mmol) and potassium carbonate (39 mg, 0.28 mmol), 3-hydroxy-N-(2-(4-methylpiperazin-1-yl)ethyl)-6-oxo-6H-benzo[c]chromene-8-carboxamide was prepared according to GP5. After purification by MPLC (RP-C18, MeOH / water, 0% to 95%), 3-hydroxy-N-(2-(4-methylpiperazin-1-yl)ethyl)-6-oxo-6H-benzo[c]chromene-8-carboxamide (27 mg, 51%) was obtained. R f =0.1 eluent (MeOH / DCM 30%). 1 HNMR(400MHz,DMSO)δ8.75(t,J=5.6Hz,1H),8.68(d,J=1.8Hz,1H),8.36(d,J=8.6Hz,1H),8.29(dd,J=8.5,1.9Hz,1H),8.22(d,J= 8.9Hz,1H),8.18(s,1H),6.88(dd,J=8.7,2.4Hz,1H),6.78(d,J=2.4Hz,1H),3.47-3.40(m,2H),2.48-2.30(m,10H),2.20(s,3H).

[0427] J) Analogs of the "A" group of esters with reverse amide substitution The synthesis of the reverse amides was based on the general intermediates described below.

[0428] Synthesis of N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-chloroacetamide [ka]

[0429] Step 1: Synthesis of 8-amino-3-(benzyloxy)-6H-benzo[c]chromen-6-one [ka]

[0430] 8-Amino-3-hydroxy-6H-benzo[c]chromen-6-one (15) (864 mg, 3.80 mmol) was dissolved in DMF (13 mL) and cooled to 0 °C. NaH (152 mg, 3.80 mmol) was then added in one portion. After stirring for 15 min, benzyl chloride (0.44 mL, 3.80 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature and continued stirring overnight. The reaction was then quenched with half-saturated NaHCO solution and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The crude product was purified by MPLC (SiO, ethyl acetate / hexanes, 0–50%) to give 8-amino-3-(benzyloxy)-6H-benzo[c]chromen-6-one (738 mg, 61%) as an ochre solid. 1 H NMR (400MHz, DMSO) δ8.02(dd,J=17.2,8.7Hz,2H),7.51-7.34(m,6H),7.14(dd,J=8.7,2.6Hz,1H),7.06-6.95(m,2H),5.79(s,2H),5.19(s,2H).

[0431] Step 2: Synthesis of N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-chloroacetamide [ka]

[0432] 8-Amino-3-(benzyloxy)-6H-benzo[c]chromen-6-one (738 mg, 2.33 mmol) was added to a solution of triethanolamine (TEA) (0.324 mL, 2.56 mmol) in DMF (16 mL). The mixture was stirred for 10 min at room temperature. Chloroacetyl chloride (0.205 mL, 2.33 mmol) was added to the mixture, and the temperature was maintained at 0-5 °C. The resulting solution was then stirred at room temperature for 4-6 h. Completion of the reaction was monitored by TLC. The solution was then added to crushed ice, and the separated precipitate was filtered and dried under vacuum. The product was recrystallized from methanol to give N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-chloroacetamide (833 mg, 91%) as a slightly yellowish solid. 1 H NMR(400MHz,DMSO)δ10.72(s,1H),8.52(d,J=2.4Hz,1H),8.31(d,J=8.8Hz,1H),8.19(d,J=8.8Hz, 1H), 8.03(dd,J=8.8,2.4Hz,1H),7.48-7.35(m,5H),7.10-7.06(m,2H),5.22(s,2H),4.32(s,2H).

[0433] Synthesis of N-(3-(hydroxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-morpholinoacetamide (55) [ka]

[0434] Step 1: Synthesis of N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-morpholinoacetamide [ka]

[0435] N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-chloroacetamide (60 mg, 0.15 mmol) was suspended in THF (5 mL) and potassium carbonate (42 mg, 0.30 mmol) was added in one portion. A minimal amount of DMF (2-3 mL) was added dropwise to solubilize the suspension. Morpholine (0.014 mL, 0.17 mmol) was then added via syringe and the reaction was heated to 80° C. for 2 h. Upon complete consumption of the starting material (as indicated by TLC), the reaction was cooled to room temperature, after which the mixture was concentrated under reduced pressure. The crude product was purified by MPLC (SiO, MeOH in DCM, 0–10%) to give N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-morpholinoacetamide (46 mg, 0.10 mmol, 68%) as a white solid. 1 H NMR (400MHz,DMSO)δ10.17(s,1H),8.60(d,J=2.3Hz,1H),8.29(d,J=8.9Hz,1H),8.21(d,J=8.7Hz,1H),8.13(dd,J=8.8,2 .4Hz,1H),7.50-7.35(m,5H),7.11-7.06(m,2H),5.23(s,2H),3.66(t,J=4.7Hz,4H),3.19(s,2H),2.55-2.52(m,4H).

[0436] Step 2: Synthesis of N-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)-2-morpholinoacetamide [ka]

[0437] A solution of N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-morpholinoacetamide (40 mg, 0.090 mmol) and Pd(OH) / C (7 mg, 0.009 mmol) in MeOH (2 mL) and DCM (2 mL) was stirred under hydrogen at atmospheric pressure overnight. The reaction mixture was filtered through a pad of Celite, and the solvent was evaporated in vacuo to give N-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)-2-morpholinoacetamide (25 mg, 78%) as an off-white solid. 1 H NMR (400 MHz, DMSO) δ 10.26 (s, 1H), 10.14 (s, 1H), 8.57 (d, J = 2.3 Hz, 1H), 8.23 (d, J = 9.0 Hz, 1H), 8.10 (d, J = 8.8 Hz, 2H), 6.83 (dd, J = 8.7, 2.5 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 3.65 (t, J = 4.8 Hz, 4H), 3.18 (s, 2H) (clean, but the four aliphatic protons are obscured by the solvent).

[0438] Synthesis of N-(3-(hydroxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-(piperidin-1-yl)acetamide (56) [ka]

[0439] Step 1: Synthesis of N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-(piperidin-1-yl)acetamide [ka]

[0440] N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-chloroacetamide (200 mg, 0.510 mmol) was suspended in THF (5 mL) and potassium carbonate (140 mg, 1.02 mmol) was added in one portion. A minimal amount of DMF (5-6 mL) was added to solubilize the suspension. Piperidine (0.055 mL, 0.56 mmol) was then added dropwise via syringe and the reaction was heated to 80° C. for 2 h. Upon complete consumption of the starting material (as indicated by TLC), the reaction was cooled to room temperature, after which the mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (MeOH in DCM, 0-10%) to give N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-(piperidin-1-yl)acetamide (154 mg, 0.51 mmol, 69%) as a white solid. 1 H NMR(400MHz,DMSO)δ10.10(s,1H),8.61(d,J=2.3Hz,1H),8.28(d,J=8.9Hz,1H),8.20(d,J=8.8Hz,1H),8.12(dd,J=8.8,2.4Hz,1H), 7.53-7.37(m,5H),7.13-7.05(m,2H),5.23(s,2H),3.13(s,2H),2.47(d,J=5.0Hz,4H),1.58(p,J=5.6Hz,4H),1.41(q,J=6.0Hz,2H).

[0441] Step 2: Synthesis of N-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)-2-(piperidin-1-yl)acetamide [ka]

[0442] A solution of N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-(piperidin-1-yl)acetamide (154 mg, 0.350 mmol) and Pd(OH) / C (34 mg, 0.035 mmol) in MeOH (3 mL) and DCM (3 mL) was stirred under hydrogen at atmospheric pressure overnight. The reaction mixture was filtered through a pad of Celite, and the solvent was evaporated in vacuo to give N-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)-2-(piperidin-1-yl)acetamide (95 mg, 77%) as a dark yellow solid. 1 H NMR(400MHz,DMSO)δ10.07(s,1H),8.58(d,J=2.3Hz,1H),8.21(d,J=8.9Hz,1H),8.09(dd,J=8.8,2.8Hz,2H),6.83(dd,J= 8.7,2.4Hz,1H),6.74(d,J=2.4Hz,1H),3.12(s,2H),2.47(d,J=5.6Hz,4H),1.59(q,J=5.6Hz,4H),1.41(q,J=6.2Hz,2H). MS(ESI+):m / z=353.

[0443] Synthesis of N-(3-(hydroxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-(4-methylpiperazin-1-yl)acetamide (57) [ka]

[0444] Step 1: Synthesis of N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-(piperidin-1-yl)acetamide [ka]

[0445] N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-chloroacetamide (200 mg, 0.510 mmol) was suspended in THF (5 mL) and potassium carbonate (140 mg, 1.02 mmol) was added in one portion. A minimal amount of DMF (5-6 mL) was added to solubilize the suspension. 1-Methylpiperazine (0.062 mL, 0.56 mmol) was then added dropwise via syringe and the reaction was heated to 80° C. for 2 h. Upon complete consumption of the starting material (as indicated by TLC), the reaction was cooled to room temperature, after which the mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (MeOH in DCM, 0-20%) to give N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-(piperidin-1-yl)acetamide (148 mg, 64%) as a white solid. 1 H NMR(400MHz,DMSO)δ10.21(s,1H),8.59(d,J=2.3Hz,1H),8.29(d,J=8.9Hz,1H),8.20(d,J=8.8Hz,1H),8.11(dd,J =8.8,2.3Hz,1H),7.55-7.30(m,5H),7.14-7.03(m,2H),5.23(s,2H),3.17(s,2H),2.68-2.66(m,8H),2.39(s,3H).

[0446] Step 2: Synthesis of N-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)-2-(4-methylpiperazin-1-yl)acetamide [ka]

[0447] A solution of N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-(piperidin-1-yl)acetamide (148 mg, 0.320 mmol), Pd(OH) / C (40 mg, 0.032 mmol) in MeOH (3 mL) and DCM (3 mL) was stirred under hydrogen at atmospheric pressure overnight. The reaction mixture was filtered through a pad of Celite, and the solvent was evaporated in vacuo to give N-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)-2-(4-methylpiperazin-1-yl)acetamide (69 mg, 58%) as a pale yellow solid. MS (ESI+): m / z = 368.

[0448] K) Analogues of the "A" group of thionoesters Synthesis of 3,8-dimethoxy-6H-benzo[c]chromene-6-thione (58) [ka]

[0449] A mixture of 3,8-dimethoxy-6H-benzo[c]chromen-6-one (described above) (140 mg, 0.154 mmol) and Lawesson's reagent (552 mg, 1.34 mmol) was refluxed overnight in toluene. The reaction was monitored by TLC and found to be incomplete, so Lawesson's reagent (884 mg, 2.19 mmol) was added and refluxing continued overnight. The reaction mixture was filtered, and the solvent was evaporated under vacuum. The crude product was purified by MPLC (SiO, EtOAc / cyclohexane, 0% to 25%) to give 3,8-dimethoxy-6H-benzo[c]chromene-6-thione (110 mg, 74%) as a yellow solid. f =0.4 (20% EtOAc / hexanes) yellow solid. 1 H NMR(400MHz,CDCl3)δ8.21(d,J=2.8Hz,1H),7.92(dd,J=8.9,6.7Hz,2H),7.39(dd,J= 8.9,2.8Hz,1H),7.03(d,J=2.6Hz,1H),6.99-6.95(dd,1H),3.96(s,3H),3.88(s,3H).

[0450] Synthesis of 3,8-dihydroxy-6H-benzo[c]thiochromen-6-one (59) [ka]

[0451] 58 was prepared in four steps from 17 according to the procedure described in Org. Lett., Vol. 7, No. 3, 2005, pp. 411-414. The product was obtained as a white solid. Analytical data were in full agreement with those previously reported in the literature.

[0452] Step 5: Synthesis of 3,8-dihydroxy-6H-benzo[c]thiochromen-6-one [ka]

[0453] In a sealed tube, a mixture of lithium chloride (65 mg, 1.5 mmol) and 3,8-dimethoxy-6H-benzo[c]thiochromen-6-one (70 mg, 0.26 mmol) in DMF (1 mL) was heated at 130° C. for 2 days. The solvent was evaporated under vacuum, and the crude product was loaded onto silica gel and purified by MPLC (SiO, methanol / dichloromethane, 0% to 10%) to give 3,8-dihydroxy-6H-benzo[c]thiochromen-6-one (28 mg, 45%) as a yellow solid. 1 H NMR(400MHz,DMSO)δ10.19(s,2H),8.32(dd,J=15.6,9.1Hz,2H),7.53(d,J=2.8Hz,1 H),7.31(dd,J=8.9,2.9Hz,1H),6.92(dd,J=8.9,2.6Hz,1H),6.87(d,J=2.5Hz,1H).

[0454] Synthesis of 3,8-dihydroxy-6H-benzo[c]thiochromene 5,5-dioxide (62) [ka]

[0455] Step 1: Synthesis of 3,8-dimethoxy-6H-benzo[c]thiochromene (60) [ka]

[0456] LAH (35 mg, 0.91 mmol) was added to a solution of 3,8-dimethoxy-6H-benzo[c]thiochromen-6-one (250 mg, 0.910 mmol) in DCM (10 mL) at 0 °C, and the mixture was stirred overnight at room temperature. Workup: 10 mL of EtO, followed by 0.05 mL of MeOH, NaOH (1N, 0.025 mL) was added, followed by 3 drops of water, and stirring was continued for 15 min. NaSO was added, and the reaction mixture was filtered and concentrated under reduced pressure. The crude product was dissolved in DCM (5 mL) and cooled to -78 °C. TFA (0.354 mL, 4.59 mmol) was added dropwise and stirred for 60 min at -78 °C, after which EtSiH (0.290 mL, 1.84 mmol) was added, and the reaction was allowed to warm to room temperature overnight. The reaction mixture was washed with saturated Na2CO3 solution, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 230 mg of crude material, which was triturated in Et2O to give 3,8-dimethoxy-6H-benzo[c]thiochromene (160 mg, 67%) as a white solid. 1 H NMR(400MHz,CDCl3)δ7.64(d,J=8.7Hz,1H),7.54(d,J=8.6Hz,1H),6.94(d,J=2.7Hz,1H),6.89(dd,J=8. 6,2.7Hz,1H),6.81(dd,J=8.7,2.7Hz,1H),6.77(d,J=2.7Hz,1H),3.84(s,3H),3.82(s,3H),3.81(s,2H).

[0457] Step 2: Synthesis of 3,8-dimethoxy-6H-benzo[c]thiochromene 5,5-dioxide (61) [ka]

[0458] m-CPBA (150 mg, 0.62 mmol) was added to a solution of 3,8-dimethoxy-6H-benzo[c]thiochromene (80 mg, 0.31 mmol) in dichloromethane (4 mL) at 0 °C, and the mixture was allowed to warm to room temperature over 2 h. 1 M NaSO solution was added to the reaction mixture. The aqueous phase was extracted with EtOAc, and the organic phase was washed twice with saturated bicarbonate solution. The organic phase was dried over sodium sulfate. The organic phase was concentrated under reduced pressure, filtered through a pad of Celite with EtOAc, and then concentrated to give 3,8-dimethoxy-6H-benzo[c]thiochromene 5,5-dioxide (66 mg, 73%) as a yellowish solid. 1 H NMR(400MHz,CDCl3)δ7.71(dd,J=8.7,4.4Hz,2H),7.52(d,J=2.8Hz,1H),7.20(dd,J=8.8,2.7Hz ,1H),7.01(dd,J=8.7,2.7Hz,1H),6.83(d,J=2.7Hz,1H),4.36(s,2H),3.91(s,3H),3.86(s,3H).

[0459] Step 3: Synthesis of 3,8-dihydroxy-6H-benzo[c]thiochromene 5,5-dioxide (62) [ka]

[0460] BBr3 (0.76 mL, 0.76 mmol) was added to a solution of 3,8-dimethoxy-6H-benzo[c]thiochromene 5,5-dioxide (55 mg, 0.19 mmol) in DCM (2 mL) at -70 °C, and the mixture was allowed to warm to room temperature overnight. TLC showed two spots. Methanol was added to the mixture at 0 °C, concentrated under reduced pressure, loaded onto silica, and purified by MPLC (SiO2, MeOH / DCM, 0% to 8%) to give 3,8-dihydroxy-6H-benzo[c]thiochromene 5,5-dioxide (23 mg, 46%) as a yellowish solid. 1H NMR(400MHz,DMSO)δ10.29(s,1H),9.87(s,1H),7.79(d,J=8.8Hz,1H),7.71(d,J=8.6Hz,1H),7.24(d,J= 2.6Hz,1H),7.11(dd,J=8.6,2.7Hz,1H),6.86(dd,J=8.5,2.6Hz,1H),6.82(d,J=2.6Hz,1H),4.65(s,2H).

