Therapeutic use of urolithin derivatives

Abstract

Methods for treating neuromuscular disorders, muscular disorders, heart diseases, pulmonary fibrosis, liver diseases, inflammatory bowel diseases, or cancer are disclosed. A method of enhancing cancer immunotherapy is also disclosed.

Description

[0001] Related Applications

[0002] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 412,078 filed on September 30, 2022 and U.S. Provisional Patent Application No. 63 / 392,606 filed on July 27, 2022. Background Art

[0003] Urolithins have potent effects on improving many health conditions, and they 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, memory loss, reduced metabolic rate, metabolic syndrome, diabetes, cardiovascular disease, hyperlipidemia, neurodegenerative diseases, cognitive disorders, mood disorders, stress, anxiety disorders, fatty liver disease, and for improving liver function and weight management. In particular, urolithins have been shown to have beneficial effects in enhancing muscle function. Summary of the invention

[0004] One aspect of the 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 dementia, or Duchenne muscular disorder), a heart disease (e.g., heart failure), a pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis), a liver disease (e.g., nonalcoholic 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.

[0005] Thus, provided herein is a method of treating a neuromuscular disorder (e.g., Chuck-Marie-Duchenne disease), a muscle disorder (e.g., hereditary inclusion body myositis, oculopharyngeal muscular dystrophy, inclusion body myopathy, Paget's disease of bone, frontotemporal dementia, or Duchenne muscular disorder), a heart disease (e.g., heart failure), a pulmonary fibrosis (e.g., idiopathic pulmonary 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 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (la), (la), (la), (la), (la), (la), (la), (la), or (la).

[0006] Unless otherwise limited, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the present 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. The full texts of all publications, patent applications, patents and other references mentioned herein are incorporated by reference. In the event of a conflict, this specification (including definitions) shall prevail. In addition, materials, methods and examples are illustrative only and are not intended to be limiting.

[0007] Other features, objects, and advantages of the invention will be apparent from the detailed description, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figure 1A : Schematic illustration of the AOM model and treatment regimen. Figure 1B : Tumor incidence of AOM-induced tumors in mice receiving a UA-containing diet or a control diet. Data are mean ± SD, n = 4 / 5, *p < 0.05 by two-sided t-test. One of two independent experiments is shown. Figure 1C : Mean lesion size of tumors induced by AOM receiving a UA-containing diet or a control diet. Data are mean ± SD, n = 4 / 5, *p < 0.05 by two-sided 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 as depicted in (A, D). Scale bar = 100 μm. Figure 1F : Relative numbers of CD45+CD3+ T cells in the colon of AOM-treated mice at week 24, data are mean±SD, n=7 / 8, **p<0.01 by two-sided t-test. Figure 1G : Organoid treatment protocols. APTK organoids were incubated in the presence of UA or DMSO for the indicated time points prior to flow cytometric analysis. Figure 1H : Quantification of lysosome formation assessed by lysosomal tracer MFI via flow cytometry after 24 h incubation in the presence of different concentrations of UA. Data are mean ± SD, n = 5 / 4 / 4, by one-way ANOVA followed by Tukey's multiple comparison test *p < 0.05, **p < 0.01. Representative results from one of two independent experiments are shown. Fig. 1I : Mitotracker signals of APTK organoids incubated in vitro for 24 h in the presence of UA (n=4 / 4 / 4). Figure 1J : Antigen presentation via MHC-I molecules 48 hours after treatment (n=5 / 4 / 4). Fig. 1I Data in and IJ are mean ± SD, **p < 0.01 by one-way ANOVA followed by Tukey's multiple comparison test. Results from one of two independent experiments are shown. Figure 1K : Experimental setup of oral UA administration in mice with established APTK-sc tumors. The treatment diet was started eleven days after tumor injection and maintained until the end of the experiment. Figure 1L : Growth curves of mice bearing subcutaneous APTK tumors receiving diets containing UA or control. Data are mean ± SD, n = 7, ***p < 0.001 by two-sided t-test. One of two independent experiments is shown. Figure 1M : End point tumor weight. Figure 1N : CD8+ T cell infiltration in APTK-sc tumors assessed by flow cytometry, total number of CD8+ T cells normalized to tumor weight. Data are mean ± SD, n = 7, *p < 0.05 and ***p < 0.001 by Mann-Whitney test. Fig.1O : Size of subcutaneous APTK tumors in Rag1- / - mice receiving a diet containing UA or a control. Figure 1K Data are mean ± SD, n = 7, depicting one of two independent experiments. Figure 1P : CD8+ T cell depletion or isotype control antibodies were applied every two days starting three days after subcutaneous injection of APTK organoids in C57BL / 6 mice. Figure 1Q : Effect of CD8+ T cell depletion on subcutaneous APTK tumor size in C57BL / 6 mice receiving UA-containing or control diet. Data are mean ± SEM, isotype n = 5, UA diet + α-CD8 n = 9, other groups n = 10, **** p < 0.0001 by one-way ANOVA followed by Tukey's multiple comparison test. The data shown represent pooled data from two experiments with comparable results. Figure 1R : α-PD-1 or isotype antibodies were injected every three days starting five days after subcutaneous injection of APTK organoids in C57BL / 6 mice. Figure 1S : Effect of α-PD-1 treatment on subcutaneous APTK tumor size in C57BL / 6 mice receiving UA-containing or control diet. Data are mean ± SEM, isotype n = 5, control diet + α-PD-1 n = 9, other groups n = 10; *p < 0.05, **p < 0.01 and ****p < 0.0001 by one-way ANOVA followed by Tukey's multiple comparison test. The data shown represent pooled data from two experiments with comparable results.

[0009] Figure 2A : Protocol for CD3+ T cell activation, treatment, and analysis. Figure 2B : Granzyme B expression in αCD3 / αCD28 stimulated CD3+ T cells in the presence of UA or DMSO after 48 h. 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 : 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 : CD44-CD62L+ScalHi T 24, 48 and 72 hours after αCD3 / αCD28 stimulation SCM Data are mean ± SD from four independent experiments, n = 4, **p < 0.01; ***p < 0.001 by two-way ANOVA followed by Tukey's multiple comparison test. Figure 2E : Frequency of CD62L+CD44-CD8+ T cells with low mitochondrial membrane potential (TMRMLo) after 48 hours in the presence or absence of UA (25 μM). Data are mean ± SD, n = 5; ****p < 0.0001 by two-sided t-test. Figure 2F : Frequency of CD95HiCD62L+CD44-CD8+ T cells 48 h after αCD3 / αCD28 stimulation in the presence or absence of UA (25 μM). Data are mean ± SD; n = 5; **** p < 0,0001 by two-sided t-test. ( Figure 2G )T SCM (n=7), ( Figure 2H )TCF1(n=7),( Fig.2I )PD1Hi(n=6)、( Figure 2J )Tim3Hi(n=6) and ( Figure 2K ) The frequency of CTLA4Hi (n = 6). Data are mean ± SD, by two-sided t test *p < 0.05; **p < 0,01; ***p < 0,001. ( Figure 2L )TNFα and ( Figure 2M ) IFNγ expression. Data are mean ± SD, n = 7 per group, **p < 0.01 and ***p < 0,001 by two-sided t test.

[0010] Figure 3A: Experimental setup for adoptive cell transfer into Ragl- / - 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 prior to transfer. Figure 3B : Number of splenic CD8+ T cells in Rag1- / - mice 1 week after adoptive transfer of UA-treated or control T cells. Data are mean ± SD, n = 7 per group, *p < 0.05 by two-sided t-test. Figure 3C : Experimental setup for adoptive cell transfer of OT-1CD3+ T cells in APTK-OVAs.c. tumor-bearing mice. Ex vivo stimulation prior to transfer Figure 3A As described in. Figure 3D : Growth curves of scAPTK-OVA tumors treated as depicted in (C), UA: n=6, DMSO: n=7, data are mean±SD, ***p<0,001 by two-sided t-test. Figure 3E : Final tumor weight of subcutaneously transplanted APTK-OVA tumors in Rag1- / - mice transplanted with TUA or TDMSO. Data are mean ± SD; **p < 0,01 by two-sided t-test. Analysis of TILs from ACT-treated Rag1- / - mice bearing APTK-OVA tumors: CD8+ TILs from APTK-OVA-induced tumors that had received UA-treated OT-I T cells (n = 6) or DMSO-treated OT-I T cells (n = 7) Figure 3F )CD44, ( Figure 3G )TCF1 and ( Figure 3H ) Expression of CD62L, data are mean ± SD, *p < 0.05 by two-sided t-test, ns not significant. Fig. 3I : Frequency of depleted Tim3HiPD-1Hi CD8+ TILs from APTKOVA-induced tumors that had received 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-sided t-test.

[0011] Figure 4A : Protocol for CD3+ T cell activation, treatment, and analysis. Figure 4B : The frequency of CD8+ T cells with low mitochondrial membrane potential (TMRMLo) after six hours of stimulation with αCD3 / αCD28 in the absence or presence of UA (50 μM). Data are mean ± SD, n = 4; * p < 0.05 by two-sided t test. The data shown represent one of two independent experiments. Figure 4C: Quantification of lysosome formation in CD8+ T cells after 6 h of stimulation with αCD3 / αCD28 in the absence or presence of UA (50 μM). Data are mean ± SD, n = 4; **p < 0.01 by two-sided t-test. The data shown represent one of two independent experiments. Figure 4D : Frequency of MitoTracker red staining of CD8+ T cells after 24 h stimulation with αCD3 / αCD28 in the absence or presence of UA. Data are mean ± SD, n = 6 (UA) or n = 4 (DMSO), **p < 0.01, ***p < 0.001, ****p < 0.0001 by one-way ANOVA followed by Tukey's multiple comparison test. Figure 4E : MitoTracker expression in T cell subsets 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, ****p < 0.0001 by one-way ANOVA followed by Tukey's multiple comparison test. Figure 4F : qPCR analysis of various autophagy / mitophagy-related genes in T cells 24 h after stimulation with αCD3 / αCD28 in the absence or presence of UA (50 μM), data are ± SEM, n = 3; *p < 0.05, **p < 0.01 by two-sided t-test. Figure 4G : Immunoblot analysis of the indicated proteins in T cells 24 h after stimulation with αCD3 / αCD28 in the absence or presence of UA (50 μM). Figure 4H : Quantification of lysosome formation in Pink1- / -CD8+ T cells after 6 h 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-sided t-test. Data shown represent one of two independent experiments. Fig. 4I : Frequency of MitotrackerHiPink1- / -CD8+ T cells after 48 h 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-sided t-test. Data shown represent one of two independent experiments. Figure 4J : T cells in Pink1- / -CD8+ T cells stimulated with αCD3 / αCD28 in the absence or presence of UA (25 and 50 μM) for 48 h SCM The frequency of , data are mean ± SD, n = 4, ***p < 0.001 by two-sided t-test. Figure 4K: Expression of TCF1 in CD62L+CD44-CD8+ cells from Pink1- / - mice after stimulation with αCD3 / αCD28 in the absence or presence of UA (50 μM) for 48 h, data are mean±SD, n=4, ***p<0.001 by two-sided t-test. Figure 4L :like Figure 1K Growth curves of Pink1- mice injected subcutaneously with APTK organoids and fed a UA- or control diet are depicted in Figure 2. Data are mean ± SD, n = 4 / group. APTK-induced tumors in Pink1- / - mice fed a UA or control diet ( Figure 4M )TCFHi、( Figure 4N )PDHi、( Fig.4O ) Frequency of Tim3Hi CD8+ TILs. Data are mean ± SD, n = 4 / group. Figure 4P : Expression of IFNγ in CD8+ TILs from Pink1- / - restimulated for three hours ex vivo with PMA / ionomycin in the presence of Brefeldin A. Data are mean ± SD, n = 4. Figure 4Q : Expression of TNFα in CD8+ TILs from Pink1- / - restimulated for three hours ex vivo with PMA / ionomycin in the presence of Brefeldin A. Data are mean ± SD, n = 4.

[0012] Figure 5A : Enhanced volcano plot of RNAseq of T cells stimulated with αCD3 / αCD28 for 48 h 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 : Heatmap of differentially expressed genes related to immune checkpoints, effector molecules, and genes encoding leukocyte migration. Figure 5C : Heatmap of differentially expressed genes associated with T cell memory versus effector fate decisions. Data were z-score normalized for display (n=3 per group). Figure 5D : The frequency of CD8+ T cells expressing TCF1Hi after 48 hours of stimulation with αCD3 / αCD28 in the presence of UA (50 μM) or TCF1 inhibitor ICG001 (10 μM) compared to DMSO control. Data are mean ± SD, n = 4, by one-way ANOVA followed by Tukey's multiple comparison test ***p < 0.001; ****p < 0.0001. Figure 5E : Compared with DMSO control, T cells were stimulated with αCD3 / αCD28 for 48 h in the presence of UA (50 μM) or TCF1 inhibitor ICG001 (10 μM). sCMData are mean ± SD, n = 4: DMSO, UA, ICG001, n = 3: UA + ICG001, by one-way ANOVA followed by Tukey's multiple comparison test, *p < 0.05, p*** < 0,001; ns not significant. One of two independent experiments is shown. Fig. 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). Figure 5G : Immunoblot analysis of fractionated T cells stimulated with αCD3 / αCD28 for 6 hours in the absence or presence of UA (50 μM); c = cytosolic, m = mitochondrial fraction. The experiment was 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. After 48 h of stimulation with αCD3 / αCD28 in the absence or presence of UA, expression of ( Fig.5I )T SCM 、( Figure 5J )CD95+、( Figure 5K ) Frequency of Pgam5- / - CD8+ T cells of TCF1. Data are mean ± SD, n = 4 / group, * p < 0.05 by one-way ANOVA followed by Tukey's multiple comparison test, ns not significant. Figure 5L : PGC-1α expression in CD8+ T cells after 48 h 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-sided t-test. One of two independent experiments is shown. Figure 5M :like Figure 1K Depicted in Figure 2, mitochondrial content of CD8+ TILs from APTK-induced tumors of wt mice fed UA or control diet. Data are mean ± SD, n = 6 / group, *p < 0.05 by two-sided t-test. After 48 h of stimulation with αCD3 / αCD28 in the absence or presence of UA (50 μM), CD8+ TILs from Pink1- / -KO mice ( Figure 5N ) or Pgam5- / - mice ( Fig.5O ) PGC-1α expression in CD8+ T cells. Data are mean ± SD, n = 4. Figure 5P : T cells were stimulated with αCD3 / αCD28 for 48 h in the presence of UA (50 μM) or PGC-1α inhibitor (PGC-1αi, 10 μM). SCMData are mean ± SD, n = 4, by one-way ANOVA followed by Tukey's multiple comparison test, p** < 0.01, ***p < 0.001, ****p < 0.0001, ns not significant.

[0013] Fig. 6A : Human PBMCs were isolated from healthy donors, T cells were purified and stimulated ex vivo with αCD3 / αCD28 in the presence of UA (50 μM) or DMSO control. Figure 6B :like Fig. 6A Human T 48 hours after stimulation as shown SCM Data are mean ± SD, p **** 0.0001 by one-way ANOVA followed by Tukey's multiple comparison test. Figure 6C : Quantification of human TMRMloCD8+ T cells 48 h after stimulation in the presence of UA or DMSO control, data are mean ± SD, p** 0.01 by two-sided t-test. Fig.6D : 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-sided t test. In Figure 6b, representative data of one of five donors with comparable results are shown. Fig. 6E : Experimental layout for CD19-CAR T cell generation and expansion. PBMCs from healthy donors were expanded in the presence of IL-7 / IL-15 for three days before VSV-LV transduction. After three days of incubation, killing of Nalm-6 cells was assessed after 24 hours of co-culture. Fig. 6F :like Fig. 6E As depicted in Figure 2, after the generation of CD19-CAR+CD8+ T cells SCM The frequency of . Data are mean ± SD; p **** 0.0001 by two-sided t-test. Data are pooled from three independent experiments. Figure 6G :The killing potential of CD19-CAR-T cells. The percentage of dead NALM-6 cells after 24 hours of 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 : Experimental layout of CEA-CART cell experiment. After CAR gene transduction (top), CAR T cells were frozen for subsequent experiments after thawing (bottom). Fig.6I : T cells in CAR+CD8+ cells specific for CEA SCMThe frequency of . Data are mean ± SD, n = 4, p **** 0.0001 by two-sided t-test. Data are pooled from two independent experiments. Figure 6J : Killing potential of CEA-specific CAR-T cells. The percentage of human CRC organoids expressing CEA that died after 72 hours of co-culture with untransduced or CAR-transduced T cells ± UA / DMSO is shown. Data are mean ± SD, n = 3; by two-way ANOVA, followed by Sidak's multiple comparison test, ***p < 0.001, p **** 0.0001, ns not significant.

[0014] Fig. 7A :and Figure 1H -I. Right, lysosome formation after 24 h as assessed by lysosomal tracer MFI via flow cytometry. Left, Mitotracker signal of APTK organoids incubated in vitro for 24 h in the presence of UA after 24 h incubation in the presence of various UA concentrations. Figure 7B :For identification of naive T cells (TN; CD44-CD62L+), effector memory cells (TEM; CD44-CD62L-), central memory cells (TCM; CD44+CD62L+) and memory stem cells (T SCM Representative gating strategy for CD44+CD62L+Sca1+) subsets. TN ( Figure 7C )、TCM( Fig.7D ) and TEM( Fig. 7E ) quantification. Data are mean ± SD, n = 4, by two-way ANOVA followed by Tukey's multiple comparison test, p* < 0,05, p** < 0,01; ***p < 0,001; ns not significant. Complete subset analysis of CD4+ cells, showing TN ( Figure 7F )、TCM( Figure 7G )、TEM( Figure 7H ) and T SCM ( Fig.7I ) Quantification. Data are mean ± SD, n = 4, by two-way ANOVA followed by Tukey's multiple comparison test, p * < 0.05, p ** < 0.01; ns not significant.

[0015] Fig. 8A : Representative gating strategy for identifying dead cells within murine T cells. Figure 8B: Analysis of murine T cell death after stimulation with different concentrations of UA at the indicated time points. Data are mean ± SD, n = 8-11, **** p < 0.0001 by two-way ANOVA followed by Tukey's multiple comparison test; ns not significant. Figure 8C : UA restricts T cell proliferation. Representative analysis of T cell proliferation over 72 h in response to UA. Fig.8D :from Figure 8C Quantification of the proliferation data obtained. The proportion of proliferation generations (Undiv., undivided cells; Gen1, divided once) as assessed by FlowJo software is shown. 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. Fig. 8E : Representative analysis of cyclin D1 expression after 48 h of αCD3 / αCD28 stimulation in the absence or presence of UA (50 μM). Data are mean ± SD, n = 4, p* < 0,05 by two-sided t-test. One of two independent experiments is shown. Figure 8F : T after αCD3 / αCD28 stimulation for 48 h in the absence or presence of UA (50 μM). SCM Data are mean ± SD, n = 5 / 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). Figure 8H Representative gating strategy. Gating of APTK in tumors of mice fed a control or UA-containing diet ( Fig.8I )TAM,( Figure 8J )M-MDSC, ( Figure 8K )PMN-MDSC and ( Figure 8L )Quantification of DC( Figure 1K Data are mean ± SD, n = 7 / group. Statistical analysis was performed by two-sided t-test. Figure 8M : T cells within CD4+ TILs from APTK-induced tumors fed control or UA-containing diets SCM Data are mean ± SD, n = 7, ns not significant by two-sided t-test.

[0016] Fig.9A : Protocol for activation, treatment and analysis of OT-1CD3+ T cells. Fig. 9B : OT-1CD44-CD62L+ScalHi T 48 hours after αCD3 / αCD28 stimulationSCM Quantification of. Data are mean ± SD, n = 4, *p < 0,05 by two-sided t-test. Data from one of two experiments are shown. Fig. 9C : Quantification and gating strategy 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-sided t-test. Data from one of two experiments are shown.

[0017] Fig. 10A : Ingenuity pathway upstream regulator analysis (IPA) of UA-treated T cells. Evaluated from RNAseq data. Appropriate upregulation is depicted by z-scores and significance is shown in the overlying blots. Genes with a log2 fold change of 1 and p < 0.05 were initially considered. Fig. 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-sided t-test. Fig. 10C : Figure 5K Representative histograms of the data depicted in . Fig. 10D : Flow cytometric analysis of lysosome formation in Pgam5- / - CD8+ T cells after stimulation with αCD3 / αCD28 for 6 h in the absence or presence of UA (50 μM), data are mean ± SD, *p < 0.05 by two-sided t-test. Fig. 10E : Mitotracker red staining of Pgam5- / -CD8+ T cells after stimulation with αCD3 / αCD28 for 24 hours in the absence or presence of UA (50 μM). Data are mean ± SD, n = 4, ***p < 0.001 by two-sided t-test. Fig.10F : Immunoblot analysis of cell fractionation 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 : Figure 5N Representative histograms of the data depicted in . Fig. 10H : Figure 5M Representative histograms of the data depicted in .

[0018] Fig.11A :Used to identify people T SCM Representative gating strategy for (CD45RA+CCR7HiCD62L+CD95+CD8+). Fig. 11B: Representative flow cytometric plots showing a dose-dependent increase in CD95hiCD62L+ cells within the CD45RA+CCR7hiCD8+ population.

[0019] Fig. 12A :For evaluating CAR expression and identifying human T cells in CAR T cell experiments SCM Representative gating strategies. Fig. 12B : Quantification of CD19CAR expression on CD8+ cells 72 hours after VSV-LV helper gene transduction in the presence of DMSO or UA (25 μM). Data are mean ± SD, n = 5, ns not significant by two-sided t test. Fig. 12C :like Fig. 6E Frequency of depleted Tim3HiPD-1HiCD8+CAR+ after activation and CD19 CAR transduction as indicated in . Data were acquired three days after transduction. Data are mean ± SD, n = 6, ns not significant by two-sided t-test.

[0020] Fig.13A : 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 month 2 of treatment and day 0. Fig. 13B : Graph showing the effect of oral administration of 66 on the myocardium in a rat model of heart failure. Short axis shortening, expressed as the difference between treatment month 2 and day 0. The difference in mean ΔLV function between sham / vehicle and MI / vehicle was assessed using an unpaired t-test followed by a Welch correction test. The difference between the MI / vehicle group and MI / 66 was then assessed using an unpaired t-test followed by a Welch correction test. n=10-19 per group. Values ​​of p<0.05 were considered statistically significant. Sham / vehicle vs. MI / vehicle: **p<0.01; ***p<0.001. MI / vehicle vs. MI / 66: #p<0.05.

[0021] Fig.14 : Graph showing the effects of 66, 77 and 77A on induction of mitophagy in human T lymphocytes. Results are presented as bar graphs.

[0022] Fig.15 : Graph showing the effect of 66 on the percentage of T memory stem cells (Tscm). Results are presented as a bar graph.

[0023] Fig.16A : Graph showing the effect of 33 treatment on cortical neurons damaged by chronic administration of Aβ1-42. Survival of cortical neurons as measured by MAP-2 immunostaining. Fig. 16B: Graph showing the effects of 33 treatment on cortical neurons damaged by chronic application of Aβ1-42 neurite networks to cortical neurons as measured by MAP-2 immunostaining. Fig. 16C : Graph showing the effect of 33 treatment on cortical neurons damaged by chronic application of Aβ1-42 microglial activation as measured by OX-1 immunostaining. Results are expressed as a percentage of control conditions (n=4-6). BDNF: Brain-derived neurotrophic factor. *p<0.05 after one-way ANOVA followed by Fisher's LSD test

[0024] Fig.17A : Graph showing the effect of 117A treatment on cortical neurons damaged by chronic administration of Aβ1-42. Survival of cortical neurons as measured by MAP-2 immunostaining. Fig. 17B : Graph showing the effect of 117A treatment on cortical neurons damaged by chronic administration of Aβ1-42. Neurite network of cortical neurons as measured by MAP-2 immunostaining. Fig. 17C : Graph showing the effect of 117A treatment on cortical neurons damaged by chronic application of Aβ1-42. Microglial activation as measured by OX-1 immunostaining. Results are expressed as a percentage of control conditions (n=4-6). BDNF: Brain-derived neurotrophic factor (BDNF). *p<0.05 after one-way ANOVA followed by Fisher's LSD test.

[0025] Fig.18A : Effects of oral administration of 33 on short-term spatial memory deficits induced by intrahippocampal injection of Aβ1-42 in aged mice (Y-maze test). The graph shows the total distance traveled during the Y-maze test. Fig.18B : Effect of oral administration of 33 on short-term spatial memory deficits induced by intrahippocampal injection of Aβ1-42 in aged mice (Y-maze test). The graph shows the time spent on the novel arm (test phase). Results are presented as box plots (n=8-11 / group). *p<0.05 after one-way Anova test followed by Fisher's test.

[0026] Fig.19A : Effects of oral administration of 33 on neurodegeneration and neuroinflammation induced by intrahippocampal injection of Aβ1-42 in aged mice. Graphs show neuronal survival. Results are presented as box plots (n=5 / group). *p<0.05 after one-way ANOVA test compared with Aβ1-42 group followed by Fisher's test. Fig.19B: Effects of oral administration of 33 on neurodegeneration and neuroinflammation induced by intrahippocampal injection of Aβ1-42 in aged mice. Graphs show hyperphosphorylation of Tau. Results are presented as box plots (n=5 / group). *p<0.05 after one-way ANOVA test compared with Aβ1-42 group followed by Fisher's test. Fig.19C : Effects of oral administration of 33 on neurodegeneration and neuroinflammation induced by intrahippocampal injection of Aβ1-42 in aged mice. Graphs show microglial activation. Results are presented as box plots (n=5 / group). *p<0.05 after one-way ANOVA test compared to Aβ1-42 groups followed by Fisher's test.

[0027] Fig. 20A : Effects of oral administration of 66 on the myocardium in a rat model of heart failure. Ejection fraction, expressed as the difference between month 2 of treatment and day 0. Fig. 20B : Effects of oral administration of 66 on the myocardium in a rat model of heart failure. Short axis shortening rate, expressed as the difference between treatment month 2 and day 0. The difference in mean ΔLV function between sham / vehicle and MI / vehicle was assessed using an unpaired t-test followed by a Welch correction test. The difference between the MI / vehicle group and MI / 66 was then assessed using an unpaired t-test followed by a Welch correction test. n=10-19 per group. Values ​​of p<0.05 were considered statistically significant. Sham / vehicle vs. MI / vehicle: **p<0.01; ***p<0.001. MI / vehicle vs. MI / VNA-052: #p<0.05.

[0028] Fig.21 : Graph showing the mitochondrial content of activated mouse T lymphocytes after treatment with 2 μM of DMSO or NCE for 72 hours. The results are presented as bar graphs.

[0029] Fig. 22 : Graph showing the percentage of mouse T memory stem cells (Tscm) in CD8+ T lymphocytes after treatment with 2 μM of DMSO or NCE for 72 hours. Results are presented as bar graphs.

[0030] Fig.23 : Graph showing the percentage of mouse human T memory stem cells (Tscm) in CD8+ T lymphocytes after 72 hours of treatment with 400 nM DMSO or 77. Results are presented as bar graphs of mean + / - SEM. ***P<0.001 after unpaired one-sided t-test. DETAILED DESCRIPTION

[0031] definition

[0032] For convenience, certain terms used in this specification, examples and appended claims are collected here before further description of the present invention. These definitions should be read in light of the remainder of this disclosure and should be as understood by those skilled in the art. Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art.

[0033] To facilitate understanding of the present invention, certain terms and phrases are defined below and throughout the specification.

[0034] As used herein, the articles "a" and "an" refer to one or more than one (ie, at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0035] The phrase "and / or" as used herein in the specification and claims should be understood to mean "either or both" of the elements so united (i.e., elements that exist together in some cases and separately in other cases). Multiple elements listed with "and / or" should be understood in the same way, i.e., "one or more" of the elements so united. In addition to the elements explicitly identified by the "and / or" clause, other elements may optionally be present, whether related or unrelated to those elements explicitly identified. Thus, as a non-limiting example, when used in conjunction with open language such as "comprising", reference to "A and / or B" may refer to only A (optionally including elements other than B) in one embodiment; to only B (optionally including elements other than A) in another embodiment; to both A and B (optionally including other elements) in yet another embodiment; and so on.

[0036] As used herein in the specification and claims, "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 inclusive, that is, including at least one element in a number of elements or a list of elements, but also including more than one element, and other items that are optionally not listed. Only terms that clearly indicate the opposite meaning, such as "only one" or "exactly one", or when used in the claims, "consisting of..." will refer to the inclusion of exactly one element in a number of elements or a list of elements. In general, the term "or" as used herein should only be interpreted as indicating exclusive alternatives (i.e., "one or the other but not both") when followed by an exclusive term (such as "either", "one of them", "only one of them" or "exactly one of them"). "Substantially consisting of...", when used in the claims, should have the usual meaning as used in the field of patent law.