[0461] Synthesis of 3,8-dihydroxy-6H-benzo[c]thiochromene 5-oxide (64) [ka]

[0462] Step 1: Synthesis of 6H-benzo[c]thiochromene-3,8-diol (63) [ka]

[0463] BBr3 (0.81 mL, 0.81 mmol) was added to a solution of 3,8-dimethoxy-6H-benzo[c]thiochromene (70 mg, 0.27 mmol) in DCM (4 mL) at 0 °C and allowed to warm to room temperature overnight. The reaction mixture was poured into methanol at 0 °C and stirred for 10 min, after which the solvent was evaporated under vacuum. The crude product was filtered through a silica pad to give 6H-benzo[c]thiochromene-3,8-diol (40 mg, 64) as a gray solid. R f =0.75 (EtOAc / hexane 50 / 50). 1 H NMR (400MHz, DMSO) δ9.56(s,1H),9.50(s,1H),7.56(d,J=8.6Hz,1H),7.44(d,J=8.5Hz,1H),6.75-6.64(m,4H),5.76(s,1H),3.78(s,2H).

[0464] Step 2: Synthesis of 3,8-dihydroxy-6H-benzo[c]thiochromene 5-oxide (64) [ka]

[0465] A solution of NaIO4 (26 mg, 0.12 mmol) in water (0.3 mL) was added to a solution of 6H-benzo[c]thiochromene-3,8-diol (28 mg, 0.12 mmol) in MeOH (1.5 mL) at room temperature, and the mixture was stirred overnight. A precipitate formed. TLC still indicated starting material. Therefore, 0.2 equivalents of NaIO4 dissolved in 0.2 mL of water was added, and stirring continued; the reaction was not complete but was quenched. DCM was added to dissolve the precipitate, and the crude product was loaded onto silica and purified by MPLC (SiO2, MeOH / DCM, 0% to 8%) to give 3,8-dihydroxy-6H-benzo[c]thiochromene 5-oxide (16 mg, 53%) as a gray solid. R f =0.3 (MeOH / DCM 5%). 1 H NMR(400MHz,DMSO)δ10.05(s,1H),9.72(s,1H),7.64(dd,J=32.7,8.5Hz,2H),7.11(d,J=2. 6Hz,1H),7.00(dd,J=8.5,2.6Hz,1H),6.83(d,J=6.7Hz,2H),4.21(dd,J=90.8,14.2Hz,2H).

[0466] l) Ester "A" group having bicyclopentane substitution Synthesis of 3-hydroxy-8-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-6H-benzo[c]chromen-6-one (65) [ka]

[0467] Step 1: Synthesis of 3-(benzyloxy)-8-(3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)bicyclo[1.1.1]pentan-1-yl)-6H-benzo[c]chromen-6-one [ka]

[0468] To a solution of 2-(3-bromobicyclo[1.1.1]pentan-1-yl)-4,4-dimethyl-4,5-dihydrooxazole (192 mg, 0.788 mmol) in 2.7 mL of anhydrous hexane was carefully added dropwise tert-butyllithium (1.7 M in pentane, 0.95 mL, 1.63 mmol). The reaction mixture was stirred at -78 °C for 60 minutes. A solution of ZnCl2 [0.5 M in THF] (1.78 mL, 0.89 mmol) was added dropwise. The reaction mixture was allowed to reach room temperature for 60 minutes. The resulting zincate solution was slowly added dropwise to a mixture of 3-(benzyloxy)-8-bromo-6H-benzo[c]chromen-6-one (200 mg, 0.525 mmol), RuPhos (49 mg, 0.105 mmol), and tris(dibenzylideneacetone)dipalladium (48 mg, 0.052 mmol) at room temperature under a N atmosphere. The reaction vessel was sealed and heated at 60 °C for 12 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was adsorbed onto SiO. The residue was purified by MPLC (SiO, EtOAc / cyclohexane, 0% to 20%) to give 3-(benzyloxy)-8-(3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)bicyclo[1.1.1]pentan-1-yl)-6H-benzo[c]chromen-6-one (90 mg, 0.19 mmol, 37%). 1 H NMR(500MHz,CDCl3)δ8.18(d,J=1.9Hz,1H),7.94(t,J=8.4Hz,2H),7.64(dd,J=8.2,1.9Hz,1H),7.45-7.35(m ,5H),6.99(dd,J=8.8,2.6Hz,1H),6.93(d,J=2.6Hz,1H),5.14(s,2H),3.97(s,2H),2.40(s,6H),1.31(s,6H).

[0469] Step 2: Synthesis of 3-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)bicyclo[1.1.1]pentane-1-carboxylic acid [ka]

[0470] A suspension of 3-(benzyloxy)-8-(3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)bicyclo[1.1.1]pentan-1-yl)-6H-benzo[c]chromen-6-one (110 mg, 0.236 mmol) in 6 mL of HCl was heated at 100° C. overnight in a sealed tube. The reaction mixture was cooled to room temperature, filtered, washed with water, and dried under high vacuum. The crude product was purified by FC elution (MeOH / DCM, 0% to 8%) to give 3-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (70 mg, 72%) as a beige solid. LCMS mass not available, TLC / MS 413. f =0.5 (10% MeOH / DCM). 1 H NMR(400MHz,DMSO)δ12.45(s,1H),8.29(dd,J=13.3,8.6Hz,2H),8.00(d,J=1.9Hz,1H),7. 81(dd,J=8.3,1.9Hz,1H),7.53-7.32(m,5H),7.13-7.06(m,2H),5.24(s,2H),2.33(s,6H).

[0471] Step 3: Synthesis of 3-(benzyloxy)-8-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-6H-benzo[c]chromen-6-one [ka]

[0472] Borane dimethyl sulfide complex (0.22 ml, 0.44 mmol, 2 M in THF, 3.0 equiv.) was added to a solution of 3-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (60 mg, 0.15 mmol, 1.0 equiv.) in THF (2 mL) at 0 °C, and stirring was continued for 2 h from 0 °C to room temperature. MeOH was added, and the crude product was loaded onto silica and purified by FC elution (MeOH / DCM, 0% to 5%) to give 3-(benzyloxy)-8-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-6H-benzo[c]chromen-6-one (847 mg, 0.12 mmol, 81%) as a beige solid. f =0.6 (MeOH / DCM 5%). 1 H NMR(400MHz,CDCl3)δ8.19(d,J=1.9Hz,1H),7.94(dd,J=8.6,3.3Hz,2H),7.65(dd,J=8.3,1.9Hz,1H),7.42(dtdd,J=14.5,8 .7,6.9,1.8Hz,5H),6.99(dd,J=8.8,2.6Hz,1H),6.94(d,J=2.5Hz,1H),5.30(s,1H),5.14(s,2H),3.74(s,2H),2.07(s,6H).

[0473] Step 4: Synthesis of 3-hydroxy-8-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-6H-benzo[c]chromen-6-one [ka]

[0474] 3-(Benzyloxy)-8-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-6H-benzo[c]chromen-6-one (45 mg, 0.11 mmol) was dissolved in MeOH (3 mL) and DCM (1 mL). PtO (6.4 mg, 0.023 mmol) was added, and the mixture was hydrogenated under atmospheric pressure for 5 h. The reaction mixture was filtered through a Celite pad and concentrated under reduced pressure. The crude product was purified by FC MeOH / DCM (0% to 10%) to give 3-hydroxy-8-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-6H-benzo[c]chromen-6-one (1.5 mg, 0.069 mmol, 62%) as a white solid. f = 0.3 (EtOAc / hexane 50%); R f =0.5 (MeOH / DCM 10%). 1 H NMR(400MHz,DMSO)δ10.31(s,1H),8.21(d,J=8.3Hz,1H),8.14(d,J=8.8Hz,1H),7.94(d,J=1.9Hz,1H),7.74(dd,J=8.2,1 .9Hz,1H),6.84(dd,J=8.7,2.4Hz,1H),6.75(d,J=2.4Hz,1H),4.58(t,J=5.5Hz,1H),3.48(d,J=5.6Hz,2H),1.96(s,6H).

[0475] Synthesis of 2.7-membered urolithin A analogues A) Lactone and Ether "A" Group Analogues Synthesis of 3,9-dihydroxydibenz[c,e]oxepin-5(7H)-one (66) [ka]

[0476] Step 1: Synthesis of 2-bromo-5-methoxybenzoate [ka]

[0477] 2-Bromo-5-methoxybenzoic acid (11.6 g, 50.0 mmol, 1.00 equiv) was dissolved in MeOH (250 mL) and the resulting solution was cooled to 0 °C in an ice bath. Stirring at 0 °C was continued for 10 min, after which SOCl (17.8 g, 150 mmol, 3.00 equiv) was added dropwise via addition funnel. The reaction was allowed to warm to room temperature, and as soon as no more starting material was observed (overnight stirring), all volatiles were evaporated, and the crude residue was taken up in diethyl ether and filtered through silica. The filtrate was concentrated under reduced pressure to give pure methyl 2-bromo-5-methoxybenzoate (12.3 g, 49.9 mmol, 99%) as a colorless oil that solidified upon storage. NMR was consistent with prior literature.

[0478] Step 2: Synthesis of dimethyl 4,4'-dimethoxy-[1,1'-biphenyl]-2,2'-dicarboxylate [ka]

[0479] 2-Bromo-5-methoxybenzoate (12.3 g, 50 mmol, 1.00 equiv.) was dissolved in DMF (60 mL), and copper powder (12.7 g, 200 mmol, 4.00 equiv.) was added to the solution in one portion. The reaction mixture was then heated to 150 °C overnight. After stirring overnight, the reaction was allowed to cool to room temperature, diluted with a large amount of water, and extracted with diethyl ether (3 × 100 mL). The combined organic layers were washed with water and brine, dried over NaSO, filtered through silica, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO, 330 g, EtOAc in hexanes, 0–30%) to afford dimethyl 4,4′-dimethoxy-[1,1′-biphenyl]-2,2′-dicarboxylate (7.5 g, 23 mmol, 91%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.49(d,J=2.7Hz,2H),7.11(d,J=8.3Hz,2H),7.06(dd,J=8.4,2.7Hz,2H),3.88(s,6H),3.63(s,6H).

[0480] Step 3: Synthesis of 4,4'-dimethoxy-[1,1'-biphenyl]-2,2'-dicarboxylic acid [ka]

[0481] Dimethyl 4,4'-dimethoxy-[1,1'-biphenyl]-2,2'-dicarboxylate (7.5 g, 23 mmol, 1.0 equiv) was dissolved in MeOH (90 mL) and 2 M aqueous NaOH (57 mL, 110 mmol, 5.0 equiv) was added dropwise via an addition funnel. The reaction was refluxed over the weekend and then cooled to room temperature, at which time the reaction mixture was concentrated under reduced pressure. The remaining organic layer was diluted slightly with water and washed with DCM to remove any organic impurities. The layers were separated, and the aqueous layer was transferred to a conical flask and acidified to pH 1 with 2 M KHSO4 with stirring. Stirring was continued for 30 min, and the formed precipitate was filtered, washed with water, and dried under high vacuum to give 4,4'-dimethoxy-[1,1'-biphenyl]-2,2'-dicarboxylic acid (6.64 g, 22.0 mmol, 97%) as a free-flowing white solid. 1 H NMR (400MHz, DMSO) δ12.43 (s, 2H), 7.33 (d, J = 2.6Hz, 2H), 7.14-7.01 (m, 4H), 3.82 (s, 6H).

[0482] Step 4: Synthesis of 3,9-dimethoxydibenzo[c,e]oxepin-5,7-dione [ka]

[0483] 4,4'-Dimethoxy-[1,1'-biphenyl]-2,2'-dicarboxylic acid (2.60 g, 10.1 mmol, 1.0 equiv.) was suspended in AcO (50 mL) and the suspension was stirred overnight. The reaction was monitored by LCMS, and after overnight stirring, the starting material had completely disappeared. The reaction mixture was then filtered and washed with diethyl ether to aid drying. The filter cake was dried under high vacuum to give 3,9-dimethoxydibenzo[c,e]oxepin-5,7-dione (2.87 g, 10.1 mmol, 99%). NMR was consistent with that reported in the literature.

[0484] Step 5: Synthesis of 3,9-dimethoxydibenz[c,e]oxepin-5(7H)-one [ka]

[0485] 3,9-Dimethoxydibenzo[c,e]oxepin-5,7-dione (150 mg, 0.530 mmol, 1.0 equiv) was suspended in DMF (5 mL) and cooled to 0 °C, after which sodium borohydride (20 mg, 0.53 mmol, 1.0 equiv) was slowly added. After 2 h, the reaction mixture was poured into hydrochloric acid (6 M, 5 mL), then diluted with water (10 mL) and stirred overnight. The product precipitated overnight and was filtered, then taken up in DCM (25 mL) and washed with water (3 × 10 mL). The organic layer was dried over anhydrous NaSO, filtered, concentrated under reduced pressure, filtered through basic alumina with DCM, and dried to give 3,9-dimethoxydibenzo[c,e]oxepin-5(7H)-one (85 mg, 0.31 mmol, 60%) as a white solid. 1 H NMR(400MHz,CDCl3)δ7.52(d,J=8.6Hz,1H),7.50-7.44(m,2H),7.19(dd,J=8.7,2.8Hz,1H),7.05 (dd,J=8.6,2.7Hz,1H),6.97(d,J=2.7Hz,1H),4.98(d,J=28.5Hz,2H),3.90(s,3H),3.87(s,3H).

[0486] Step 5: Synthesis of 3,9-dihydroxydibenz[c,e]oxepin-5(7H)-one [ka]

[0487] 3,9-Dimethoxydibenz[c,e]oxepin-5(7H)-one (75 mg, 0.28 mmol, 1.0 equiv) was dissolved in DCM (6 mL), cooled to 0 °C in an ice bath, and stirring was continued for 5 min. BBr3 (0.83 mL, 1 M in DCM, 0.83 mmol, 3.00 equiv) was then added dropwise to the reaction mixture. Upon complete addition, the mixture was left in the ice bath and allowed to warm to room temperature over 2 h. Once no more starting material was observed, the reaction mixture was added dropwise to 0 °C-chilled methanol (10 mL) and stirred for an additional 10 min. The mixture was then concentrated, loaded onto silica, and purified by flash column chromatography (SiO, 12 g, MeOH in DCM, 0–5%) to give 3,9-dihydroxydibenzo[c,e]oxepin-5(7H)-one (19 mg, 0.8 mmol, 28%) as a white solid. 1 H NMR(400MHz,MeOD)δ7.49(dd,J=8.5,7.3Hz,2H),7.28(d,J=2.7Hz,1H),7.14(dd,J=8.6 ,2.7Hz,1H),6.97(dd,J=8.4,2.6Hz,1H),6.93(d,J=2.6Hz,1H),4.96(d,J=19.5Hz,2H).

[0488] Synthesis of 5,7-dihydrodibenz[c,e]oxepin-3,9-diol (67) [ka]

[0489] Step 1: Synthesis of 3,9-bis((tert-butyldimethylsilyl)oxy)dibenz[c,e]oxepin-5(7H)-one [ka]

[0490] TBSCl (174 mg, 1.15 mmol, 2.2 equiv) was dissolved in DCM (9 mL), and the resulting solution was cooled to 0 °C in an ice bath and stirred for 5 min. Next, imidazole (89 mg, 1.3 mmol, 2.5 equiv) was added slowly in small portions, and stirring was continued for 15 min after the addition was complete. 3,9-dihydroxydibenz[c,e]oxepin-5(7H)-one (127 mg, 0.520 mmol, 1.0 equiv) was then added to the reaction mixture, which became heterogeneous upon addition of the substrate. Therefore, DMF (1 mL) was added to homogenize the mixture. After stirring at room temperature overnight, the DCM was removed on a rotary evaporator, and the remaining DMF solution was quenched with a large amount of water and extracted with diethyl ether (3 × 10 mL). The combined organic layers were washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to give the crude product, which was further purified by MPLC (SiO, 40 g, EtOAc in hexanes, 0–20%) to give 3,9-bis((tert-butyldimethylsilyl)oxy)dibenz[c,e]oxepin-5(7H)-one (199 mg, 0.42 mmol, 82%) as a white solid. 1 H NMR(400MHz,CDCl3)δ7.47-7.38(m,3H),7.10(dd,J=8.6,2.6Hz,1H),6.97(dd,J=8.4,2.6H z,1H),6.90(d,J=2.6Hz,1H),4.88(d,2H),1.01(d,J=1.9Hz,18H),0.25(d,J=8.8Hz,12H).