[0037] As used herein in the specification and claims, the phrase "at least one" when referring 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 does not necessarily include at least one of each element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than the elements explicitly identified in the list of elements to which the phrase "at least one" refers, whether related or unrelated to the explicitly identified elements. Thus, as a non-limiting example, in one embodiment, "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") may refer to at least one (optionally including more than one) A without B (and optionally including elements other than B); in another embodiment, to at least one (optionally including more than one) B without A (and optionally including elements other than A); in yet another embodiment, to at least one (optionally including more than one) A, and at least one (optionally including more than one) B (and optionally including other elements); and so on.

[0038] It should also be understood that in any method claimed herein that includes more than one step or action, the order of the steps or actions of the method is not necessarily limited to the order in which the steps or actions of the method are listed unless the context dictates otherwise.

[0039] In the claims and the foregoing specification, all transitional phrases such as "comprises," "comprising," "carrying," "having," "containing," "involving," "holding," "consisting of," etc. shall be understood 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 set forth in Section 2111.03 of the United States Patent Office Manual of Patent Examining Procedures.

[0040] Certain compounds contained in the compositions of the present invention may exist in specific geometric or stereoisomeric forms. In addition, the polymers of the present invention may also be optically active. The present invention contemplates all such compounds as falling within the scope of the present invention, including cis and trans isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, their racemic mixtures and other mixtures thereof. Additional asymmetric carbon atoms may be present in substituents (such as alkyl). All such isomers and mixtures thereof are intended to be included in the present invention.

[0041] "Geometric isomers" means isomers that differ in the orientation of the substituted atoms relative to the carbon-carbon double bond, relative to the cycloalkyl ring, or relative to a bridged bicyclic system. The atoms on each side of the carbon-carbon double bond (except H) can be in the E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are on the same side) configuration. "R", "S", "S*", "R*", "E", "Z", "cis" and "trans" represent the configuration relative to the core molecule. Some of the disclosed compounds may exist in the form of "atropisomers" or as "atropisomers". Atropisomers are stereoisomers that arise due to hindered rotation around a single bond, where the steric strain barrier to rotation is high enough to allow separation of conformational isomers. The compounds of the present invention can be prepared as individual isomers by isomer-specific synthesis, or can be prepared as individual isomers by separation from a mixture of isomers. Conventional resolution techniques include forming salts of the free bases of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base); forming salts of the acid forms of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid); forming esters or amides of each isomer of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary); or resolving isomeric mixtures of starting materials or final products using various well-known chromatographic methods.

[0042] For example, if a specific enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, in the case where the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereomeric salts are formed with an appropriate optically active acid or base, followed by separation of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and the pure enantiomers are subsequently recovered.

[0043] The percent purity by mole fraction is the ratio of the number of moles of an enantiomer (or diastereomer) relative to the number of moles of an enantiomer (or diastereomer) plus the number of moles of its optical isomers. When the stereochemistry of a disclosed compound is named or depicted by structure, the purity of the named or depicted stereoisomer relative to the other stereoisomers is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% by mole fraction. When a single enantiomer is named or depicted by structure, the purity of the depicted or named enantiomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% by mole fraction. When an individual diastereomer is named or depicted by structure, the purity of the depicted or named diastereomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% by mole fraction.

[0044] When a disclosed compound is named or depicted by a structure without indicating stereochemistry and the compound has at least one chiral center, it is understood that the name or structure encompasses the enantiomers of the compound without the corresponding optical isomers, the 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 a structure without indicating stereochemistry and has two or more chiral centers, it is understood that the name or structure encompasses the diastereomers without other diastereomers, a plurality of diastereomers without other diastereoisomer pairs, a mixture of diastereomers, a mixture of diastereoisomer pairs, a mixture of diastereomers in which one diastereomer is enriched relative to one or more other diastereomers, or a mixture of diastereomers in which one or more diastereomers are enriched relative to other diastereomers. The present invention encompasses all of these forms.

[0045] The structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, by replacing hydrogen with deuterium or tritium, or replacing carbon with 13 C- or 14 Compounds produced by C-enriched carbon substitution are within the scope of the present invention.

[0046] The term "prodrug" as used herein encompasses compounds that are converted to therapeutically active agents under physiological conditions. Common methods for preparing prodrugs include hydrolysis under physiological conditions to reveal selected portions of the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal.

[0047] 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, which participates in the delivery or transport of the subject chemical from one organ or part of the body to another organ or part of the body. 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 be used 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, ethyl cellulose and cellulose acetate; (4) tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, 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) ethanol; (20) phosphate buffer solution; and (21) other non-toxic compatible substances used in pharmaceutical preparations. In certain embodiments, the pharmaceutical composition of the present invention is non-pyrogenic, that is, it does not cause a significant increase in body temperature when administered to a patient.

[0048] The term "pharmaceutically acceptable salt" refers to relatively nontoxic inorganic and organic acid addition salts of one or more of the compounds. These salts can be prepared in situ during the final isolation and purification of one or more of the compounds, or by reacting one or more purified compounds in their free base form with a suitable organic or inorganic acid alone and isolating the salt so formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate, among others. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts," J. Pharm. Sci. 66: 1-19.)

[0049] In other cases, the compounds useful in the methods of the invention may contain one or more acidic functional groups and thus be able to form pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these cases, the term "pharmaceutically acceptable salt" refers to relatively nontoxic inorganic and organic base addition salts of one or more compounds. These salts can also be prepared in situ during the final separation and purification of one or more of the compounds, or can be prepared by reacting one or more purified compounds with a suitable base (such as a pharmaceutically acceptable hydroxide, carbonate or bicarbonate of a metal cation) in its free acid form, with ammonia or with a pharmaceutically acceptable organic primary amine, secondary amine or tertiary amine. Representative alkali metal salts or alkaline earth metal salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts and aluminum salts, etc. Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. (see, for example, Berge et al., supra).

[0050] The term "pharmaceutically acceptable co-crystal" refers to a solid coformer that does not form formal ionic interactions with a small molecule.

[0051] A "therapeutically effective amount" (or "effective amount") of a compound for use in therapy means an amount of the compound in a formulation that, when administered as part of a desired dosing regimen (to a mammal, preferably a human), will relieve symptoms, ameliorate symptoms, or slow the onset of a disease condition, at a reasonable benefit / risk ratio applicable to any drug treatment, according to clinically acceptable criteria for the condition or disorder being treated or for cosmetic purposes.

[0052] The terms "preventive or therapeutic" treatment are art-recognized and include administering one or more of the subject compositions to a host. If the treatment is administered prior to clinical manifestation of an unwanted condition (e.g., a disease or other unwanted condition of the host animal), the treatment is preventive (i.e., it protects the host from developing the unwanted condition), while if the treatment is administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., intended to alleviate, ameliorate, or stabilize an existing unwanted condition or its side effects).

[0053] The term "patient" or "subject" refers to a mammal in need of a particular treatment. In certain embodiments, the patient is a primate, canine, feline, or equine. In certain embodiments, the patient is a human.

[0054] Aliphatic chains include alkyl, alkenyl and alkynyl categories defined below. Straight chain aliphatic chains are limited to the unbranched carbon chain portion. As used herein, the term "aliphatic group" refers to a straight, branched or cyclic aliphatic hydrocarbon group, and includes saturated and unsaturated aliphatic groups, such as alkyl, alkenyl or alkynyl.

[0055] "Alkyl" refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having a specified number of carbon atoms or up to 30 carbon atoms (if not specified). For example, an alkyl group of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those moieties that are positional isomers of these moieties. Alkyl groups of 10 to 30 carbon atoms include decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, and tetracosyl. In certain embodiments, a straight or branched alkyl group has 30 or fewer carbon atoms in its backbone (e.g., for a straight chain of C 1 -C 30 , for the branched chain C 3 -C 30 ), and more preferably 20 or less carbon atoms. The alkyl group may be substituted or unsubstituted.

[0056] As used herein, the term "heteroalkyl" refers to an alkyl moiety as defined above containing one or more oxygen, sulfur, nitrogen, phosphorus or silicon atoms in the place of a carbon atom.

[0057] As used herein, the term "haloalkyl" refers to an alkyl group as defined above substituted with at least one halogen.

[0058] As used herein, the term "hydroxyalkyl" refers to an alkyl group, as defined herein, substituted with at least one hydroxy group.

[0059] As used herein, the term "alkylene" refers to an alkyl group having a specified number of carbons, such as 2 to 12 carbon atoms, which contains two points of attachment to the rest of the compound on its longest carbon chain. Non-limiting examples of alkylene include methylene-(CH 2 )-, ethylene-(CH 2 CH 2 )-、n-propylene-(CH 2 CH 2 CH 2 )-, isopropylidene-(CH 2 CH(CH 3 ))-, etc. The alkylene group may be a cyclic or acyclic, branched or unbranched carbon chain portion, and may be optionally substituted with one or more substituents.

[0060] "Cycloalkyl" means a monocyclic or bicyclic or bridged or spirocyclic or polycyclic saturated carbocyclic ring each having 3 to 12 carbon atoms. Preferred cycloalkyls have 3 to 10 carbon atoms in their ring structure, and more preferably have 3 to 6 carbon atoms in the ring structure. Cycloalkyls may be substituted or unsubstituted.

[0061] As used herein, the term "halocycloalkyl" refers to a cycloalkyl group as defined above substituted with at least one halogen.

[0062] "Cycloheteroalkyl" or "heterocycloalkyl" refers to a cycloalkyl moiety as defined above containing one or more oxygen, sulfur, nitrogen, phosphorus or silicon atoms in place of a carbon atom. Preferred cycloheteroalkyls have 4-8 carbon atoms and heteroatoms in their ring structure, and more preferably have 4-6 carbon atoms and heteroatoms in the ring structure. Cycloheteroalkyl or heterocycloalkyl may be substituted or unsubstituted.

[0063] Unless otherwise specified the number of carbons, "lower alkyl" as used herein refers to an alkyl as defined above, but having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl in its backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Throughout the application, preferred alkyl is a lower alkyl. In certain embodiments, the substituents designated as alkyl herein are lower alkyl.

[0064] "Alkenyl" refers to any cyclic or acyclic, branched or unbranched, unsaturated carbon chain moiety having the number of carbon atoms specified, or, if no limit to the number of carbon atoms is specified, up to 26 carbon atoms; and having one or more double bonds located in the moiety. Examples of alkenyl groups of 6 to 26 carbon atoms are hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosenyl, docosenyl, tricosenyl, and tetracosenyl in various isomeric forms, wherein the one or more unsaturated bonds may be located in any position in the moiety and may have a (Z) or (E) configuration around the one or more double bonds.

[0065] "Alkynyl" refers to an alkenyl-scoped alkyl moiety, but having one or more triple bonds located within the moiety.

[0066] As used herein, the term "aryl" includes 3 to 12 substituted or unsubstituted monocyclic aromatic groups, wherein each atom of the ring is carbon (i.e., carbocyclic aromatic group) or wherein one or more atoms are heteroatoms (i.e., heteroaryl). Preferably, aryl includes 5 to 12 rings, more preferably 6 to 10 rings. The term "aryl" also includes a polycyclic system with two or more rings, wherein two or more carbons are shared by two adjacent rings, wherein at least one ring in the ring is aromatic, for example, other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclic radicals. Carbocyclic aromatic groups include benzene, naphthalene, phenanthrene, phenol, aniline, etc. Heteroaryl includes substituted or unsubstituted aromatic 3 to 12 ring structures, more preferably 5 to 12 rings, more preferably 5 to 10 rings, and its ring structure includes one to four heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, etc. Aryl and heteroaryl groups may be monocyclic, bicyclic or polycyclic.

[0067] The term "halo", "halo" or "halogen" as used herein means halogen, and includes, for example and without limitation, fluorine, chlorine, bromine, iodine, etc. in both radioactive and non-radioactive forms. In a preferred embodiment, halo is selected from the group consisting of fluorine, chlorine and bromine.

[0068] The term "heterocyclyl" or "heterocyclic group" refers to a 3- to 12-membered ring structure, more preferably a 5- to 12-membered ring, more preferably a 5- to 10-membered ring, the ring structure of which contains 1 to 4 heteroatoms. The heterocycle may be monocyclic, bicyclic, spirocyclic or polycyclic. Heterocyclic groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, xanthene, 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, phenpyrazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinone and pyrrolidone, sultams, sultones, and the like. The heterocycle may be substituted at one or more positions with substituents as described above, such as halogen, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphite, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, -CF 3 , -CN, etc.

[0069] The term "substituted" refers to a portion of a substituent having a replacement hydrogen on one or more carbons of the main chain. It should be understood that "substituted" or "substituted by..." includes implicit conditions, i.e., such substitution is based on the allowed valence of the substituted atom and the substituent, and the substitution produces a stable compound, for example, it does not spontaneously undergo transformations such as by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is considered to include all allowed substituents of organic compounds. In a broad sense, allowable substituents include non-cyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Allowable substituents can be one or more substituents and are the same or different for appropriate organic compounds. For the purposes of the present invention, heteroatoms such as nitrogen can have hydrogen substituents and / or any allowable substituents of organic compounds that satisfy the valence of heteroatoms as described herein. Substituents may include any of the substituents described herein, for example, halogen, hydroxy, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphite, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, arylalkyl or aromatic or heteroaromatic moieties. In preferred embodiments, the substituents on the substituted alkyl are selected from C 1-6 Alkyl, C 3-6 In some embodiments, the substituted alkyl radicals are substituted alkyl radicals, such as cycloalkyl, halogen, carbonyl, cyano or hydroxyl radicals. In a more preferred embodiment, the substituents on the substituted alkyl radicals are selected from fluorine, carbonyl, cyano or hydroxyl radicals. It will be appreciated by those skilled in the art that the substituents themselves may be substituted where appropriate. Unless specifically stated as "unsubstituted", references to chemical moieties herein are to be understood to include substituted variants. For example, references to "aryl" or moieties implicitly include substituted and unsubstituted variants.

[0070] As used herein, the definition of each expression (eg, alkyl, m, n, etc.), when it occurs more than one time in any structure, is intended to be independent of its definition elsewhere in the same structure.

[0071] As used herein, "small molecule" refers to a small organic molecule or inorganic molecule having a molecular weight lower than about 3,000 Daltons. In general, the molecular weight of the small molecule that can be used for the present invention is less than 3,000 Daltons (Da). The small molecule can be, for example, at least about 100Da to about 3,000Da (e.g., about 100Da to about 3,000Da, about 100Da to about 2500Da, about 100Da to about 2,000Da, about 100Da to about 1,750Da, about 100Da to about 1,500Da, about 100Da to about 1,250Da, about 100Da to about 1,000Da, about 100Da to about 750Da, about 100Da to about 500Da, about 200Da to about 1500Da, about 500Da to about 1000Da, about 300Da to about 1000Da, or about 100Da to about 250Da).

[0072] In some embodiments, "small molecule" refers to an organic, inorganic or organometallic compound that generally has a molecular weight of less than about 1000. In some embodiments, a small molecule is an organic compound that is about 1 nm in size. In some embodiments, small molecule drugs of the present invention encompass oligopeptides and other biomolecules that have a molecular weight of less than about 1000.

[0073] An "effective amount" is an amount sufficient to produce a beneficial or desired result. For example, a therapeutic amount is an amount that achieves a desired therapeutic effect. This amount may be the same or different from a preventive effective amount, which is the amount necessary to prevent the onset of a disease or disease symptom. An effective amount may be administered in one or more administrations, applications, or doses. The therapeutically effective amount of a composition depends on the composition selected. The composition may be administered once or more per day to once or more per week; including once every other day. Those skilled in the art will appreciate that certain factors may affect the dosage and schedule required to effectively treat a subject, including but not limited to the severity of the disease or condition, previous treatment, the general health and / or age of the subject, and other diseases present. In addition, treatment of a subject with a therapeutically effective amount of a composition described herein may include a single treatment or a series of treatments.

[0074] The terms "decrease," "reduce," "reduced," "reduction," "decrease," and "inhibit" are generally used herein to refer to a statistically significant amount of decrease relative to a reference. However, for the avoidance of doubt, "reduce", "reduction" or "decrease" or "inhibit" generally means a decrease of at least 10% compared to a reference level, and can include, for example, a decrease 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% compared to a reference level, up to and including, for example, the complete absence of a given entity or parameter, or a decrease of between 10-99% compared to the absence of a given treatment.

[0075] The terms "increased", "increase" or "enhance" or "activate" are generally used herein to mean an increase by a statistically significant amount; for the avoidance of any doubt, the terms "increased", "increase" or "enhance" or "activate" mean an increase of at least 10% compared to a reference level, such as an increase of 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, or any increase between 10%-100%, 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 compared to a reference level, or any increase between 2-fold and 10-fold or more.

[0076] As used herein, the term "modulate" includes up-regulation and down-regulation, eg, enhancing or inhibiting a response.

[0077] "Radiopharmaceutical" as defined herein refers to an agent containing at least one radioactive isotope that emits radiation. Radioactive agents are routinely used in nuclear medicine for the diagnosis and / or therapy of various diseases. Radiolabeled agents, such as radiolabeled antibodies, contain a radioisotope (RI) that acts as a radiation source. As contemplated herein, the term "radioisotope" includes metal and non-metallic radioisotopes. Radioisotopes are selected based on the medical application of radiolabeled agents. When the radioisotope is a metal radioisotope, a chelating agent is generally used to bind the metal radioisotope to the rest of the molecule. When the radioisotope is a non-metallic radioisotope, the non-metallic radioisotope is generally directly or via a joint to the rest of the molecule.

[0078] For purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Edition, 1986-87, inside cover.

[0079] Treatment

[0080] One aspect of the present invention relates to a method of 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, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (Ia),

[0081]

[0082]

[0083] in

[0084] A is

[0085] X 1 Selected from O and S;

[0086] Y 1 It is O;

[0087] R 1 , R 4 , R 5 and R 8 independently selected from H and halogen;

[0088] R 3 and R 6 Independently selected from H, CN, OH, CF 3 , halogen and alkyl;

[0089] R 2 and R 7One of is H, OH or OAc, and R 2 and R 7 The other one is 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 ;

[0090] Each occurrence of R 9 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;

[0091] R 10 Selected from 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, SO 3 H.SO 2 -alkyl and SO 2 - haloalkyl;

[0092] Each occurrence of R 11 is selected from H and alkyl; and

[0093] Each occurrence of R 12 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl and alkyl-heterocycloalkyl;

[0094] or a pharmaceutically acceptable salt thereof.

[0095] In some embodiments, the compound, provided that if X 1 and Y 1 O, R respectively 2 is OH, and R 1 , R 3 , R 4 , R 5 , R 6 and R 8 Each is H, then R 7 is not OBn, and if X 1 and Y 1 O, R respectively 7 is OH, and R 1 , R 3 , R 4 , R 5 , R 6 and R 8 Each is H, then R 2 Not OCH 2 C(O)NH 2 .

[0096] In some embodiments, A is

[0097] In some embodiments, R 2 is H. In other embodiments, R 2 is OH. In other embodiments, R 2 It's OAc.

[0098] In some embodiments, the compound, wherein R 2 is selected from haloalkyl, substituted cycloalkyl, alkynyl-R 9 , OR 10 and C(O)NR 11 R 12 ; R 9 is selected from OH, substituted cycloalkyl and heterocycloalkyl; R 10 is selected from the group consisting of alkyl, substituted cycloalkyl, heterocycloalkyl, and alkyl-heterocycloalkyl; and R 11 is H and R 12 is alkyl-heterocycloalkyl.

[0099] In some embodiments, R 7 is H. In other embodiments, R 7 is OH. In other embodiments, R 7 It's OAc.

[0100] In some embodiments, the compound, wherein R 7 is selected from haloalkyl, substituted cycloalkyl, alkynyl-R 9 , OR10 and C(O)NR 11 R 12 ; R 9 is selected from OH, substituted cycloalkyl and heterocycloalkyl; R 10 is selected from the group consisting of alkyl, substituted cycloalkyl, heterocycloalkyl, and alkyl-heterocycloalkyl; and R 11 is H and R 12 is alkyl-heterocycloalkyl.

[0101] In some embodiments, each occurrence of substituted cycloalkyl is independently substituted with OH, halogen, or hydroxyalkyl.

[0102] In some embodiments, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 Each is H. In other embodiments, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 In other embodiments, one of R 1 , R 3 , R 4 , R 5 , R 6 and R 8 Two of them are not H.

[0103] In some embodiments, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 In other embodiments, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 Two of them are independently alkyl or halogen.

[0104] In some embodiments, the compound of formula (Ia) is selected from:

[0105]

[0106] In some embodiments, the compound of formula (Ia) is selected from:

[0107]

[0108]

[0109]

[0110]

[0111]

[0112] In some embodiments, the compound of formula (Ia) is selected from:

[0113]

[0114] In some embodiments, the compound of formula (Ia) is selected from:

[0115]

[0116] In some embodiments, the compound of formula (Ia) is selected from:

[0117]

[0118] In some embodiments, the compound of formula (Ia) is selected from:

[0119]

[0120] Another aspect of the present invention relates to a method of 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, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (Ic),

[0121]

[0122] in

[0123] A is

[0124] One of n and m is 0; and the other of n and m is 1;

[0125] X 1 and Y 1 Each is O;

[0126] R 1 , R 2 , R 3 , R 6 , R 7 and R 8 Independently selected from H, OH, OCH 3 ,OAc,NH 2 , halogen, CN, CF 3 , CO2 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 ;

[0127] R 4 and R 5 independently selected from H, halogen and alkyl;

[0128] Each occurrence of R 9 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;

[0129] R 10 Selected from 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, SO 3 H.SO 2 -alkyl and SO 2 - haloalkyl;

[0130] Each occurrence of R 11 is selected from H and alkyl; and

[0131] Each occurrence of R 12 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl and alkyl-heterocycloalkyl;

[0132] or a pharmaceutically acceptable salt thereof.

[0133] In some embodiments, A is selected from

[0134] In some embodiments, R 2 and R 7 Each is OH. In other embodiments, R 2 and R 7 In other embodiments, R 2 is OH; and R 7 is H or O-alkyl. In other embodiments, R 2 is H or O-alkyl; and R 7 It's OH.

[0135] In some embodiments, wherein R 1 , R 3 , R 4 , R 5 , R 6 and R 8 Each is H. In other embodiments, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 In other embodiments, one of R 1 , R 3 , R 4 , R 5 , R 6 and R 8 In other embodiments, two of R 1 , R 3 , R 4 , R 5 , R 6 and R 8 In other embodiments, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 Two of them are alkyl or halogen.

[0136] In some embodiments, the compound of formula (Ic) is selected from:

[0137]

[0138]

[0139] In some embodiments, the compound of formula (Ic) is selected from:

[0140]

[0141] In some embodiments, the compound of formula (Ic) is selected from:

[0142]

[0143] Another aspect of 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, a cancer or a cognitive disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (Id),

[0144]

[0145] in

[0146] A is

[0147] Y 2 It is O;

[0148] Y 3 and Y 4 are independently selected from H, halogen and alkyl; or, together with the carbon to which they are bound, are combined to form a cycloalkyl or heterocycloalkyl;

[0149] R 1 , R 4 , R 5 and R 8 independently selected from H and halogen;

[0150] R 2 , R 3 , R 6 and R 7 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 ;

[0151] Each occurrence of R 9 Independently selected from OH, NH2 , 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;

[0152] R 10 Selected from 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, SO 3 H.SO 2 -alkyl and SO 2 - haloalkyl;

[0153] Each occurrence of R 11 is selected from H and alkyl; and

[0154] Each occurrence of R 12 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl and alkyl-heterocycloalkyl;

[0155] or a pharmaceutically acceptable salt thereof.

[0156] In some embodiments, the compound, provided that when Y 2 It's O, R 2 and R 7 Each is OH, and R 1 , R 3 , R 4 , R 5 , R 6 and R 8 When each is H, then Y 3 and Y 4 Not halogen at the same time.

[0157] In some embodiments, A is selected from

[0158] In some embodiments, R 2 and R 7 Each is OH. In other embodiments, R 2 and R 7 One of them is OH, and R 2 and R 7In other embodiments, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 In other embodiments, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 Two of them are alkyl or halogen.

[0159] In some embodiments, the compound of formula (Id) is selected from:

[0160]

[0161]

[0162] In some embodiments, the compound of formula (Id) is selected from:

[0163]

[0164]

[0165] In some embodiments, the compound of formula (Id) is selected from:

[0166]

[0167]

[0168] In some embodiments, the compound of formula (Id) is selected from:

[0169]

[0170] Another aspect of the present invention relates to a method of 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, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (Ie),

[0171]

[0172] in

[0173] A is

[0174] n and m are both 0; or one of n and m is 0, and the other of n and m is 1;

[0175] X1 It is O;

[0176] Y 1 Selected from NH, N-CH 3 , Nt-Bu, N-cycloalkyl, and N-heterocycloalkyl;

[0177] R 1 , R 2 , R 3 , R 6 , R 7 and R 8 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 ;

[0178] R 4 and R 5 independently selected from H, alkyl and halogen;

[0179] Each occurrence of R 9 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;

[0180] R 10 Selected from 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, SO 3 H.SO2 -alkyl and SO 2 - haloalkyl;

[0181] Each occurrence of R 11 is selected from H and alkyl; and

[0182] Each occurrence of R 12 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl and alkyl-heterocycloalkyl;

[0183] or a pharmaceutically acceptable salt thereof.

[0184] In some embodiments, the compound, provided that R 1 , R 2 , R 3 , R 6 , R 7 and R 8 No more than two of them are OH or OCH 3 ,

[0185] If A is And R 1 , R 3 , R 4 , R 5 , R 6 and R 8 Each is H, then R 2 and R 7 Not OH and OCH at the same time 3 or both 10 ,and

[0186] If A is And R 1 , R 3 , R 4 , R 5 , R 6 and R 8 Each is H, then R 2 and R 7 Different is OR 10 .

[0187] In some embodiments, wherein 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.

[0188] In some embodiments, A is selected from In other embodiments, A is selected from

[0189] In some embodiments, wherein R 2 and R7 Each is OH.

[0190] In some embodiments, wherein R 2 and R 7 One of them is OH, and R 2 and R 7 In other embodiments, the other of R is not OH. 2 and R 7 In other embodiments, R 2 is OH, and R 7 is O-alkyl; or R 2 is an O-alkyl group, and R 7 It's OH.

[0191] In some embodiments, wherein R 1 , R 3 , R 4 , R 5 , R 6 and R 8 Each is H. In other embodiments, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 In other embodiments, the compound, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 In other embodiments, two of R 1 , R 3 , R 4 , R 5 , R 6 and R 8 In other embodiments, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 Two of them are alkyl or halogen.

[0192] In some embodiments, the compound of formula (Ie) is selected from:

[0193]

[0194] In some embodiments, the compound of formula (Ie) is selected from:

[0195]

[0196]

[0197]

[0198] In some embodiments, the compound of formula (Ie) is selected from:

[0199]

[0200] In one embodiment, the compound of formula (Ie) is selected from:

[0201]

[0202]

[0203] Another aspect of the present invention relates to a method of 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, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (If),

[0204]

[0205] in

[0206] A is selected from

[0207] n and m are both 0; or one of n and m is 0, and the other of n and m is 1;

[0208] o and p are both 0; or one of o and p is 0, and the other of o and p is 1;

[0209] q is 0 or 1;

[0210] r and s are both 0; or one of r and s is v, and the other of r and s is 1;

[0211] X 1 and X 2 Each is O;

[0212] 3 3 is O or N(alkyl);

[0213] Y 1 It is S;

[0214] Y 2 Selected from O, CH 2 , NH, N-alkyl, S, S(O) and SO 2 ;

[0215] Y 3 and Y 4 are independently selected from H, halogen, OH and alkyl, or are combined with the carbon to which they are bound to form a cycloalkyl or cycloheteroalkyl group;

[0216] Y 5 Selected from CH 2 , NH, N-alkyl, N-arylalkyl, N-cycloalkyl, and N-heterocycloalkyl;

[0217] Each occurrence of Y 6 independently selected from O, S, S(O), SO 2 , NH, N-alkyl, N-alkylaryl, and N-cycloalkyl;

[0218] Y 7 is selected from O, NH and N-alkyl;

[0219] Y 8 Selected from O and S;

[0220] R 1 , R 2 , R 3 , R 6 , R 7 and R 8 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 ,

[0221] R 4 and R 5 independently selected from H, alkyl and halogen;

[0222] Each occurrence of R 9 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;

[0223] R 10 Selected from 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, SO 3 H.SO 2 -alkyl and SO 2 - haloalkyl;

[0224] Each occurrence of R 11 is selected from H and alkyl; and

[0225] Each occurrence of R 12 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl and alkyl-heterocycloalkyl;

[0226] or a pharmaceutically acceptable salt thereof.

[0227] In some embodiments, the compound, provided that if Y 2 Yes CH 2 , Y 3 or Y 4 One of them is not H, or Y 3 or Y 4 Together with the carbon to which they are bound, they form a cycloalkyl or heterocycloalkyl radical, and if Y 2 is 0, then one of r and s is 0, and the other of r and s is 1.

[0228] In some embodiments, A is and n and m are both 0. In other embodiments, A is

[0229] In some embodiments, A is In other embodiments, A is selected from

[0230] In some embodiments, A is

[0231] In other embodiments, A is selected from

[0232] In some embodiments, A is selected from

[0233] In other embodiments, A is selected from

[0234] In some embodiments, R 2 and R 7 Each is OH. In other embodiments, R 2 and R 7 One of them is OH, and R 2 and R 7 In other embodiments, the other of R is not OH. 2 and R 7 In other embodiments, R 2 is OH, and R 7 is O-alkyl; or R 2 is an O-alkyl group, and R 7 It's OH.

[0235] In some embodiments, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 Each is H. In other embodiments, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 In other embodiments, one of R 1 , R 3 , R 4 , R 5 , R 6 and R 8 In other embodiments, two of R 1 , R 3 , R 4 , R 5 , R 6 and R 8 In other embodiments, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 Two of them are alkyl or halogen.

[0236] In some embodiments, the compound of formula (If) is selected from:

[0237]

[0238]

[0239] In some embodiments, the compound of formula (If) is selected from:

[0240]

[0241]

[0242]

[0243] In some embodiments, the compound of formula (If) is selected from:

[0244]

[0245] Another aspect of the present invention relates to a method of 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, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (Ih),

[0246]

[0247] in

[0248] A is selected from

[0249] n and m are both 0; or one of n and m is 0, and the other of n and m is 1;

[0250] r and s are both 0; or one of r and s is 0, and the other of r and s is 1;

[0251] X 1 It is O;

[0252] Y 1 is selected from O, NH, N-alkyl and N-cycloalkyl;

[0253] Y 2 It is O;

[0254] Y 3 and Y 4 are independently selected from H, halogen and alkyl, or, together with the carbon to which they are bound, are combined to form cycloalkyl or cycloheteroalkyl;

[0255] R 1 , R 4 , R 5and R 8 independently selected from H and halogen;

[0256] R 3 and R 6 Independently selected from H, CN, OH, CF 3 , halogen and alkyl;

[0257] R 2 and R 7 One of them is NH 2 NHCH 3 and N(CH 3 ) 2 , and R 2 and R 7 The other one is H, halogen, OCH 3 , 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 ;

[0258] Each occurrence of R 9 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;

[0259] R 10 Selected from 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, SO 3 H.SO 2 -alkyl and SO 2- haloalkyl;

[0260] Each occurrence of R 11 is selected from H and alkyl; and

[0261] Each occurrence of R 12 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl and alkyl-heterocycloalkyl;

[0262] or a pharmaceutically acceptable salt thereof

[0263] In some embodiments, the compound, provided that if A is R 1 , R 3 , R 4 , R 5 , R 6 and R 8 Each is H, and R 7 Yes NH 2 , then R 2 Not OH.

[0264] In some embodiments, Y 1 is selected from O, NH and N-alkyl.

[0265] In some embodiments, A is and n and m are both 0. In other embodiments, A is In other embodiments, A is

[0266] In some embodiments, A is and one of n or m is 0, and the other of n or m is 1. In other embodiments, A is In other embodiments, A is selected from

[0267] In some embodiments, A is and r and s are both O. In other embodiments, A is selected from, In other embodiments, A is selected from

[0268] In some embodiments, wherein R 2 Selected from NH 2 NHCH 3 and N(CH 3 ) 2 .

[0269] In some embodiments, R 7 is selected from the group consisting of H, OH, halogen, O-alkyl and haloalkyl.

[0270] In some embodiments, R 7 Selected from alkynyl-R 9 OR 10 ; R 9 is OH; and R 10 is alkyl-heterocycloalkyl.

[0271] In some embodiments, wherein R 1 , R 3 , R 4 , R 5 , R 6 and R 8 Each is H. In other embodiments, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 In other embodiments, one of R 1 , R 3 , R 4 , R 5 , R 6 and R 8 In other embodiments, two of R 1 , R 3 , R 4 , R 5 , R 6 and R 8 In other embodiments, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 Two of them are independently alkyl or halogen.

[0272] In some embodiments, the compound of formula (Ih) is selected from:

[0273]

[0274]

[0275] In some embodiments, the compound of formula (Ih) is selected from:

[0276]

[0277]

[0278]

[0279] In some embodiments, the compound of formula (Ih) is selected from:

[0280]

[0281]

[0282] In some embodiments, the compound of formula (Ih) is selected from:

[0283]

[0284]

[0285] In some embodiments, the compound of formula (Ih) is selected from:

[0286]

[0287] Another aspect of the invention relates to a method of 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, the method comprising administering to a subject in need thereof an effective amount of a compound having the following structure:

[0288]

[0289] In some embodiments of any of the disclosed methods, the compound, wherein R 2 and R 7 Each is OH. In other embodiments, R 2 is OH, and R 7 is not OH. In other embodiments, R 2 is OH, and R 7 Not OCH 3 In other embodiments, R 2 is OH, and R 7 Not H.

[0290] In some embodiments of any of the disclosed compounds, R 2 is OH, and R 7 OCH 3 In other embodiments, R 2 is OH, and R 7 is H. In other embodiments, R 2 is OH, and R 7 is alkynyl-R 9 In other embodiments, R 2 is OH, and R7 Yes OR 10 In other embodiments, R 2 is OH, and R 7 Yes OR 10 .

[0291] In some embodiments of any of the disclosed methods, the compound, wherein R 2 is OH, and R 7 yes

[0292] In some embodiments of any of the disclosed compounds, the compound is selected from Table 1.

[0293] Table 1.

[0294]

[0295]

[0296] In some embodiments of any of the disclosed methods, the compound is an atropisomer. Additionally, unless otherwise indicated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, by replacing hydrogen with deuterium or tritium, or replacing carbon with 13 C- or 14 Compounds produced by substitution of C-enriched carbon are within the scope of the present invention. Such compounds can be used, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present invention. For example, with respect to the variable R 1 In terms of (C 1 -C 4 )alkyl or -O-(C 1 -C 4 The alkyl group may be suitably deuterated (e.g., -CD 3 ,-OCD 3 ).

[0297] Any of the compounds of the invention may also be radiolabeled for use in the preparation of radiopharmaceuticals.

[0298] In one embodiment of any of the above methods, a neuromuscular disorder, a muscle disorder, a heart disease, a pulmonary fibrosis, a liver disease, an inflammatory bowel disease, or a cancer is treated. In one embodiment of any of the above methods, a neuromuscular disorder is treated.

[0299] In one embodiment of any of the above methods, a muscle disorder is treated.

[0300] In one embodiment of any of the above methods, heart disease is treated.

[0301] In one embodiment of any of the above methods, pulmonary fibrosis is treated.

[0302] In one embodiment of any of the above methods, a liver disease is treated.

[0303] In one embodiment of any of the above methods, inflammatory bowel disease is treated.

[0304] In one embodiment of any of the above methods, cancer is treated.

[0305] In one embodiment of any of the above methods, a cognitive disorder is treated.

[0306] In one embodiment of any of the above methods, the neuromuscular disorder is Chuck-Marie-Douglas disease.

[0307] In one embodiment of any of the above methods, the muscle disorder is hereditary inclusion body myositis, oculopharyngeal muscular dystrophy, inclusion body myopathy, Paget's disease of bone, frontotemporal dementia, or Duchenne muscular disorder.

[0308] In one embodiment of any of the above methods, the heart disease is heart failure.

[0309] In one embodiment, the compound reduces heart failure following myocardial infarction in a subject.

[0310] In one embodiment, the compound reduces heart failure when administered to a subject following a myocardial infarction in the subject.

[0311] In one embodiment, the compound reduces left ventricular systolic dysfunction following myocardial infarction in a subject.

[0312] In one embodiment, the compound reduces left ventricular systolic dysfunction when administered to a subject following a myocardial infarction in the subject.

[0313] In one embodiment, the subject has an increase in ejection fraction (ie, the percentage of the total volume of blood in the heart that is pumped out with each heartbeat).

[0314] In one embodiment, the subject has an increase in fractional shortening (ie, the percentage by which the left ventricle dimension decreases during contraction).

[0315] In one embodiment of any 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 heart or artery disorder.

[0316] In one embodiment of any of the above methods, the liver disease is nonalcoholic steatohepatitis.

[0317] In one embodiment of any of the above methods, the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

[0318] In one embodiment of any of the above methods, the cancer is responsive to immunotherapy.

[0319] In one embodiment of any of the above methods, the compound inhibits tumor growth.

[0320] In one embodiment of any of the above methods, the subject is concurrently treated with cancer immunotherapy.

[0321] In one embodiment of any of the above methods, the compound enhances the effectiveness of cancer immunotherapy.

[0322] In one embodiment of any of the above methods, the compound enhances the anti-tumor response of cancer immunotherapy in the subject.

[0323] In one embodiment of any of the above methods, the compound enhances the immune response to tumor cells in the subject.

[0324] In one embodiment of any of the above methods, the compound promotes T memory stem cells (T SCM )’s formation.

[0325] In one embodiment of any of the above methods, the compound promotes chimeric antigen receptor (CAR) T memory stem cells (T SCM )’s formation.

[0326] In one embodiment of any of the above methods, the compound promotes anti-tumor CD8+ T cell immunity.

[0327] In one embodiment of any of the above methods, the compound promotes anti-tumor function following adoptive cell transfer. In one embodiment of any 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.

[0328] In one embodiment of any of the above methods, the subject is concurrently treated with an immune checkpoint inhibitor.

[0329] In one embodiment of any of the above methods, the cancer is colorectal cancer.

[0330] In one embodiment of any of the above methods, the subject is concurrently treated with pembrolizumab, nivolumab, or ipilimumab.

[0331] Also provided herein is a method of enhancing the effectiveness of cancer immunotherapy in a subject in need thereof, the method comprising administering a compound of Formula (Ia)-(Ic), (Id), (Ie), (If), (Ih), (Ij), or (Ik).

[0332] Also provided herein is a method of enhancing the effectiveness of cancer immunotherapy in a subject in need thereof, the method comprising administering a compound of Formula (Ia)-(Ic), (Id), (Ie), (If), (Ih), (Ij) or (Ik) to a subject already being treated with cancer immunotherapy.

[0333] Pharmaceutical compositions, routes of administration and dosing

[0334] 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, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of Formula (Ia), (Ic), (Id), (Ie), (If), or (Ih) and a pharmaceutically acceptable carrier.

[0335] In one embodiment of the above methods, a neuromuscular disorder is treated.

[0336] In one embodiment of the above methods, a muscle disorder is treated.

[0337] In one embodiment of the above methods, heart disease is treated.

[0338] In one embodiment of the above methods, pulmonary fibrosis is treated.

[0339] In one embodiment of the above methods, a liver disease is treated.

[0340] In one embodiment of the above methods, inflammatory bowel disease is treated.

[0341] In one embodiment of the above methods, cancer is treated.

[0342] In one embodiment of the above methods, the neuromuscular disorder is Chuck-Marie-Duce disease.

[0343] In one embodiment of the above methods, the muscle disorder is hereditary inclusion body myositis, oculopharyngeal muscular dystrophy, inclusion body myopathy, Paget's disease of bone, frontotemporal dementia, or Duchenne muscular disorder.

[0344] In one embodiment of the above methods, the heart disease is heart failure.

[0345] In one embodiment of the above methods, the liver disease is nonalcoholic steatohepatitis.

[0346] In one embodiment of the above methods, the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

[0347] 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.

[0348] In certain embodiments, pharmaceutical compositions comprise a plurality of compounds of the invention and a pharmaceutically acceptable carrier.

[0349] In certain embodiments, the pharmaceutical compositions of the present invention further comprise at least one additional pharmaceutically active agent other than the compounds of the present invention. The at least one additional pharmaceutically active agent may be an agent useful for treating ischemia-reperfusion injury.

[0350] 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.

[0351] As stated above, "effective amount" refers to any amount sufficient to achieve the desired biological effect. In conjunction with the teachings provided herein, by selecting between various active compounds and trade-offs (such as efficacy, relative bioavailability, patient weight, severity of adverse side effects and mode of administration), a preventive or therapeutic treatment regimen that does not cause substantial unwanted toxicity but is effective for treating a particular subject can be planned. The effective amount for any particular application may vary depending on factors such as the disease or illness being treated, the specific compound of the present invention being administered, the size of the subject, or the severity of the disease or illness. One of ordinary skill in the art can empirically determine the effective amount of a specific compound of the present invention and / or other therapeutic agents without excessive experimentation. A maximum dose, i.e., the highest safe dose according to some medical diagnosis, can be used. Multiple doses per day can be considered to achieve appropriate systemic levels of the compound. Appropriate systemic levels can be determined, for example, by measuring the peak or sustained plasma levels of the patient's drug. "Dosage" and "dosage" are used interchangeably herein.

[0352] The formulations of the present invention may be administered in a pharmaceutically acceptable solution which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants and optionally other therapeutic ingredients.

[0353] The pharmaceutical composition of the present invention contains an effective amount of a compound as described herein and a therapeutic agent optionally contained in a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" means one or more compatible solid or liquid fillers, diluents or encapsulating materials that are suitable for administration to humans or other vertebrates. The term "carrier" refers to a natural or synthetic organic or inorganic ingredient that is combined with an active ingredient to facilitate application. The components of the pharmaceutical composition can also be blended with the compounds of the present invention and with each other in such a manner that there is no interaction that substantially impairs the desired drug efficiency.

[0354] Those skilled in the relevant art will appreciate that, based on the description of the invention contained herein, other suitable modifications and adaptations of the compositions and methods described herein are apparent and may be made without departing from the scope of the invention or any embodiment thereof, given the information known to those skilled in the art, based on the description of the invention contained herein. Now that the invention has been described in detail, the invention will be more clearly understood by reference to the following examples, which are included herein only for illustrative purposes and are not intended to limit the invention.

[0355] Example

[0356] The present invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

[0357] Example 1: Synthesis of representative compounds used in the method of the present invention

[0358] Unless otherwise stated, all reactions were performed using oven-dried glassware and under an inert atmosphere (nitrogen). Unless otherwise stated, all solvents were used as purchased. Commercial reagents were used as purchased without further purification. Organic solutions were concentrated on a Büchi rotary evaporator under reduced pressure.

[0359] Use Merck Kieselgel 60F254 (230-400 mesh) fluorescently treated silica to carry out thin layer chromatography, and visualize under UV light (254 and 366nm) and / or by dyeing with potassium permanganate aqueous solution. Record the H NMR spectrum at 400MHz on a Bruker spectrometer in deuterated solvents or at 60MHz on a Nanalysis NMReady-60PRO spectrometer, wherein the residual proton solvent is as an internal standard. Record the C NMR spectrum at 100MHz on a Bruker spectrometer in deuterated solvents, wherein the central peak of the deuterated solvent is as an internal standard. Chemical shift (δ) is given in parts per million (ppm), and coupling constant (J) is given in Hertz (Hz) rounded to the nearest 0.1Hz. The H NMR spectrum is reported as δ / ppm (multiplicity, proton number, coupling constant J / Hz) relative to tetramethylsilane low field. 13 C NMR spectra are reported as δ / ppm. TLC-MS data were obtained on an Advion Expression CMS coupled to a Plate Express TLC-plate reader. Medium pressure liquid chromatography (MPLC) was performed on a Biotage IsoleraFour with a built-in UV detector and a fraction collector with an Interchim silica gel column.

[0360] Synthesis of 1.6-membered urolithin A analogs

[0361] A) Ester "A" group analogs via Hurtley reaction

[0362] General Procedure 1A (GP1a)

[0363] Using NaOH and CuSO 4 General procedure for the cyclization of (GP1a), using the synthesis of 3-hydroxy-8-methoxy-6H-benzo[c]chromen-6-one (1) as a general example.

[0364]

[0365] A mixture of 2-bromo-5-methoxybenzoic acid (0.500 g, 2.16 mmol, 1.0 eq), resorcinol (0.477 g, 4.33 mmol, 2.0 eq) and sodium hydroxide (0.2 g, 4.98 mmol, 2.4 eq) in water (10 mL) was heated under reflux for 30 minutes. After the addition of copper sulfate (5% aqueous solution, 2.5 mL), the mixture was refluxed again overnight to form a precipitate which was filtered off and 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).

[0366] General Procedure 1B (GP1b)

[0367] Use Na 2 CO 3 General procedure for the cyclization of CuI(GP1b) and CuI(GP1b), using the synthesis of 3-hydroxy-6-oxo-6H-benzo[c]chromene-8-carboxylic acid (2) as a general example.

[0368]

[0369] Resorcinol (8.9 g, 81.6 mmol, 2.0 equiv) was dissolved in water and sodium carbonate (8.60 g, 81.6 mmol, 2.0 equiv) was added, and the mixture was heated to 50 ° C until all the materials were dissolved. Then, acid (10.00 g, 40.8 mmol, 1.0 equiv) was added and stirring was continued at 50 ° C for 1 hour. After that, CuI (0.77 g, 4.08 mmol) was added in one go, and the reaction was stirred overnight. A precipitate was formed, which was filtered and washed twice with 1M 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).

[0370] 8-Bromo-3-hydroxy-6H-benzo[c]chromen-6-one (3) Synthesis

[0371]

[0372] The compound was prepared according to GPla starting from resorcinol (3.93 g, 35.7 minol) 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 slightly brown solid. 1 HNMR (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).

[0373] N-(3-Hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)acetamide (4) Synthesis

[0374]

[0375] 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. 1 H 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).

[0376] 4 Deprotection gave 8-amino-3-hydroxy-6H-benzo[c]chromen-6-one (5)

[0377]

[0378] 8-Fluoro-3-hydroxy-6H-benzo[c]chromen-6-one (6) Synthesis

[0379]

[0380] 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 slightly brown solid. 1 HNMR (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).

[0381] B) Amide "A" Group Analogs

[0382] 3 , 8-Dihydroxyphenanthridin-6(5H)-one (18) Synthesis

[0383]

[0384] Step 1: Synthesis of 3,8-dimethoxyphenanthridin-6(5H)-one

[0385]

[0386] 2,7-dimethoxy-9H-fluorene-9-one (1.10 g, 4.57 mmol) was added to cold sulfuric acid (10 mL) at 0°C, and then sodium azide (387 mg, 5.95 mmol) was carefully added. The reaction mixture was stirred at 0°C for 3 hours. EtOAc (10 mL) was added and the mixture was poured into ice water and stirred for 1 hour. The slightly brown precipitate was filtered and the aqueous phase was extracted 3 times with EtOAc. The organic phase was dried over sodium sulfate and evaporated under vacuum. The reaction mixture was purified by MPLC (SiO 2 The crude material was purified by HPLC (EtOAc / cyclohexane 0% to 80%) to give 3,8-dimethoxyphenanthridin-6(5H)-one (150 mg, 13%) as a brown solid. f=0.4 (EtOAc / hexane 50%). 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).

[0387] Step 2: Synthesis of 3,8-dihydroxyphenanthridin-6(5H)-one

[0388]

[0389] 18 According to GP2, 3,8-dimethoxyphenanthridin-6(5H)-one (90 mg, 0.35 mmol) and BBr 3 (1M in THF, 2.10 ml, 2.10 mmol) was prepared and analyzed by MPLC (SiO 2 , MeOH / DCM 0% to 10%)) to give 3,8-dihydroxyphenanthridin-6(5H)-one (70 mg, 87%) as a slightly brown solid. f = 0.2 (MeOH 10% in DCM). 1 H NMR (400MHz, DMSO) δ 11.91-11.20 (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).

[0390] 3,8-Dihydroxy-5-methylphenanthridin-6(5H)-one (20) Synthesis

[0391]

[0392] Step 1: Synthesis of 3,8-dimethoxy-5-methylphenanthridin-6(5H)-one (19)

[0393]

[0394] NaH (60% dispersion in mineral oil, 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 at 0°C for 30 minutes. Then, MeI (0.122 ml, 1.96 mmol) was added and stirring was continued at room temperature for 2 hours. The reaction mixture was poured into saturated NH 4 The product was dissolved in aqueous Cl solution and extracted 3 times with EtOAc. The combined organic phases were dried over sodium sulfate and concentrated under vacuum. 2 The crude product was purified by HPLC (EtOAc / cyclohexane 0% to 40%) to give 3,8-dimethoxy-5-methylphenanthridin-6(5H)-one (176 mg, 67%). f = 0.3 eluent (EtOAc / hexane 50%). 1 H NMR (400 MHz, CDCl 3 )δ8.10 (dd, J=9.2, 8.0Hz, 2H), 7.93 (d, J=2.8Hz, 1H), 7.32 (dd, J=8.9, 2.9Hz, 1H), 6.93-6.86 (m, 2H), 3.95 (s, 3H), 3.93 (s, 3H), 3.80 (s, 3H).

[0395] Step 2: Synthesis of 3,8-dihydroxy-5-methylphenanthridin-6(5H)-one (20)

[0396]

[0397] 20 was prepared according to GP2 starting from 3,8-dimethoxy-5-methylphenanthridin-6(5H)-one (150 mg, 0.550 mmol). 2 , MeOH / DCM 0% to 10%)) to give 3,8-dihydroxy-5-methylphenanthridin-6(5H)-one (120 mg, 89%) as a beige solid. 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).

[0398] 5-Cyclopropyl-3,8-dihydroxyphenanthridin-6(5H)-one (twenty one) Synthesis

[0399]

[0400] Step 1: Synthesis of 5-cyclopropyl-3,8-dimethoxyphenanthridin-6(5H)-one

[0401]

[0402] 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), and the resulting mixture was heated at room temperature with N 2 The balloon was degassed for 10 min. Then, Cu(OAc) was added in one portion. 2 (171 mg, 0.940 mmol, 2.0 equiv), and the vial was sealed and placed in a preheated 130 °C oil bath for 2 hours. After complete consumption of the starting material, the reaction was cooled to room temperature and then quenched with water, extracted with EtOAc, and purified by Na 2 SO 4 Dry and concentrate under vacuum. 2 The crude product was purified by HPLC-MS / MS (500 μl, 25 g, EtOAc in Hex 0%-50%) to give 5-cyclopropyl-3,8-dimethoxyphenanthridin-6(5H)-one (50 mg, 36%) as a brown solid. 1 H NMR (400 MHz, CDCl 3 )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, 2.8Hz, 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).

[0403] Step 2: Synthesis of 5-cyclopropyl-3,8-dihydroxyphenanthridin-6(5H)-one

[0404]

[0405] 5-Cyclopropyl-3,8-dimethoxyphenanthridin-6(5H)-one (20 mg, 0.070 mmol, 1.0 eq.) was dissolved in DCM (1 mL) and cooled to 0°C in an ice bath and stirring was continued for 5 minutes. 3 (0.20 ml, 1 M in DCM, 0.020 mmol, 3.0 equiv) was added dropwise to the reaction mixture. After the addition was complete, the mixture was left in an ice bath and allowed to warm to room temperature over the course of 2 hours. When the starting material could no longer be observed (TLC), the reaction mixture was added dropwise to 0 ° C cold methanol (10 mL) and stirred for another 10 minutes. The mixture was then concentrated and supported on silica to be analyzed by MPLC (SiO 2 , 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).

[0406] C) Sulfonamide "A" Group Analogs

[0407] 3,8-Dihydroxy-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (twenty two) Synthesis

[0408]

[0409] Step 1: Synthesis of N-(2-bromo-5-methoxyphenyl)-3-methoxybenzenesulfonamide

[0410]

[0411] 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. After warming to room temperature, the starting material was no longer observable by TLC, and the reaction mixture was concentrated under vacuum. The reaction mixture was diluted with EtOAc and washed with 1N HCl aqueous solution. The organic phase was purified by Na 2 SO 4 Drying and concentration in vacuo gave N-(2-bromo-5-methoxyphenyl)-3-methoxybenzenesulfonamide (3.28 g, 99%) as a brown oil. 1 H NMR (400 MHz, CDCl 3 ) 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).

[0412] Step 2: Synthesis of N-benzyl-N-(2-bromo-5-methoxyphenyl)-3-methoxybenzenesulfonamide

[0413]

[0414] N-(2-bromo-5-methoxyphenyl)-3-methoxybenzenesulfonamide (5.90 g, 18.9 mmol, 1.0 equiv) was dissolved in MeCN (53 mL) and K was added in one portion. 2 CO 3 Benzyl bromide (2.98 g, 17.4 mmol, 1.1 equiv) was added dropwise at room temperature, and after completion of the addition, the reaction mixture was heated to 60 ° C in an oil bath for 3 hours. After complete consumption of the starting material (as shown by TLC), the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum and loaded on silica to analyze by MPLC (SiO 2 , 240 g, EtOAc in Hex 0%-10%) to give N-benzyl-N-(2-bromo-5-methoxyphenyl)-3-methoxybenzenesulfonamide (6.83 g, 93%) as a light brown solid. 1 H NMR (400 MHz, CDCl 3)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), 6.4 8 (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).

[0415] Step 3: Synthesis of 6-benzyl-3,8-dimethoxy-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide

[0416]

[0417] 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) was then added. 2 (291 mg, 1.30 mmol, 0.3 eq) and KOAc (1.69 g, 17.3 mmol, 4.0 eq). After the reagents were completely dissolved, the flask was placed in a 140 °C oil bath and stirring was continued for a period of 48 hours. The reaction mixture was then concentrated to complete dryness using a rotary evaporator at 90 °C. The reaction mixture was loaded on silica and analyzed by MPLC (SiO 2 , 80 g, EtOAc in Hex 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).

[0418] Step 4: Synthesis of 6-benzyl-3,8-dihydroxy-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide

[0419]

[0420] 6-Benzyl-3,8-dimethoxy-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (180 mg, 0.470 mmol, 1.0 eq.) was dissolved in DCM (2 mL) and cooled to 0°C in an ice bath and stirring was continued for 5 minutes. 3 (1.89 ml, 1 M in DCM, 1.88 mmol, 4.0 equiv) was added dropwise to the reaction mixture. After the addition was complete, the mixture was left in an ice bath and allowed to warm to room temperature over the course of 2 hours. When the starting material could no longer be observed (TLC), the reaction mixture was added dropwise to 0 ° C cold methanol (20 mL) and stirred for another 10 minutes. The mixture was then concentrated, supported on silica, and analyzed by MPLC (SiO 2 , 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 light yellow solid. 1 HNMR (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).

[0421] Step 5: Synthesis of 3,8-dihydroxy-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide

[0422]

[0423] 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) was added in one portion. 2 / C (26 mg). Then, the reaction mixture was evacuated and concentrated by N 2 Backfill three times and then place under hydrogen atmosphere (balloon). The reaction mixture was stirred for 4 hours and filtered through silica and concentrated under vacuum after complete consumption of the starting material (as indicated by TLC). The crude product was supported on silica and analyzed by MPLC (SiO 2 , 12 g, EtOAc in Hex 0%-50%) to give 3,8-dihydroxy-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (65 mg, 67%) as a white solid. 1H 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).

[0424] D) Ether "A" Group Analogs

[0425] 6H-Benzo[c]chromene-3,8-diol (twenty three) Synthesis

[0426]

[0427] Step 1: Synthesis of 3,8-bis((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one

[0428]

[0429] Urolithin A (12 g 53 mmol) was added to a solution of imidazole (9.0 g, 0.13 mol) in (100 mL) and stirred for 1 hour. No reaction occurred, so DMF (20 mL) was added and stirring continued overnight. The DCM was removed in vacuo. Water was added and the mixture was washed with Et 2 The mixture was extracted with O(3*), and the organic layer was washed with water twice and brine in sequence. 2 SO 4 Dry, filter through silica and concentrate. 2 The crude product was purified by evaporation (4% to 20% by weight, EtOAc / cyclohexane 0% to 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 (400 MHz, CDCl 3 )δ7.89 (d, J=8.8Hz, 1H), 7.85-7.80 (m, 1H), 7.76 (d, J=2.6Hz, 1H), 7.29 (dd, 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).

[0430] Step 2: Synthesis of ((6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane)

[0431]

[0432] InBr 3 3,8-bis((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one (1.8 g, 4.0 mmol) (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 hour. The reaction mixture was cooled to room temperature and filtered. The solvent was evaporated under vacuum and analyzed by MPLC (SiO 2 The crude material was purified by HPLC-MS / MS (5% ethanol, cyclohexane / dichloromethane 0% to 10%) to afford ((6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane) as a white solid, 81 mg, 88%). 1 H NMR (400 MHz, CDCl 3 )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, 2.5 Hz, 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).