[0491] Step 2: Synthesis of 3,9-bis((tert-butyldimethylsilyl)oxy)-5,7-dihydrobenzo[c,e]oxepin [ka]

[0492] 3,9-Bis((tert-butyldimethylsilyl)oxy)dibenz[c,e]oxepin-5(7H)-one (200 mg, 0.430 mmol, 1.0 equiv.) was dissolved in toluene (5 mL) and EtSiH (0.27 mL, 1.7 mmol, 4.0 equiv.) was added in one portion. The reaction mixture was heated to 70 °C in a preheated oil bath. After stirring at 70 °C for 5 min, InBr (15 mg, 0.04 mmol, 0.10 equiv.) was added in one portion. A sudden color change to orange, along with gas evolution, could be observed. Stirring was continued for 1 h, after which TLC showed no further starting material. The reaction mixture was cooled, filtered, and the precipitate was washed with DCM. The filtrate was loaded onto silica and the crude product was purified by flash column chromatography (SiO, 25 g, DCM in hexanes, 0–10%) to give 3,9-bis((tert-butyldimethylsilyl)oxy)-5,7-dihydrobenzo[c,e]oxepin (194 mg, 0.430 mmol, 99%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ7.36(d,J=8.3Hz,2H),6.94(dd,J=8.3,2.5Hz,2H),6.90(d,J=2.5Hz,2H),4.31(s,4H),1.01(s,18H),0.24(s,12H).

[0493] Step 3: Synthesis of 5,7-dihydrodibenz[c,e]oxepin-3,9-diol [ka]

[0494] 3,9-Bis((tert-butyldimethylsilyl)oxy)-5,7-dihydrobenzo[c,e]oxepin (194 mg, 0.430 mmol, 1.0 equiv) was dissolved in MeOH (12 mL), the reaction mixture was cooled to 0 °C, and AcCl (167 mg, 2.12 mmol, 5.0 equiv) was added dropwise via syringe. Upon complete addition, the reaction mixture was cooled to room temperature and continued stirring over the weekend. The reaction was quenched with water, extracted into diethyl ether (3 × 15 mL), and the combined organic layers were washed with NaHCO and brine, dried over NaSO, filtered through silica with a diethyl ether rinse, and then concentrated to give pure 5,7-dihydrodibenzo[c,e]oxepin-3,9-diol (71 mg, 0.31 mmol, 73%) as a white solid. 1 H NMR (400MHz, DMSO) δ9.55(s,2H),7.30(d,J=8.2Hz,2H),6.87(dd,J=8.2,2.6Hz,2H),6.84(d,J=2.5Hz,2H),4.13(s,4H).

[0495] B) Analogues of the "A" group of amines Synthesis of 6-methyl-6,7-dihydro-5H-dibenzo[c,e]azepine-3,9-diol (68) [ka]

[0496] Step 1: Synthesis of 4,4'-dimethoxy-2'-(methylcarbamoyl)-[1,1'-biphenyl]-2-carboxylic acid [ka]

[0497] 3,9-Dimethoxydibenzo[c,e]oxepin-5,7-dione (569 mg, 2.00 mmol, 1.0 equiv) was dissolved in CHCl (20 mL), and to the resulting solution was added a 2 M solution of MeNH (1.20 mL, 2.40 mmol, 1.2 equiv) in one portion. A precipitate formed upon addition of MeNH, and the complete disappearance of the starting material could be observed by LCMS. The precipitate was filtered through a glass frit (Por. 4), and the filter cake was dried under vacuum to give pure 4,4'-dimethoxy-2'-(methylcarbamoyl)-[1,1'-biphenyl]-2-carboxylic acid (631 mg, 2.00 mmol, 99%) as a light brown solid. LCMS showed a clean product, which was carried on to the next step.

[0498] Step 2: Synthesis of 3,9-dimethoxy-6-methyl-5H-dibenzo[c,e]azepine-5,7(6H)-dione [ka]

[0499] 4,4'-Dimethoxy-2'-(methylcarbamoyl)-[1,1'-biphenyl]-2-carboxylic acid (631 mg, 2.00 mmol, 1.00 equiv.) was suspended in AcO (20 mL) and KOAc (393 mg, 4.00 mmol, 2.00 equiv.) was added in one portion. The reaction was stirred overnight, and LCMS showed complete conversion of the starting material. Therefore, the suspension was filtered, and the filter cake was dried under high vacuum to give 3,9-dimethoxy-6-methyl-5H-dibenzo[c,e]azepine-5,7(6H)-dione (595 mg, 2.00 mmol, 99%). 1 H NMR (400MHz, CDCl3) δ7.51(d,J=8.7Hz,2H),7.38(d,J=2.8Hz,2H),7.16(dd,J=8.7,2.8Hz,2H),3.90(s,6H),3.54(s,3H).

[0500] Step 3: Synthesis of 3,9-dimethoxy-6-methyl-6,7-dihydro-5H-dibenz[c,e]azepine [ka]

[0501] 3,9-Dimethoxy-6-methyl-5H-dibenzo[c,e]azepine-5,7(6H)-dione (541 mg, 1.82 mmol, 1.0 equiv) was suspended in THF (15 mL) and BH*THF (7.28 mL, 7.28 mmol, 1 M, 4.0 equiv) was added dropwise over 5 min at room temperature. Upon complete addition, the reaction was heated to reflux and stirred overnight. The reaction was then quenched with MeOH (200 mL) and stirring at 50 °C continued for 30 min. The volatiles were then evaporated and the crude material was purified by MPLC (SiO, 40 g, MeOH in EtOAc, 0–50%) to afford 3,9-dimethoxy-6-methyl-6,7-dihydro-5H-dibenzo[c,e]azepine (485 mg, 1.80 mmol, 99%) as an orange-brown solid. 1 H NMR (400MHz, CDCl3) δ7.38(d,J=8.4Hz,2H),6.97(dd,J=8.4,2.7Hz,2H),6.91(d,J=2.7Hz,2H),3.86(s,6H),3.37(s,4H),2.48(s,3H).

[0502] Step 4: Synthesis of 6-methyl-6,7-dihydro-5H-dibenzo[c,e]azepine-3,9-diol [ka]

[0503] 3,9-Dimethoxy-6-methyl-6,7-dihydro-5H-dibenz[c,e]azepine (376 mg, 1.40 mmol, 1.0 equiv) was dissolved in DCM (10 mL) and cooled to 0 °C in an ice bath, and stirring was continued for 5 min. BBr3 (6.28 mL, 1 M in DCM, 6.28 mmol, 4.5 equiv) was then added dropwise to the reaction mixture. Upon complete addition, the mixture was left in the ice bath and allowed to warm to room temperature over 2 h. Once no more starting material was observed, the reaction mixture was added dropwise to 0 °C-chilled methanol (10 mL) and stirred for an additional 10 min. The mixture was then concentrated, loaded onto silica, and purified by flash column chromatography (SiO, 40 g, MeOH in DCM, 0–5%) to give 6-methyl-6,7-dihydro-5H-dibenzo[c,e]azepine-3,9-diol (190 mg, 0.790 mmol, 56%) as an orange pale solid. 1 H NMR (400MHz, DMSO) δ10.92-10.62(m,2H),7.37(d,J=8.2Hz,2H),7.10-6.93(m,4H),3.16(s,4H),2.83(d,J=4.6Hz,3H).

[0504] Synthesis of 2,2'-bis(bromomethyl)-4,4'-dimethoxy-1,1'-biphenyl as a general intermediate Step 1: Synthesis of (4,4'-dimethoxy-[1,1'-biphenyl]-2,2'-diyl)dimethanol [ka]

[0505] LiAlH (251 mg, 6.61 mmol) was carefully added to a solution of 4,4'-dimethoxy-[1,1'-biphenyl]-2,2'-dicarboxylic acid (described above) (1.00 g, 3.30 mmol) in THF (8 mL) at 0 °C and refluxed for 4 h (reaction monitored by TLC). After Fieser workup, 850 mg of (4,4'-dimethoxy-[1,1'-biphenyl]-2,2'-diyl)dimethanol (810 mg, 2.90 mmol, 89%) was obtained as a white solid.1 H NMR (400MHz, CDCl3) δ7.08-7.03(m,4H),6.87(dd,J=8.3,2.8Hz,2H),4.40-4.28(m,4H),3.86(s,6H),2.20(s,2H).

[0506] Step 2: Synthesis of 2,2'-bis(bromomethyl)-4,4'-dimethoxy-1,1'-biphenyl [ka]

[0507] To a solution of (4,4'-dimethoxy-[1,1'-biphenyl]-2,2'-diyl)dimethanol (0.800 g, 2.92 mmol) and CBr4 (4.84 g, 14.6 mmol) in CHCl2 (40 mL) cooled to 0 °C under an argon atmosphere was added a solution of PPh3 (3.06 g, 11.7 mmol) in CHCl2 (20 mL) in small portions.

[0508] The reaction was stirred at room temperature for 48 hours, then concentrated, and the crude product was purified by MPLC on silica gel (EtOAc / hexanes: 0% to 10%) to give 2,2'-bis(bromomethyl)-4,4'-dimethoxy-1,1'-biphenyl (0.88 g, 2.20 mmol, 75%) as a colorless oil. f =0.5 (EtOAc / cyclohexane 10%). 1 H NMR(400MHz,CDCl3)δ7.17(d,J=8.4Hz,2H),7.05(d,J=2.7Hz,2H),6.91(dd,J =8.4,2.7Hz,2H),4.31(d,J=10.0Hz,2H),4.17(d,J=10.0Hz,2H),3.87(s,6H).

[0509] Synthesis of 6-cyclobutyl-6,7-dihydro-5H-dibenzo[c,e]azepine-3,9-diol (69) [ka]

[0510] Step 1: Synthesis of 6-cyclobutyl-3,9-dimethoxy-6,7-dihydro-5H-dibenz[c,e]azepine [ka]

[0511] Cyclobutylamine (28 mg, 0.39 mmol) was added to a suspension of 2,2'-bis(bromomethyl)-4,4'-dimethoxy-1,1'-biphenyl (130 mg, 0.325 mmol) and sodium carbonate (138 mg, 130 mmol) in THF (2 mL), and the mixture was refluxed in THF for 3 hours. The reaction mixture was filtered, and the solvent was removed in vacuo to give 6-cyclobutyl-3,9-dimethoxy-6,7-dihydro-5H-dibenzo[c,e]azepine (100 mg, 0.323 mmol, 99%) as a colorless oil. f = 0.3 (EtOH). 1 H NMR(400MHz,CDCl3)δ7.36(d,J=8.4Hz,2H),6.95(dd,J=8.4,2.7Hz,2H),6.87(d,J=2.7Hz,2H),3.86(s ,6H),3.28(s,4H),3.12(p,J=8.0Hz,1H),2.21-2.12(m,2H),2.05(d,J=9.6Hz,2H),1.82-1.65(m,2H).

[0512] Step 2: Synthesis of 6-cyclobutyl-6,7-dihydro-5H-dibenzo[c,e]azepine-3,9-diol [ka]

[0513] BBr3 (0.87 ml, 0.87 mmol, 1.0 M in DCM) was added to a solution of 6-cyclobutyl-3,9-dimethoxy-6,7-dihydro-5H-dibenzo[c,e]azepine (90 mg, 0.29 mmol) in anhydrous DCM (3 mL) at 0 °C, and stirring was continued overnight. Methanol (2 mL) was added at 0 °C, and the mixture was evaporated under vacuum. The crude product was purified by silica gel flash chromatography (methanol / DCM: 0% to 10%) to give 6-cyclobutyl-6,7-dihydro-5H-dibenzo[c,e]azepine-3,9-diol hydrochloride (35 mg, 0.97 mmol, 33%) as a beige solid. R f =0.3(MeOH / DCM 8%). MS(ESI+):m / z=282. 1 H NMR(400MHz,DMSO)δ10.72(s,1H),9.85(s,2H),7.37(d,J=9.0Hz,2H),6.99(dd,J=5.9,2.8Hz,4H), 3.89(s,2H),3.74(d,J=8.7Hz,1H),3.51(s,2H),2.37-2.21(m,4H),1.75(dt,J=28.5,10.0Hz,2H).

[0514] Synthesis of 6-isopropyl-6,7-dihydro-5H-dibenz[c,e]azepine-3,9-diol (70) [ka]

[0515] Step 1: Synthesis of 6-isopropyl-3,9-dimethoxy-6,7-dihydro-5H-dibenz[c,e]azepine [ka]

[0516] Isopropylamine (27 mg, 0.45 mmol) was added to a suspension of 2,2'-bis(bromomethyl)-4,4'-dimethoxy-1,1'-biphenyl (150 mg, 0.375 mmol) and sodium carbonate (159 mg, 1.50 mmol) in THF (2 mL), and the mixture was refluxed in THF for 3 h. The reaction mixture was filtered, and the solvent was removed in vacuo to give 6-isopropyl-3,9-dimethoxy-6,7-dihydro-5H-dibenz[c,e]azepine (110 mg, 0.323 mmol, 99%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.44-7.33(m,2H),6.99(d,J=7.3Hz,4H),3.87(s,6H),3.65(s,4H),3.14-3.00(m,1H),1.38(d,J=6.4Hz,6H).

[0517] Step 2: Synthesis of 6-isopropyl-6,7-dihydro-5H-dibenzo[c,e]azepine-3,9-diol [ka]

[0518] BBr3 (1.87 ml, 1.87 mmol, 1.0 M in DCM) was added to a solution of 6-isopropyl-3,9-dimethoxy-6,7-dihydro-5H-dibenzo[c,e]azepine (111 mg, 0.370 mmol) in anhydrous DCM (3 mL) at 0 °C, and stirring was continued overnight. Methanol (2 mL) was added at 0 °C, and the mixture was evaporated under vacuum. The crude product was purified by silica gel flash chromatography (methanol / DCM: 0% to 10%) to give 6-6-isopropyl-6,7-dihydro-5H-dibenzo[c,e]azepine-3,9-diol (35 mg, 0.97 mmol, 35%) as a beige solid. R f =0.3 (MeOH / DCM 8%). 1H NMR(400MHz,DMSO)δ10.19(s,1H),9.84(s,2H),7.37(d,J=8.3Hz,2H),7.05(d,J=2.6Hz,2H), 6.99(dd,J=8.4,2.5Hz,2H),3.92(s,J=4.3Hz,4H),3.63-3.51(m,1H),1.40(d,J=6.5Hz,6H).

[0519] C) Analogues of the "A" group of imides Synthesis of 3,9-dihydroxy-5H-dibenzo[c,e]azepine-5,7(6H)-dione (71) [ka]

[0520] Step 1: Synthesis of 2'-carbamoyl-4,4'-dimethoxy-[1,1'-biphenyl]-2-carboxylic acid [ka]

[0521] 3,9-Dimethoxydibenzo[c,e]oxepin-5,7-dione (100 mg, 0.350 mmol, 1.0 equiv.) was suspended in 25% aqueous NH3 (0.70 mL, 0.42 mmol, 1.2 equiv.) for 30 min until complete disappearance of the starting material was confirmed by LCMS (too polar to monitor by TLC). The reaction mixture was filtered through a glass frit (Por. 4), and the filter cake was dried under vacuum to give pure 2'-carbamoyl-4,4'-dimethoxy-[1,1'-biphenyl]-2-carboxylic acid (106 mg, 0.350 mmol, 99%) as a white solid. LCMS showed clean product after filtration, which was used in the next step without further purification.

[0522] Step 2: Synthesis of 3,9-dimethoxy-5H-dibenzo[c,e]azepine-5,7(6H)-dione [ka]

[0523] 2'-Carbamoyl-4,4'-dimethoxy-[1,1'-biphenyl]-2-carboxylic acid (106 mg, 0.350 mmol, 1.0 equiv.) was suspended in AcO (4 mL) and KOAc (69 mg, 0.70 mmol, 2.0 equiv.) was added in one portion. The reaction mixture was stirred overnight at room temperature and then filtered through a small glass frit (Por. 4). The precipitate was dried in vacuo to give 3,9-dimethoxy-5H-dibenzo[c,e]azepine-5,7(6H)-dione (65 mg, 0.23 mmol, 65%) as a white solid. 1 H NMR (400MHz, DMSO) δ11.69(s,1H),7.71(dd,J=8.7,1.5Hz,2H),7.40-7.36(m,2H),7.31(dt,J=8.8,2.4Hz,2H),3.86(s,6H).