[0433] Step 3: Synthesis of 6H-benzo[c]chromene-3,8-diol

[0434]

[0435] 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 vacuum and analyzed by MPLC (SiO 2 , EtOAc in Hex 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).

[0436] 6-Methyl-6H-benzo[c]chromene-3,8-diol ( twenty four) Synthesis

[0437]

[0438] Step 1: Synthesis of 3,8-bis((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-ol

[0439]

[0440] DIBAL-H (2.10 mL, 2.10 mmol) was slowly added 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 eluent (cyclohexane / DCM 1:1). The reaction was complete within 1 hour of stirring. After Fieser workup, the product was used in the step without further purification. 1 H NMR (400 MHz, CDCl 3 )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).

[0441] Step 2: Synthesis of 4,4′-bis((tert-butyldimethylsilyl)oxy)-2′-(1-hydroxyethyl)-[1,1′-biphenyl]-2-ol

[0442]

[0443] 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 Et 2 DMF (5% ethyl acetate, 1 ... 1 H NMR (400 MHz, CDCl 3)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), 1.3 0(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).

[0444] Step 3: ((6-methyl-6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane)

[0445]

[0446] 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 vacuum and purified by column (SiO 2 , 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. 1 H NMR (400 MHz, CDCl 3 )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).

[0447] Step 4: 6-Methyl-6H-benzo[c]chromene-3,8-diol

[0448]

[0449] 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 vacuum and analyzed by MPLC (SiO 2 , EtOAc in Hex 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).

[0450] 6,6-Dimethyl-6H-benzo[c]chromene-3,8-diol (25) Synthesis

[0451]

[0452] Step 1: Synthesis of 4,4′-bis((tert-butyldimethylsilyl)oxy)-2′-(2-hydroxypropan-2-yl)-[1,1′-biphenyl]-2-ol

[0453]

[0454] 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 Et 2 D (0, 1.00 mL, 3.00 mmol, 3.0 equiv). The reaction was completed within 1 hour. The reaction mixture was diluted with ether, filtered through a pad of silica, washed with ether and concentrated to afford the synthesis of 4,4′-bis((tert-butyldimethylsilyl)oxy)-2′-(2-hydroxypropan-2-yl)-[1,1′-biphenyl]-2-ol (489 mg, quantitative) as a thick colorless oil, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3)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=2.4H z, 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).

[0455] Step 2: Synthesis of ((6,6-dimethyl-6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane)

[0456]

[0457] 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 vacuum and analyzed by MPLC (SiO 2 , 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 (400 MHz, CDCl 3 ) 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 (dd, 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).

[0458] Step 3: Synthesis of 6,6-dimethyl-6H-benzo[c]chromene-3,8-diol

[0459]

[0460] 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 vacuum and analyzed by MPLC (SiO 2 , EtOAc in Hex 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. 1 H 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).

[0461] E) Ester "A" group analogs with a pyridine ring

[0462] 3,8-Dihydroxy-6H-isochromeno[4,3-b]pyridin-6-one (27) Synthesis

[0463]

[0464] Step 1: Synthesis of 3,8-dimethoxy-6H-isochromeno[4,3-b]pyridin-6-one (26)

[0465]

[0466] 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 at 0° C. for 15 minutes, and this solution was added dropwise to 5-methoxypyridin-3-ol (1.18 g, 9.42 mmol) in water (1 mL) and HCl (3N, 1 mL) and TiCl at 0° C. 3 (0.25 ml, 1.88 mmol) and continued stirring at room temperature overnight. Saturated Na 2 CO 3 After extraction with EtOAc 3 times, the combined organic phases were dried over sodium sulfate and concentrated under vacuum. 2The crude product was purified by evaporation (0% to 30% by volume, EtOAc / cyclohexane) to give 3,8-dimethoxy-6H-isochromeno[4,3-b]pyridin-6-one (85 mg, 18%) as a white solid. f =0.25 (EtOAc / hexane 20%). 1 H NMR (400 MHz, CDCl 3 )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).

[0467] Step 2: Synthesis of 3,8-dihydroxy-6H-isochromeno[4,3-b]pyridin-6-one (27)

[0468]

[0469] 27 was prepared according to GP2 starting from 3,8-dimethoxy-6H-isochromeno[4,3-b]pyridin-6-one 26 (120 mg, 0.460 mmol). The chromatograms were analyzed by MPLC (SiO 2 , EtOAc / cyclohexane 5% to 90%)) to give 3,8-dihydroxy-6H-isochromeno[4,3-b]pyridin-6-one (20 mg, 19%) as a white solid. 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).

[0470] 3,8-Dihydroxy-5H-chromeno[4,3-b]pyridin-5-one (28) Synthesis

[0471]

[0472] Step 1: Synthesis of methyl 2-(2-chloro-4-methoxyphenyl)-5-methoxynicotinate

[0473]

[0474] 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 hours. TLC showed complete conversion of the starting material. Saturated NH 4 Cl solution and the aqueous phase was extracted 3 times with EtOAc. The combined organic phases were dried over sodium sulfate and concentrated under vacuum. 2 The crude product was purified by HPLC (EtOAc / hexanes 0% to 60%) to give methyl 2-(2-chloro-4-methoxyphenyl)-5-methoxynicotinate (160 mg, 87%) as a colorless oil. f = 0.3 (EtOAc / hexane 50%). 1 H NMR (400 MHz, CDCl 3 )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).

[0475] Step 2: Synthesis of 3,8-dimethoxy-5H-chromeno[4,3-b]pyridin-5-one

[0476]

[0477] In a microwave container, 2-(2-chloro-4-methoxyphenyl)-5-methoxynicotinic acid methyl ester (900 mg, 2.92 mmol, 1.0 eq), copper(I)thiophene-2-carboxylate (278 mg, 1.46 mmol, 0.5 eq), Cs 2 CO 3 To a mixture of 476 mg, 1.46 mmol, 0.5 eq. of methyl methacrylate (476 mg, 1.46 mmol, 0.5 eq.) in deionized water (10 mL) was added TMEDA (339 mg, 2.92 mmol, 1.0 eq.). 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 washed with EtOAc and saturated NH 4 The organic phase was dried over sodium sulfate and concentrated under vacuum. 2The crude product was purified by HPLC (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 (400 MHz, CDCl 3 )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).

[0478] Step 3: Synthesis of 3,8-dihydroxy-5H-chromeno[4,3-b]pyridin-5-one

[0479]

[0480] 28 was prepared according to GP2 starting from 3,8-dimethoxy-5H-chromeno[4,3-b]pyridin-5-one (120 mg, 0.460 mmol) and analyzed by MPLC (SiO 2 , MeOH / DCM 0% to 10%)) to give 3,8-dihydroxy-5H-chromeno[4,3-b]pyridin-5-one (26 mg, 56%) as a white solid. f =0.1 (EtOAc / hexane 80%). 1 H 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).

[0481] F) Preparation of Ester "A" Ring Analogs with Ether Substitution by Mitsunobu Reaction The Mitsunobu goal was achieved starting from two common intermediates (CI1 and CI2) described below.

[0482] Synthesis of CI1

[0483]

[0484] Step 1: Synthesis of 3-(benzyloxy)-8-bromo-6H-benzo[c]chromen-6-one

[0485]

[0486] To a suspension of 3 (synthesis as above) (500 mg, 1.72 mmol, 1.0 equiv) in DMF (5 mL) was added K 2 CO 3 In 4-nitro-2-nitropropene (400mg, 1.2mmol) 2-nitropropene (400mg, 1.2mmol) 3-(benzyloxy)-8-bromo-6H-benzo [c] chromene-6-ketone (400mg, 61%) was added dropwise over a period of 1 minute to obtain 3-(benzyloxy)-8-bromo-6H-benzo [c] chromene-6-ketone (400mg, 61%) of 1.89mmol, 2.2 equivalents. 1 H 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).

[0487] Step 2: Synthesis of 3-(Benzyloxy)-8-hydroxy-6H-benzo[c]chromen-6-one CI1

[0488]

[0489] 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 was added Pd 2 dba 3 (43 mg, 0.18 mmol, 0.1 eq.) was added followed by tBuXPhos (175 mg, 0.370 mmol, 0.2 eq.). The MW vial was then sealed and degassed with nitrogen for 10 min. KOH (412 mg, 7.34 mmol, 4.4 eq.) was then added in H 2O (3 mL) was slowly added to the reaction mixture, which was then stirred in a preheated oil bath at 90° C. for 3 hours. After 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 6M HCl aqueous solution. The mixture was extracted with ethyl acetate (3×10 mL), and the combined organic phases were purified by centrifugation with anhydrous Na 2 SO 4 Dry and concentrate under vacuum. 2 The crude material was purified by HPLC-MS / MS (HPLC-MS / ... 1 H 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).

[0490] Synthesis of CI2

[0491]

[0492] Step 1: Synthesis of 8-(benzyloxy)-3-((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one

[0493]

[0494] 8-(Benzyloxy)-3-hydroxy-6H-benzo[c]chromene-6-one (1.46 g, 4.59 mmol) was dissolved in 12 ml of anhydrous THF. 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 at room temperature for 3 hours. TLC showed no more starting material. The reaction mixture was extracted twice with EtOAc and HCl (1 M). The organic phase was washed with water and brine in turn, then dried over sodium sulfate to give 8-(benzyloxy)-3-((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromene-6-one (1.83 g, 92%) as a slightly brown solid. 1 H NMR (400 MHz, CDCl 3)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).

[0495] Step 2: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-hydroxy-6H-benzo[c]chromen-6-one C2

[0496]

[0497] 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) and dichloromethane (10 ml), Pd(OH)2 / C (368 mg, 0.5 mmol, 0.12 equiv) was added, and the reaction mixture was hydrogenated overnight at atmospheric pressure. The mixture was filtered through a pad of celite, and the solvent was evaporated under vacuum 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 (400 MHz, CDCl 3 )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).

[0498] Synthesis of 3-hydroxy-8-(oxetane-3-ylmethoxy)-6H-benzo[c]chromen-6-one (29)

[0499]

[0500] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-(oxetan-3-ylmethoxy)-6H-benzo[c]chromen-6-one

[0501]

[0502] 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]chromene-6-one (150 mg, 0.430 mmol) and oxetanes-3-ylmethanol (58 mg, 0.65 mmol) in THF (2 mL) at 0 °C, and stirring was continued at room temperature overnight. TLC indicated that the starting material was completely converted. The reaction mixture was supported on silica gel and analyzed by MPLC (SiO 2 , EtOAc / cyclohexane 0% to 30%) to give 280 mg of a mixture of 3-((tert-butyldimethylsilyl)oxy)-8-(oxetan-3-ylmethoxy)-6H-benzo[c]chromen-6-one and reduced DIAD. f = 0.3 (EtOAc / hexane 20 / 80). After purification, a significant amount of reduced DIAD was present in the NMR, which is therefore not described further as it was used crude in the next step.

[0503] Step 2: Synthesis of 3-hydroxy-8-(oxetan-3-ylmethoxy)-6H-benzo[c]chromen-6-one

[0504]

[0505] KHF at room temperature 2 (108 mg, 1.38 mmol) was added in one portion to 3-((tert-butyldimethylsilyl)oxy)-8-(oxetan-3-ylmethoxy)-6H-benzo[c]chromen-6-one (285 mg, 0.690 mmol) (PPh 3 0 and reduced DIAD) in MeOH (5 ml) and stirred for 4 hours. The formed white precipitate 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. 1 H 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).

[0506] 3-Hydroxy-8-(2-(4-methylpiperazin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one (30) Synthesis

[0507]

[0508] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-(2-(4-methylpiperazin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one)

[0509]

[0510] 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) and purified on MPLC (SiO 2 , MeOH / DCM 0% to 20%) to afford 3-((tert-butyldimethylsilyl)oxy)-8-(2-(4-methylpiperazin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one (60 mg, 55%) as a slightly yellow oil. NMR still showed a significant amount of reduced DIAD, but the impure / crude material was carried forward to the next step. f =0.4 (20% MeOH / DCM).

[0511] Step 2: Synthesis of 3-hydroxy-8-(2-(4-methylpiperazin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one

[0512]

[0513] Acetyl chloride (0.046 ml, 0.64 mmol, 5.0 equivalents) was added to a solution of 3-((tert-butyldimethylsilyl)oxy)-8-(2-(4-methylpiperazine-1-yl)ethoxy)-6H-benzo[c]chromene-6-one (60 mg, 0.13 mmol, 1.0 equivalents) in MeOH (2 ml) at room temperature, and the reaction mixture was stirred overnight. Methanol was evaporated under vacuum, the crude product was diluted with EtOAc and washed with saturated sodium carbonate solution. The aqueous layer was extracted with EtOAc, and the combined organic phases were dried over sodium sulfate. The column chromatography was performed by MPLC (SiO 2The crude product was purified by HPLC-MS / MS (5% ethanol, 0.048 mmol, MeOH / DCM 0% to 30%) to afford 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).

[0514] (S)-3-Hydroxy-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one (31) Synthesis

[0515]

[0516] Step 1: Synthesis of (S)-3-((tert-butyldimethylsilyl)oxy)-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one

[0517]

[0518] (S)-3-((tert-Butyldimethylsilyl)oxy)-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one (synthesis according to 29) was prepared starting from C2 (80 mg, 0.23 mmol) and (R)-tetrahydrofuran-3-ol (31 mg, 0.35 mmol) to give (S)-3-((tert-Butyldimethylsilyl)oxy)-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one (45 mg, 47%) as a slightly yellow oil. f =0.6 (EtOAc / hexane 1 / 1). 1 H NMR (400 MHz, CDCl 3 )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), 6.90-6.80 (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).

[0519] Step 2: Synthesis of (S)-3-hydroxy-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one

[0520]

[0521] 31 was prepared according to the synthesis of 29 from (S)-3-((tert-butyldimethylsilyl)oxy)-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one (40 mg, 0.097 mmol) and KHF 2 (27 mg, 0.34 mmol) was used to prepare (S)-3-hydroxy-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one (22 mg, 76%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ7.92-7.76 (m, 2H), 7.69 (s, 1H), 7.29 (ddd, J=11.3, 8.8, 2.8Hz, 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).

[0522] 3-Hydroxy-8-(2-(2-methoxyethoxy)ethoxy)-6H-benzo[c]chromen-6-one (32) Synthesis

[0523]

[0524] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-(2-(2-methoxyethoxy)ethoxy)-6H-benzo[c]chromen-6-one

[0525]

[0526] 3-((tert-Butyldimethylsilyl)oxy)-8-(2-(2-methoxyethoxy)ethoxy)-6H-benzo[c]chromen-6-one (synthesis according to 29) was prepared starting from C2 (100 mg, 0.29 mmol) and 2-(2-methoxyethoxy)ethan-1-ol (42 mg, 0.35 mmol) to give 3-((tert-Butyldimethylsilyl)oxy)-8-(2-(2-methoxyethoxy)ethoxy)-6H-benzo[c]chromen-6-one (125 mg, 47%) as a slightly yellow oil contaminated with reduced DIAD. f =0.5 (EtOAc / hexane 1 / 1). 1 H NMR (400 MHz, CDCl 3)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).

[0527] Step 2: Synthesis of 3-hydroxy-8-(2-(2-methoxyethoxy)ethoxy)-6H-benzo[c]chromen-6-one

[0528]

[0529] 32 According to the synthesis of 29, (100 mg, 0.220 mmol) and KHF 2 (70 mg, 0.90 mmol) was prepared and analyzed by MPLC (SiO 2 , EtAOc / hexanes 0% to 30%) to give 3-hydroxy-8-(2-(2-methoxyethoxy)ethoxy)-6H-benzo[c]chromen-6-one (24 mg, 32%) as a white solid as a mixture of two compounds. 1 H NMR (400 MHz, CDCl 3 )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, 4.4Hz, 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).

[0530] 3-Hydroxy-8-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one (33) Synthesis

[0531]

[0532] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one

[0533]

[0534] The compound was prepared according to the synthesis of 29 starting from C2 (100 mg, 0.29 mmol) and tetrahydro-2H-pyran-4-ol (36 mg, 0.35 mmol) to give 3-((tert-butyldimethylsilyl)oxy)-8-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one (64 mg, 51%) as a slightly yellow oil. f =0.67 (EtOAc / hexane 4 / 6). 1 H NMR (400 MHz, CDCl 3 )δ7.98-7.81(m, 2H), 7.77(dd, J=7.3, 2.7Hz, 1H), 7.42-7.27(m, 1H), 6.96 -6.80 (m, 2H), 4.61 (dtt, J=44.2, 7.8, 3.9Hz, 1H), 4.01 (ddd, J=10.4, 5.9, 3.9Hz, 2H), 3.62 (ddt, J=11.9, 7.8, 3.7Hz, 2H), 2.06 (dt, 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).

[0535] Step 2: Synthesis of 3-hydroxy-8-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one

[0536]

[0537] 33 was prepared 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 2 (38 mg, 0.49 mmol) was used to prepare 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. 1H 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).

[0538] 3-Hydroxy-8-((tetrahydro-2H-pyran-3-yl)oxy)-6H-benzo[c]chromen-6-one (34) Synthesis

[0539]

[0540] Step 1: Synthesis of 3-(benzyloxy)-8-((tetrahydro-2H-pyran-3-yl)oxy)-6H-benzo[c]chromen-6-one

[0541]

[0542] 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. Ph 3 (79 mg, 0.30 mmol, 1.5 eq) and tetrahydro-2H-pyran-3-ol (31 mg, 0.30 mmol, 1.5 eq), and the reaction mixture was cooled to 0 ° C in an ice bath and stirred in an ice bath for 5 minutes. Then a solution of di-tert-butyl-diazene-1,2-dicarboxylate (69 mg, 0.30 mmol, 1.5 eq) (DTAD) in THF (0.1 mL) was added dropwise to the reaction mixture. After the addition was completed, the reaction mixture turned dark yellow and continued to stir overnight at room temperature. After stirring overnight, the starting material was still present, so PPh 3 (79 mg, 0.30 mmol, 1.5 eq.), tetrahydro-2H-pyran-3-ol (31 mg, 0.30 mmol, 1.5 eq.) and a solution of di-tert-butyl-diazene-1,2-dicarboxylate (DTAD) in THF (0.1 mL) were added to the reaction mixture to complete the reaction. After stirring for another 2 hours at room temperature, the reaction mixture was concentrated under vacuum and loaded onto silica to be analyzed by MPLC (SiO 2, 12 g, EtOAc in Hex 0%-35%) to give 3-(benzyloxy)-8-((tetrahydro-2H-pyran-3-yl)oxy)-6H-benzo[c]chromen-6-one (50 mg, 62%) as a light yellow solid. 1 H NMR (400 MHz, CDCl 3 )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).

[0543] Step 2: Synthesis of 3-hydroxy-8-((tetrahydro-2H-pyran-3-yl)oxy)-6H-benzo[c]chromen-6-one

[0544]

[0545] 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) was added in one portion. 2 / C (20 mg). Then, the reaction mixture was evacuated and concentrated by N 2 The mixture was backfilled three times and then placed under a hydrogen atmosphere (balloon). The reaction mixture was stirred for 2 hours and after complete consumption of the starting material (as indicated by TLC) filtered through silica and concentrated under vacuum to give a crude product which was supported on silica and analyzed by MPLC (SiO 2 , 12 g, EtOAc in Hex 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. 1H 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).

[0546] 3-Hydroxy-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one (35) Synthesis

[0547]

[0548] Step 1: Synthesis of 3-(benzyloxy)-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one

[0549]

[0550] 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). PPh 3 (124mg, 0.470mmol, 1.5 equivalents) and tetrahydrofuran-3-ol (42mg, 0.47mmol, 1.5 equivalents), and the reaction mixture was cooled to 0 ° C in an ice bath and stirred in an ice bath for 5 minutes. Then a solution of di-tert-butyl-diazene-1,2-dicarboxylate (109mg, 0.470mmol, 1.5 equivalents) (DTAD) in THF (0.2mL) was added dropwise to the reaction mixture. After the addition was completed, the reaction mixture turned dark yellow and continued to stir overnight at room temperature. After stirring overnight, the starting material still existed, so PPh 3A solution of 1,2-dihydrofuran-3-ol (124 mg, 0.470 mmol, 1.5 eq.), tetrahydrofuran-3-ol (42 mg, 0.47 mmol, 1.5 eq.) and di-tert-butyl-diazene-1,2-dicarboxylate (109 mg, 0.470 mmol, 1.5 eq.) (DTAD) in THF (0.2 mL) was added to the reaction mixture to complete the reaction. After stirring for another 2 hours at room temperature, the reaction mixture was concentrated under vacuum and loaded onto silica to be analyzed by MPLC (SiO 2 , 12 g, EtOAc in Hex 0%-35%) to give 3-(benzyloxy)-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one (100 mg, 82%) as a light yellow solid. The NMR after purification still showed a significant amount of reduced DTAD, but the reaction was carried forward to the next step crude material, so the NMR is not reported here.

[0551] Step 2: Synthesis of 3-hydroxy-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one

[0552]

[0553] 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) was added in one portion. 2 / C (60 mg). Then, the reaction mixture was evacuated and concentrated by N 2 The mixture was backfilled three times and then placed under a hydrogen atmosphere using a balloon. The reaction mixture was stirred for 2 hours and filtered through silica after complete consumption of the starting material (as indicated by TLC), and concentrated under reduced pressure to give a crude product which was supported on silica and purified by flash column chromatography (SiO 2 , 12 g, EtOAc in Hex 0%-50%) to give 3-hydroxy-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one (65 mg, 72%) as a white solid. 1H 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).

[0554] 3-Hydroxy-8-(oxetan-3-yloxy)-6H-benzo[c]chromen-6-one (36) Synthesis

[0555]

[0556] Step 1: Synthesis of 3-(benzyloxy)-8-(oxetan-3-yloxy)-6H-benzo[c]chromen-6-one

[0557]

[0558] Cyanomethylidene tributylphosphane (150 mg, 0.630 mmol, 2.5 eq) was added in one portion to a solution of 3-(benzyloxy)-8-hydroxy-6H-benzo[c]chromen-6-one (80 mg, 0.25 mmol, 1.0 eq) and oxetane-3-ol (56 mg, 0.75 mmol, 3.0 eq) in toluene (1.3 mL) at room temperature, and the reaction mixture was heated to 120 °C in a sealed vial for 2 hours. After complete conversion of the starting material, the reaction mixture was cooled to room temperature, concentrated and loaded onto silica for analysis by MPLC (SiO 2 , 12 g, EtOAc in Hex 0%-30%) to give 3-(benzyloxy)-8-(oxetan-3-yloxy)-6H-benzo[c]chromen-6-one (74 mg, 79%) as a light 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).

[0559] Step 2: Synthesis of 3-hydroxy-8-(oxetan-3-yloxy)-6H-benzo[c]chromen-6-one

[0560]

[0561] 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) was added in one portion. 2 / C (15 mg). Then, the reaction mixture was evacuated and concentrated by N 2 The mixture was backfilled three times and then placed under a hydrogen atmosphere using a balloon. The reaction mixture was stirred for 4 hours and after complete consumption of the starting material (as indicated by TLC), filtered through silica and concentrated under reduced pressure to give a crude product which was supported on silica and purified by flash column chromatography (SiO 2 , 12 g, EtOAc in Hex 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).

[0562] 8-((2-oxaspiro[3.3]hept-6-yl)oxy)-3-hydroxy-6H-benzo[c]chromen-6-one (37) Synthesis

[0563]

[0564] Step 1: Synthesis of 8-((2-oxaspiro[3.3]hept-6-yl)oxy)-3-(benzyloxy)-6H-benzo[c]chromen-6-one

[0565]

[0566] Cyanomethylidene tributylphosphane (95 mg, 0.39 mmol, 2.5 eq) 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 eq) and 2-oxaspiro[3.3]heptan-6-ol (39 mg, 0.35 mmol, 2.2 eq) in toluene (3.0 mL) at room temperature, and the reaction mixture was heated to 120° C. in a sealed vial for 2 hours. After complete conversion of the starting material, the reaction mixture was cooled to room temperature, concentrated and loaded onto silica for analysis by flash column chromatography (SiO 2 , 12 g, EtOAc in Hex 0%-30%) to give 8-((2-oxaspiro[3.3]hept-6-yl)oxy)-3-(benzyloxy)-6H-benzo[c]chromen-6-one (40 mg, 0.10 mmol, 61%) as a light 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).

[0567] Step 2: Synthesis of 8-((2-oxaspiro[3.3]hept-6-yl)oxy)-3-hydroxy-6H-benzo[c]chromen-6-one

[0568]

[0569] 8-((2-oxaspiro[3.3]hept-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) was added in one portion. 2 / C (14 mg). Then, the reaction mixture was evacuated and concentrated by N 2The mixture was backfilled three times and then placed under a hydrogen atmosphere using a balloon. The reaction mixture was stirred for 4 hours and after complete consumption of the starting material (as indicated by TLC), filtered through silica and concentrated under vacuum to give a crude product which was loaded onto silica and purified by flash column chromatography (SiO 2 , 12 g, EtOAc in Hex 0%-50%) to give 8-((2-oxaspiro[3.3]hept-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).

[0570] In a similar manner, the 9-substituted analog 38 was prepared according to the following scheme:

[0571] Synthesis of 3-hydroxy-9-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one (38)

[0572]

[0573] Step 1: Synthesis of 9-bromo-3-hydroxy-6H-benzo[c]chromen-6-one

[0574]

[0575] A mixture of 2,4-dibromobenzoic acid (5.00 g, 17.9 mmol, 1.0 eq.), resorcinol (3.93 g, 35.7 mmol, 2.0 eq.) and sodium hydroxide (1.71 g, 42.9 mmol, 2.4 eq.) in water (15 ml) was heated under reflux for 60 min. After addition of copper sulfate (5% aqueous solution, 10 mL), the mixture was refluxed again overnight and a precipitate was formed which was filtered off and 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. 1H NMR (400MHz, DMSO) δ 10.44 (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).

[0576] Step 2: Synthesis of 3-(benzyloxy)-9-bromo-6H-benzo[c]chromen-6-one

[0577]

[0578] 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 K 2 CO 3 In 4-nitro-2-nitropropene (2-nitropropene)-1-nitropropene (2-nitropropene)-1-nitropropene (2-nitropropene)-1-nitropropene (2-nitropropene)-1-nitropropene (2-nitropropene)-1-nitropropene (2-nitropropene)-1-nitropropene (2-nitropropene)-1-nitropropene (2-nitropropene)-1-nitropropene (2-nitropropene)-1-nitropropene (2-nitropropene)-1-nitropropene (2-nitropropene)-1-nitropropene (2-nitropropene)-1-nitropropene (2-nitropropene)-1-nitropropene (2-nitropropene)-1-nitropropene (2-nitropropene)-1-nitropropene (2-nitropropene)-1-nitropropene (2-nitropropene)-1-nitropropene ( 1 HNMR (400 MHz, CDCl 3 )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).

[0579] Step 3: Synthesis of 3-(Benzyloxy)-9-hydroxy-6H-benzo[c]chromen-6-one

[0580]

[0581] 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 Pd 2 dba 3(49mg, 0.21mmol, 0.1 eq), followed by tBuXPhos (200mg, 0.42mmol, 0.2 eq). The MW vial was then sealed and degassed with nitrogen for 10 minutes. Then, a solution of KOH (471mg, 8.39mmol, 4.4 eq) in H2O (3mL) was slowly added to the reaction mixture and placed in a preheated oil bath at 90°C for 3 hours. After 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 a 6M HCl aqueous solution. The mixture was extracted with ethyl acetate (3x10 mL), and the combined organic phase was purified by anhydrous Na 2 SO 4 Dry and concentrate under vacuum. 2 The crude material was purified by HPLC-MS / MS (HPLC-MS / ... 1 H NMR (400 MHz, CDCl 3 )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).

[0582] Step 4: Synthesis of 3-(benzyloxy)-9-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one

[0583]

[0584] Cyanomethylidene tributylphosphane (227 mg, 0.940 mmol, 2.5 eq) 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 eq) and tetrahydro-2H-pyran-4-ol (77 mg, 0.71 mmol, 2.0 eq) in toluene (3.8 mL) at room temperature and the reaction mixture was heated to 120° C. in a sealed vial for 2 hours. After complete conversion of the starting material, the reaction mixture was cooled to room temperature, concentrated and loaded onto silica for analysis by MPLC (SiO 2 , 12 g, EtOAc in Hex 0%-30%) to give 3-(benzyloxy)-9-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one (135 mg, 89%) as a light yellow foam. 1H NMR (400 MHz, CDCl 3 )δ8.28 (d, J=8.8Hz, 1H), 7.86 (d, J=8.9Hz, 1H), 7.51-7.32 (m, 6H), 7.03 (d d, J=8.9, 2.4Hz, 1H), 6.97 (dd, J=8.8, 2.6Hz, 1H), 6.91 (d, J=2.5Hz, 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).