[0524] Step 3: Synthesis of 3,9-dihydroxy-5H-dibenzo[c,e]azepine-5,7(6H)-dione [ka]

[0525] 3,9-Dimethoxy-5H-dibenzo[c,e]azepine-5,7(6H)-dione (100 mg, 0.350 mmol, 1.0 equiv) was dissolved in DCM (2 mL) and cooled to 0 °C in an ice bath, and stirring was continued for 5 min. BBr3 (1.41 mL, 1 M in DCM, 1.41 mmol, 4.0 equiv) was then added dropwise to the reaction mixture. Upon complete addition, the mixture was left in the ice bath and allowed to warm to room temperature over 2 h. Once no more starting material was observed, the reaction mixture was added dropwise to 0 °C-chilled methanol (10 mL) and stirred for an additional 10 min. The mixture was then concentrated, loaded onto silica, and purified by flash column chromatography (SiO2, 12 g, MeOH in DCM, 0–5%) to give 3,9-dihydroxy-5H-dibenzo[c,e]azepine-5,7(6H)-dione (56 mg, 0.22 mmol, 62%) as a white solid. 1H NMR(400MHz,DMSO)δ9.66(s,2H),7.13(d,J=2.6Hz,1H),7.03(s,1H),7.00(d,J=8.3Hz,1H) ,6.93(s,1H),6.90(dd,J=8.3,2.6Hz,1H),6.87-6.84(m,2H),6.77(dd,J=8.2,2.6Hz,1H).

[0526] D) Thioether and sulfone "A" group analogues Synthesis of 5,7-dihydrodibenzo[c,e]thiepin-3,9-diol (72)

[0527] Step 1: Synthesis of 3,9-dimethoxy-5,7-dihydrodibenzo[c,e]thiepin [ka]

[0528] A mixture of 2,2'-bis(bromomethyl)-4,4'-dimethoxy-1,1'-biphenyl (as described above) (220 mg, 0.55 mmol) and sodium sulfide hydrate (69 mg, 0.71 mmol) in DMF (3 mL) was heated at 100 °C for 20 min. After cooling, the mixture was poured into water (10 mL), and the precipitate was filtered and washed with water (2 × 3 mL). The precipitate was taken up in CHCl (15 mL), the solution was dried over NaSO, and the solvent was evaporated under reduced pressure to give 3,9-dimethoxy-5,7-dihydrodibenzo[c,e]thiepine (140 mg, 0.510 mmol, 93%) as a yellowish solid.

[0529] 1 H NMR (400MHz, CDCl3) δ7.19(d,J=8.4Hz,2H),6.91(dd,J=8.3,2.7Hz,2H),6.87(d,J=2.6Hz,2H),3.86(s,6H),3.56(d,J=12.7Hz,2H),3.27(s,2H). Step 2: Synthesis of 5,7-dihydrodibenzo[c,e]thiepin-3,9-diol [ka]

[0530] BBr3 (0.59 mL, 0.59 mmol, 1 M in DCM) was added to a solution of 3,9-dimethoxy-5,7-dihydrodibenzo[c,e]thiepine (54 mg, 0.20 mmol) in DCM (2 mL) at -78 °C, and stirring was continued overnight at room temperature. Methanol (5 mL) was added at 0 °C, and the solvent was removed under reduced pressure. The crude product was purified by MPLC (SiO2, MeOH / DCM, 0% to 8%) to give 5,7-dihydrodibenzo[c,e]thiepine-3,9-diol (18 mg, 0.074 mmol, 37%) as a beige solid. f =0.3 (MeOH / DCM 5%). 1 H NMR (400MHz, DMSO) δ9.46 (s, 2H), 7.09-6.91 (m, 2H), 6.78-6.67 (m, 4H), 3.28 (s, 4H).

[0531] Synthesis of 3,9-dihydroxy-5,7-dihydrodibenzo[c,e]thiepin 6,6-dioxide (73) [ka]

[0532] Step 1: Synthesis of 3,9-dimethoxy-5,7-dihydrodibenzo[c,e]thiepin 6,6-dioxide [ka]

[0533] MCPBA (170 mg, 0.690 mmol) was added to a solution of 3,9-dimethoxy-5,7-dihydrodibenzo[c,e]thiepine (90 mg, 0.33 mmol) in DCM (2 mL) at 0 °C, and the reaction mixture was stirred overnight at room temperature. NaSO (1 M solution) was added, and the mixture was stirred for 10 min. After that, saturated NaHCO solution was added, and the mixture was extracted twice with saturated NaHCO solution. The organic phase was dried over sodium sulfate, filtered, and evaporated in vacuo. The crude product was purified by MPLC (SiO, EtOAc / cyclohexane, 0%–30%) to give 3,9-dimethoxy-5,7-dihydrodibenzo[c,e]thiepine 6,6-dioxide (90 mg, 0.30 mmol, 89%) as a white solid. 1 H NMR (400MHz, CDCl3) δ7.38(d,J=8.4Hz,2H),7.03(dd,J=8.4,2.6Hz,2H),6.99(d,J=2.6Hz,2H),4.07-3.93(q,4H),3.88(s,6H).

[0534] Step 2: Synthesis of 3,9-dihydroxy-5,7-dihydrodibenzo[c,e]thiepin 6,6-dioxide [ka]

[0535] A solution of BBr3 (1.0 mL, 1.0 mmol, 1 M in DCM, 3.5 equiv.) was added to a solution of 3,9-dimethoxy-5,7-dihydrodibenzo[c,e]thiepine 6,6-dioxide (90 mg, 0.30 mmol, 1.0 equiv.) in DCM (2 mL) at 0 °C, and stirring was continued overnight at room temperature. Methanol (5 mL) was added at 0 °C, and the solvent was removed under reduced pressure. The crude product was purified by MPLC (EtOAc / hexane, 0% to 70%) to give 3,9-dihydroxy-5,7-dihydrodibenzo[c,e]thiepine 6,6-dioxide (46 mg, 0.17 mmol, 56%) as a beige solid. f =0.3 (MeOH / DCM 5%). 1H NMR (400MHz, DMSO) δ9.76(s,2H),7.26(d,J=8.1Hz,2H),6.94-6.83(m,4H),4.29(d,J=13.7Hz,2H),3.73(d,J=13.7Hz,2H).

[0536] E) Analogues of the "A" group of amides Synthesis of 3,9-dihydroxy-6,7-dihydro-5H-dibenz[c,e]azepin-5-one (74) [ka]

[0537] Step 1: Synthesis of 2-(azidomethyl)-1-bromo-4-methoxybenzene [ka] 1-Bromo-2-(bromomethyl)-4-methoxybenzene (5.00 g, 17.9 mmol, 1.0 equiv) was dissolved in DMF (60 mL) and NaN (5.81 g, 89.3 mmol, 5.0 equiv) was added in one portion. The reaction mixture was then heated to 90 °C and stirred overnight. After stirring overnight, the reaction mixture was cooled to room temperature, quenched with water (300 mL), and extracted with cyclohexane (3 × 75 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give pure 2-(azidomethyl)-1-bromo-4-methoxybenzene (4.32 g, 17.8 mmol, 99%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.47(d,J=8.8Hz,1H),6.95(d,J=3.0Hz,1H),6.76(dd,J=8.8,3.0Hz,1H),4.45(s,2H),3.81(s,3H).

[0538] Step 2: Synthesis of 5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate [ka]

[0539] Methyl 2-bromo-5-methoxybenzoate (10.0 g, 40.8 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (140 mL). To this solution, B2pin2 (11.4 g, 44.9 mmol, 1.1 equiv.), Pd(dppf)Cl2 (1.49 g, 2.04 mmol, 0.1 equiv.), and KOAc (12.0 g, 122 mmol, 3.0 equiv.) were added. The reaction mixture was thoroughly degassed using a N2 balloon for 10 minutes. The reaction mixture was then placed in an oil bath preheated to 85 °C and stirred overnight. Upon complete consumption of the starting material, the reaction mixture was cooled to room temperature and quenched with water. The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by MPLC (SiO2, 240 g, EtOAc in hexanes, 0-15%) to give methyl 5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (9.51 g, 32.6 mmol, 78%) as a pale yellow oil. 1 H NMR (400MHz, CDCl3) δ7.27(d,J=6.1Hz,1H),7.09(s,1H),6.88(dd,J=8.1,2.6Hz,1H),3.73(s,3H),3.67(s,3H),1.23(s,12H).

[0540] Step 3: Synthesis of (4-methoxy-2-(methoxycarbonyl)phenyl)boronic acid [ka]

[0541] 5-Methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.33 g, 4.55 mmol, 1.0 equiv.) was dissolved in a mixture of acetone (23 mL) and water (23 mL), and NHOAc (1.05 g, 13.7 mmol, 3.0 equiv.) plus NaIO (2.92, 13.7 mmol, 3.0 equiv.) was added in one portion. Upon complete addition, the mixture was warmed slightly and stirred overnight. After the disappearance of the starting material (as indicated by TLC), the reaction mixture was filtered, the white precipitate was washed with acetone, and the mother liquor was concentrated to give pure (4-methoxy-2-(methoxycarbonyl)phenyl)boronic acid (590 mg, 2.81 mmol, 62%) as a white solid. Analytical data were consistent with literature results.

[0542] Step 4: Synthesis of 2'-(azidomethyl)-4,4'-dimethoxy-[1,1'-biphenyl]-2-carboxylate [ka]

[0543] A 20 mL Biotage MW vial was charged with (4-methoxy-2-(methoxycarbonyl)phenyl)boronic acid (563 mg, 2.68 mmol, 1.10 equiv), 2-(azidomethyl)-1-bromo-4-methoxybenzene (590 mg, 2.44 mmol, 1.0 equiv), Pd(OAc) (27 mg, 0.12 mmol, 0.05 equiv), and XPhos (116 mg, 0.24 mmol, 0.1 equiv). All reagents were dissolved in THF (15 mL). The reaction mixture was degassed using a N balloon for 10 min, after which a solution of NaCO (775 mg, 7.31 mmol, 3.0 equiv) in water (5 mL) was added dropwise at room temperature. Upon completion of the addition, the reaction mixture was heated to 80 °C in an oil bath and stirred overnight. After stirring overnight, the reaction mixture was cooled to room temperature and quenched with water. The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by MPLC (SiO, 25 g, EtOAc in hexanes, 0–20%) to give methyl 2′-(azidomethyl)-4,4′-dimethoxy-[1,1′-biphenyl]-2-carboxylate (367 mg, 1.12 mmol, 46%) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ7.47(d,J=2.7Hz,1H),7.15(d,J=8.4Hz,1H),7.08(dd,J=8.4,2.8Hz,1H),7.04(d,J=8.4Hz,1H ),6.96(d,J=2.6Hz,1H),6.87(dd,J=8.4,2.7Hz,1H),4.09(d,J=3.1Hz,2H),3.89(s,3H),3.86(s,3H),3.63(s,3H).

[0544] Step 5: Synthesis of 3,9-dimethoxy-6,7-dihydro-5H-dibenz[c,e]azepin-5-one [ka]

[0545] 2'-(Azidomethyl)-4,4'-dimethoxy-[1,1'-biphenyl]-2-carboxylate (50 mg, 0.15 mmol, 1.0 equiv.) was dissolved in MeOH (8 mL), and Pd(OH)2 / C (16 mg, 0.02 mmol, 0.15 equiv.) plus NaOMe (33 mg, 0.15 mmol, 1.0 equiv.) was added to the solution, which was degassed three times with N2 and then replaced with a hydrogen atmosphere three times. The reaction mixture was stirred overnight at room temperature, filtered through a Celite pad, and purified by MPLC (SiO2, EtOAc in hexanes, 0-30%) to give 3,9-dimethoxy-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one (22 mg, 0.08 mmol, 53%) as a white solid. 1 H NMR(400MHz,DMSO)δ8.53(s,1H),7.45(t,J=8.4Hz,2H),7.28(d,J=2.8Hz,1H),7.11(dd,J=8.6,2.7Hz,1H), 6.94(dd,J=12.2,3.8Hz,2H),3.84(dd,J=9.5,3.6Hz,1H),3.82(s,3H),3.78(s,3H),3.18(d,J=14.8Hz,1H).

[0546] Step 6: Synthesis of 3,9-dihydroxy-6,7-dihydro-5H-dibenz[c,e]azepin-5-one [ka]

[0547] 3,9-Dimethoxy-6,7-dihydro-5H-dibenz[c,e]azepin-5-one (64 mg, 0.24 mmol, 1.0 equiv) was dissolved in DCM (2 mL) and cooled to 0 °C in an ice bath, and stirring was continued for 5 min. BBr3 (0.95 mL, 1 M in DCM, 0.95 mmol, 4.0 equiv) was then added dropwise to the reaction mixture. Upon complete addition, the mixture was left in the ice bath and allowed to warm to room temperature over 2 h. Once no more starting material was observed, the reaction mixture was added dropwise to 0 °C-chilled methanol (10 mL) and stirred for an additional 10 min. The mixture was then concentrated, loaded onto silica, and purified by flash column chromatography (SiO2, 12 g, MeOH in DCM, 0–5%) to give 3,9-dihydroxy-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one (25 mg, 0.10 mmol, 44%) as an orange solid. 1 H NMR(400MHz,DMSO)δ8.39(t,J=6.1Hz,1H),7.33(d,J=8.4Hz,2H),7.15(d,J=2.6Hz,1H),6.97(dd,J=8. 6,2.6Hz,1H),6.80(dd,J=8.4,2.3Hz,1H),6.71(d,J=2.3Hz,1H),3.80(ddd,J=35.6,14.6,6.1Hz,2H).

[0548] Synthesis of 3,9-dihydroxy-6-methyl-6,7-dihydro-5H-dibenz[c,e]azepin-5-one (75) [ka]

[0549] Step 1: Synthesis of 3,9-dimethoxy-6-methyl-6,7-dihydro-5H-dibenz[c,e]azepin-5-one [ka]

[0550] 3,9-Dimethoxy-6,7-dihydro-5H-dibenz[c,e]azepin-5-one (80 mg, 0.30 mmol, 1.0 equiv) was dissolved in DMF (3.0 mL). The solution was cooled to 0 °C in an ice bath and stirred for 10 min. 60% NaH in petroleum (14 mg, 0.36 mmol, 1.2 equiv) was then added in one portion. The reaction was stirred until hydrogen gas evolution had completely ceased, at which point MeI (0.13 g, 0.89 mmol, 3.0 equiv) was added dropwise. The reaction was then warmed to room temperature and stirred for 3 h until the starting material had disappeared (as indicated by TLC). The reaction was quenched with ice water (10 mL), the aqueous solution was extracted with diethyl ether (3 × 10 mL), and the organic layer was washed with water and brine, dried over NaSO, and concentrated to give 3,9-dimethoxy-6-methyl-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one (84 mg, 0.30 mmol, 99%) as a white solid. 1 H NMR(400MHz,CDCl3)δ7.35(dd,J=16.3,8.4Hz,2H),7.14(d,J=2.7Hz,1H),6.96(dd,J=8.5 ,2.7Hz,1H),6.90-6.81(m,2H),4.10-3.75(m,2H),3.10(s,3H),3.00(s,3H),2.90(s,3H).

[0551] Step 2: Synthesis of 3,9-dihydroxy-6-methyl-6,7-dihydro-5H-dibenz[c,e]azepin-5-one [ka]

[0552] 3,9-Dimethoxy-6-methyl-6,7-dihydro-5H-dibenz[c,e]azepin-5-one (84 mg, 0.84 mmol, 1.0 equiv) was dissolved in DCM (1 mL) and cooled to 0 °C in an ice bath, and stirring was continued for 5 min. BBr3 (1.20 mL, 1 M in DCM, 1.20 mmol, 4.0 equiv) was then added dropwise to the reaction mixture. Upon complete addition, the mixture was left in the ice bath and allowed to warm to room temperature over 2 h. Once no more starting material was observed, the reaction mixture was added dropwise to 0 °C-chilled methanol (10 mL) and stirred for an additional 10 min. The mixture was then concentrated, loaded onto silica, and purified by flash column chromatography (SiO, 12 g, MeOH in DCM, 0–5%) to give 3,9-dihydroxy-6-methyl-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one (40 mg, 0.16 mmol, 52%) as a pale orange solid. 1 H NMR(400MHz,DMSO)δ9.65(s,2H),7.35(dd,J=16.3,8.4Hz,2H),7.14(d,J=2.7Hz,1 H),6.96(dd,J=8.5,2.7Hz,1H),6.90-6.81(m,2H),4.20-3.85(m,2H),3.02(s,3H).