[0585] Step 5: Synthesis of 3-hydroxy-9-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one

[0586]

[0587] 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) was added in one portion. 2 / C (70 mg). Then, the reaction mixture was evacuated and concentrated by N 2 The mixture was backfilled three times and then placed under a hydrogen atmosphere (balloon). The reaction mixture was stirred for 4 hours and after complete consumption of the starting material (as indicated by TLC), filtered through silica and concentrated under vacuum to give a crude product which was supported on silica and analyzed by MPLC (SiO 2 , 12 g, EtOAc in Hex 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. 1H 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).

[0588] G) Ester "A" ring analogs with alkynyl substitution prepared by the Sonogashira reaction

[0589] 3-Hydroxy-8-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (39) Synthesis

[0590]

[0591] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one

[0592]

[0593] To a solution of S8-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 were then added propargyl alcohol (501 mg, 8.94 mmol, 2.5 equiv), Pd(PPh 3 ) 2 Cl 2 (251 mg, 0.360 mmol, 0.1 eq.) and CuI (68 mg, 0.36 mmol, 0.1 eq.), and the reaction was heated at room temperature with N 2 Degas for 10 minutes. Triethylamine (724 mg, 7.15 mmol, 2.0 eq.) was added once and the reaction mixture was placed in a preheated oil bath at 90 °C. After complete conversion of the starting material (as indicated by TLC), the reaction mixture was cooled to room temperature and quenched with water and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with anhydrous Na 2 SO 4Dry and concentrate under vacuum. 2 The crude product was purified by HPLC-MS / MS (5% HPLC-MS / MS, 80 g, EtOAc in Hex 0%-40%) to afford 3-((tert-butyldimethylsilyl)oxy)-8-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (490 mg, 36%) as a slightly brown solid. 1 H NMR (400 MHz, CDCl 3 )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).

[0594] Step 2: Synthesis of 3-hydroxy-8-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one

[0595]

[0596] 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, and the resulting yellow solution was stirred for 10 minutes. KHF was then added in one portion. 2 (66 mg, 0.82 mmol, 2.0 equiv.), and the reaction was stirred at room temperature overnight. After complete consumption of the starting material (as indicated by TLC), the reaction mixture was filtered through a glass frit (Por. 4), and the filter residue 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).

[0597] Alternatively, the hydrogenation of the above compounds was carried out as follows:

[0598] Step 3: Synthesis of 3-hydroxy-8-(3-hydroxypropyl)-6H-benzo[c]chromen-6-one (40)

[0599]

[0600] 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 eq) was hydrogenated at atmospheric pressure overnight. The reaction mixture was filtered through a pad of celite and the solvent was concentrated by evaporation under vacuum 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).

[0601] 3-Hydroxy-8-(3-methoxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (41) Synthesis

[0602]

[0603] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-(3-methoxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one

[0604]

[0605] 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 were then added 3-methoxyprop-1-yne (224 mg, 3.19 mmol, 3.5 equiv), Pd(PPh 3 ) 2 Cl 2(64 mg, 0.09 mmol, 0.1 eq.) and CuI (17 mg, 0.09 mmol, 0.1 eq.), and the reaction was heated at room temperature with N 2 Degas for 10 minutes. Triethylamine (277 mg, 2.74 mmol, 3.0 equiv) was added once and the reaction mixture was placed in a preheated oil bath at 90 ° C. After complete conversion of the starting material (as indicated by TLC), the reaction mixture was cooled to room temperature and quenched with water and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry and concentrate under vacuum. 2 The crude product was purified by HPLC-MS / MS (400 μl, 40 g, EtOAc in Hex 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 slightly brown solid. 1 H NMR (400 MHz, CDCl 3 )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).

[0606] Step 2: Synthesis of 3-hydroxy-8-(3-methoxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one

[0607]

[0608] 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) and cooled to room temperature in an ice bath, and the resulting yellow solution was stirred for 10 minutes. KHF was then added in one portion. 2 (63 mg, 0.81 mmol, 2.0 equiv.), and the reaction was stirred overnight. After complete consumption of the starting material (as indicated by TLC), the reaction mixture was filtered through a glass frit (Por. 4), and the filter residue 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. 1H 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).

[0609] Synthesis of 3-Hydroxy-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-6H-benzo[c]chromen-6-one (42)

[0610]

[0611] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-6H-benzo[c]chromen-6-one

[0612]

[0613] 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 were then added 2-methylbut-3-yn-2-ol (269 mg, 3.19 mmol, 3.5 equiv), Pd(PPh 3 ) 2 Cl 2 (64 mg, 0.090 mmol, 0.1 eq.) and CuI (17 mg, 0.090 mmol, 0.1 eq.), and the reaction was heated at room temperature with N 2 Degas for 10 minutes. Triethylamine (277 mg, 2.74 mmol, 3.0 equiv) was added once and the reaction mixture was placed in a preheated oil bath at 90 ° C. After complete conversion of the starting material (as indicated by TLC), the reaction mixture was cooled to room temperature and quenched with water and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry and concentrate under vacuum. 2 The crude product was purified by HPLC-MS / MS (400 μl, 0.5 min, 450 μl, 10 μl, 50 μl, 20 μl, 40 μl, 0.5 min, 450 μl, 20 μl, 30 μl, 10 μl, 20 μl, 30 μl, 40 μl, 0.5 min, 45 ...30 μl, 40 μl, 0.5 min, 450 μl, 20 μl, 30 μl, 30 μl, 20 μl, 3 1 H NMR (400 MHz, CDCl 3)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).

[0614] Step 2: Synthesis of 3-hydroxy-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-6H-benzo[c]chromen-6-one

[0615]

[0616] 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) and cooled to room temperature in an ice bath, and the resulting yellow solution was stirred for 10 minutes. KHF was then added in one portion. 2 (89 mg, 1.1 mmol, 2.0 equiv.), and the reaction was stirred overnight. After complete consumption of the starting material (as indicated by TLC), the reaction mixture was filtered through a glass frit (Por. 4), and the filter residue was washed with MeOH and dried under vacuum to give 3-hydroxy-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-6H-benzo[c]chromene-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).

[0617] Synthesis of 3-hydroxy-8-((1-hydroxycyclobutyl)ethynyl)-6H-benzo[c]chromen-6-one (43)

[0618]

[0619] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-((1-hydroxycyclobutyl)ethynyl)-6H-benzo[c]chromen-6-one

[0620]

[0621] 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 were then added 1-ethynylcyclobutan-1-ol (208 mg, 2.16 mmol, 3.5 equiv), Pd(PPh 3 ) 2 Cl 2 (43 mg, 0.060 mmol, 0.1 eq.) and CuI (12 mg, 0.060 mmol, 0.1 eq.), and the reaction was heated at room temperature with N 2 Degas for 10 minutes. Triethylamine (187 mg, 1.85 mmol, 3.00 equiv) was added once and the reaction mixture was placed in a preheated oil bath at 90 ° C. After 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 x 20 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry and concentrate under vacuum. 2 The crude product was purified by HPLC-MS / MS (HPLC-MS / MS: 400 μl, 500 μl, 1% to 40% EtOAc in Hex) to afford 3-((tert-butyldimethylsilyl)oxy)-8-((1-hydroxycyclobutyl)ethynyl)-6H-benzo[c]chromen-6-one (195 mg, 75%) as a slightly yellow solid. 1 H NMR (400 MHz, CDCl 3 )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, 1H), 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).

[0622] Step 2: Synthesis of 3-hydroxy-8-((1-hydroxycyclobutyl)ethynyl)-6H-benzo[c]chromen-6-one

[0623]

[0624] 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) and cooled to room temperature in an ice bath, and the resulting yellow solution was stirred for 10 min. KHF was then added in one portion. 2 The mixture was stirred overnight at 4 °C for 2 hours at 4 °C for 1 h. (72 mg, 0.93 mmol, 2.0 eq.), and the reaction was stirred overnight. After complete consumption of the starting material (as indicated by TLC), the reaction mixture was filtered through a glass frit (Por. 4), and the filter residue was washed with MeOH and dried under vacuum to give 3-hydroxy-8-((1-hydroxycyclobutyl)ethynyl)-6H-benzo[c]chromene-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).

[0625] Synthesis of 3-Hydroxy-9-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (44)

[0626]

[0627] Step 1: Synthesis of 9-bromo-3-((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one

[0628]

[0629] 9-bromo-3-hydroxy-6H-benzo[c]chromene-6-one (610mg, 2.10mmol, 1.0 equivalent) was suspended in DMF (10mL), and triethylamine (636mg, 6.29mmol, 3.0 equivalent) was added at once. The reaction mixture was cooled to 0°C in an ice bath and stirred at this temperature for 10 minutes. Subsequently, TBSCl (411mg, 2.72mmol, 1.3 equivalent) was added at once, and the reaction mixture was warmed to room temperature and stirred for another 2 hours. After the starting material was completely converted (as indicated by TLC), the reaction mixture was quenched with a half-saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the combined organic phase was purified by anhydrous Na 2 SO4 Dry. By MPLC (SiO 2 The crude product was purified by HPLC-MS / MS (500 μl, 80 g, EtOAc in Hex 0%-15%) to afford 9-bromo-3-((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one (566 mg, 67%) as a light brown solid. 1 H NMR (400 MHz, CDCl 3 )δ8.10 (d, J=8.4Hz, 1H), 8.04 (d, J=1.8Hz, 1H), 7.75 (d, J=8.5Hz, 1H), 7.52 (dd, J=8.5, 1.8Hz, 1H), 6.84-6.67 (m, 2H), 0.90 (s, 9H), 0.17 (s, 6H).

[0630] Step 2: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-9-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one

[0631]

[0632] 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 were then added propargyl alcohol (208 mg, 2.16 mmol, 3.5 equiv), Pd(PPh 3 ) 2 Cl 2 (43 mg, 0.060 mmol, 0.1 eq.) and CuI (12 mg, 0.060 mmol, 0.1 eq.), and the reaction was heated at room temperature with N 2 Bubble for 10 minutes. Triethylamine (187 mg, 1.85 mmol, 3.0 equiv) was added once and the reaction mixture was placed in a preheated oil bath at 90 ° C. After the starting material was completely converted (as indicated by TLC), the reaction mixture was cooled to room temperature, quenched with water, and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry and concentrate under vacuum. 2 The crude product was purified by HPLC-MS / MS (400 μl, 40 g, EtOAc in Hex 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 slightly yellow solid. 1H 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).

[0633] Step 2: Synthesis of 3-hydroxy-9-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one

[0634]

[0635] 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 was then added in one portion. 2 (72 mg, 0.93 mmol, 2.0 equiv.), and the reaction was stirred overnight. After complete consumption of the starting material (as indicated by TLC), the reaction mixture was filtered through a glass frit (Por. 4), and the filter residue was washed with MeOH and dried under vacuum to give 3-hydroxy-8-((1-hydroxycyclobutyl)ethynyl)-6H-benzo[c]chromene-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).

[0636] 3-((tert-Butyldimethylsilyl)oxy)-8-(3-(4-methylpiperazin-1-yl)prop-1-yn-1-yl)- Synthesis of 6H-Benzo[c]chromen-6-one

[0637]

[0638] Methanesulfonyl chloride (0.037 mL, 0.47 mmol) was added to 3-((tert-butyldimethylsilyl)oxy)-8-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (140 mg, 0.360 mmol) and NEt at 0 °C. 3 (0.150ml, 1.10mmol) in THF (5mL), and the reaction mixture was stirred at room temperature for 1 hour. TLC showed that the starting material was completely converted. N-methylpiperazine (111mg, 1.10mmol) was added, and the mixture was heated at 60 ° C overnight. Saturated ammonium chloride solution was added, and the aqueous layer was extracted 3 times with EtOAc. The combined organic layer was dried over sodium sulfate and concentrated under vacuum. By MPLC (SiO 2 The crude product was purified by HPLC-MS / MS (5% to 40% by volume, 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.

[0639] 3-((tert-butyldimethylsilyl)oxy)-8-(3-(4-methylpiperazin-1-yl)propyl)-6H-benzo[c] Synthesis of Chromen-6-one

[0640]

[0641] 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) 2 A suspension of 1-(4-(tert-butyldimethylsilyl)oxy)-8-(3-(4-methylpiperazin-1-yl)propyl)-6H-benzo[c]chromen-6-one (64 mg, 95%) was hydrogenated at atmospheric pressure overnight. The reaction mixture was filtered through a pad of celite and the solvent was concentrated by evaporation under vacuum to give 3-((tert-butyldimethylsilyl)oxy)-8-(3-(4-methylpiperazin-1-yl)propyl)-6H-benzo[c]chromen-6-one (64 mg, 95%) as a slightly yellow oil which was used in the next step without further purification.

[0642] Synthesis of 3-hydroxy-8-(3-(4-methylpiperazin-1-yl)propyl)-6H-benzo[c]chromen-6-one (45)

[0643]

[0644] 45 was prepared 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 2 (22 mg, 0.28 mmol) was prepared and analyzed by MPLC (SiO2 , MeOH / DCM 5% to 30%) to give 3-hydroxy-8-(3-(4-methylpiperazin-1-yl)propyl)-6H-benzo[c]chromen-6-one (36 mg, 73%) as a slightly yellow solid. f =0.4 (MeOH / DCM 30 / 70). 1 H NMR (400 MHz, CDCl 3 )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).

[0645] 3-((tert-Butyldimethylsilyl)oxy)-8-(3-morpholinoprop-1-yn-1-yl)-6H-benzo[c] Synthesis of En-6-Ketone

[0646]

[0647] Methanesulfonyl chloride (0.04ml, 0.51mmol) was added to a solution of 3-((tert-butyldimethylsilyl)oxy)-8-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromene-6-one (150mg, 0.39mmol) and NEt3(0.160ml, 1.18mmol) in THF (5mL) at 0°C, and the reaction mixture was stirred at room temperature for 1 hour. TLC showed that the starting material was completely converted. Morpholine (0.100ml, 1.18mmol) was added, and the mixture was heated at 60°C overnight. Saturated ammonium chloride solution was added, and the reaction mixture was extracted 3 times with EtOAc. The combined organic layer was dried over sodium sulfate and concentrated under vacuum. The product was purified by MPLC (SiO 2 The crude product was purified by HPLC-MS / MS (5% to 40% by weight, 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.

[0648] 3-((tert-butyldimethylsilyl)oxy)-8-(3-morpholinopropyl)-6H-benzo[c]chromen-6-one synthesis

[0649]

[0650] 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) 2 / C (31 mg, 0.22 mmol) was hydrogenated at atmospheric pressure overnight. The reaction mixture was filtered through a pad of celite and the solvent was concentrated under vacuum to give 3-((tert-butyldimethylsilyl)oxy)-8-(3-morpholinopropyl)-6H-benzo[c]chromen-6-one (70 mg, 69%) as a slightly yellow oil. 1 H NMR (400 MHz, CDCl 3 )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=4.7 Hz, 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).

[0651] Synthesis of 3-Hydroxy-8-(3-morpholinopropyl)-6H-benzo[c]chromen-6-one (46)

[0652]

[0653] 46 was prepared from 3-((tert-butyldimethylsilyl)oxy)-8-(3-morpholinopropyl)-6H-benzo[c]chromen-6-one (70 mg, 0.15 mmol) and KHF 2 (24 mg, 0.31 mmol) was prepared and analyzed by MPLC (SiO 2 , MeOH / DCM 5% to 30%)) to give 3-hydroxy-8-(3-morpholinopropyl)-6H-benzo[c]chromen-6-one (70 mg, 69%) as a slightly yellow solid. f =0.4 (MeOH / DCM 30 / 70). 1H 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).

[0654] 3-((tert-Butyldimethylsilyl)oxy)-8-(3-(piperidin-1-yl)prop-1-yn-1-yl)-6H-benzo Synthesis of [c]chromen-6-one

[0655]

[0656] Methanesulfonyl chloride (0.0980 ml, 1.26 mmol) was added to 3-((tert-butyldimethylsilyl)oxy)-8-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (240 mg, 0.630 mmol) and NEt at 0°C. 3 (0.260ml, 1.89mmol) in THF (10mL), and the reaction mixture was stirred at room temperature for 1 hour. TLC showed that the starting material was completely converted. Piperidine (0.081ml, 0.82mmol) was added, and the mixture was heated at 60 ° C overnight. Saturated ammonium chloride solution was added, and the reaction mixture was extracted 3 times with EtOAc. The combined organic layer was dried over sodium sulfate and concentrated under vacuum. By MPLC (SiO 2 The crude product was purified by HPLC-MS / MS (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 (400 MHz, CDCl 3 )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).

[0657] Synthesis of 3-hydroxy-8-(3-(piperidin-1-yl)prop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (47)

[0658]

[0659] 47 was prepared 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 2 (21 mg, 0.27 mmol) was prepared and analyzed by MPLC (SiO 2 , EtOAc / cyclohexane 0% to 80%) to give 3-hydroxy-8-(3-(piperidin-1-yl)prop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (37 mg, 83%) as a slightly yellow solid. f =0.4 (EtOAc / hexane 40%). 1 H NMR (400 MHz, CDCl 3 )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, 2.4 Hz, 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).

[0660]

[0661] (3-(3-((tert-Butyldimethylsilyl)oxy)-6-oxo-6H-benzo[c]chromen-8-yl)propan-2- Synthesis of tert-butyl (1-alkyne)carbamate

[0662] Pd(PPh 3 ) 2 Cl 2 A thoroughly degassed solution of 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 with NEt 3 (0.330 ml, 2.38 mmol, 4.0 equiv), and the mixture was heated at 70°C overnight. The reaction mixture was washed with saturated NH 4The precipitate was diluted with Cl solution and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated under vacuum. 2 The crude product was purified by evaporation with 4% ethanol (0.2% ethanol, 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 slightly yellow foam. f =0.4 (EtOAc / hexane 20%). 1 H NMR (400 MHz, CDCl 3 )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).

[0663] (3-(3-((tert-Butyldimethylsilyl)oxy)-6-oxo-6H-benzo[c]chromen-8-yl)propyl)amino Synthesis of tert-Butyl Formate

[0664] 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 A suspension of 1,4-dihydro-1-(2-[ ... 2 The crude product was purified by evaporation in 4% ethanol (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 slightly tinted oil. f =0.4 (EtOAc / hexane 20%). 1 H NMR (400 MHz, CDCl 3)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).

[0665] Synthesis of tert-butyl (3-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)propyl)carbamate (48)

[0666]

[0667] 48 was prepared from tert-butyl (3-(3-((tert-butyldimethylsilyl)oxy)-6-oxo-6H-benzo[c]chromen-8-yl)propyl)carbamate (170 mg, 0.350 mmol) and KHF 2 (55 mg, 0.70 mmol) was used to prepare the product. 2 , EtOAc / cyclohexane 0% to 20%) to afford 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).

[0668] Synthesis of 8-(3-aminopropyl)-3-hydroxy-6H-benzo[c]chromen-6-one hydrochloride (49)

[0669]

[0670] HCl (4M 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, and a precipitate formed. The solvent was concentrated under vacuum, and the crude product was triturated in Et2O, 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 (400 MHz, DMSO) δ 10.36 (s, 1H), 8.22 (d, J = 8.3 Hz, 1H), 8.14 (d, J = 8.8 Hz, 1H), 8.05 (d, J = 1.9 Hz, 1H), 7.83 (s, 3H), 7.76 (dd, J = 8.3, 2.0 Hz, 1H), 6.85 (dd, J = 8.7, 2.4 Hz, 1H), 6.76 (dd, J = 2.4, 1.2 Hz, 1H), 2.81 (q, J = 7.7, 6.4 Hz, 4H), 1.98-1.85 (m, 2H). H) Spiro (oxetane and azetidine) "A" ring analogs

[0671] Synthesis of Spiro[benzo[c]chromene-6,3′-oxetane]-3,8-diol (50)

[0672]

[0673] Step 1: Synthesis of 2-bromo-4′-chloro-2′-fluoro-4-methoxy-1,1′-biphenyl

[0674]

[0675] 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 Na 2 CO 3 (2.70 g, 25.6 mmol) was added to a solution of 1% 4-nitropropene (2.70 g, 25.6 mmol) and the reaction mixture was heated at 80 °C overnight. The reaction mixture was diluted with saturated sodium carbonate solution and extracted twice with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The results were analyzed by MPLC (SiO 2 The crude product was purified by HPLC (0% to 8% DCM / cyclohexane) to afford 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).

[0676] Step 2: Synthesis of 2-bromo-4′-chloro-2′-fluoro-[1′-biphenyl]-4-ol

[0677]

[0678] At 0°C, BBr 3 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) was added 4-nitropropane-2-yl (1M in DCM, 6.97 ml, 6.97 mmol) 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 under vacuum. The crude product was diluted with saturated sodium bicarbonate solution and extracted with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under vacuum 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. 1 H NMR (400 MHz, CDCl 3 )δ7.23-7.01 (m, 5H), 6.79 (dd, J=8.4, 2.6Hz, 1H).

[0679] Step 3: Synthesis of 4-(benzyloxy)-2-bromo-4′-chloro-2′-fluoro-1,1′-biphenyl

[0680]

[0681] Benzyl bromide (0.470ml, 3,98mmol) was added to a solution of 2-bromo-4'-chloro-2'-fluoro-[1,1'-biphenyl]-4-ol (1.00g, 3.31mmol) and potassium carbonate (0.916g, 6.63mmol) in ACN (10ml), and the mixture was heated at 60°C overnight. The crude material 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 vacuum. The crude product was purified by MPLC (25g silica column, EtOAc / cyclohexane 0% to 10%) to give 4-(benzyloxy)-2-bromo-4'-chloro-2'-fluoro-1,1'-biphenyl (1.10g, 85%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3) 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).

[0682] Step 4: Synthesis of 3-(4-(Benzyloxy)-4′-chloro-2′-fluoro-[1,1′-biphenyl]-2-yl)oxetane-3-ol

[0683]

[0684] nBuLi (1.6M in hexanes, 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 light red solution was stirred at −78° C. for 45 minutes, then a solution of oxetane-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 washed with NH 4 Cl saturated solution was quenched and extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The crude product was purified by MPLC (25g silica column, EtOAc / cyclohexane 0% to 50%) to give 3-(4-(benzyloxy)-4′-chloro-2′-fluoro-[1,1′-biphenyl]-2-yl)oxetane-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).

[0685] Step 5: Synthesis of 8-(Benzyloxy)-3-chlorospiro[benzo[c]chromene-6,3′-oxetane

[0686]

[0687] 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)oxetane-3-ol (377 mg, 0.980 mmol) in 4 ml of DMF at 0°C and the reaction was allowed to warm to room temperature overnight. The crude material was extracted with a 1 / 2 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 column, EtOAc / cyclohexane 0% to 5%) to give 8-(benzyloxy)-3-chlorospiro[benzo[c]chromene-6,3′-oxetane] (290 mg, 81%) as a yellow solid. f = 0.3 (EtOAc / hexane 10%). 1 H NMR (400 MHz, CDCl 3 )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).

[0688] Step 6: Synthesis of 8-(Benzyloxy)spiro[benzo[c]chromene-6,3′-oxetan-3-ol

[0689]

[0690] t-BuXPhos (9 mg, 0.020 mmol) was added to the Pd 2 dba 3 (2.3 mg, 0.099 mmol) in dioxane (1 ml), degassed and stirred for 5 minutes. 8-(benzyloxy)-3-chlorospiro[benzo[c]chromene-6,3′-oxetane] (45 mg, 0.12 mmol) was added at room temperature, followed by a solution of KOH (15 mg, 0.27 mmol) in water (0.3 ml), and the mixture was heated at 90°C overnight. Water was added and the mixture was extracted 3 times with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered and evaporated under vacuum. The crude product was purified by MPLC (25 g silica column, EtOAc / cyclohexane 0% to 30%) to give 8-(benzyloxy)spiro[benzo[c]chromene-6,3′-oxetane]-3-ol (30 mg, 0.87 mmol, 70%) as a white solid.f =0.3 (EtOAc / hexane 20%). 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).

[0691] Step 7: Synthesis of spiro[benzo[c]chromene-6,3′-oxetane]-3,8-diol

[0692]

[0693] 8-(Benzyloxy)spiro[benzo[c]chromene-6,3′-oxetan-3-ol (40 mg, 0.12 mmol) and Pd(OH) 2 A suspension of 1-(4-(2-(4-(2-(4-piperidin-2-yl)-1-yl)-2-nitropropene)-1-yl)-4-nitropropene-1-yl)-2 ... 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).

[0694] Synthesis of spiro[azetidine-3,6′-benzo[c]chromene]-3′,8′-diol (51)

[0695]

[0696] Step 1: Synthesis of tert-butyl 3-(4′-chloro-2′-fluoro-4-methoxy-[1,1′-biphenyl]-2-yl)-3-hydroxyazetidine-1-carboxylate

[0697]

[0698] nBuLi (1.6M in hexane, 2.69ml, 4.31mmol) was added dropwise to a solution of 4-(benzyloxy)-2-bromo-4'-chloro-2'-fluoro-1,1'-biphenyl (900mg, 2.29mmol) in anhydrous THF (8ml) at -78°C. The light red solution was stirred at -78°C for 45 minutes, then a solution of tert-butyl 3-oxoazetidine-1-carboxylate (1.84g, 10.8mmol) in anhydrous THF (5ml) was added dropwise, and the reaction was allowed to warm to room temperature over 5 hours. The reaction mixture was washed with NH 4 Cl saturated solution was quenched and extracted with ethyl acetate. The organic phase was dried over sodium sulfate. The crude product was purified by MPLC (80g silica column, EtOAc / cyclohexane 0% to 50%) to give tert-butyl 3-(4′-chloro-2′-fluoro-4-methoxy-[1,1′-biphenyl]-2-yl)-3-hydroxyazetidine-1-carboxylate (400mg, 36%) as a mixture of two compounds in the form of a colorless oil. f =0.3 (EtOAc / hexane 50 / 50). 1 H NMR (400 MHz, CDCl 3 )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=2.6Hz, 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).

[0699] Step 2: Synthesis of tert-butyl 3′-chloro-8′-methoxyspiro[azetidine-3,6′-benzo[c]chromene]-1-carboxylate

[0700]

[0701] NaH (12mg, 0.30mmol) is added to a solution of 3-(4′-chloro-2′-fluoro-4-methoxy-[1,1′-biphenyl]-2-yl)-3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (67mg, 0.16mmol) in DMF 3ml at 0°C, and the reaction mixture is stirred for 3 hours. A saturated solution of NH4Cl is added and the aqueous phase is extracted twice with ethyl acetate. The combined organic phase is dried over sodium sulfate, filtered and concentrated under vacuum. The crude material is purified by MPLC (EtOAc / cyclohexane 0% to 8%) to obtain 3′-chloro-8′-methoxyspiro [azetidine-3,6′-benzo [c] chromene] -1-carboxylic acid tert-butyl ester (30mg, 47%) as a slightly yellow solid. 1 H NMR (400 MHz, CDCl 3 ) 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).

[0702] Step 3: Synthesis of tert-butyl 3′-hydroxy-8′-methoxyspiro[azetidine-3,6′-benzo[c]chromene]-1-carboxylate

[0703]

[0704] 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 Pd 2 dba 3 (9 mg, 0.04 mmol, 0.1 eq.) and tBuXPhos (38 mg, 0.080 mmol, 0.2 eq.) were added to the solution. 2 The mixture was degassed with a balloon for 10 minutes. Subsequently, a solution of KOH (67 mg, 1.2 mmol, 3.0 equiv) in water (0.3 mL) was added in one portion, after which the reaction mixture was placed in a preheated oil bath at 90 °C. Stirring was continued overnight, then the reaction was cooled to room temperature, quenched with water, the aqueous phase was extracted with ethyl acetate (3 x 10 mL), and the combined organic layers were purified by Na 2 SO 4 Dry and concentrate under reduced pressure. 2The crude material was purified by HPLC-MS / MS (200 μl, 20 g, EtOAc in Hex 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 light yellow solid. f = 0.3 (EtOAc / hexane 20%), slightly yellow 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).

[0705] Step 4: Synthesis of spiro[azetidine-3,6′-benzo[c]chromene]-3′,8′-diol hydrobromide

[0706]

[0707] At 0°C, BBr 3 (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), and the mixture was allowed to warm to room temperature overnight. Methanol was added to the mixture at 0°C, concentrated under vacuum and loaded on silica, then purified by FC eluent MeOH / DCM 0% to 8% to give spiro[azetidine-3,6′-benzo[c]chromene]-3′,8′-diol hydrobromide (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).

[0708] I) Ester "A" ring analogs with peptide substitutions

[0709] Synthesis of 3-acetoxy-6-oxo-6H-benzo[c]chromene-8-carboxylic acid as a common intermediate

[0710]

[0711] 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 was still a suspension (nothing dissolved). HCl 1M was added to the suspension and stirred at room temperature for 30 minutes. The white suspension was filtered off and the solid was washed with cold water and dried under vacuum to give (17) (400 mg, 57%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )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).