[0553] Synthesis of 3,9-dihydroxy-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (76) [ka]

[0554] Step 1: Synthesis of 2-(2-bromo-5-methoxyphenyl)acetic acid [ka]

[0555] Bromine (1.92 g, 12.0 mmol, 1.0 equiv) was added dropwise to a solution of 2-(3-methoxyphenyl)acetic acid (2.00 g, 12.0 mmol, 1.0 equiv) in DCM (40 mL) at 0 °C. Upon complete addition of the bromine, the reaction was allowed to warm to room temperature and stirred overnight while shielded from light with aluminum foil. The dark red solution was discolored with sodium thiosulfate solution (1 M), washed with water (50 mL), and separated. The aqueous layer was extracted with DCM (2 × 25 mL), and the combined organic layers were dried over NaSO, filtered, and evaporated to dryness to give 2-(2-bromo-5-methoxyphenyl)acetic acid (2.80 g, 11.0 mmol, 95%) as a pale red solid. 1 H NMR(400MHz,CDCl3)δ10.07(s,1H),7.45(d,J=8.8Hz,1H),6.85(d,J=3.0Hz,1H),6.72(dd,J=8.8,3.0Hz,1H),3.79(s,2H),3.78(s,3H).

[0556] Step 2: Synthesis of 2-(2-bromo-5-methoxyphenyl)acetate [ka]

[0557] 2-(2-Bromo-5-methoxyphenyl)acetic acid (6.63 g, 27.1 mmol, 1.0 equiv) was dissolved in MeOH (90 mL), and a catalytic amount of concentrated sulfuric acid (0.2 mL) was added to the mixture, which was then refluxed for 4 h. It was then cooled to room temperature, quenched with water, and extracted into ethyl acetate (3 × 100 mL). The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over NaSO, and concentrated under reduced pressure. The crude product was purified by MPLC (SiO, 240 g, EtOAc in hexanes, 0–20%) to give methyl 2-(2-bromo-5-methoxyphenyl)acetate (6.44 g, 24.9 mmol, 92%) as a colorless oil. 1H NMR (400MHz, CDCl3) δ7.47(d,J=8.8Hz,1H),6.87(d,J=3.0Hz,1H),6.74(dd,J=8.8,3.0Hz,1H),3.81(s,3H),3.78(s,2H),3.75(s,3H).

[0558] Step 3: Synthesis of 2-(5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate [ka]

[0559] Methyl 2-(2-bromo-5-methoxyphenyl)acetate (2.00 g, 7.72 mmol, 1.0 equiv) was dissolved in 1,4-dioxane (150 mL) and B2pin2 (3.53 g, 13.9 mmol, 1.8 equiv), Pd(PPh3)2Cl2 (542 mg, 0.770 mmol, 0.1 equiv), and KOAc (3.03 g, 30.9 mmol, 4.0 equiv). The reaction mixture was degassed with a N2 balloon for 10 min and then placed in a preheated oil bath at 100 °C overnight. After stirring overnight, the mixture was cooled to room temperature, quenched with saturated aqueous NH4Cl, and extracted into ethyl acetate (3 × 75 mL). The combined organic layers were dried over anhydrous NaSO, concentrated under reduced pressure, and the crude product was purified by MPLC (SiO, 120 g, EtOAc in hexanes, 0–20%) to give methyl 2-(5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (1.32 g, 4.31 mmol, 56%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.78(d,J=8.3Hz,1H),6.80(dd,J=8.3,2.5Hz,1H),6.74(d,J=2.5Hz,1H),3.96(s,2H),3.81(s,3H),3.66(s,3H),1.30(s,12H).

[0560] Step 4: Synthesis of 2-(4,4'-dimethoxy-2'-nitro-[1,1'-biphenyl]-2-yl)acetate [ka]

[0561] Methyl 2-(5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (670 mg, 2.19 mmol, 1.0 equiv.) and 1-iodo-4-methoxy-2-nitrobenzene (733 mg, 2.63 mmol, 1.2 equiv.) were dissolved in THF (2 mL). To this solution was added Pd2dba3 (100 mg, 0.110 mmol, 0.05 equiv.) and tBuXPhos (93 mg, 0.22 mmol, 0.1 equiv.). The resulting mixture was degassed for 10 min using a N2 balloon, followed by the dropwise addition of a solution of Na2CO3 (696 mg, 6.56 mmol, 3.0 equiv.) in water (4 mL). The reaction mixture was then heated to 60 °C overnight (until complete disappearance of starting material by TLC), cooled to room temperature, quenched with saturated aqueous NH4Cl, extracted with ethyl acetate (3 × 50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude material was purified by MPLC (SiO2, 40 g, EtOAc in hexanes, 0–35%) to give methyl 2-(4,4'-dimethoxy-2'-nitro-[1,1'-biphenyl]-2-yl)acetate (490 mg, 1.48 mmol, 68%) as a green oil. 1 H NMR(400MHz,CDCl3)δ7.48(d,J=2.7Hz,1H),7.23(d,J=8.5Hz,1H),7.14(dd,J=8.5,2.7Hz,1H),7.03(d,J=8.4Hz, 1H),6.92(d,J=2.6Hz,1H),6.83(dd,J=8.4,2.7Hz,1H),3.91(s,3H),3.84(s,3H),3.59(s,3H),3.48-3.33(m,2H).

[0562] Step 5: Synthesis of 3,9-dimethoxy-5,7-dihydro-6H-dibenz[b,d]azepin-6-one [ka]

[0563] Methyl 2-(4,4'-dimethoxy-2'-nitro-[1,1'-biphenyl]-2-yl)acetate (485 mg, 1.46 mmol, 1.0 equiv) was dissolved in HO (3 mL), AcOH (2 mL), and EtOH (3 mL). Powdered iron (818 mg, 14.6 mmol, 10.0 equiv) was added to the mixture, which was stirred for 2 h until TLC showed no more starting material. The reaction mixture was then filtered through a pad of Celite, concentrated under reduced pressure (AcOH was removed by azeotropic distillation with cyclohexane), and purified by MPLC (SiO2, 40 g, EtOAc in hexane, 0-85%) to give 3,9-dimethoxy-5,7-dihydro-6H-dibenzo[b,d]azepin-6-one (150 mg, 0.560 mmol, 38%) as a white solid. 1 H NMR(400MHz,DMSO)δ9.93(s,1H),7.50(d,J=8.7Hz,1H),7.44(d,J=9.0Hz,1H),7.00-6. 94(m,2H),6.85(dd,J=8.7,2.6Hz,1H),6.72(d,J=2.6Hz,1H),3.80(s,3H),3.78(s,3H).

[0564] Step 6: Synthesis of 3,9-dihydroxy-5,7-dihydro-6H-dibenz[b,d]azepin-6-one [ka]

[0565] 3,9-Dimethoxy-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (70 mg, 0.26 mmol, 1.0 equiv) was dissolved in DCM (2 mL), cooled to 0 °C in an ice bath, and stirring was continued for 5 min. BBr3 (1.30 mL, 1 M in DCM, 1.30 mmol, 5.0 equiv) was then added dropwise to the reaction mixture. Upon complete addition, the mixture was left in the ice bath and allowed to warm to room temperature over 2 h. Once no more starting material was observed, the reaction mixture was added dropwise to 0 °C-chilled methanol (10 mL) and stirred for an additional 10 min. The mixture was then concentrated, loaded onto silica, and purified by flash column chromatography (SiO2, 12 g, MeOH in DCM, 0–5%) to give 3,9-dihydroxy-5,7-dihydro-6H-dibenzo[b,d]azepin-6-one (35 mg, 0.15 mmol, 56%) as a pale yellow solid. 1 H NMR(400MHz,DMSO)δ9.82(s,1H),9.56(s,2H),7.33(d,J=8.5Hz,1H),7.27(d,J=8.4Hz,1H),6.77(dd,J= 8.4,2.5Hz,1H),6.69(d,J=2.5Hz,1H),6.63(dd,J=8.5,2.5Hz,1H),6.55(d,J=2.5Hz,1H),3.20(s,2H).

[0566] Synthesis of 3,9-dihydroxy-5-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (77) [ka]

[0567] Step 1: Synthesis of 3,9-dimethoxy-5-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one [ka]

[0568] 3,9-Dimethoxy-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (85 mg, 0.32 mmol, 1.0 equiv) was dissolved in DMF (3.2 mL). The solution was cooled to 0 °C in an ice bath and stirred for 10 min. 60% NaH in petroleum (14 mg, 0.36 mmol, 1.2 equiv) was then added in one portion. The reaction was stirred until hydrogen gas evolution had completely ceased, at which point MeI (0.060 g, 0.38 mmol, 1.2 equiv) was added dropwise. The reaction was then warmed to room temperature and stirred for 3 h until the starting material had disappeared (as indicated by TLC). The reaction was quenched with ice water (10 mL), the aqueous solution was extracted with diethyl ether (3 × 10 mL), and the organic layer was washed with water and brine, dried over NaSO, and concentrated to give 3,9-dimethoxy-5-methyl-5,7-dihydro-6H-dibenzo[b,d]azepin-6-one (60 mg, 0.21 mmol, 67%) as a pale yellow solid. 1 H NMR (400MHz, CDCl3) δ7.46(dd,J=8.4,5.6Hz,2H),6.98-6.85(m,4H),3.89(s,3H),3.86(s,3H),3.56-3.39(dd,2H),3.33(s,3H).

[0569] Step 1: Synthesis of 3,9-dihydroxy-5-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one [ka]

[0570] 3,9-Dimethoxy-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (58 mg, 0.20 mmol, 1.0 equiv) was dissolved in DCM (2 mL), cooled to 0 °C in an ice bath, and stirring was continued for 5 min. BBr3 (0.82 mL, 1 M in DCM, 0.82 mmol, 4.0 equiv) was then added dropwise to the reaction mixture. Upon complete addition, the mixture was left in the ice bath and allowed to warm to room temperature over 2 h. Once no more starting material was observed, the reaction mixture was added dropwise to 0 °C-chilled methanol (10 mL) and stirred for an additional 10 min. The mixture was then concentrated, loaded onto silica, and purified by flash column chromatography (SiO, 12 g, MeOH in DCM, 0–5%) to give 3,9-dihydroxy-5-methyl-5,7-dihydro-6H-dibenzo[b,d]azepin-6-one (30 mg, 0.12 mmol, 57%) as a pale orange solid. 1 H NMR (400MHz, DMSO) δ9.74(s,1H),9.57(s,1H),7.31(dd,J=8.4,2.3Hz,2H),6.82-6.71(m,4H),3.31-3.20(m,2H),3.15(s,3H).

[0571] Compound 77A was prepared by using the appropriate methyl-substituted iodophenyl intermediate in the Pd coupling step of the above synthesis of 76, which gave the methyl-substituted analog of 76. The remaining steps are similar to those used to give compound 77, i.e., amidomethylation followed by deprotection. [ka]

[0572] Example 2: Synthesis of additional exemplary compounds Unless otherwise stated, reactions were not carried out under an inert atmosphere and all solvents and commercially available reagents were used as received.

[0573] Chromatographic purification refers to purification using a CombiFlash® Companion purification system or a Biotage SP1 purification system. When the product was purified using an Isolute® SPE Si II cartridge, "Isolute SPE Si cartridge" refers to a prepacked polypropylene column containing unbonded activated silica with irregular particles, with an average size of 50 μm and a nominal porosity of 60 Å. Fractions containing the desired product (identified by TLC and / or LCMS analysis) were pooled, and the organic fraction was recovered by evaporation to obtain the final product. When thin-layer chromatography (TLC) is used, the term refers to silica gel TLC plates equipped with a fluorescent indicator (254 nm), typically 3 x 6 cm silica gel (e.g., Fluka 60778) on an aluminum foil plate. Microwave experiments were performed using a Biotage Initiator 60™ with a single-mode resonator and dynamic field tuning. Temperatures between 40 and 250 °C can be achieved, and pressures up to 30 bar can be reached.

[0574] NMR spectra were acquired on a Bruker Avance 400 MHz, 5 mm QNP probe H, C, F, P, single Z gradient, two channel instrument running TopSpin 2.1 or a Bruker Avance III 400 MHz, 5 mm BBFO Plus probe, single Z gradient, two channel instrument running TopSpin 3.0.

[0575] LC-MS analysis conditions Method 1: Experiments were performed on a Waters Acquity SQD2 mass spectrometer coupled to a Waters Acquity UPLC binary pump / PDA detector. The spectrometer had an electrospray source operating in positive and negative ion mode. Further detection was achieved using an Acquity UPLC HSS C18 1.7 μm, 100 × 2.1 mm column maintained at 40 °C and a flow rate of 0.4 mL / min. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% MeCN containing 0.1% formic acid (solvent B) for the first 0.4 min, followed by a gradient up to 5% solvent A and 95%.

[0576] Method 2: Experiments were performed on a Waters Acquity SQD2 mass spectrometer coupled to a Waters Acquity UPLC binary pump / PDA detector. The spectrometer had an electrospray source operating in positive and negative ion mode. Further detection was achieved using an Acquity UPLC BEH Shield RP18 1.7 μm 100 × 2.1 mm column maintained at 40 °C and a flow rate of 0.4 mL / min. The initial solvent system was 95% water containing 0.03% aqueous ammonia (solvent A) and 5% MeCN containing 0.03% aqueous ammonia (solvent B) for the first 0.4 min, followed by a gradient up to 5% solvent A and 95% MeCN for the next 5.4 min. The final solvent system was held constant for an additional 0.8 min.

[0577] Method 3: Experiments were performed on a Waters Acquity ZQ mass spectrometer coupled to a Waters Acquity UPLC binary pump / PDA detector. The spectrometer had an electrospray source operating in positive and negative ion mode. Further detection was achieved using an Acquity UPLC BEH C18 1.7 μm 100 × 2.1 mm column maintained at 40 °C and a flow rate of 0.4 mL / min. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% MeCN containing 0.1% formic acid (solvent B) for the first 0.4 min, followed by a gradient up to 5% solvent A and 95% MeCN over the next 5.6 min. The final solvent system was held constant for an additional 0.8 min.

[0578] Method 4: Experiments were performed on a Waters Acquity ZQ mass spectrometer coupled to a Waters Acquity UPLC binary pump / PDA detector. The spectrometer had an electrospray source operating in positive and negative ion mode. Further detection was achieved using an Acquity UPLC BEH C18 1.7 μm 100 × 2.1 mm column maintained at 40 °C and a flow rate of 0.4 mL / min. The initial solvent system was 95% water containing 0.03% aqueous ammonia (solvent A) and 5% MeCN containing 0.03% aqueous ammonia (solvent B) for the first 0.4 min, followed by a gradient up to 5% solvent A and 95% MeCN for the next 4 min. The final solvent system was held constant for an additional 0.8 min.

[0579] Method 5: Experiments were performed on a Waters Acquity ZQ mass spectrometer coupled to a Waters Acquity H-class UPLC equipped with a DAD detector and a QDa. The spectrometer had an electrospray source operating in positive and negative ion mode. Further detection was achieved using an Acquity UPLC CSH 1.7 μm 50 × 2.1 mm column maintained at 40 °C and a flow rate of 1.0 mL / min. The initial solvent system was 97% water containing 0.1% formic acid (solvent A) and 3% MeCN containing 0.1% formic acid (solvent B) for the first 0.4 min, followed by a gradient up to 1% solvent A and 99% MeCN for the next 1.4 min. The final solvent system was held constant for an additional 0.5 min.

[0580] Method 6: Experiments were performed on a Waters Acquity ZQ mass spectrometer coupled to a Waters Acquity H-class UPLC equipped with a DAD detector and a QDa. The spectrometer had an electrospray source operating in positive and negative ion mode. Further detection was achieved using an Acquity BEH UPLC 1.7 μm 50 × 2.1 mm column maintained at 40 °C and a flow rate of 0.8 mL / min. The initial solvent system was 97% 7.66 mM aqueous ammonia (solvent A) and 3% 7.66 mM MeCN in ammonia (solvent B) for the first 0.4 min, followed by a gradient up to 3% solvent A and 97% solvent B over the next 1.6 min. The final solvent system was held constant for an additional 0.5 min.