[0712] General procedure for peptide coupling using FDPP and deprotection using potassium carbonate

[0713] Synthesis of 8-((2-morpholinoethyl)carbamoyl)-6-oxo-6H-benzo[c]chromen-3-yl acetate (52)

[0714]

[0715] Step 1: Synthesis of 8-((2-morpholinoethyl)carbamoyl)-6-oxo-6H-benzo[c]chromen-3-yl acetate

[0716]

[0717] DIPEA (0.15ml, 0.86mmol) is added to a solution of 3-acetoxy-6-oxo-6H-benzo [c] chromene-8-formic acid (80mg, 0.21mmol) in DMF (2mL), then pentafluorophenyl diphenylphosphinate (91mg, 0.24mmol) is added, and the mixture is stirred for 15 minutes, then 2-morpholino second-1-amine (28mg, 0.21mmol) is added dropwise and continued to stir for 1 hour. The reaction mixture is extracted 3 times with EtOAc and a saturated solution of bicarbonate 1 / 2. The organic phase merged is dried over sodium sulfate and concentrated under vacuum. By MPLC (SiO 2The crude material was purified by HPLC (5% by weight, MeOH / DCM 0% to 10%) to afford 8-((2-morpholinoethyl)carbamoyl)-6-oxo-6H-benzo[c]chromen-3-yl acetate (45 mg, 51%). f =0.3 (10% MeOH / DCM). 1 H NMR (400 MHz, CDCl 3 )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 (d d, 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).

[0718] Step 2: Synthesis of 3-hydroxy-N-(2-morpholinoethyl)-6-oxo-6H-benzo[c]chromene-8-carboxamide

[0719]

[0720] 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 on silica gel and analyzed by MPLC (SiO 2 , MeOH / dichloromethane 0% to 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) (two missing protons were obscured by the solvent).

[0721] Synthesis of 3-hydroxy-6-oxo-N-(2-(piperidin-1-yl)ethyl)-6H-benzo[c]chromene-8-carboxamide (53)

[0722]

[0723] Step 1: Synthesis of 6-oxo-8-((2-(piperidin-1-yl)ethyl)carbamoyl)-6H-benzo[c]chromen-3-yl acetate

[0724]

[0725] 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). 2 , MeOH / DCM 0% to 10%) to afford 6-oxo-8-((2-(piperidin-1-yl)ethyl)carbamoyl)-6H-benzo[c]chromen-3-yl acetate 19 as a white solid (65 mg, 49%). f =0.3 (MeOH / DCM 10%). 1 H NMR (400 MHz, CDCl 3 )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).

[0726] Step 2: Synthesis of 3-hydroxy-6-oxo-N-(2-(piperidin-1-yl)ethyl)-6H-benzo[c]chromene-8-carboxamide

[0727]

[0728] 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). The 3-hydroxy-6-oxo-N-(2-(piperidin-1-yl)ethyl)-6H-benzo[c]chromene-8-carboxamide was purified by MPLC (SiO 2 , MeOH / DCM 5% to 35%) to afford 3-hydroxy-6-oxo-N-(2-(piperidin-1-yl)ethyl)-6H-benzo[c]chromene-8-carboxamide 53 as a white solid (15 mg, 34%). 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).

[0729] -Hydroxy-N-(2-(4-methylpiperazin-1-yl)ethyl)-6-oxo-6H-benzo[c]chromene-8-carboxamide (54) Synthesis

[0730]

[0731] Step 1: Synthesis of 8-((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)-6-oxo-6H-benzo[c]chromen-3-yl acetate

[0732]

[0733] The compound was prepared according to GP4 from 3-acetoxy-6-oxo-6H-benzo[c]chromene-8-carboxylic acid (120 mg, 0.260 mmol), pentafluorophenyl diphenylphosphite (113 mg, 0.290 mmol) and DIPEA (0.187 ml, 1.070 mmol) and analyzed by MPLC (SiO 2 , MeOH / DCM 0% to 10%) to give 8-((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)-6-oxo-6H-benzo[c]chromen-3-yl ester 20 (73 mg, 59%) as a white solid. f = 0.3 eluent (MeOH / DCM 10%). 1NMR (400 MHz, CDCl 3 )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=2.2H z, 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).

[0734] Step 2: Synthesis of hydroxy-N-(2-(4-methylpiperazin-1-yl)ethyl)-6-oxo-6H-benzo[c]chromene-8-carboxamide

[0735]

[0736] 3-Hydroxy-N-(2-(4-methylpiperazin-1-yl)ethyl)-6-oxo-6H-benzo[c]chromene-8-carboxamide was prepared from 8-((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)-6-oxo-6H-benzo[c]chromene-3-yl acetate 20 (60 mg, 0.14 mmol) and potassium carbonate (39 mg, 0.28 mmol) according to GP5 to give 3-hydroxy-N-(2-(4-methylpiperazin-1-yl)ethyl)-6-oxo-6H-benzo[c]chromene-8-carboxamide (27 mg, 51%) after purification by MPLC (RP-C18, MeOH / water 0% to 95%). f = 0.1 eluent (MeOH / DCM 30%). 1 H NMR (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).

[0737] J) Ester "A" Group Analogs with Reverse Amide Substitution

[0738] The synthesis of the reverse amide is based on the common intermediates described below.

[0739] Synthesis of N-(3-(Benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-chloroacetamide

[0740]

[0741] Step 1: Synthesis of 8-amino-3-(benzyloxy)-6H-benzo[c]chromen-6-one

[0742]

[0743] 8-Amino-3-hydroxy-6H-benzo[c]chromen-6-one 15 (864 mg, 3.80 mmol) was dissolved in DMF (13 mL) and then cooled to 0°C. NaH (152 mg, 3.80 mmol) was then added in one portion. After stirring for 15 minutes, benzyl chloride (0.44 ml, 3.80 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature and continued to stir overnight. Afterwards, half-saturated NaHCO 3 The reaction was quenched with ethyl acetate (3 x 25 ml). The combined organic layers were purified by Na2SO 4- Dry and concentrate under reduced pressure. 2 The crude product was purified by HPLC-MS / MS (5% elution, ethyl acetate / Hex 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) δ 8.02 (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).

[0744] Step 2: Synthesis of N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-chloroacetamide

[0745]

[0746] 8-amino-3-(benzyloxy)-6H-benzo [c] chromene-6-one (738mg, 2.33mmol) is added to a solution of DMF (16ml) containing TEA (0.324ml, 2.56mmol). The mixture is stirred at room temperature for 10 minutes. Chloroacetyl chloride (0.205ml, 2.33mmol) is added to the above mixture, and the temperature is maintained between 0 ℃ and 5 ℃. Then the resulting solution is stirred at room temperature for 4-6 hours. The completion of the reaction is monitored by TLC. Then the solution is added to crushed ice, and the precipitate separated by filtration is dried under vacuum. The product is recrystallized from methanol to obtain N-(3-(benzyloxy)-6-oxo-6H-benzo [c] chromene-8-yl)-2-chloroacetamide (833mg, 91%) as a light yellow 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).

[0747] Synthesis of N-(3-(Hydroxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-morpholinoacetamide (55)

[0748]

[0749] Step 1: Synthesis of N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-morpholinoacetamide

[0750]

[0751] N-(3-(benzyloxy)-6-oxo-6H-benzo [c] chromene-8-yl)-2-chloroacetamide (60mg, 0.15mmol) is suspended in THF (5ml), and potassium carbonate (42mg, 0.30mmol) is added once. A minimum amount of DMF (2-3ml) is added dropwise to dissolve the suspension. Then morpholine (0.014mL, 0.17mmol) is added via a syringe, and the reactant is heated to 80 ℃ for 2 hours. After the complete consumption of the starting material (as indicated by TLC), the reactant is cooled to room temperature, and then the mixture is concentrated under reduced pressure. By MPLC (SiO 2 The crude product was purified by HPLC-MS / MS (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).

[0752] Step 2: Synthesis of N-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)-2-morpholinoacetamide

[0753]

[0754] N-(3-(Benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-morpholinoacetamide (40 mg, 0.090 mmol) and Pd(OH) 2 A solution of 1-(4 ... 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 4 aliphatic protons are obscured by the solvent)

[0755] Synthesis of N-(3-(Hydroxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-(piperidin-1-yl)acetamide (56)

[0756]

[0757] Step 1: Synthesis of N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-(piperidin-1-yl)acetamide

[0758]

[0759] N-(3-(benzyloxy)-6-oxo-6H-benzo [c] chromene-8-yl)-2-chloroacetamide (200mg, 0.510mmol) is suspended in THF (5ml), and potassium carbonate (140mg, 1.02mmol) is added once. Minimum DMF (5-6ml) is added to dissolve the suspension. Piperidine (0.055mL, 0.56mmol) is then added dropwise via a syringe, and the reactant is heated to 80°C for 2 hours. After the complete consumption of starting material (as indicated by TLC), the reactant is cooled to room temperature, and then the mixture is concentrated under reduced pressure. The crude product is purified by flash column chromatography (MeOH 0%-10% in DCM), to obtain N-(3-(benzyloxy)-6-oxo-6H-benzo [c] chromene-8-yl)-2-(piperidin-1-yl) acetamide (154mg, 0.51mmol, 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.OHz, 2H).

[0760] Step 2: Synthesis of N-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)-2-(piperidin-1-yl)acetamide

[0761]

[0762] N-(3-(Benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-(piperidin-1-yl)acetamide (154 mg, 0.350 mmol) and Pd(OH) 2 A solution of 4-(4-(4-(2-piperidin-1-yl)-2-yl)-4-nitropropene (2-nitropropene)-1-yl)-2 ... 1H 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).

[0763] MS (ESI+): m / z=353

[0764] N-(3-(Hydroxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-(4-methylpiperazin-1-yl)acetamide (57) Synthesis

[0765]

[0766] Step 1: Synthesis of N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-(piperidin-1-yl)acetamide

[0767]

[0768] N-(3-(benzyloxy)-6-oxo-6H-benzo [c] chromene-8-yl)-2-chloroacetamide (200mg, 0.510mmol) is suspended in THF (5ml), and potassium carbonate (140mg, 1.02mmol) is added once. A minimum amount of DMF (5-6ml) is added to dissolve the suspension. Then l-methylpiperazine (0.062mL, 0.56mmol) is added dropwise via a syringe, and the reactant is heated to 80°C for 2 hours. After the starting material is completely consumed (as indicated by TLC), the reactant is cooled to room temperature, and the mixture is then concentrated under reduced pressure. The crude product is purified by flash column chromatography (MeOH 0%-20% in DCM) to obtain N-(3-(benzyloxy)-6-oxo-6H-benzo [c] chromene-8-yl)-2-(piperidin-1-yl) acetamide (148mg, 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).

[0769] Step 2: Synthesis of N-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)-2-(4-methylpiperazin-1-yl)acetamide

[0770]

[0771] N-(3-(Benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-(piperidin-1-yl)acetamide (148 mg, 0.320 mmol), Pd(OH) 2 A solution of 4-(4-(4-(2-(2-(4-piperazine-1-yl)-3-yl)-4-nitropropene)-2-nitropropene)-3-nitropropene ...

[0772] MS (ESI+): m / z=368.

[0773] K) Thiocarbonyl Ester "A" Group Analogs

[0774] Synthesis of 3,8-dimethoxy-6H-benzo[c]chromene-6-thione (58)

[0775]

[0776] A mixture of 3,8-dimethoxy-6H-benzo [c] chromene-6-one (previously described above) (140 mg, 0.154 mmol) and Lawesson's reagent (552 mg, 1.34 mmol) was refluxed in toluene overnight. The reaction was monitored by TLC, which showed that the reaction was incomplete, so Lawesson's reagent (884 mg, 2.19 mmol) was added and refluxed overnight. The reaction mixture was filtered out and the solvent was evaporated under vacuum. The reaction mixture was filtered out by MPLC (SiO 2 The crude material was purified by HPLC (EtOAc / cyclohexane 0% to 25%) to afford 3,8-dimethoxy-6H-benzo[c]chromene-6-thione (110 mg, 74%) as a yellow solid. f = 0.4 (EtOAc / hexane 20%), yellow solid. 1H 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).

[0777] Synthesis of 3,8-dihydroxy-6H-benzo[c]thiochromene-6-one (59)

[0778]

[0779] 58 was prepared from 17 in 4 steps according to the procedure described in Org. Lett., Vol. 7, No. 3, 2005, 411-414. The product was obtained as a white solid. The analytical data matched well with those previously reported in the literature.

[0780] Step 5: Synthesis of 3,8-dihydroxy-6H-benzo[c]thiochromene-6-one

[0781]

[0782] 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 material was loaded on silica gel and analyzed by MPLC (SiO 2 , 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).

[0783] Synthesis of 3,8-dihydroxy-6H-benzo[c]thiochromene 5,5-dioxide (62)

[0784]

[0785] Step 1: Synthesis of 3,8-dimethoxy-6H-benzo[c]thiochromene (60)

[0786]

[0787] 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 at room temperature overnight. Workup: 10 ml of Et 2 O, followed by 0.05 ml of MeOH, 0.025 ml of NaOH 1N, and then 3 drops of water, and stirring was continued for 15 minutes. 2 SO 4 The reaction mixture was filtered off and concentrated under vacuum. The crude material was dissolved in DCM (5 ml) and cooled to -78 °C, TFA (0.354 mL, 4.59 mmol) was added dropwise and stirred at -78 °C for 60 minutes, then EtSi was added. 3 H (0.290 ml, 1.84 mmol) and the reaction was allowed to warm to room temperature overnight. 2 CO 3 The saturated solution was washed and the organic layer was dried over sodium sulfate and concentrated under vacuum to give 230 mg of crude material which was dissolved in Et 2 Trituration in 0 afforded 3,8-dimethoxy-6H-benzo[c]thiochromene (160 mg, 67%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )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).

[0788] Step 2: Synthesis of 3,8-dimethoxy-6H-benzo[c]thiochromene 5,5-dioxide (61)

[0789]

[0790] 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 hours. 2 S 2 O 3The solution was added to the reaction mixture. The aqueous phase was extracted with EtOAc, and the organic phase was washed twice with a saturated solution of bicarbonate. The organic phase was dried over sodium sulfate. The organic phase was concentrated under vacuum and filtered through a celite pad using EtOAc, then concentrated to give 3,8-dimethoxy-6H-benzo[c]thiochromene 5,5-dioxide (66 mg, 73%) as a slightly yellow solid. 1 H NMR (400 MHz, CDCl 3 )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), 7.0 1 (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).

[0791] Step 3: Synthesis of 3,8-dihydroxy-6H-benzo[c]thiochromene 5,5-dioxide (62)

[0792]

[0793] BBr was heated at -70 °C 3 3,8-dimethoxy-6H-benzo[c]thiochromene 5,5-dioxide (55 mg, 0.19 mmol) (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, and the mixture was allowed to warm to room temperature overnight. TLC showed 2 spots. Methanol was added to the mixture at 0°C, concentrated under vacuum and loaded on silica, then analyzed by MPLC (SiO 2 , MeOH / DCM 0% to 8%) to give 3,8-dihydroxy-6H-benzo[c]thiochromene 5,5-dioxide (23 mg, 46%) as a slightly yellow solid. 1 H 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).

[0794] Synthesis of 3,8-dihydroxy-6H-benzo[c]thiochromene 5-oxide (64)

[0795]

[0796] Step 1: Synthesis of 6H-benzo[c]thiochromene-3,8-diol (63)

[0797]

[0798] At 0°C, BBr 3 (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 and allowed to warm to room temperature overnight. The reaction mixture was poured into methanol at 0°C and stirred for 10 minutes, then the solvent was evaporated under vacuum. The crude material was filtered through a pad of celite to give 6H-benzo[c]thiochromene-3,8-diol (40 mg, 64%) as a grey solid. 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).

[0799] Step 2: 3,8-Dihydroxy-6H-benzo[c]thiochromene 5-oxide (64) Synthesis

[0800]

[0801] A solution of NaIO4 (26 mg 0.12 mmol) in 0.3 mL of water was added to a solution of 6H-benzo[c]thiochromene-3,8-diol (28 mg, 0.12 mmol) in 1.5 mL of MeOH at room temperature, and the mixture was stirred overnight. A precipitate was formed. TLC showed that the starting material was still present. Therefore, 0.2 equivalents of NaIO4 dissolved in 0.2 mL of water was added. 4 and continued stirring; the reaction was incomplete but stopped. DCM was added to dissolve the precipitate, and the crude material was loaded on silica and analyzed by MPLC (SiO 2 , MeOH / DCM 0% to 8%) to give 3,8-dihydroxy-6H-benzo[c]thiochromene 5-oxide (16 mg, 53%) as a grey solid. f =0.3 (MeOH / DCM 5%). 1H 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).

[0802] 1) Ester "A" group having dicyclopentane substitution

[0803] Synthesis of 3-hydroxy-8-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-6H-benzo[c]chromen-6-one (65)

[0804]

[0805] 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

[0806]

[0807] To a cooled -78 °C 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 was carefully added tert-butyl lithium (1.7 M in pentane, 0.95 ml, 1.63 mmol) dropwise. The reaction mixture was stirred at -78 °C for 60 min. 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 min. 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 N2 atmosphere. The reaction vessel was sealed and heated at 60°C for 12 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was adsorbed on SiO2. The product was analyzed by MPLC (SiO 2 , 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 (500 MHz, CDCl 3)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), 6.9 9 (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).

[0808] Step 2: Synthesis of 3-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)bicyclo[1.1.1]pentane-1-carboxylic acid

[0809]

[0810] 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 6M HCl was heated at 100°C in a sealed tube overnight. The reaction mixture was cooled to room temperature, then filtered and washed with water and dried under high vacuum. The crude material was purified by FC eluent 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 massless TLC / MS 413. R 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).

[0811] Step 3: Synthesis of 3-(benzyloxy)-8-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-6H-benzo[c]chromen-6-one

[0812]

[0813] Borane dimethyl sulfide complex (0.22 ml, 0.44 mmol, 2M 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 from 0°C to room temperature for 2 hours. MeOH was added and the crude material was loaded on silica and purified by FC eluent 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 (47 mg, 0.12 mmol, 81%) as a beige solid. f =0.6 (MeOH / DCM 5%). 1 H NMR (400 MHz, CDCl 3 )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).

[0814] Step 4: Synthesis of 3-hydroxy-8-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-6H-benzo[c]chromen-6-one

[0815]

[0816] 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 3 ml of MeOH and 1 ml of DCM. PtO was added. 2 (6.4 mg, 0.023 mmol) and the mixture was hydrogenated at atmospheric pressure for 5 hours. The reaction mixture was filtered through a pad of celite and concentrated under vacuum. The crude material was purified by FC MeOH / DCM 0% to 10% to give 3-hydroxy-8-(3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl)-6H-benzo[c]chromene-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).

[0817] 2. Synthesis of 7-membered urolithin A analogs

[0818] A) Lactone and Ether "A" Group Analogs

[0819] Synthesis of 3,9-dihydroxydibenzo[c,e]oxepin-5(7H)-one (66)

[0820]

[0821] Step 1: Synthesis of 2-bromo-5-methoxybenzoate

[0822]

[0823] 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 was continued at 0° C. for 10 min, and then SOCl was added dropwise via a dropping funnel. 2 The reaction mixture was stirred overnight at 4 ℃ for 1 hr at 4 ℃ for 2 hours. The reaction mixture was stirred overnight ...

[0824] Step 2: Synthesis of dimethyl 4,4′-dimethoxy-[1,1′-biphenyl]-2,2′-dicarboxylate

[0825]

[0826] 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 go. Subsequently, the reaction mixture was heated to 150 ° C overnight. After overnight stirring, the reactant was cooled to room temperature and diluted with a large amount of water and extracted with ether (3x100 mL). The combined organic layer was washed with water and brine, and the mixture was purified by Na 2 SO 4 Dry, filter through silica and concentrate in vacuo. 2 The crude product was purified by HPLC-MS / MS (5% by volume, 5% by volume, 4% by volume, 0% to 30% by volume, 330 g, EtOAc in Hex 0%-30%) to give dimethyl 4,4'-dimethoxy-[1,1'-biphenyl]-2,2'-dicarboxylate (7.5 g, 23 mmol, 91%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) 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).

[0827] Step 3: Synthesis of 4,4′-dimethoxy-[1,1′-biphenyl]-2,2′-dicarboxylic acid

[0828]

[0829] 4,4'-dimethoxy-[1,1'-biphenyl]-2,2'-dimethyl dicarboxylate (7.5 g, 23 mmol, 1.0 equiv) was dissolved in MeOH (90 mL) and 2M NaOH aqueous solution (57 mL, 110 mmol, 5.0 equiv) was added dropwise via an addition funnel. The reactants were refluxed over the weekend and then allowed to cool to room temperature before the reaction mixture was concentrated under vacuum. The remaining organic layer was slightly diluted with water and washed with DCM to remove all organic impurities. The layers were separated and the aqueous layer was transferred to a conical flask and washed with 2M KHSO under stirring. 4 Acidify to pH 1. 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) δ 12.43 (s, 2H), 7.33 (d, J = 2.6Hz, 2H), 7.14-7.01 (m, 4H), 3.82 (s, 6H).

[0830] Step 4: Synthesis of 3,9-dimethoxydibenzo[c,e]oxazepine-5,7-dione

[0831]

[0832] 4,4′-dimethoxy-[1,1′-biphenyl]-2,2′-dicarboxylic acid (2.60 g, 10.1 mmol, 1.0 equiv) was suspended in Ac 2 O (50mL), and the suspension was stirred overnight. The reaction was monitored by LCMS, and after stirring overnight, the starting material disappeared completely. The reaction mixture was then filtered and washed with ether to facilitate drying. The filter cake was dried under high vacuum to give 3,9-dimethoxydibenzo[c,e]oxazepine-5,7-dione (2.87 g, 10.1 mmol, 99%). NMR was consistent with that reported in the literature.

[0833] Step 5: Synthesis of 3,9-dimethoxydibenzo[c,e]oxazepine-5(7H)-one

[0834]

[0835] 3,9-Dimethoxydibenzo[c,e]oxazepine-5,7-dione (150 mg, 0.530 mmol, 1.0 equiv) was suspended in DMF (5 mL) and cooled to 0 °C, followed by the slow addition of sodium borohydride (20 mg, 0.53 mmol, 1.0 equiv). After 2 hours, the reaction mixture was poured into aqueous HCl (6 M, 5 mL), which was then diluted with water (10 mL) and stirred overnight. The product was precipitated overnight and filtered, then dissolved in DCM (25 mL) and washed with water (3 x 10 mL). The organic layer was washed with anhydrous Na 2 SO 4 Dry, filter, concentrate in vacuo, filter through basic alumina with DCM, and dry to give 3,9-dimethoxydibenzo[c,e]oxepin-5(7H)-one (85 mg, 0.31 mmol, 60%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )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).

[0836] Step 5: Synthesis of 3,9-dihydroxydibenzo[c,e]oxazepine-5(7H)-one

[0837]

[0838] 3,9-Dimethoxydibenzo[c,e]oxepin-5(7H)-one (75 mg, 0.28 mmol, 1.0 eq.) was dissolved in DCM (6 mL) and cooled to 0°C in an ice bath and stirred for 5 minutes. 3 (0.83 ml, 1 M in DCM, 0.83 mmol, 3.00 equiv) was added dropwise to the reaction mixture. After the addition was complete, the mixture was left in an ice bath and allowed to warm to room temperature over the course of 2 hours. When the starting material could no longer be observed, the reaction mixture was added dropwise to 0 ° C cold methanol (10 mL) and stirred for another 10 minutes. The mixture was then concentrated and supported on silica to be purified by flash column chromatography (SiO 2 , 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).

[0839] Synthesis of 5,7-dihydrodibenzo[c,e]oxazepine-3,9-diol (67)

[0840]

[0841] Step 1: Synthesis of 3,9-bis((tert-butyldimethylsilyl)oxy)dibenzo[c,e]oxazol-5(7H)-one

[0842]

[0843] TBSCl (174 mg, 1.15 mmol, 2.2 eq) was dissolved in DCM (9 mL), and the resulting solution was cooled to 0 ° C in an ice bath and stirred for 5 minutes. Imidazole (89 mg, 1.3 mmol, 2.5 eq) was then added slowly in batches, and stirring continued for 15 minutes after the addition was complete. 3,9-dihydroxydibenzo[c,e]oxazolidinone-5(7H)-one (127 mg, 0.520 mmol, 1.0 eq) was subsequently added to the reaction mixture, which became uneven after the addition of the substrate. DMF (1 mL) was therefore added to homogenize the mixture. Stirring was continued overnight at room temperature, and then DCM was removed in a rotary evaporator, and the remaining DMF solution was quenched with a large amount of water and extracted with ether (3x10 mL). The combined organic layers were washed with water and brine, and the mixture was purified by anhydrous Na 2 SO 4 Drying, filtration and concentration gave a crude product which was analyzed by MPLC (SiO 2 , 40 g, EtOAc in Hex 0%-20%) to give 3,9-bis((tert-butyldimethylsilyl)oxy)dibenzo[c,e]oxepin-5(7H)-one (199 mg, 0.42 mmol 82%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ7.47-7.38 (m, 3H), 7.10 (dd, J=8.6, 2.6Hz, 1H), 6.97 (dd, J=8.4, 2.6Hz, 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).

[0844] Step 2: Synthesis of 3,9-bis((tert-butyldimethylsilyl)oxy)-5,7-dihydrodibenzo[c,e]oxepin

[0845]

[0846] 3,9-Bis((tert-butyldimethylsilyl)oxy)dibenzo[c,e]oxepin-5(7H)-one (200 mg, 0.430 mmol, 1.0 equiv) was dissolved in toluene (5 mL) and Et 3SiH (0.27ml, 1.7mmol, 4.0 equivalents). The reaction mixture was heated to 70 ° C in a preheated oil bath. After stirring at 70 ° C for 5 minutes, InBr3 (15mg, 0.04mmol, 0.10 equivalents) was added at once. A rapid color change to orange and gas evolution was observed, and stirring was continued for 1 hour, and TLC did not show any more starting material. The reaction mixture was cooled, filtered and washed with DCM. The filtrate was supported on silica and filtered by flash column chromatography (SiO 2 The crude material was purified by HPLC-MS / MS (20% HPLC-MS / MS, 25 g, DCM in Hex 0%-10%) to afford 3,9-bis((tert-butyldimethylsilyl)oxy)-5,7-dihydrodibenzo[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).

[0847] Step 3: Synthesis of 5,7-dihydrodibenzo[c,e]oxazepine-3,9-diol

[0848]

[0849] 3,9-bis((tert-butyldimethylsilyl)oxy)-5,7-dihydrodibenzo[c,e]oxazepine (194 mg, 0.430 mmol, 1.0 equiv) was dissolved in MeOH (12 mL), and the reaction mixture was cooled to 0 °C, and AcCl (167 mg, 2.12 mmol, 5.0 equiv) was added dropwise via a syringe. After the addition was complete, the reaction mixture was allowed to reach room temperature and stirring was continued over the weekend. The reaction was quenched with water and extracted into ether (3x15 mL), and the combined organic layers were washed with NaHCO 3 and brine, and washed with Na 2 SO 4 Drying and filtering through silica, washing with ether, and concentration afforded 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).

[0850] B) Amine "A" Group Analogs

[0851] 6-Methyl-6,7-dihydro-5H-dibenzo[c _ Synthesis of e]azepine-3,9-diol (68)

[0852]

[0853] Step 1: Synthesis of 4,4′-dimethoxy-2′-(methylcarbamoyl)-[1,1′-biphenyl]-2-carboxylic acid

[0854]

[0855] 3,9-Dimethoxydibenzo[c,e]oxepin-5,7-dione (569 mg, 2.00 mmol, 1.0 equiv) was dissolved in CHCl 3 (20 mL), and to the resulting solution was added 2 M MeNH 2 Solution (1.20mL, 2.40mmol, 1.2 equivalents). After adding MeNH2, a precipitate is formed, and the complete disappearance of the starting material can be observed by LCMS. The precipitate is filtered through a glass frit (Por.4), and the filter residue is dried under vacuum to obtain pure 4,4'-dimethoxy-2'-(methylcarbamoyl)-[1,1'-biphenyl]-2-carboxylic acid (631mg, 2.00mmol, 99%) as a light brown solid. LCMS shows a clean product, which is further used in the next step.

[0856] Step 2: Synthesis of 3,9-dimethoxy-6-methyl-5H-dibenzo[c,e]azepine-5,7(6H)-dione

[0857]

[0858] 4,4′-dimethoxy-2′-(methylaminocarbonyl)-[1,1′-biphenyl]-2-carboxylic acid (631 mg, 2.00 mmol, 1.00 equiv) was suspended in Ac 2 O (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, so the suspension was filtered and the residue 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 (400 MHz, CDCl 3) 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).

[0859] Step 3: Synthesis of 3,9-dimethoxy-6-methyl-6,7-dihydro-5H-dibenzo[c,e]azepine

[0860]

[0861] 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 BH2O was added dropwise over the course of 5 min at room temperature. 3 *THF (7.28 mL, 7.28 mmol, 1 M, 4.0 equiv.). After the addition was complete, the reaction was heated to reflux and stirred overnight. Afterwards, the reaction was quenched with MeOH (200 mL) and stirred at 50 °C for 30 min. The volatiles were then evaporated and analyzed by MPLC (SiO 2 The crude material was purified by HPLC-MS / MS (5% ethanol, 40 g, MeOH in EtOAc 0%-50%) to give 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 (400 MHz, CDCl 3 ) 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).

[0862] Step 4: Synthesis of 6-methyl-6,7-dihydro-5H-dibenzo[c,e]azepine-3,9-diol

[0863]

[0864] 3,9-Dimethoxy-6-methyl-6,7-dihydro-5H-dibenzo[c,e]azepine (376 mg, 1.40 mmol, 1.0 eq) was dissolved in DCM (10 mL) and cooled to 0°C in an ice bath and stirring was continued for 5 minutes. 3(6.28 ml, 1 M in DCM, 6.28 mmol, 4.5 equiv) was added dropwise to the reaction mixture. After the addition was complete, the mixture was left in an ice bath and allowed to warm to room temperature over the course of 2 hours. When the starting material could no longer be observed, the reaction mixture was added dropwise to 0 ° C cold methanol (10 mL) and stirred for another 10 minutes. The mixture was then concentrated and loaded on silica to be purified by flash column chromatography (SiO 2 , 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 a light orange solid. 1 H NMR (400MHz, DMSO) δ 10.92-10.62 (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).

[0865] Synthesis of 2,2'-bis(bromomethyl)-4,4'-dimethoxy-1,1'-biphenyl as a common intermediate

[0866] Step 1: Synthesis of (4,4′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)dimethanol

[0867]

[0868] LiAlH 4 (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) and then refluxed for 4 hours (reaction monitored by TLC). After Fieser work-up, 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 (400 MHz, CDCl 3 ) 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).

[0869] Step 2: Synthesis of 2,2′-bis(bromomethyl)-4,4′-dimethoxy-1,1′-biphenyl

[0870]

[0871] To (4,4′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)dimethanol (0.800 g, 2.92 mmol) and CBr cooled to 0° C. under an argon atmosphere was added. 4 (4.84 g, 14.6 mmol) in CH 2 Cl 2 PPh was added in batches to the solution (40 mL) 3 (3.06 g, 11.7 mmol) in CH2Cl2 (20 mL). 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 (400 MHz, CDCl 3 ) 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).

[0872] Synthesis of 6-cyclobutyl-6,7-dihydro-5H-dibenzo[c,e]azepine-3,9-diol (69)

[0873]

[0874] Step 1: Synthesis of 6-cyclobutyl-3,9-dimethoxy-6,7-dihydro-5H-dibenzo[c,e]azepine

[0875]

[0876] 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 off and the solvent was removed under vacuum 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 (EtOAc). 1 HNMR (400 MHz, CDCl 3)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=8.0 Hz, 1H), 2.21-2.12 (m, 2H), 2.05 (d, J=9.6Hz, 2H), 1.82-1.65 (m, 2H).

[0877] Step 2: Synthesis of 6-cyclobutyl-6,7-dihydro-5H-dibenzo[c,e]azepine-3,9-diol

[0878]

[0879] At 0°C, BBr 3 (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 3 ml of anhydrous DCM 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 flash chromatography on silica gel (methanol / DCM: 0% to 10%) to give 6-cyclobutyl-6,7-dihydro-5H-dibenzo[c,e]azepine-3,9-diol hydrobromide (35 mg, 0.97 mmol, 33%) as a beige solid. 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).

[0880] Synthesis of 6-isopropyl-6,7-dihydro-5H-dibenzo[c,e]azepine-3,9-diol (70)

[0881]

[0882] Step 1: Synthesis of 6-isopropyl-3,9-dimethoxy-6,7-dihydro-5H-dibenzo[c,e]azepine

[0883]

[0884] 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 hours. The reaction mixture was filtered off and the solvent was removed under vacuum to give 6-isopropyl-3,9-dimethoxy-6,7-dihydro-5H-dibenzo[c,e]azepine (110 mg, 0.323 mmol, 99%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 )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).

[0885] Step 2: Synthesis of 6-isopropyl-6,7-dihydro-5H-dibenzo[c,e]azepine-3,9-diol

[0886]

[0887] At 0°C, BBr 3 (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 3 ml of anhydrous DCM 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 flash chromatography on silica gel (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. f =0.3 (MeOH / DCM 8%). 1 H 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).

[0888] C) Imide "A" Group Analogs

[0889] Synthesis of 3,9-dihydroxy-5H-dibenzo[c,e]azepine-5,7(6H)-dione (71)

[0890]

[0891] Step 1: Synthesis of 2′-carbamoyl-4,4′-dimethoxy-[1,1′-biphenyl]-2-carboxylic acid

[0892]

[0893] 3,9-dimethoxydibenzo[c,e]oxepin-5,7-dione (100 mg, 0.350 mmol, 1.0 equivalent) was suspended in 25% NH 3 The mixture was stirred for 30 minutes in an aqueous solution (0.70 mL, 0.42 mmol, 1.2 equivalents) until the complete disappearance of the starting material was confirmed by LCMS (polarity was too high to be monitored by TLC). The reaction mixture was filtered through a glass frit (Por.4), and the filter residue 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 a clean product after filtration, and the product was used in the next step without further purification.

[0894] Step 2: Synthesis of 3,9-dimethoxy-5H-dibenzo[c,e]azepine-5,7(6H)-dione

[0895]

[0896] 2′-Carbamoyl-4,4′-dimethoxy-[1,1′-biphenyl]-2-carboxylic acid (106 mg, 0.350 mmol, 1.0 equivalent) was suspended in A c 2O (4 mL), and KOAc (69 mg, 0.70 mmol, 2.0 equiv) was added in one portion. The reaction mixture was stirred at room temperature overnight before being filtered through a small glass frit (Por. 4). The precipitate was dried under vacuum 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) δ 11.69 (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).

[0897] Step 3: Synthesis of 3,9-dihydroxy-5H-dibenzo[c,e]azepine-5,7(6H)-dione

[0898]

[0899] 3,9-Dimethoxy-5H-dibenzo[c,e]azepine-5,7(6H)-dione (100 mg, 0.350 mmol, 1.0 eq.) was dissolved in DCM (2 mL) and cooled to 0°C in an ice bath and stirred for 5 minutes. 3 (1.41 ml, 1 M in DCM, 1.41 mmol, 4.0 equiv) was added dropwise to the reaction mixture. After the addition was complete, the mixture was left in an ice bath and allowed to warm to room temperature over the course of 2 hours. When the starting material could no longer be observed, the reaction mixture was added dropwise to 0 ° C cold methanol (10 mL) and stirred for another 10 minutes. The mixture was then concentrated and supported on silica to be purified by flash column chromatography (SiO 2 , 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. 1 H 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).

[0900] D) Thioether and Sulfone "A" Group Analogs

[0901] Synthesis of 5,7-dihydrodibenzo[c,e]thiazol-3,9-diol (72)

[0902] Step 1: Synthesis of 3,9-dimethoxy-5,7-dihydrodibenzo[c,e]thiazepine

[0903]

[0904] A mixture of 2,2'-bis(bromomethyl)-4,4'-dimethoxy-1,1'-biphenyl (procedure 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 minutes. After cooling, the mixture was poured into water (10 mL), and the precipitate was filtered and washed with water (2 x 3 mL). The precipitate was dissolved in CHCl 3 (15 mL), and the solution was added with Na 2 SO 4Drying and evaporation of the solvent in vacuo gave 3,9-dimethoxy-5,7-dihydrodibenzo[c,e]thiazepine (140 mg, 0.510 mmol, 93%) as a slightly yellow solid. 1 H NMR (400 MHz, CDCl 3 ) 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).

[0905] Step 2: Synthesis of 5,7-dihydrodibenzo[c,e]thiazol-3,9-diol

[0906]

[0907] BBr was heated at -78 °C 3 Solution (0.59 ml, 0.59 mmol, 1 M in DCM) was added to a solution of 3,9-dimethoxy-5,7-dihydrodibenzo[c,e]thiazepine (54 mg, 0.20 mmol) in DCM 2 ml and stirring was continued at room temperature overnight. Methanol (5 ml) was added at 0°C and the solvent was removed in vacuo. The results were analyzed by MPLC (SiO 2 The crude material was purified by HPLC (0.1% to 8% MeOH / DCM) to afford 5,7-dihydrodibenzo[c,e]thiazepine-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).

[0908] Synthesis of 3,9-dihydroxy-5,7-dihydrodibenzo[c,e]thiazol 6,6-dioxide (73)

[0909]

[0910] Step 1: Synthesis of 3,9-dimethoxy-5,7-dihydrodibenzo[c,e]thiazol 6,6-dioxide

[0911]

[0912] MCPBA (170 mg, 0.690 mmol) was added to 3,9-dimethoxy-5,7-dihydrodibenzo[c,e]thiazepine (90 mg, 0.33 mmol) in DCM (2 ml) at 0°C and the reaction mixture was stirred at room temperature overnight. Na2S was added 2 O 3 1 M solution, and the mixture was stirred for 10 min, then NaHCO 3 Saturated solution with NaHCO 3 The mixture was extracted twice with saturated solution. The organic phase was dried over sodium sulfate, filtered and evaporated under vacuum. 2 The crude material was purified by HPLC-MS / MS (5% ethanol, EtOAc / cyclohexane 0% to 30%) to give 3,9-dimethoxy-5,7-dihydrodibenzo[c,e]thiazepine 6,6-dioxide (90 mg, 0.30 mmol, 89%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) 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).

[0913] Step 2: Synthesis of 3,9-dihydroxy-5,7-dihydrodibenzo[c,e]thiazol 6,6-dioxide

[0914]

[0915] At 0°C, BBr 3 Solution (1.0 ml, 1.0 mmol, 1 M in DCM, 3.5 eq) was added to a solution of 3,9-dimethoxy-5,7-dihydrodibenzo[c,e]thiazol 6,6-dioxide (90 mg, 0.30 mmol, 1.0 eq) in DCM (2 mL) and stirring was continued at room temperature overnight. Methanol (5 mL) was added at 0 °C and the solvent was removed in vacuo. The crude material was purified by MPLC (EtOAc / Hex 0% to 70%) to give 3,9-dihydroxy-5,7-dihydrodibenzo[c,e]thiazol 6,6-dioxide (46 mg, 0.17 mmol, 56%) as a beige solid. f =0.3 (MeOH / DCM 5%). 1 H 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)

[0916] E) Amide "A" Group Analogs

[0917] Synthesis of 3,9-dihydroxy-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one (74)

[0918]

[0919] Step 1: Synthesis of 2-(azidomethyl)-1-bromo-4-methoxybenzene

[0920]

[0921] 1-Bromo-2-(bromomethyl)-4-methoxybenzene (5.00 g, 17.9 mmol, 1.0 equiv) was dissolved in DMF (60 mL) and NaN was added in one portion. 3 (5.81 g, 89.3 mmol, 5.0 equiv.). The reaction mixture was then heated to 90 °C and continued to stir overnight. After overnight stirring, the reaction mixture was cooled to room temperature, quenched with water (300 mL), and extracted with cyclohexane (3 x 75 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Drying and concentration in vacuo gave pure 2-(azidomethyl)-1-bromo-4-methoxybenzene (4.32 g, 17.8 mmol, 99%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) 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).

[0922] Step 2: Synthesis of 5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

[0923]

[0924] Methyl 2-bromo-5-methoxybenzoate (10.0, 40.8 mmol, 1.0 equiv) was dissolved in 1,4-dioxane (140 mL). To this solution was added B 2 pin 2 (11.4 g, 44.9 mmol, 1.1 eq), Pd(dppf)Cl 2 (1.49 g, 2.04 mmol, 0.1 eq) and KOAc (12.0 g, 122 mmol, 3.0 eq), and using N 2The reaction mixture was repeatedly degassed with a balloon for 10 minutes, after which the reaction mixture was placed in an oil bath preheated to 85°C and stirred overnight. After complete consumption of the starting material, the reaction mixture was cooled to room temperature and then quenched with water. The layers were separated and the aqueous phase was extracted with ethyl acetate (2x100 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry and concentrate under vacuum. 2 The crude product was purified by HPLC-MS / MS (5% ethanol, 240 g, EtOAc in Hex 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 light yellow oil. 1 H NMR (400 MHz, CDCl 3 ) 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).

[0925] Step 3: Synthesis of (4-methoxy-2-(methoxycarbonyl)phenyl)boronic acid

[0926]

[0927] 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 NH 4 OAc (1.05 g, 13.7 mmol, 3.0 equiv) and NaIO 4 4-(4-methoxy-2-(methoxycarbonyl)phenyl)boronic acid (590mg, 2.81mmol, 62%) was obtained.

[0928] Step 4: Synthesis of 2′-(azidomethyl)-4,4′-dimethoxy-[1,1′-biphenyl]-2-carboxylate

[0929]

[0930] 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) 2 (27 mg, 0.12 mmol, 0.05 eq.), XPhos (116 mg, 0.24 mmol, 0.1 eq.), and all reagents were dissolved in THF (15 mL). 2 The reaction mixture was degassed with a balloon for 10 min, and then Na 2 CO 3 (775mg, 7.31mmol, 3.0 equivalents) in water (5mL). After completion of the addition, the reaction mixture was heated to 80 ° C in an oil bath and continued to stir overnight. After overnight stirring, 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 (2x10mL). The combined organic layer was washed with anhydrous Na 2 SO 4 Dry and concentrate under vacuum. 2 The crude product was purified by HPLC-MS / MS (20% RH, 25 g, EtOAc in Hex 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 (400 MHz, CDCl 3 )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).

[0931] Step 5: Synthesis of 3,9-dimethoxy-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one

[0932]

[0933] 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 eq.) and NaOMe (33 mg, 0.15 mmol, 1.0 eq.) were added to the solution, and the solution was heated with N 2 Degassing three times followed by hydrogen atmosphere exchange three times. The reaction mixture was stirred at room temperature overnight and then filtered through a celite pad and analyzed by MPLC (SiO 2 , EtOAc in Hex 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).

[0934] Step 6: Synthesis of 3,9-dihydroxy-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one

[0935]

[0936] 3,9-Dimethoxy-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one (64 mg, 0.24 mmol, 1.0 eq.) was dissolved in DCM (2 mL) and cooled to 0°C in an ice bath and stirred for 5 minutes. 3 ) (0.95 ml, 1 M in DCM, 0.95 mmol, 4.0 equiv) was added dropwise to the reaction mixture. After the addition was complete, the mixture was left in an ice bath and allowed to warm to room temperature over the course of 2 hours. When the starting material could no longer be observed, the reaction mixture was added dropwise to 0 ° C cold methanol (10 mL) and stirred for an additional 10 minutes. The mixture was then concentrated and supported on silica to be purified by flash column chromatography (SiO 2 , 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. 1H 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).

[0937] Synthesis of 3,9-dihydroxy-6-methyl-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one (75)

[0938]

[0939] Step 1: Synthesis of 3,9-dimethoxy-6-methyl-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one

[0940]

[0941] 3,9-Dimethoxy-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one (80 mg, 0.30 mmol, 1.0 equiv) was dissolved in DMF (3.0 mL) and the solution was cooled to 0 °C in an ice bath and continued to stir for 10 minutes before adding 60% NaH in petroleum (14 mg, 0.36 mmol, 1.2 equiv) in one portion. The reaction was stirred until hydrogen evolution completely ceased, at which time MeI (0.13 g, 0.89 mmol, 3.0 equiv) was added dropwise. The reaction was then allowed to warm to room temperature and stirred for 3 hours until the starting material disappeared (as indicated by TLC). The reaction was quenched with ice water (10 mL), and the aqueous solution was extracted with ether (3x10 mL), and the organic layer was washed with water and brine, and the reaction mixture was purified by Na 2 SO 4 Drying and concentration gave 3,9-dimethoxy-6-methyl-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one (84 g, 0.30 mmol, 99%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ7.35 (dd, J=16.3, 8,4Hz, 2H), 7.14 (d, J=2.7Hz, 1H), 6.96 (dd, J=8.5, 2.7Hz, 1 H), 6.90-6.81(m, 2H), 4.10-3.75(m, 2H), 3.10(s, 3H), 3.00(s, 3H), 2.90(s, 3H).

[0942] Step 2: Synthesis of 3,9-dihydroxy-6-methyl-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one

[0943]

[0944] 3,9-Dimethoxy-6-methyl-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one (84 mg, 0.84 mmol, 1.0 eq.) was dissolved in DCM (1 mL) and cooled to 0°C in an ice bath and stirred for 5 minutes. 3 (1.20 ml, 1 M in DCM, 1.20 mmol, 4.0 equiv) was added dropwise to the reaction mixture. After the addition was complete, the mixture was left in an ice bath and allowed to warm to room temperature over the course of 2 hours. When the starting material could no longer be observed, the reaction mixture was added dropwise to 0 ° C cold methanol (10 mL) and stirred for an additional 10 minutes. The mixture was then concentrated and supported on silica to be purified by flash column chromatography (SiO 2 , 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 light 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).

[0945] Synthesis of 3,9-dihydroxy-5,7-dihydro-6H-dibenzo[b,d]azepin-6-one (76)

[0946]

[0947] Step 1: Synthesis of 2-(2-bromo-5-methoxyphenyl)acetic acid

[0948]

[0949] Bromine (1.92 g, 12.0 mmol, 1.0 equiv) was added dropwise to a solution of 3-methoxyphenyl)acetic acid (2.00 g, 12.0 mmol, 1.0 equiv) in DCM (40 mL) at 0 °C. After the bromine addition was complete, 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 into DCM (2 x 25 mL) and the combined organic layers were purified by Na 2 SO 4 Drying, filtration, and evaporation to dryness gave 2-(2-bromo-5-methoxyphenyl)acetic acid (2.80 g, 11.0 mmol, 95%) as a light red solid.

[0950] 1 H NMR (400 MHz, CDCl 3 ) 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).

[0951] Step 2: Synthesis of 2-(2-bromo-5-methoxyphenyl)acetate

[0952]

[0953] 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 hours before being cooled to room temperature, quenched with water and extracted into ethyl acetate (3 x 100 mL). The organic layer was washed with saturated sodium bicarbonate solution and brine and washed with Na 2 SO 4 Dry and concentrate under vacuum. 2 The crude product was purified by HPLC-MS / MS (50% by weight, 240 g, EtOAc in Hex 0%-20%) to give methyl 2-(2-bromo-5-methoxyphenyl)acetate (6.44 g, 24.9 mmol, 92%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) 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).

[0954] Step 3: Synthesis of 2-(5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

[0955]

[0956] Methyl 2-(2-bromo-5-methoxyphenyl)acetate (2.00 g, 7.72 mmol, 1.0 equivalent) was dissolved in 1,4-dioxane (150 mL), and B was added thereto. 2 pin 2 (3.53 g, 13.9 mmol, 1.8 equiv), Pd(PPh 3 ) 2 Cl 2 (542 mg, 0.770 mmol, 0.1 eq) and KOAc (3.03 g, 30.9 mmol, 4.0 eq). 2 The resulting reaction mixture was degassed with a balloon for 10 minutes before being placed in a preheated oil bath at 100 °C overnight. After stirring overnight, the mixture was cooled to room temperature and heated with saturated NH 4 The solution was quenched with aqueous Cl solution and extracted into ethyl acetate (3x75 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry, concentrate under vacuum and analyze by MPLC (SiO 2 The crude material was purified by HPLC-MS / MS (50% RH, 120 g, EtOAc in Hex 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 (400 MHz, CDCl 3 ) 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).

[0957] Step 4: Synthesis of 2-(4,4′-dimethoxy-2′-nitro-[1,1′-biphenyl]-2-yl)acetate

[0958]

[0959] 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 eq.) and 1-iodo-4-methoxy-2-nitrobenzene (733 mg, 2.63 mmol, 1.2 eq.) were dissolved in THF (2 mL), and Pd was added to the solution. 2 dba 3 (100 mg, 0.110 mmol, 0.05 eq) and tBuXPhos (93 mg, 0.22 mmol, 0.1 eq). 2 The resulting mixture was degassed with a balloon for 10 min, after which Na 2 CO 3 (696 mg, 6.56 mmol, 3.0 equiv) in water (4 mL). The reaction mixture was then heated to 60 °C overnight (until the starting material disappeared completely on TLC), then allowed to cool to room temperature and washed with saturated NH 4 The mixture was quenched with aqueous Cl solution, extracted with ethyl acetate (3 x 50 mL), and washed with anhydrous Na 2 SO 4 Dry and concentrate under vacuum. 2 The resulting crude material was purified by HPLC-MS / MS (50% RH, 40 g, EtOAc in Hex 0%-35%) to afford 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 (400 MHz, CDCl 3 )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).

[0960] Step 5: Synthesis of 3,9-dimethoxy-5,7-dihydro-6H-dibenzo[b,d]azepin-6-one

[0961]

[0962] Methyl 2-(4,4′-dimethoxy-2′-nitro-[1,1′-biphenyl]-2-yl)acetate (485 mg, 1.46 mmol, 1.0 equiv) was dissolved in H 2O (3mL), AcOH (2mL) and EtOH (3mL), and powdered Fe (818mg, 14.6mmol, 10.0equiv) was added to the mixture, which was stirred for 2 hours until TLC showed no more starting material. The reaction mixture was then filtered through a celite pad and concentrated under reduced pressure (AcOH was removed by azeotropic distillation with cyclohexane) and analyzed by MPLC (SiO 2 , 40 g, EtOAc in Hex 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).

[0963] Step 6: Synthesis of 3,9-dihydroxy-5,7-dihydro-6H-dibenzo[b,d]azepin-6-one

[0964]

[0965] 3,9-Dimethoxy-5,7-dihydro-6H-dibenzo[b,d]azepin-6-one (70 mg, 0.26 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 minutes. 3 (1.30 ml, 1 M in DCM, 1.30 mmol, 5.0 equiv) was added dropwise to the reaction mixture. After the addition was complete, the mixture was left in an ice bath and allowed to warm to room temperature over the course of 2 hours. When the starting material could no longer be observed, the reaction mixture was added dropwise to 0 ° C cold methanol (10 mL) and stirred for another 10 minutes. The mixture was then concentrated and supported on silica to be purified by flash column chromatography (SiO 2 , 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 light yellow solid. 1H 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).

[0966] Synthesis of 3,9-dihydroxy-5-methyl-5-7-dihydro-6H-dibenzo[b,d]azepin-6-one (77)

[0967]

[0968] Step 1: Synthesis of 3,9-dimethoxy-5-methyl-5,7-dihydro-6H-dibenzo[b,d]azepin-6-one

[0969]

[0970] 3,9-dimethoxy-5,7-dihydro-6H-dibenzo[b,d]azepin-6-one (85 mg, 0.32 mmol, 1.0 equiv) was dissolved in DMF (3.2 mL) and the solution was cooled to 0 °C in an ice bath and continued to stir for 10 minutes before adding 60% NaH in petroleum (14 mg, 0.36 mmol, 1.2 equiv) in one portion. The reaction was stirred until hydrogen evolution completely ceased, at which time MeI (0.060 g, 0.38 mmol, 1.2 equiv) was added dropwise. The reaction was then allowed to warm to room temperature and stirred for 3 hours until the starting material disappeared (as indicated by TLC). The reaction was quenched with ice water (10 mL), and the aqueous solution was extracted with ether (3x10 mL), and the organic layer was washed with water and brine, and the reaction mixture was purified by Na 2 SO 4 Drying and concentration gave 3,9-dimethoxy-5-methyl-5,7-dihydro-6H-dibenzo[b,d]azepin-6-one (60 mg, 0.21 mmol, 67%) as a light yellow solid. 1 H NMR (400 MHz, CDCl 3 ) 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).

[0971] Step 1: Synthesis of 3,9-dihydroxy-5-methyl-5,7-dihydro-6H-dibenzo[b,d]azepin-6-one

[0972]

[0973] 3,9-Dimethoxy-5,7-dihydro-6H-dibenzo[b,d]azepin-6-one (58 mg, 0.20 mmol, 1.0 eq.) was dissolved in DCM (2 mL) and cooled to 0°C in an ice bath and stirred for 5 minutes. 3 (0.82 ml, 1 M in DCM, 0.82 mmol, 4.0 equiv) was added dropwise to the reaction mixture. After the addition was complete, the mixture was left in an ice bath and allowed to warm to room temperature over the course of 2 hours. When the starting material could no longer be observed, the reaction mixture was added dropwise to 0 ° C cold methanol (10 mL) and stirred for an additional 10 minutes. The mixture was then concentrated and supported on silica to be purified by flash column chromatography (SiO 2 , 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 light 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).

[0974] Compound 77A was prepared by employing the appropriate methyl substituted iodophenyl intermediate in the Pd coupling step of the above synthesis of 76, which provided the methyl substituted analog of 76. The remaining steps were similar to those employed to provide compound 77, i.e., amidomethylation followed by deprotection.

[0975]

[0976] Example 2: Synthesis of Additional Representative Compounds

[0977] Unless otherwise noted, reactions were not carried out under an inert atmosphere and all solvents and commercially available reagents were used as received.

[0978] Purification by chromatography refers to the use of Companion Purification System or Biotage SP1 Purification System. In the case of products purified using an SPE Si II column, the term "Isolute SPE Si column" refers to a pre-packed polypropylene column containing unbonded activated silica having an average particle size of 50 μm and a nominal particle size of 10 μm. Irregular particles with low porosity. The fractions containing the desired product (identified by TLC and / or LCMS analysis) are combined and the organic fraction is recovered by evaporation to give the final product. Where thin layer chromatography (TLC) is used, this refers to silica gel TLC plates, typically 3×6 cm silica gel (e.g. Fluka 60778) on aluminum foil plates with a fluorescent indicator (254 nm). The Biotage Initiator 60 TM Microwave experiments were performed using the Biotage Initiator 60™ using a single mode resonator and dynamic field tuning. Temperatures of 40°C-250°C were achievable and pressures up to 30 bar could be reached.

[0979] NMR spectra were acquired on a Bruker Avance 400 MHz, 5 mm QNP probe H, C, F, P, single Z gradient, dual channel instrument running TopSpin 2.1 or on a Bruker Avance III 400 MHz, 5 mm BBFO Plus probe, single Z gradient, dual channel instrument running TopSpin 3.0.

[0980] Analytical LC-MS conditions

[0981] Method 1: Experiment was performed on a WatersAcquity SQD2 mass spectrometer connected to a Waters Acquity UPLC binary pump / PDA detector. The mass spectrometer has an electrospray source operating in positive and negative ion modes. Additional detection was performed using an Acquity UPLC HSS C18 1.7 μm, 100 x 2.1 mm column and 0.4 mL / min flow rate maintained at 40°C. The initial solvent system for the first 0.4 minutes was 95% water (solvent A) containing 0.1% formic acid and 5% MeCN (solvent B) containing 0.1% formic acid, followed by a gradient of up to 5% solvent A and 95%.

[0982] Method 2: Experiments were performed on a Waters Acquity SQD2 mass spectrometer connected to a Waters Acquity UPLC binary pump / PDA detector. The mass spectrometer had an electrospray source operating in positive and negative ion modes. Additional detection was performed using an Acquity UPLC BEH Shield RP18 1.7 μm 100 x 2.1 mm. The column was maintained at 40°C and the flow rate was 0.4 mL / min. The initial solvent system for the first 0.4 minutes was 95% water (solvent A) containing 0.03% ammonia and 5% MeCN (solvent B) containing 0.03% ammonia, followed by a gradient that reached 5% solvent A and 95% solvent B in the subsequent 5.4 minutes. The final solvent system was kept constant for another 0.8 minutes.

[0983] Method 3: Experiments were performed on a Waters Acquity ZQ mass spectrometer connected to a Waters Acquity UPLC binary pump / PDA detector. The mass spectrometer had an electrospray source operating in positive and negative ion modes. Additional detection was performed using an Acquity UPLC BEHC18 1.7 μm, 100 x 2.1 mm column maintained at 40° C. and a 0.4 mL / min flow rate. The initial solvent system for the first 0.4 minutes was 95% water (solvent A) containing 0.1% formic acid and 5% MeCN (solvent B) containing 0.1% formic acid, followed by a gradient reaching 5% solvent A and 95% solvent B over the next 5.6 minutes. The final solvent system was kept constant for another 0.8 minutes.