[0581] A) Analogues of the "A" group of esters General Procedure B

[0582] N-(8-methoxy-6-oxo-6H-benzo[c]chromen-3-yl)methanesulfonamide (79) [ka]

[0583] GP B1 3-(Methylsulfonamido)phenyl 2-bromo-5-methoxybenzoate (Intermediate 1) To a suspension of 2-bromo-5-methoxybenzoic acid (642 mg, 2.78 mmol) in DCM (10 mL) were added a few drops of oxalyl chloride (0.27 mL, 3.06 mmol) and one drop of DMF. The solution was stirred at room temperature for 1 hour, and the solvent was removed under reduced pressure. The resulting mixture was redissolved in DCM (5 mL), and a suspension of N-(3-hydroxyphenyl)methanesulfonamide (520 mg, 2.78 mmol) in DCM (5 mL) was added, followed by TEA (0.58 mL, 4.17 mmol). The resulting mixture was stirred for 4 hours, then diluted with DCM and washed with saturated aqueous NH4Cl. The organic extract was filtered through PTFE, concentrated under reduced pressure and the crude product was purified by silica (ISCO 12 g) chromatography using 0-50% EtOAc in cyclohexane as eluent to give the product, 3-(methylsulfonamido)phenyl 2-bromo-5-methoxybenzoate, as a colorless oil (1 g, 90%). LCMS (Method 5): t 1.43 min; m / z 398.0 / 400.0 [MH] - . 1 H NMR(400MHz,CDCl3)δ7.61(1H,d,J=8.9Hz),7.52(1H,d,J=3.1Hz),7.41(1H,t,J=8.1Hz) ,7.19-7.08(3H,m),6.98(1H,dd,J=8.9,3.1Hz),6.77(1H,s),3.87(3H,s),3.07(6H,s).

[0584] GP B2 N-(8-methoxy-6-oxo-6H-benzo[c]chromen-3-yl)methanesulfonamide (79) A mixture of 3-(methylsulfonamido)phenyl 2-bromo-5-methoxybenzoate (Intermediate 1) (900 mg, 2.26 mmol), SPhos (92 mg, 0.225 mmol), palladium(II) acetate (50 mg, 0.225 mmol), and sodium acetate (369 mg, 4.5 mmol) in DMA (45 mL) was placed in a sealed tube and degassed and purged with argon (three times). The mixture was heated to 130 °C for 3 h, then cooled, diluted with water (400 mL), and extracted with DCM (3 × 50 mL). The combined organic extracts were washed with brine and evaporated under reduced pressure at 80 °C to remove residual DMA. The crude mixture was recrystallized from MeCN to give the product, N-(8-methoxy-6-oxo-6H-benzo[c]chromen-3-yl)methanesulfonamide, as a cream-colored solid (200 mg, 27%). LCMS (Method 3):R t =3.85min;m / z=320.0[M+H] + . 1 H NMR(400MHz:DMSO-d6)δ10.22(1H,s),8.30(1H,d,J=8.6Hz),8.25(1H,d,J=9.2Hz),7.65( 1H,d,J=2.8Hz),7.54(1H,dd,J=8.9,2.8Hz),7.22-7.19(2H,m),3.92(3H,s),3.11(3H,s).

[0585] 3-Chloro-8-hydroxy-6H-benzo[c]chromen-6-one (80) [ka]

[0586] GP C1 3-Chloro-8-methoxy-6H-benzo[c]chromen-6-one (Intermediate 2) To a solution of 4-chloro-2-hydroxyphenylboronic acid (253 mg, 1.47 mmol) in DME (8.0 mL) and water (2.0 mL) was added methyl 2-bromo-5-methoxybenzoate (300 mg) and cesium carbonate (1.60 g, 4.90 mmol), followed by tetrakis(triphenylphosphine)palladium(0) (141 mg, 0.122 mmol). The reaction mixture was heated in a microwave oven for 30 minutes at 120°C. The mixture was diluted with EtOAc (100 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was passed through a phase separator and concentrated under reduced pressure. The residue was purified by silica chromatography, eluting with 5-15% EtOAc in cyclohexane, followed by trituration with MeOH and drying in a vacuum oven to give the title compound as a white solid (112 mg, 35%). LCMS (Method 1). t =5.51 min; m / z=261.0, 263.1[M+H] + . 1 H NMR(400MHz:CDCl3)δ7.99(1H,d,J=8.8Hz),7.91(1H,d,J=8.3Hz),7.81(1H,d,J=2.8Hz),7.44-7.36(2H,m),7.31(1H,dd,J=8.6,2.0Hz),3.95(3H,s);

[0587] GP C2 3-Chloro-8-hydroxy-6H-benzo[c]chromen-6-one (80) To a solution of 3-chloro-8-methoxy-6H-benzo[c]chromen-6-one (Intermediate 2) (70 mg, 0.268 mmol) in anhydrous DCM (10 mL) was added dropwise a solution of boron tribromide in DCM (1.0 M, 5.4 mL, 5.36 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 3 days. Water (20 mL) was added and the mixture was diluted with DCM (10 mL). The mixture was stirred at room temperature for 10 minutes. The resulting precipitate was filtered off and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. The precipitate was dissolved in MeOH / DCM and concentrated under reduced pressure. The combined residue was purified by silica chromatography eluting with 2-4% MeOH in DCM to give the title compound as a white solid (28 mg, 42%). LCMS (Method 1): R t =4.55 min; m / z=247.1, 249.0[M+H] + . 1 H NMR (400MHz:DMSO-d6) δ10.54(1H,s),8.35-8.31(2H,m),7.63-7.61(2H,m),7.51-7.42(2H,m).

[0588] General Procedure D Synthesis of 2-(dimethylamino)-N-(6-oxo-6H-benzo[c]chromen-3-yl)acetamide (81) [ka]

[0589] GP D1 6-Oxo-6H-benzo[c]chromen-3-yl trifluoromethanesulfonate (Intermediate 3) A mixture of 6-hydroxy-6H-benzo[c]chromen-6-one (2.50 g, 11.78 mmol), N-phenyl-bis(trifluoromethanesulfonimide) (5.05 g, 14.1 mmol), and DIPEA (4.1 mL, 23.6 mmol) in DCM (50 mL) was stirred at room temperature under nitrogen. A catalytic amount of DMAP was added, and the mixture was stirred for 48 h. The resulting red solution was washed with 1 M HCl (50 mL), and the DCM layer was dried (PTFE frit) and evaporated. The crude residue was recrystallized from DCM / cyclohexane to give the product as a cream-colored solid. The mother liquor was purified by silica chromatography using 20-100% DCM in cyclohexane as the eluent. This afforded an additional 1.22 g of product (total yield 2.86 g, 71%). LCMS (Method 5): R t = 1.60 min (m / z not detected - poor ionization). 1 H NMR(CDCl3)δ8.43(1H,dd,J=1.3,8.0Hz),8.16(1H,d,J=8.9Hz),8.11(1H,d,J=8.0Hz),7 .92-7.87(1H,m),7.69-7.64(1H,m),7.34(1H,d,J=2.3Hz),7.30(1H,dd,J=2.5,8.9Hz).

[0590] GP D2 Synthesis of 2-(dimethylamino)-N-(6-oxo-6H-benzo[c]chromen-3-yl)acetamide (81) A mixture of 6-oxo-6H-benzo[c]chromen-3-yl trifluoromethanesulfonate (Intermediate 3) (344 mg, 1.0 mmol), 2-(dimethylamino)acetamide (153 mg, 1.5 mmol), tBuXPhos-Pd-G3 (24 mg, 0.03 mmol), and tribasic potassium phosphate (318 mg, 1.5 mmol) in a septum-sealed vial was degassed (evacuated and flushed with argon three times). Warm, degassed (argon-sparged) tert-butanol (8.5 mL) was added via syringe, and the mixture was heated at 95 °C for 2 h. The cooled mixture was diluted with water (15 mL), and the resulting mixture was filtered and dried under reduced pressure to give a gray solid. This was taken up in DCM (15 mL) and filtered through a 2 g flash Si(II) cartridge, then further eluted with 2% MeOH in DCM to give the title compound (125 mg, 42%) as a white solid. LCMS (Method 3): R t =2.72min;m / z=296.9[M+H] + . 1 H NMR (400MHz,DMSO-d6)δ10.14(1H,s),8.37(1H,d,J=8.1Hz),8.29(1H,d,J=8.8Hz),8.23(1H,dd,J=1.1,7.9Hz),7.9 6-7.90(1H,m),7.88(1H,d,J=2.1Hz),7.68(1H,dd,J=2.1,8.7Hz),7.66-7.60(1H,m),3.13(2H,s),2.30(6H,s).

[0591] General Procedure E Synthesis of methyl (6-oxo-6H-benzo[c]chromen-3-yl)carbamate (82) [ka]

[0592] A mixture of 6-oxo-6H-benzo[c]chromen-3-yl trifluoromethanesulfonate (Intermediate 3) (250 mg, 0.73 mmol), methyl carbamate (82 mg, 1.09 mmol), alkyl palladium(II) chloride dimer (2.7 mg, 0.007 mmol), JackiePhos (29 mg, 0.036 mmol), and KCO (301 mg, 2.18 mmol) in toluene (6.0 mL) was sparged with argon for 5 minutes. The reaction vessel was then sealed, and the mixture was heated at 110 °C for 1 hour. The cooled reaction mixture was diluted with DCM (20 mL) and water (20 mL) to give a suspension in the aqueous phase. The organic phase was separated, and the aqueous phase was washed with DCM (20 mL). The aqueous phase was filtered, and the collected dark solid was taken up in 6% MeOH in DCM. The solution was filtered through a 5 g flash Si(II) cartridge and then further eluted with 6% MeOH in DCM to give the title compound (129 mg, 65%) as a white solid. LCMS (Method 3): t =4.05min;m / z=269.9[M+H] + . 1 HNMR(400MHz,DMSO-d6)δ10.12(1H,s),8.32(1H,d,J=8.1Hz),8.28(1H,d,J=8.8Hz),8.22(1H,dd ,J=1.1,7.9Hz),7.95-7.89(1H,m),7.65-7.58(2H,m),7.45(1H,dd,J=2.1,8.7Hz),3.72(3H,s).

[0593] General Procedure F 3-Bromo-8-methoxy-6H-benzo[c]chromen-6-one (84) [ka]

[0594] GP F1 8-Methoxy-6-oxo-6H-benzo[c]chromen-3-yl trifluoromethanesulfonate (83) (Intermediate 4) 3-Hydroxy-8-methoxy-6H-benzo[c]chromen-6-one (1 g, 4.13 mmol) was dissolved in pyridine (10 mL) and the mixture was cooled in ice water. Trifluoromethanesulfonic anhydride (1 mL, 6.19 mmol) was added dropwise, and the resulting brown mixture was stirred at 0 °C to room temperature for 2 h. The mixture was concentrated under reduced pressure, and the residue was dissolved in DCM, washed with 1 M HCl, brine, dried (PTFE frit), and concentrated under reduced pressure. The resulting residue was passed through a silica pad (12 g), and the product was eluted with 50–100% DCM in cyclohexane to give the compound as white crystals (1.2 g, 80%). 1 H NMR(400MHz,CDCl3)δ8.56(1H,d,J=9.1Hz),8.48(1H,d,J=8.8Hz),7.80(1H,d,J=2.5Hz),7.75(1H ,d,J=2.8Hz),7.65(1H,dd,J=2.8,8.8Hz),7.59(1H,dd,J=2.7,9.0Hz),4.00(3H,s);LCMS(Method 1):R t =5.64min;m / z=375.0[M+H] + .

[0595] GP F2 8-Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6H-benzo[c]chromen-6-one (Intermediate 5) A mixture of 8-methoxy-6-oxo-6H-benzo[c]chromen-3-yl trifluoromethanesulfonate (Intermediate 4) (1.0 g, 2.67 mmol), potassium acetate (393 mg, 4.0 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with DCM (65 mg, 0.08 mmol), 1,1-bis(diphenylphosphino)ferrocene (44 mg, 0.08 mmol), and dioxane (20 mL) was sparged with argon. Bis(pinacolato)diboron (746 mg, 2.94 mmol) was added, and after an additional hour of degassing, the mixture was heated at 90° C. under argon for 19 hours. The cooled mixture was partitioned between ether (25 mL) and water (25 mL), the phases were separated, and the aqueous phase was extracted with ether (2 x 25 mL). The combined organic extracts were washed with saturated brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography on a 20 g Si-(II) cartridge, eluting with DCM followed by 10% EtOAc in DCM. The resulting product was triturated with cyclohexane (10 mL) and then dried under reduced pressure to give the title compound (0.76 g, 81%) as an off-white solid. LCMS (Method 5): R t =1.65min;m / z=353.1[M+H] + , and R t = 1.11 min; m / z = 271.1 [M-Pin+H] + .

[0596] GP F3 3-Bromo-8-methoxy-6H-benzo[c]chromen-6-one (84) A suspension of 8-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6H-benzo[c]chromen-6-one (Intermediate 5) (352 mg, 1.0 mmol) in MeOH (10 mL) was treated with a solution of copper(II) bromide (670 mg, 3.0 mmol) in water (10 mL). The resulting mixture was heated at reflux for 16 h and then cooled. The cooled mixture was extracted with ether (2 × 25 mL) followed by DCM (2 × 25 mL). The combined organic phases were filtered through a hydrophobic frit and concentrated under reduced pressure. The residue was purified by flash chromatography on a 5 g Si-(II) cartridge eluting with [1:1] DCM / cyclohexane followed by DCM to afford the title compound (240 mg, 78%) as a white solid. 1H NMR (400MHz, CDCl3) δ8.00(1H,d,J=8.9Hz),7.84(1H,d,J=8.7Hz),7.80(1H,d,J=3.0Hz),7.53(1H,d,J=1.9Hz),7.46-7.39(2H,m),3.95(3H,s); LCMS (Method 5):R t =1.53 min; m / z=304.8, 306.8[M+H] + .

[0597] Step G 8-(Difluoromethyl)-3-(methoxymethoxy)-6H-benzo[c]chromen-6-one (85) [ka]

[0598] GP G1 8-Bromo-3-(methoxymethoxy)-6H-benzo[c]chromen-6-one (Intermediate 6) 8-Bromo-3-hydroxy-6H-benzo[c]chromen-6-one (1.0 g, 3.44 mmol), K2CO3 (1.42 g, 10.31 mmol), and chloromethyl methyl ether (0.39 mL, 5.15 mmol) were suspended in acetone (10 mL) and the mixture was stirred for 3 h. An additional aliquot of chloromethyl methyl ether (0.39 mL, 5.15 mmol) was added and the mixture was stirred for 2 h. The mixture was concentrated under reduced pressure and partitioned between DCM and water. The DCM layer was washed with brine, dried (PTFE frit), and evaporated to give the product as a white solid (1 g, 86%). 1 H NMR (400MHz, CDCl3) δ8.50(1H,s),7.9-7.88(3H,m),7.07-7.02(2H,m),5.25-5.24(2H,m),3.51(3H,s).

[0599] GP G2 3-(Methoxymethoxy)-8-vinyl-6H-benzo[c]chromen-6-one (Intermediate 7) A mixture of 8-bromo-3-(methoxymethoxy)-6H-benzo[c]chromen-6-one (Intermediate 6) (1 g, 2.98 mmol), potassium vinyltrifluoroborate (520 mg, 3.88 mmol), TEA (1.2 mL, 8.95 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (122 mg, 0.15 mmol) complexed with DCM in isopropanol (20 mL) and water (10 mL) was placed in a sealed tube, degassed, and purged with argon (three times). The mixture was heated at 90 °C under argon for 2 h. The cooled mixture was concentrated under reduced pressure, and the residue was partitioned between EtOAc and water. The EtOAc layer was washed with brine, dried (PTFE frit), and concentrated under reduced pressure. The resulting residue was purified by silica chromatography using 0-50% DCM in cyclohexane as eluent to give the product as a white solid (705mg, 71%). 1HNMR(400MHz,CDCl3)δ8.37(1H,d,J=1.9Hz),7.98(1H,d,J=8.5Hz),7.94(1H,d,J=8.7Hz),7.84(1H,dd,J=2.0,8.4Hz),7. 07-7.02(2H,m),6.81(1H,dd,J=10.9,17.6Hz),5.91(1H,d,J=17.6Hz),5.40(1H,d,J=11.0Hz),5.25(2H,s),3.51(3H,s).

[0600] GP G3 3-(Methoxymethoxy)-6-oxo-6H-benzo[c]chromene-8-carbaldehyde (Intermediate 8) To a solution of 3-(methoxymethoxy)-8-vinyl-6H-benzo[c]chromen-6-one (Intermediate 7) (700 mg, 2.48 mmol) in THF (40 mL) was added osmium tetroxide (0.25 mL, 0.025 mmol), followed by a solution of sodium periodate (1.59 g, 7.44 mmol). The resulting solution was stirred for 18 h to give a white suspension. The mixture was concentrated under reduced pressure, and the residue was partitioned between DCM and water. The DCM layer was washed with aqueous sodium sulfite and brine and then dried (PTFE frit) to give a white solid (700 mg, quantitative). 1 H NMR(400MHz,CDCl3)δ10.11(1H,s),8.83(1H,d,J=1.8Hz),8.30(1H,dd,J=1.8,8.4Hz),8.16( 1H,d,J=8.4Hz),8.04-8.00(1H,m),7.10-7.07(2H,m),5.27(2H,s),3.52(3H,s);LCMS(Method 6):R t =1.41min;m / z=284.2[M+1] + .

[0601] GP G4 8-(Difluoromethyl)-3-(methoxymethoxy)-6H-benzo[c]chromen-6-one (Intermediate 9) A suspension of 3-(methoxymethoxy)-6-oxo-6H-benzo[c]chromene-8-carbaldehyde (Intermediate 8) (190 mg, 0.67 mmol) in DCM (3 mL) was placed under argon. DAST (0.26 mL, 2.01 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 18 h. The resulting solution was neutralized with saturated aqueous NaHCO3, and the DCM layer was washed with brine, dried (PTFE frit), and concentrated under reduced pressure. The residue was purified by silica chromatography using 0-70% DCM in cyclohexane as eluent to give the product as a pale yellow solid (175 mg, 85%). 1 H NMR(400MHz,CDCl3,258114)δ8.49(1H,d,J=1.1Hz),8.12(1H,d,J=8.4Hz),7.98(1H,d,J=8.5Hz),7 .96-7.92(1H,m),7.09-7.05(2H,m),6.76(1H,t,J=56.1Hz),5.26(2H,s),3.51(3H,s);LCMS(Method 6):R t = 1.550 min (m / z not detected - poor ionization).

[0602] GP G5 8-(Difluoromethyl)-3-hydroxy-6H-benzo[c]chromen-6-one (85) A solution of 8-(difluoromethyl)-3-(methoxymethoxy)-6H-benzo[c]chromen-6-one (Intermediate 9) (65 mg, 0.21 mmol) and 2,2'-bipyridyl in MeCN was placed in a sealed tube under argon and cooled in ice-water. Trifluoromethyl trifluoromethanesulfonate (0.08 mL, 0.42 mmol) was added, and the solution was stirred for 18 h. The resulting mixture was stirred with water (0.5 mL) for 30 min, then concentrated under reduced pressure, and the residue was partitioned between EtOAc and water. The EtOAc layer was washed with brine, dried (PTFE frit), and concentrated under reduced pressure. The crude residue was purified by silica chromatography using 0-5% MeOH in DCM as the eluent to give the product as a pale yellow solid. The product was further purified by silica chromatography using 0-50% EtOAc in cyclohexane as the eluent to give the title compound as a white solid (25 mg, 45% yield). 1 H NMR(400MHz,DMSO-d6)δ10.50(1H,s),8.41(1H,d,J=8.5Hz),8.35(1H,d,J=1.1Hz),8.21(1H,d,J=8.9Hz),8. 04(1H,d,J=8.4Hz),7.21(1H,t,J=55.6Hz),6.88(1H,dd,J=2.4,8.7Hz),6.78(1H,d,J=2.4Hz).LCMS(Method 3):R t = 4.03 min; m / z = 260.9 [M−H] - .

[0603] Step H 3-Amino-8-methoxy-6H-benzo[c]chromen-6-one (86) [ka]

[0604] GP H1 3-((diphenylmethylene)amino)-8-methoxy-6H-benzo[c]chromen-6-one (Intermediate 10) A glass vial was charged with a mixture of 8-methoxy-6-oxo-6H-benzo[c]chromen-3-yl trifluoromethanesulfonate (Intermediate 4) (300 mg, 0.802 mmol), benzophenone imine (0.20 mL, 1.20 mmol), cesium carbonate (392 mg, 1.20 mmol), and XPhos-Pd-G3 (76 mg, 0.080 mmol) in THF (4.0 mL). The reaction mixture was degassed, purged with nitrogen (three times), and heated at 80 °C for 2 h. The cooled mixture was partitioned between EtOAc (×2) and water, and the combined organic extracts were washed with brine, dried (MgSO4), and concentrated under reduced pressure. The resulting residue was purified by silica chromatography using 5–95% EtOAc in cyclohexane as eluent to give the product as a white solid (250 mg, 77%). 1 H NMR(400MHz,DMSO-d6)δ8.23(1H,d,J=9.0Hz),8.05(1H,d,J=8.5Hz),7.61(1H,d,J=2.8Hz),7.72-7.66(2H,m),7.53-7.46(4H,m),7 .36-7.31(2H,m),7.33(1H,ob.s),7.27-7.21(2H,m),6.79(1H,d,J=2.0Hz),6.73(1H,dd,J=2.0,8.4Hz),3.89(3H,s).LCMS(Method 5):R t =1.94min;m / z=406.3[M+H] + .

[0605] GP H1 3-Amino-8-methoxy-6H-benzo[c]chromen-6-one (86) A solution of 3-((diphenylmethylene)amino)-8-methoxy-6H-benzo[c]chromen-6-one (Intermediate 10) (250 mg, 0.617 mmol) in THF (3.0 mL) was treated with 2 M HCl (3.1 mL) and stirred at room temperature for 10 minutes. The precipitate was collected by filtration, then dissolved in MeOH and applied to an SCX-2 cartridge equilibrated with MeOH; after washing with MeOH / DCM, the title compound was eluted with 7 M NH in MeOH to give the product as a beige solid (50 mg, 34%). 1H NMR(400MHz,DMSO-d6)δ8.15(1H,d,J=8.8Hz),7.94(1H,d,J=8.6Hz),7.61(1H,d,J=2.8Hz),7.49(1H,dd, LCMS (Method 1):R t =3.91min;m / z=242.3[M+H] + .

[0606] The following examples in Table A were prepared using methods similar to those described above, utilizing the general procedures (GP) indicated. TIFF2025527175000300.tif223165TIFF2025527175000301.tif208165TIFF2025527175000302.tif222165TIFF2025527175000303.tif207165* = Salts were prepared by treatment with 1.1 equivalents of aqueous hydrochloric acid and lyophilization. NMR spectra were obtained in d6-DMSO unless otherwise noted.

[0607] B) Ether and Amide "A" Group Analogues Step I 2-Chloro-3,8-dihydroxy-6H-benzo[c]chromen-6-one (114) and 2-chloro-6H-benzo[c]chromene-3,8-diol (115) [ka]

[0608] 2-Chloro-3,8-dihydroxy-6H-benzo[c]chromen-6-one (114) 2-Chloro-3,8-dihydroxy-6H-benzo[c]chromen-6-one was prepared from 113 using general procedure C2. 1H NMR(400MHz,DMSO-d6)δ10.25(1H,brs),8.24(1H,s),8.19(1H,dJ=8.8Hz),7.51(1H,dJ=2.6Hz),7.31(1H,ddJ=2.7,8.7Hz),6.91(1H,s); LCMS (Method 3):R t = 3.52 min; m / z = 260.9 [M−H] - .

[0609] GP I1 3,8-Bis((tert-butyldimethylsilyl)oxy)-2-chloro-6H-benzo[c]chromen-6-one (Intermediate 11) A suspension of 2-chloro-3,8-dihydroxy-6H-benzo[c]chromen-6-one (114) (2.37 g, 9.04 mmol) in DMF (15 mL) was treated with imidazole (2.46 g, 36.14 mmol) followed by TBDMSCl, and the resulting mixture was stirred at room temperature for 18 h. The reaction was partitioned between EtOAc (×3) and water, and the combined organic extracts were washed with brine, dried (PTFE frit), and concentrated under reduced pressure. The resulting residue was purified by silica chromatography using 0–25% DCM in cyclohexane as eluent to give the product as a white solid (2.0 g, 45%). 1 H NMR(400MHz,CDCl3)δ7.94(1H,s),7.85(1H,dJ=8.7Hz),7.76(1H,dJ=2.6Hz),7.31(1 H,ddJ=2.7,8.7Hz),6.89(1H,s),1.05(9H,s),1.01(9H,s),0.28(6H,s),0.26(6H,s).

[0610] GP I2 4,4'-Bis((tert-butyldimethylsilyl)oxy)-5-chloro-2'-(hydroxymethyl)-[1,1'-biphenyl]-2-ol (Intermediate 12) To a solution of 3,8-bis((tert-butyldimethylsilyl)oxy)-2-chloro-6H-benzo[c]chromen-6-one (Intermediate 11) (385 mg, 0.784 mmol) in 2-Me THF (10 mL) was added DIBAL-H (1.0 M in THF; 1.60 mL, 1.60 mmol) dropwise, and the resulting solution was stirred at room temperature for 1 h. The mixture was cooled in an ice bath and then quenched by the addition of 15% aqueous NaOH (0.1 mL), followed by water (0.16 mL). After stirring for 30 min, Na2SO4 was added, and the resulting mixture was stirred at room temperature for 18 h. The mixture was filtered through Celite®, the pad was washed with DCM, and the combined organic layers were concentrated under reduced pressure to give a yellow solid (388 mg, quantitative). 1 H NMR(400MHz,CDCl3)δ7.24(1H,s),7.04(1H,dJ=8.3Hz),6.98(1H,s),6.88(1H,s),6.79(1H,dJ=7. 7Hz),6.42(1H,s),4.27(2H,m),1.23(1H,m),1.02(9H,s),0.98(9H,s),0.20(6H,s),0.19(6H,s).

[0611] GP I3 ((2-chloro-6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane) (Intermediate 13) To a solution of 4,4'-bis((tert-butyldimethylsilyl)oxy)-5-chloro-2'-(hydroxymethyl)-[1,1'-biphenyl]-2-ol (Intermediate 12) (388 mg, 0.783 mmol) and triphenylphosphine (308 mg, 1.17 mmol) in 2-Me THF (5.0 mL) was added DEAD (0.18 mL) dropwise, and the mixture was stirred for 30 min at room temperature. The resulting solution was concentrated under reduced pressure and purified by silica chromatography using 0-50% EtOAc in cyclohexane as the eluent to give the semi-pure product. LCMS analysis indicated that in addition to the desired product, approximately 70% of the fully deprotected diol was obtained. The crude reaction mixture was carried on to the next step without purification.

[0612] GP I4 2-Chloro-6H-benzo[c]chromene-3,8-diol (115) A solution of crude ((2-chloro-6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane) (Intermediate 13) (0.783 mmol) in MeOH (5.0 mL) was treated with 4 M HCl in dioxane (1.96 mL, 7.83 mmol), and the reaction was stirred at room temperature for 18 h. The resulting mixture was concentrated under reduced pressure, and the residue was partitioned between DCM (×2) and water. The combined organic extracts were washed with brine, dried (NaSO), and concentrated under reduced pressure, and the crude residue was purified by silica chromatography using 0–50% EtOAc in cyclohexane as eluent to afford the title compound as a pale yellow solid (60 mg, 31% yield). 1 H NMR(400MHz,DMSO-d6)δ10.22(1H,brs),9.60(1H,brs),7.66(1H,s),7.54(1H,dJ= 8.3Hz),6.74(1H,dJ=7.5Hz),6.62(1H,s),6.53(1H,s),4.99(2H,s);LCMS(Method 3):R t = 3.57 min; m / z = 246.9 [M−H] - .

[0613] Procedure J 3,8-Dihydroxy-2-methyl-6H-benzo[c]chromen-6-one (116) and 2,6,6-trimethyl-6H-benzo[c]chromene-3,8-diol (117) [ka]

[0614] 3,8-Dihydroxy-2-methyl-6H-benzo[c]chromen-6-one (116) Using general procedures A and C2, 3,8-dihydroxy-2-methyl-6H-benzo[c]chromen-6-one was prepared. 1H NMR(400MHz,DMSO-d6)δ10.15(2H,brs),8.11(1H,dJ=8.9Hz),7.92(1H,s),7.50( 1H,dJ=2.7Hz),7.31(1H,ddJ=2.7,8.7Hz),6.74(1H,s),2.21(3H,s);LCMS(Method 3):R t =3.45min;m / z=242.9[M+1] + .

[0615] GP J1 3,8-Bis((tert-butyldimethylsilyl)oxy)-2-methyl-6H-benzo[c]chromen-6-one (Intermediate 14) 3,8-Bis((tert-butyldimethylsilyl)oxy)-2-methyl-6H-benzo[c]chromen-6-one was prepared from 3,8-dihydroxy-2-methyl-6H-benzo[c]chromen-6-one (120) using general procedure I1. 1 H NMR(400MHz,CDCl3)δ7.89(1H,dJ=8.7Hz),7.76(1H,dJ=2.7Hz),7.71(1H,s),7.28(1H,ddJ= 2.6,8.8Hz),6.78(1H,s),2.29(3H,s),1.03(9H,s),1.01(9H,s),0.27(6H,s),0.26(6H,s).

[0616] GP J2 4,4'-Bis((tert-butyldimethylsilyl)oxy)-2'-(2-hydroxypropan-2-yl)-5-methyl-[1,1'-biphenyl]-2-ol (Intermediate 15) To a solution of 3,8-bis((tert-butyldimethylsilyl)oxy)-2-methyl-6H-benzo[c]chromen-6-one (Intermediate 14) (300 mg, 0.637 mmol) in 2-Me THF (6.0 mL) was added MeMgCl (3.0 M in THF; 0.64 mL, 1.92 mmol), and the resulting solution was stirred at room temperature for 18 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (twice), then dried (Na2SO4), and concentrated under reduced pressure to give the title compound as a colorless oil (320 mg, quantitative). 1 H NMR(400MHz,CDCl3)δ7.10(1H,dJ=2.5Hz),6.94(1H,dJ=8.2Hz),6.86(1H,s),6.75(1H,ddJ=2.5,8.2Hz),6.43(1H,s),5.08( 1H,s),2.13(3H,s),2.04(1H,s),1.53(3H,s),1.42(3H,s),1.03(9H,s),1.01(9H,s),0.26(3H,s),0.25(3H,s),0.24(6H,s).

[0617] GP J3 ((2,6,6-trimethyl-6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane) (Intermediate 16) A solution of 4,4'-bis((tert-butyldimethylsilyl)oxy)-2'-(2-hydroxypropan-2-yl)-5-methyl-[1,1'-biphenyl]-2-ol (Intermediate 15) (320 mg, 0.637 mmol) in toluene (5.0 mL) was treated with PTSA·HO, and the resulting mixture was heated at 50°C for 1 h. The resulting solution was directly purified by silica chromatography using DCM as the eluent to give the product as a colorless oil (280 mg, 90%). 1H NMR(400MHz,CDCl3)δ7.48(1H,dJ=8.4Hz),6.38(1H,s),6.77(1H,ddJ=2.4,8.4Hz),6.68(1H,dJ=2.4Hz), 6.39(1H,s),2.19(3H,s),1.57(6H,s),1.02(9H,s),0.99(9H,s),0.23(6H,s),0.21(6H,s).LCMS(Method 3):R t = 3.57 min; m / z = 246.9 [M−H] - .

[0618] GP J4 2,6,6-trimethyl-6H-benzo[c]chromene-3,8-diol (117) A suspension of ((2,6,6-trimethyl-6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane) (Intermediate 16) (270 mg, 0.557 mmol) in MeOH (5.0 mL) was treated with solid KF (97 mg, 1.67 mmol), and the resulting suspension was stirred at room temperature for 18 h. The resulting mixture was adsorbed onto HMN and purified by silica chromatography using 0–30% EtOAc in cyclohexane as eluent to give the semi-pure product as a pale yellow oil (121 mg). Further purification by trituration with a mixture of DCM and n-pentane gave the title compound as a white solid (91 mg, 64%). 1 H NMR(400MHz,DMSO-d6)δ9.40(1H,s),9.32(1H,s),7.47(1H,dJ=8.4Hz),7.38(1H,s),6.71(1H ,ddJ=2.3,8.4Hz),6.66(1H,dJ=2.3Hz),6.31(1H,s),2.09(3H,s),1.50(6H,s);LCMS(Method 3):R t =3.80min;m / z=257.1[M+H] + .

[0619] Compound 117A was prepared by the following method. [ka]

[0620] Step 1: Synthesis of 3-hydroxy-8-methoxy-2,9-dimethyl-6H-benzo[c]chromen-6-one [ka]

[0621] 4-Methylbenzene-1,3-diol (2.03 g, 16.3 mmol, 2.00 equiv) plus NaCO (2.60 g, 24.5 mmol, 3.00 equiv) was dissolved in water (10 mL). Upon complete dissolution, 2-bromo-5-methoxy-4-methylbenzoic acid (2.00 g, 8.16 mmol, 1.00 equiv) was added in one portion. The mixture was heated at 60 °C in an oil bath for 1 h, after which CuI (777 mg, 4.08 mmol, 0.50 equiv) was added in one portion. Stirring was continued at 60 °C overnight, after which the reaction was cooled to room temperature and filtered. The filter cake was suspended in 1 M hydrochloric acid and filtered again. The remaining filter cake was dried under high vacuum overnight to give 3-hydroxy-8-methoxy-2,9-dimethyl-6H-benzo[c]chromen-6-one (1.27 g, 4.70 mmol, 58%) as a gray solid. f =0.30 (EtOAc / cyclohexane 40%). 1 H NMR (400MHz, DMSO) δ10.12(s,1H),8.08(s,1H),7.95(s,1H),7.52(s,1H),6.73(s,1H),3.90(s,3H),2.33(s,3H),2.21(s,3H).

[0622] Step 2: Synthesis of 3,8-dihydroxy-2,9-dimethyl-6H-benzo[c]chromen-6-one [ka]

[0623] 3-Hydroxy-8-methoxy-2,9-dimethyl-6H-benzo[c]chromen-6-one (1.17 g, 4.30 mmol, 1.00 equiv) was suspended in DCM (44 mL) and cooled to 0 °C in an ice bath. BBr3 (13.0 mL, 13.0 mmol, 4.00 equiv) was added dropwise as a 1 M solution in DCM. Upon completion of the addition, the reaction was stirred at 0 °C for an additional 30 min before warming to room temperature. The reaction was stopped by quenching with methanol at 0 °C upon complete consumption of the starting material as indicated by TLC. The methanol solution was concentrated under reduced pressure, and the crude product was purified using flash column chromatography (0–10% MeOH in DCM) to give 3,8-dihydroxy-2,9-dimethyl-6H-benzo[c]chromen-6-one (520 mg, 2.03 mmol, 47%) as a gray solid. f = 0.2 (MeOH / DCM 10%). 1 H NMR (400MHz, DMSO) δ 10.15 (s, 1H), 10.04 (s, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 7.51 (s, 1H), 6.72 (s, 1H), 2.31 (s, 3H), 2.21 (s, 3H).

[0624] Step 3: Synthesis of 3,8-bis((tert-butyldimethylsilyl)oxy)-2,9-dimethyl-6H-benzo[c]chromen-6-one [ka]

[0625] 3,8-Dihydroxy-2,9-dimethyl-6H-benzo[c]chromen-6-one (520 mg, 2.03 mmol, 1.00 equiv) was suspended in DMF (10 mL) and TBSCl (765 mg, 5.07 mmol, 2.50 equiv) was added in one portion. Subsequently, TEA (1.40 mL, 10.1 mmol, 5.00 equiv) was added dropwise, and the reaction was stirred for 3 h. After 3 h, the reaction was monitored by TLC and observed to have stopped due to solubility issues and could not proceed further. Therefore, water was added to the reaction mixture and it was extracted with EtOAc (3 times). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (0-10% EA in hexanes) to give 3,8-bis((tert-butyldimethylsilyl)oxy)-2,9-dimethyl-6H-benzo[c]chromen-6-one (290 mg, 0.60 mmol, 30%) as a white solid. f =0.4 (10% EtOAc / cyclohexane). 1 H NMR(400MHz,CDCl3)δ7.78(s,1H),7.71(s,1H),7.66(s,1H),6.78(s,1H),2. 39(s,3H),2.29(s,3H),1.04(s,9H),1.03(s,9H),0.30(s,6H),0.27(s,6H).

[0626] Step 4: Synthesis of 4,4'-bis((tert-butyldimethylsilyl)oxy)-2'-(2-hydroxypropan-2-yl)-5,5'-dimethyl-[1,1'-biphenyl]-2-ol [ka]

[0627] 3,8-Bis((tert-butyldimethylsilyl)oxy)-2,9-dimethyl-6H-benzo[c]chromen-6-one (290 mg, 0.60 mmol, 1.00 equiv) was dissolved in THF (5 mL) and the reaction was cooled to 0 °C in an ice bath. Subsequently, MeMgBr (0.60 mL, 1.79 mmol, 3.00 equiv) (3 M in EtO) was added in one portion. The reaction was stirred for 10 minutes at 0 °C and then allowed to warm to room temperature. After continuing stirring at room temperature for 1 hour, the reaction was quenched with water and extracted with EtOAc (3 x). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (0–20% EA in hexanes) to give 4,4′-bis((tert-butyldimethylsilyl)oxy)-2′-(2-hydroxypropan-2-yl)-5,5′-dimethyl-[1,1′-biphenyl]-2-ol (260 mg, 0.50 mmol, 84%) as a colorless oil, which was used directly in the next step, albeit as an inseparable mixture with the undesired product.

[0628] Step 5: Synthesis of ((2,6,6,9-tetramethyl-((6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane) [ka]

[0629] 4,4'-Bis((tert-butyldimethylsilyl)oxy)-2'-(2-hydroxypropan-2-yl)-5,5'-dimethyl-[1,1'-biphenyl]-2-ol (260 mg, 0.50 mmol, 1.00 equiv) was dissolved in toluene (5 mL) and PTSA (9.6 mg, 0.05 mmol, 10 mol%) was added. The mixture was heated to 70 °C for 10 min, after which the starting material was completely converted. The mixture was concentrated under reduced pressure, and the residue was directly purified by flash column chromatography (0-10% EtOAc / cyclohexane) to give the desired ((2,6,6,9-tetramethyl-((6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane) (175 mg, 0.35 mmol, 70%) as a yellowish solid. f = 0.4 (10% EtOAc / cyclohexane). 1 H NMR(400MHz,CDCl3)δ7.39(d,J=6.2Hz,2H),6.61(s,1H),6.38(s,1H),2.23(s,3H) ),2.20(s,3H),1.56(s,6H),1.02(s,9H),1.01(s,9H),0.23(s,6H),0.22(s,6H).

[0630] Step 6: Synthesis of 2,6,6,9-tetramethyl-6H-benzo[c]chromene-3,8-diol [ka]

[0631] ((2,6,6,9-Tetramethyl-((6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane) (175 mg, 0.35 mmol, 1.00 equiv) was dissolved in MeOH (5 mL) and 0.5 mL of DCM was added to completely dissolve the mixture. KHF (110 mg, 1.40 mmol, 4.00 equiv) was then added in one portion and the reaction was stirred overnight. The reaction mixture was concentrated under reduced pressure and directly subjected to purification by flash column chromatography (0–5% MeOH in DCM) to afford 2,6,6,9-tetramethyl-6H-benzo[c]chromene-3,8-diol UA-845 (40 mg, 0.15 mmol, 42%) as an orange solid. f = 0.27 (MeOH / DCM 6%). 1 H NMR (400MHz, DMSO) δ9.28(s,1H),9.25(s,1H),7.38(s,2H),6.65(s,1H),6.29(s,1H),2.14(s,3H),2.09(s,3H),1.45(s,6H).MS(APCI+):m / z=271.1.

[0632] Step K 1-Fluoro-3,8-...

Claims

1. A composition for use in the treatment of neuromuscular disorders, muscle disorders, heart disease, pulmonary fibrosis, liver disease, inflammatory bowel disease, cancer, or cognitive impairment in a subject requiring treatment, comprising a compound of formula (Ia): 【Chemistry 1】 [In the formula, A is 【Chemistry 2】 And, X １ It is selected from O and S, Y １ It is O, R １ , R ４ , R ５ , and R ８ It is selected independently from H and halogen, R ３ and R ６ are independently selected from H, CN, OH, CF ３ , halogen, and alkyl, R ２ is OH and R ７ Halogen, CN, CF ３ CO ２ H, NO ２ NHAc, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, alkyl-R ９ Alkenil-R ９ Alkinyl-R ９ , OR １０ NHR １０ , NR １１ C(O)R １２ , C(O)NR １１ R １２ , and NR １１ SO ２ R １２ Selected from, Each has an R ９ OH, NH ２ O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH ３ ) C(O)-alkyl, NHSO ２ - Alkyl, N(CH ３ ) SO ２ - Independently selected from alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, R １０ C ２ -C １２ Alkyl, C(O)-alkyl, hydroxyalkyl, aminoalkyl, alkyl-O-alkyl, alkyl-O-alkyl-OH, alkyl-O-alkyl-O-alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, alkyl-heterocycloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, Reuters ３ H, SO ２ - Alkyl and SO ２ - Selected from haloalkyl groups, Each has an R １１ is selected from H and alkyl, Each has an R １２ [Selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, aralkyl, heteroaralkyl, alkyl-cycloalkyl, and alkyl-heterocycloalkyl] or containing a pharmaceutically acceptable salt thereof, The aforementioned neuromuscular disorder is Charcot-Marie-Tooth disease; The aforementioned muscle disorders are hereditary inclusion body myositis, oculopharyngeal muscular dystrophy, inclusion body myopathy with Paget's disease of bone, or frontotemporal dementia; The composition wherein the cardiac disease is heart failure, myocardial infarction, coronary artery disease (CAD), congestive heart failure (CHF), angina pectoris, stroke, arrhythmia, fibrillation, peripheral artery disease (PAD), or a heart or arterial disorder.

2. A is, 【Transformation 3】 The composition according to claim 1.

3. R ９ This is selected from OH, substituted cycloalkyl, and heterocycloalkyl. R １０ is selected from alkyl, substituted cycloalkyl, heterocycloalkyl, and alkylheterocycloalkyl, and R １１ H is R １２ The composition according to claim 1, wherein is alkyl-heterocycloalkyl.

4. R ７ This refers to haloalkyl, substituted cycloalkyl, and alkynyl-R ９ , OR １０ , and C(O)NR １１ R １２ Selected from, R ９ This is selected from OH, substituted cycloalkyl, and heterocycloalkyl. R １０ These include alkyl, substituted cycloalkyl, heterocycloalkyl, and alkyl Selected from heterocycloalkyl, and R １１ H is R １２ The composition according to claim 1, wherein is alkyl-heterocycloalkyl.

5. The composition according to claim 4, wherein each of the substituted cycloalkyl groups is independently substituted with an OH group, a halogen, or a hydroxyalkyl group.

6. (i) R １ , R ３ , R ４ , R ５ , R ６ , and R ８ Each of these is H, or (ii) One of R1, R3, R4, R5, R6, and R8 is not H, or (iii) The composition according to claim 1, wherein two of R1, R3, R4, R5, R6, and R8 are not H.

7. R １ , R ３ , R ４ , R ５ , R ６ , and R ８ The composition according to claim 6, wherein one of the elements is a halogen, or one of R3 and R5 is an alkyl group.

8. The aforementioned compound, 【Chemistry 4】 A composition according to claim 1, selected from the following.

9. The aforementioned compound, 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 Selected from, The aforementioned compound, 【Chemistry 9】 A composition according to claim 1, selected from the following.

10. A composition for use in the treatment of neuromuscular disorders, muscle disorders, heart disease, pulmonary fibrosis, liver disease, inflammatory bowel disease, cancer, or cognitive impairment in a subject requiring treatment, comprising a compound of formula (Ic): 【Chemistry 10】 [In the formula, A is 【Chemistry 11】 And, One of n and m is 0, and the other of n and m is 1. X １ and Y １ Each of these is O, R １ 、 R ２ 、 R ３ 、 R ６ 、 R ７ 、 and R ８ is independently selected from H, OH, OCH ３ 、 OAc, NH ２ 、 halogen, CN, CF ３ 、 CO ２ H, NO ２ 、 NHAc, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, alkyl-R ９ 、 alkenyl-R ９ 、 alkynyl-R ９ 、 OR １０ 、 NHR １０ 、 NR １１ C(O)R １２ 、 C(O)NR １１ R １２ 、 and NR １１ SO ２ R １２ and is independently selected from R ４ and R ５ It is independently selected from H, halogen, and alkyl. Each existing R ９ is independently selected from OH, NH ２ , O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH ３ ), C(O)-alkyl, NHSO ２ -alkyl, N(CH ３ ), SO ２ -alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; R １０ C ２ -C １２ Alkyl, hydroxyalkyl, aminoalkyl, alkyl-O-alkyl, alkyl-O-alkyl-OH, alkyl-O-alkyl-O-alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, alkyl-heterocycloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, Reuters ３ H, SO ２ - Alkyl and SO ２ - Selected from haloalkyl groups, Each has an R １１ is selected from H and alkyl, Each has an R １２ [Selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, aralkyl, heteroaralkyl, alkyl-cycloalkyl, and alkyl-heterocycloalkyl] or containing a pharmaceutically acceptable salt thereof, The aforementioned neuromuscular disorder is Charcot-Marie-Tooth disease; The aforementioned muscle disorders are hereditary inclusion body myositis, oculopharyngeal muscular dystrophy, inclusion body myopathy with Paget's disease of bone, or frontotemporal dementia; The composition wherein the cardiac disease is heart failure, myocardial infarction, coronary artery disease (CAD), congestive heart failure (CHF), angina pectoris, stroke, arrhythmia, fibrillation, peripheral artery disease (PAD), or a heart or arterial disorder.

11. A is, 【Chemistry 12】 A composition according to claim 10, selected from the following.

12. (i) R ２ and R ７ These are, respectively, OH, or (ii) R2 and R7 are each O-alkyl, or (iii) R2 is OH, and R7 is H or O-alkyl, or The composition according to claim 10, wherein (iv) R2 is H or O-alkyl and R7 is OH.

13. (i) R １ , R ３ , R ４ , R ５ , R ６ , and R ８ These are H, or (ii) One of R1, R3, R4, R5, R6, and R8 is not H, or (iii) The composition according to claim 10, wherein two of R1, R3, R4, R5, R6, and R8 are not H.

14. R １ , R ３ , R ４ , R ５ , R ６ , and R ８ The composition according to claim 10, wherein one of R1, R3, R4, R5, R6, and R8 is alkyl or halogen.

15. The aforementioned compound, 【Chemistry 13】 A composition according to claim 10, selected from the following.

16. The aforementioned compound, 【Chemistry 14】 Selected from, or The aforementioned compound, 【Chemistry 15】 The composition according to claim 10.

17. A composition according to any one of claims 1 to 16, for use in the treatment of neuromuscular disorders.

18. A composition according to any one of claims 1 to 16, for use in the treatment of muscle disorders.

19. A composition according to any one of claims 1 to 16, for use in the treatment of pulmonary fibrosis.

20. The composition according to claim 19, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.

21. A composition according to any one of claims 1 to 16, for use in the treatment of liver disease.

22. The composition according to claim 21, wherein the liver disease is non-alcoholic steatohepatitis.

23. A composition according to any one of claims 1 to 16, for use in the treatment of inflammatory bowel disease.

24. The composition according to claim 23, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

25. A composition according to any one of claims 1 to 16, for use in the treatment of cancer.

26. The composition according to claim 25, wherein the cancer is responsive to immunotherapy.

27. The composition according to claim 25, wherein the compound suppresses tumor growth.

28. The subject is the composition according to claim 25, which is simultaneously treated with cancer immunotherapy.

29. The compound enhances the effectiveness of the cancer immunotherapy, or The compound enhances the antitumor response to the cancer immunotherapy in the subject, or The composition according to claim 28, wherein the compound enhances the immune response against tumor cells in a target.

30. The aforementioned compound is a T memory stem cell (T ＳＣＭ ) promotes formation, or The aforementioned compound promotes antitumor CD8+ T cell immunity, or The composition according to claim 25, wherein the compound promotes an antitumor effect during adoptive cell transfer.

31. The composition according to claim 25, wherein the cancer is bladder cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head and neck cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, prostate cancer, or skin cancer.

32. The composition according to claim 25, wherein the cancer is colorectal cancer.

33. The composition according to claim 28, wherein the subject is simultaneously receiving treatment with an immune checkpoint inhibitor.

34. The composition according to claim 32, wherein the subject is simultaneously treated with pembrolizumab, nivolumab, or ipilimumab.

35. A composition according to any one of claims 1 to 16, for use in the treatment of heart disease.

36. The aforementioned compound, when administered to a subject after a myocardial infarction, reduces heart failure, or The compound reduces left ventricular systolic dysfunction after myocardial infarction, or The composition according to claim 35, wherein the compound increases the ejection rate and / or shortening rate.

37. A composition according to any one of claims 1 to 16, for use in the treatment of cognitive impairment.

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