[0984] Method 4: Experiments were performed on a Waters Acquity ZQ mass spectrometer connected to a Waters Acquity UPLC binary pump / PDA detector. The mass spectrometer had an electrospray source operating in positive and negative ion modes. Additional detection was performed using an Acquity UPLC BEHC18 1.7 μm, 100 x 2.1 mm column maintained at 40° C. and a flow rate of 0.4 mL / min. The initial solvent system for the first 0.4 minutes was 95% water (solvent A) containing 0.03% ammonia and 5% MeCN (solvent B) containing 0.03% ammonia, followed by a gradient reaching 5% solvent A and 95% solvent B in the next 4 minutes. The final solvent system was kept constant for another 0.8 minutes.

[0985] Method 5: Experiments were performed on a Waters Acquity ZQ mass spectrometer connected to a Waters Acquity H-class UPLC with a DAD detector and QDa. The mass spectrometer had an electrospray source operating in positive and negative ion modes. Additional detection was performed using an Acquity UPLC CSH 1.7 μm, 50 x 2.1 mm column maintained at 40° C. and a 1.0 mL / min flow rate. The initial solvent system for the first 0.4 minutes was 97% water (solvent A) containing 0.1% formic acid and 3% MeCN (solvent B) containing 0.1% formic acid, followed by a gradient reaching 1% solvent A and 99% solvent B in the subsequent 1.4 minutes. The final solvent system was kept constant for another 0.5 minutes.

[0986] Method 6: Experiments were performed on a Waters Acquity ZQ mass spectrometer connected to a Waters Acquity H-class UPLC with a DAD detector and QDa. The mass spectrometer had an electrospray source operating in positive and negative ion modes. Additional detection was performed using an Acquity BEH UPLC 1.7 μm, 50x2.1 mm column maintained at 40° C. and a flow rate of 0.8 mL / min. The initial solvent system for the first 0.4 minutes was 97% of 7.66 mM ammonia in water (solvent A) and 3% of 7.66 mM ammonia in MeCN (solvent B), followed by a gradient of 3% solvent A and 97% solvent B in the subsequent 1.6 minutes. The final solvent system was kept constant for another 0.5 minutes.

[0987] A) Ester "A" Group Analogs

[0988] General Procedure B

[0989] N-(8-Methoxy-6-oxo-6H-benzo[c]chromen-3-yl)methanesulfonamide (79)

[0990]

[0991] GP B1

[0992] 2-Bromo-5-methoxybenzoic acid 3-(methylsulfonamido)phenyl ester (Intermediate 1)

[0993] Oxalyl chloride (0.27mL, 3.06mmol) and 1 drop of DMF were added dropwise to a suspension of 2-bromo-5-methoxybenzoic acid (642mg, 2.78mmol) in DCM (10mL). The solution was stirred at room temperature for 1 hour and the solvent was removed in a vacuum. The resulting mixture was redissolved in DCM (5mL), and a suspension of N-(3-hydroxyphenyl) methanesulfonamide (520mg, 2.78mmol) in DCM (5mL) was added, followed by TEA (0.58mL, 4.17mmol). The resulting mixture was stirred for 4 hours, then diluted with DCM and treated with saturated NH 4 The organic extract was filtered through PTFE and concentrated in vacuo, and the crude product was purified by chromatography on silica (ISCO 12 g) using 0%-50% EtOAc in cyclohexane as eluent to give the product 3-(methylsulfonamido)phenyl 2-bromo-5-methoxybenzoate (1 g, 90%) as a colorless oil. LCMS (Method 5): R t 1.43min; m / z 398.0 / 400.0[MH] - . 1H NMR (400 MHz, CDCl 3 ) 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).

[0994] GP B2

[0995] N-(8-Methoxy-6-oxo-6H-benzo[c]chromen-3-yl)methanesulfonamide (79)

[0996] A mixture of 2-bromo-5-methoxybenzoic acid 3-(methylsulfonamido)phenyl ester (intermediate 1) (900mg, 2.26mmol), SPhos (92mg, 0.225mmol), palladium (II) acetate (50mg, 0.225mmol) and sodium acetate (369mg, 4.5mmol) in DMA (45mL) is placed in a sealed tube, degassed and purged with argon (x3). The mixture is heated to 130°C for 3 hours, then cooled and diluted with water (400mL), and extracted into DCM (3x 50mL), and the combined organic extracts are washed with brine, and evaporated in vacuo at 80°C to remove residual DMA. The crude mixture is recrystallized from MeCN to obtain the product N-(8-methoxy-6-oxo-6H-benzo[c]chromen-3-yl)methanesulfonamide (200mg, 27%) as a cream solid. LCMS (method 3): R t =3.85min; m / z=320.0[M+H] + . 1 H NMR (400 MHz: DMSO-d 6 ) 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).

[0997] 3-Chloro-8-hydroxy-6H-benzo[c]chromen-6-one (80)

[0998]

[0999] GP C1

[1000] 3-Chloro-8-methoxy-6H-benzo[c]chromen-6-one (Intermediate 2)

[1001] To a solution of 4-chloro-2-hydroxyphenylboronic acid (253mg, 1.47mmol) in DME (8.0mL) and water (2.0mL) was added methyl 2-bromo-5-methoxybenzoate (300mg) and cesium carbonate (1.60g, 4.90mmol), followed by tetrakis(triphenylphosphine)palladium(0) (141mg, 0.122mmol). The reaction mixture was heated in a microwave at 120°C for 30 minutes. The mixture was diluted with EtOAc (100mL) and washed with water (10mL) and brine (10mL). The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 5%-15% EtOAc in cyclohexane, then ground in MeOH, and dried in a vacuum oven to give the title compound (112mg, 35%) as a white solid. LCMS (method 1). R t =5.51min; m / z=261.0, 263.1[M+H] + . 1 H NMR (400 MHz: CDCl 3 ) 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);

[1002] GP C2

[1003] 3-Chloro-8-hydroxy-6H-benzo[c]chromen-6-one (80)

[1004] To a solution of 3-chloro-8-methoxy-6H-benzo [c] chromene-6-one (intermediate 2) (70mg, 0.268mmol) in anhydrous DCM (10mL) was added dropwise a solution of boron tribromide in DCM (1.0M, 5.4mL, 5.36mmol) under nitrogen. The reaction mixture was stirred at room temperature for 3 days. Water (20mL) was added and the mixture was diluted with DCM (10mL). The mixture was stirred at room temperature for 10 minutes. The obtained precipitate was filtered out, and the aqueous layer was extracted with DCM (2x 50mL). The combined organic layer was passed through a phase separation column and concentrated under reduced pressure. The precipitate was dissolved in MeOH / DCM and concentrated in vacuo. The combined residue was purified by chromatography on silica with 2%-4% MeOH eluted in DCM to obtain the title compound (28mg, 42%) as a white solid. LCMS (method 1): R t=4.55min; m / z=247.1, 249.0[M+H] + . 1 H NMR (400 MHz: DMSO-d 6 ) δ10.54 (1H, s), 8.35-8.31 (2H, m), 7.63-7.61 (2H, m), 7.51-7.42 (2H, m).

[1005] General Procedure D

[1006] 2-(Dimethylamino)-N-(6-oxo-6H-benzo[c]chromen-3-yl)acetamide (81)

[1007]

[1008] GP D1

[1009] 6-Oxo-6H-benzo[c]chromen-3-yl trifluoromethanesulfonate (Intermediate 3)

[1010] A mixture of 6-hydroxy-6H-benzo[c]chromene-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 hours. The resulting red solution was washed with 1M HCl (50 mL), and the DCM layer was dried (PTFE glass 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 chromatography on silica using 20%-100% DCM in cyclohexane as eluent. This gave additional product 1.22 g (overall yield 2.86 g, 71%). LCMS (method 5): R t = 1.60 min (no m / z-poor ionization detected). 1 H NMR (CDCl 3 )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).

[1011] GP D2

[1012] 2-(Dimethylamino)-N-(6-oxo-6H-benzo[c]chromen-3-yl)acetamide (81)

[1013] The 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 tripotassium phosphate (318 mg, 1.5 mmol) in a septum sealed vial was degassed (vacuumed and flushed with argon for 3 cycles). Warm degassed (argon flushed) tert-butanol (8.5 mL) was added via a syringe, and the mixture was heated at 95 ° C for 2 hours. The cooled mixture was diluted with water (15 mL), and the resulting mixture was filtered and dried in vacuo to give a gray solid. It was dissolved in DCM (15 mL) and filtered through a 2 g fast Si (II) column, and the column was 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] + .

[1014] 1 H NMR (400 MHz, DMSO-d 6 )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), 7.96-7.90 ( 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).

[1015] General ProcedureE

[1016] Methyl (6-oxo-6H-benzo[c]chromen-3-yl)carbamate (82)

[1017]

[1018] Trifluoromethanesulfonic acid 6-oxo-6H-benzo[c]chromen-3-yl ester (Intermediate 3) (250 mg, 0.73 mmol), methyl carbamate (82 mg, 1.09 mmol), allylpalladium(II) chloride dimer (2.7 mg, 0.007 mmol), JackiePhos (29 mg, 0.036 mmol) and K 2 CO 3The mixture of (301mg, 2.18mmol) in toluene (6.0mL) was purged 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 (20mL) and water (20mL) to obtain a suspension in the aqueous phase. The organic phase was separated, and the aqueous phase was washed with DCM (20mL). The aqueous phase was filtered, and the recovered black solid was dissolved in 6% MeOH in DCM. This solution was filtered through 5g fast Si (II) columns, and the column was further eluted with 6% MeOH in DCM to obtain (129mg, 65%) as a white solid. LCMS (method 3): R t =4.05min; m / z=269.9[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[1019] General Procedure F

[1020] 3-Bromo-8-methoxy-6H-benzo[c]chromen-6-one (84)

[1021]

[1022] GP F1

[1023] 8-Methoxy-6-oxo-6H-benzo[c]chromen-3-yl trifluoromethanesulfonate (83) (Intermediate 4)

[1024] 3-hydroxy-8-methoxy-6H-benzo [c] chromene-6-one (1g, 4.13mmol) is dissolved in pyridine (10mL) and the mixture is cooled in ice water. Trifluoromethanesulfonic anhydride (1mL, 6.19mmol) is added dropwise, and the resulting brown mixture is stirred at 0°C to reach room temperature for 2 hours. The mixture is concentrated in vacuo, and the residue is dissolved in DCM and washed with 1M Hcl, brine, dried (PTFE glass frit) and concentrated in vacuo. The resulting residue is passed through a silica pad (12g), and the product is eluted with 50%-100% DCM in cyclohexane to obtain a compound (1.2g, 80%) as white crystals. 1 H NMR (400 MHz, CDCl 3) 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 = 2.8 Hz), 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] + .

[1025] GP F2

[1026] 8-Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6H-benzo[c]chromen-6-one (Intermediate 5)

[1027] 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) complex with DCM (65 mg, 0.08 mmol), 1,1-bis(diphenylphosphino)ferrocene (44 mg, 0.08 mmol) and dioxane (20 mL) was purged with argon. Bis(pinacolato)diboron (746 mg, 2.94 mmol) was added and after further degassing for a period of time, the mixture was heated at 90° C. under argon for 19 hours. The cooled mixture was distributed between ether (25 mL) and water (25 mL), and 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 (Na 2 SO 4 ) and purified by HPLC. 2 SO 4 ) and concentrated in vacuo. The residue was purified by flash chromatography on a 20 g Si-(II) column eluted with DCM followed by 10% EtOAc in DCM. The resulting product was triturated with cyclohexane (10 mL) and then dried in vacuo 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 =1.11min; m / z=271.1[M-Pin+H] + .

[1028] GP F3

[1029] 3-Bromo-8-methoxy-6H-benzo[c]chromen-6-one (84)

[1030] 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 hours and then cooled. The cold mixture was extracted with ether (2x25 mL) and then with DCM (2x25 mL) and the combined organic phases were filtered through a hydrophobic frit and then concentrated in vacuo. The residue was purified by flash chromatography on a 5 g Si-(II) column and eluted with [1:1] DCM / cyclohexane and then DCM to give the title compound (240 mg, 78%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) 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);

[1031] LCMS (Method 5), R t =1.53min; m / z=304.8, 306.8[M+H] + .

[1032] Program G

[1033] 8-(Difluoromethyl)-3-(methoxymethoxy)-6H-benzo[c]chromen-6-one (85)

[1034]

[1035] GP G1

[1036] 8-Bromo-3-(methoxymethoxy)-6H-benzo[c]chromen-6-one (Intermediate 6)

[1037] 8-Bromo-3-hydroxy-6H-benzo[c]chromen-6-one (1.0 g, 3.44 mmol), K 2 CO 3The mixture was stirred for 3 hours. The mixture was concentrated in vacuo and dispersed 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 (400 MHz, CDCl 3 )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).

[1038] GP G2

[1039] 3-(Methoxymethoxy)-8-vinyl-6H-benzo[c]chromen-6-one (Intermediate 7)

[1040] A mixture of 8-bromo-3-(methoxymethoxy)-6H-benzo[c]chromene-6-one (intermediate 6) (1g, 2.98mmol), potassium vinyl trifluoroborate (520mg, 3.88mmol), TEA (1.2mL, 8.95mmol) and a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and DCM (122mg, 0.15mmol) in isopropanol (20mL) and water (10mL) was placed in a sealed tube, evacuated and purged with argon (x3). The mixture was heated at 90°C under argon for 2 hours. The cooled mixture was concentrated in vacuo, and the residue was dispersed between EtOAc and water. The EtOAc layer was washed with brine, dried (PTFE glass frit) and concentrated in vacuo. The resulting residue was purified by chromatography on silica using 0%-50% DCM in cyclohexane as eluent to give the product as a white solid (705 mg, 71%). 1 H NMR (400 MHz, CDCl 3 ) 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).

[1041] GP G3

[1042] 3-(Methoxymethoxy)-6-oxo-6H-benzo[c]chromene-8-carbaldehyde (Intermediate 8)

[1043] 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 sodium periodate (1.59 g, 7.44 mmol) and the resulting solution was stirred for 18 hours to give a white suspension. The mixture was concentrated in vacuo and the residue was partitioned between DCM and water and the DCM layer was washed with aqueous sodium sulfite, brine and then dried (PTFE frit) to give a white solid (700 mg, quantitative). 1 H NMR (400 MHz, CDCl 3 )δ10.11 (1H, s), 8.83 (1H, d, J=1.8 Hz), 8.30 (1H, dd, J=1.8, 8.4 Hz), 8.16 (1H, d, J=8.4 Hz), 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] + .

[1044] GP G4

[1045] 8-(Difluoromethyl)-3-(methoxymethoxy)-6H-benzo[c]chromen-6-one (Intermediate 9)

[1046] 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 hours. The resulting solution was washed with saturated NaHCO 3 The aqueous solution was neutralized and the DCM layer was washed with brine, dried (PTFE frit) and concentrated in vacuo. The residue was purified by chromatography on silica using 0%-70% DCM in cyclohexane as eluent to give the product as a pale yellow solid (175 mg, 85%). 1 H NMR (400 MHz, CDCl 3, 258114) δ 8.49 (1H, d, J = 1.1 Hz), 8.12 (1H, d, J = 8.4 Hz), 7.98 (1H, d, J = 8.5 Hz), 7.96-7.92 (1H, m), 7.09-7.05 (2H, m), 6.76 (1H, t, J = 56.1 Hz), 5.26 (2H, s), 3.51 (3H, s); LCMS (method 6): R t = 1.55 min (no m / z-poor ionization detected).

[1047] GP G5

[1048] 8-(Difluoromethyl)-3-hydroxy-6H-benzo[c]chromen-6-one (85)

[1049] Under argon, 8-(difluoromethyl)-3-(methoxymethoxy)-6H-benzo[c]chromene-6-one (intermediate 9) (65mg, 0.21mmol) and 2,2'-bipyridine are placed in a sealed tube based on a solution in MeCN and cooled in ice water. Trifluoromethyl trifluoromethanesulfonate (0.08mL, 0.42mmol) is added and the solution is stirred for 18 hours. The resulting mixture is stirred with water (0.5mL) for 30 minutes, then concentrated in a vacuum, and the residue is distributed between EtOAc and water. The EtOAc layer is washed with brine, dried (PTFE glass frit) and concentrated in a vacuum. The crude residue is purified by chromatography on silica using 0%-5% MeOH in DCM as eluent to obtain the product as a light yellow solid. The product was further purified by chromatography on silica using 0%-50% EtOAc in cyclohexane as eluent to give the title compound as a white solid (25 mg, 45% yield). 1 H NMR (400 MHz, DMSO-d 6 )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 =4.03min; m / z=260.9[MH] - .

[1050] Program H

[1051] 3-Amino-8-methoxy-6H-benzo[c]chromen-6-one (86)

[1052]

[1053] GP H1

[1054] 3-((Diphenylmethylene)amino)-8-methoxy-6H-benzo[c]chromen-6-one (Intermediate 10)

[1055] Into a glass vial, trifluoromethanesulfonic acid 8-methoxy-6-oxo-6H-benzo [c] chromene-3-yl ester (intermediate 4) (300mg, 0.802mmol), benzophenone imine (0.20mL, 1.20mmol), cesium carbonate (392mg, 1.20mmol) and XPhos-Pd-G3 (76mg, 0.080mmol) in THF (4.0mL) are loaded. The reaction mixture is evacuated and purged with nitrogen (x 3), and heated at 80 ℃ for 2 hours. The cooled mixture is distributed between EtOAc (x 2) and water, and the combined organic extraction is washed with salt water, dried (MgSO 4 ) and concentrated under vacuum. The resulting residue was purified by chromatography on silica using 5%-95% EtOAc in cyclohexane as eluent to give the product as a white solid (250 mg, 77%). 1 H NMR (400 MHz, DMSO-d 6 )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] + .

[1056] GP H1

[1057] 3-Amino-8-methoxy-6H-benzo[c]chromen-6-one (86)

[1058] 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 2M HCl (3.1 mL) and stirred at room temperature for 10 minutes. The precipitate was collected by filtration, dissolved in MeOH and applied to an SCX-2 column equilibrated with MeOH; after washing with MeOH / DCM, the column was heated to 40° C. using 7M NH in MeOH. 3 The title compound was eluted to give the product as a beige solid (50 mg, 34%). 1 H NMR (400 MHz, DMSO-d 6 ) 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, J = 2.8, 8.8 Hz), 6.67 (1H, dd, J=2.3, 8.6Hz), 6.54 (1H, d, J=2.3Hz), 5.82 (2H, s), 3.92 (3H, s); LCMS (Method 1): R t =3.91min; m / z=242.3[M+H]+ 。

[1059] The following examples in Table A were prepared using methods similar to those described above by utilizing the General Procedure (GP) shown.

[1060] Table A

[1061]

[1062]

[1063]

[1064]

[1065]

[1066] * = Salts were prepared after treatment with 1.1 equivalents of aqueous HCl and lyophilization. NMR spectra were taken at d unless otherwise stated. 6 - obtained in DMSO.

[1067] B) Ether and Amide "A" Group Analogs

[1068] Program I

[1069] 2-Chloro-3,8-dihydroxy-6H-benzo[c]chromen-6-one (114) and

[1070] 2-Chloro-6H-benzo[c]chromene-3,8-diol (115)

[1071]

[1072] 2-Chloro-3,8-dihydroxy-6H-benzo[c]chromen-6-one(114)

[1073] 2-Chloro-3,8-dihydroxy-6H-benzo[c]chromen-6-one was prepared from 113 using general procedure C2. 1 H NMR (400 MHz, DMSO-d 6 ) δ10.25 (1H, br s), 8.24 (1H, s), 8.19 (1H, d J = 8.8Hz), 7.51 (1H, d J = 2.6Hz), 7.31 (1H, dd J = 2.7, 8.7Hz), 6.91 (1H, s);

[1074] LCMS (Method 3): R t =3.52min; m / z = 260.9 [MH] - .

[1075] GP I1

[1076] 3,8-Bis((tert-butyldimethylsilyl)oxy)-2-chloro-6H-benzo[c]chromen-6-one (Intermediate 11)

[1077] By 2-chloro-3,8-dihydroxy-6H-benzo [c] chromene-6-one (114) (2.37g, 9.04mmol) in DMF (15mL) suspension imidazole (2.46g, 36.14mmol) treatment, then with TBDMSCl treatment, and the resulting mixture was stirred at room temperature for 18 hours. Reactant was distributed between EtOAc (x 3) and water, and the combined organic extracts were washed with brine, dried (PTFE glass frit) and concentrated in a vacuum. The resulting residue was purified by chromatography on silica using 0%-25% DCM in cyclohexane as eluent to obtain the product (2.0g, 45%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ7.94 (1H, s), 7.85 (1H, d J = 8.7Hz), 7.76 (1H, d J = 2.6Hz), 7.31 (1H, dd J=2.7, 8.7Hz), 6.89 (1H, s), 1.05 (9H, s), 1.01 (9H, s), 0.28 (6H, s), 0.26 (6H, s).

[1078] GP I2

[1079] 4,4′-Bis((tert-butyldimethylsilyl)oxy)-5-chloro-2′-(hydroxymethyl)-[1,1′-biphenyl]-2-ol (Intermediate 12)

[1080] 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 hour. 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 minutes, NaxSO 4 and the resulting mixture was stirred at room temperature for 18 hours. Filtered and washed the pad with DCM, and the combined organic layers were concentrated in vacuo to give a yellow solid (388 mg, quantitative). 1 H NMR (400 MHz, CDCl 3 )δ7.24(1H, s), 7.04(1H, d J=8.3Hz), 6.98 (1H, s), 6.88 (1H, s), 6.79 (1H, dJ=7.7Hz), 6.42 (1H, s), 4.2 7(2H,m), 1.23(1H,m), 1.02(9H,s), 0.98(9H,s), 0.20(6H,s), 0.19(6H,s).

[1081] GP I3

[1082] ((2-Chloro-6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane) (Intermediate 13)

[1083] 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 at room temperature for 30 minutes. The resulting solution was concentrated in vacuo and purified by chromatography on silica using 0%-50% EtOAc in cyclohexane as eluent to give a semi-pure product. LCMS analysis gave the desired product plus about 70% of the fully deprotected diol. The crude reaction mixture was used in the next stage without purification.

[1084] GP I4

[1085] 2-Chloro-6H-benzo[c]chromene-3,8-diol (115)

[1086] 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 4M HCl in dioxane (1.96 mL, 7.83 mmol) and the reaction was stirred at room temperature for 18 hours. The resulting mixture was concentrated in vacuo and the residue was partitioned between DCM (x2) and water. The combined organic extracts were washed with brine, dried (Na2SO4) and purified by X-ray distillation. 2 SO 4 ) and concentrated in vacuo, and the crude residue was purified by chromatography on silica using 0%-50% EtOAc in cyclohexane as eluent to give the title compound (60 mg, 31% yield) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ10.22 (1H, br s), 9.60 (1H, br s), 7.66 (1H, s), 7.54 (1H, d J = 8.3Hz), 6.74 (1H, d J = 7.5Hz), 6.62 (1H, s), 6.53 (1H, s), 4.99 (2H, s); LCMS (Method 3): R t =3.57min; m / z = 246.9 [MH] - .

[1087] Program J

[1088] 3,8-Dihydroxy-2-methyl-6H-benzo[c]chromen-6-one (116) and

[1089] 2,6,6-Trimethyl-6H-benzo[c]chromene-3,8-diol (117)

[1090]

[1091] 3,8-Dihydroxy-2-methyl-6H-benzo[c]chromen-6-one (116)

[1092] 3,8-Dihydroxy-2-methyl-6H-benzo[c]chromen-6-one was prepared using general procedures A and C2. 1 H NMR (400 MHz, DMSO-d 6)δ10.15 (2H, br s), 8.11 (1H, d J = 8.9Hz), 7.92 (1H, s), 7.50 (1H, d J = 2.7Hz), 7.31 (1H, dd J = 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] + .

[1093] GP J1

[1094] 3,8-Bis((tert-butyldimethylsilyl)oxy)-2-methyl-6H-benzo[c]chromen-6-one (Intermediate 14)

[1095] 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 NM1R (400MHz, CDCl 3 ) δ7.89 (1H, d J = 8.7Hz), 7.76 (1H, d J = 2.7Hz), 7.71 (1H, s), 7.28 (1H, dd J=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).

[1096] GP J2

[1097] 4,4′-Bis((tert-butyldimethylsilyl)oxy)-2′-(2-hydroxypropan-2-yl)-5-methyl-[1,1′-biphenyl]-2-ol (Intermediate 15)

[1098] 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-MeTHF (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 washed with saturated NH 4 The mixture was quenched with aqueous Cl solution and extracted with EtOAc (x 2), followed by drying (Na 2 SO 4 ) and concentrated in vacuo to give the title compound (320 mg, quantitative) as a colorless oil. 1H NMR (400 MHz, CDCl 3 )δ7.10 (1H, d J=2.5Hz), 6.94 (1H, d J=8.2Hz), 6.86 (1H, s), 6.75 (1H, dd J=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).

[1099] GP J3

[1100] ((2,6,6-Trimethyl-6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane) (Intermediate 16)

[1101] 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. 2 O and the resulting mixture was heated at 50° C. for 1 h. The resulting solution was directly purified by chromatography on silica using DCM as eluent to give the product as a colorless oil (280 mg, 90%). 1 H NMR (400 MHz, CDCl 3 )δ7.48 (1H, d J=8.4Hz), 6.38 (1H, s), 6.77 (1H, dd J=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 =3.57min; m / z = 246.9 [MH] - .

[1102] GP J4

[1103] 2,6,6-Trimethyl-6H-benzo[c]chromene-3,8-diol (117)

[1104] 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 hours. The resulting mixture was adsorbed onto HMN and purified by chromatography on silica using 0%-30% EtOAc in cyclohexane as eluent to give the semi-pure product (121 mg) as a pale yellow oil. Further purification was obtained by trituration from a mixture of DCM and n-pentane to give the title compound (91 mg, 64%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ9.40 (1H, s), 9.32 (1H, s), 7.47 (1H, d J=8.4Hz), 7.38 (1H, s), 6.71 (1H, dd J=2.3, 8.4Hz), 6.66 (1H, d J=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] + .

[1105] Compound 117A was prepared by the following method.

[1106]

[1107] Step 1: Synthesis of 3-hydroxy-8-methoxy-2,9-dimethyl-6H-benzo[c]chromen-6-one

[1108]

[1109] 4-Methylbenzene-1,3-diol (2.03 g, 16.3 mmol, 2.00 eq.) and Na 2 CO 3(2.60g, 24.5mmol, 3.00 equiv) was dissolved in water (10mL), and 2-bromo-5-methoxy-4-methylbenzoic acid (2.00g, 8.16mmol, 1.00 equiv) was added in one portion after complete dissolution, and the mixture was heated to 60°C in an oil bath for 1 hour, after which CuI (777mg, 4.08mmol, 0.50 equiv) was added in one portion. Stirring was continued at 60°C overnight, after which the reactants were cooled to room temperature and filtered. The filter cake was suspended in 1M HCl aqueous solution 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]chromene-6-one (1.27g, 4.70mmol, 58%) as a gray solid. f = 0.30 (EtOAc / cyclohexane 40%). 1 H NMR (400MHz, DMSO) δ 10.12 (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).

[1110] Step 2: Synthesis of 3,8-dihydroxy-2,9-dimethyl-6H-benzo[c]chromen-6-one

[1111]

[1112] 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. BBr as a 1 M solution in DCM was added dropwise. 3 (13.0mL, 13.0mmol, 4.00 equivalents). After the addition was complete, the reactant was stirred at 0°C for another 30 minutes and then allowed to warm to room temperature. As indicated by TLC, after complete consumption of the starting material, the reaction was terminated by quenching with methanol at 0°C. 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]chromene-6-one (520mg, 2.03mmol, 47%) as a gray solid. f =0.2 (MeOH / DCM 10%). 1H 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).

[1113] Step 3: Synthesis of 3,8-bis((tert-butyldimethylsilyl)oxy)-2,9-dimethyl-6H-benzo[c]chromen-6-one

[1114]

[1115] 3,8-dihydroxy-2,9-dimethyl-6H-benzo [c] chromene-6-ketone (520mg, 2.03mmol, 1.00 equivalent) is suspended in DMF (10mL), and disposable TBSCl (765mg, 5.07mmol, 2.50 equivalent) is added. Then TEA (1.40mL, 10.1mmol, 5.00 equivalent) is added dropwise, and reactant is stirred for 3 hours. After this, by TLC monitoring reaction, and find that due to solubility problem, reaction stagnates and can't be further promoted. Therefore water is added to reaction mixture and with EtOAc (3x) extraction reaction mixture. The organic layer merged is filtered through anhydrous Na 2 SO 4 Dry, filter and concentrate under vacuum. The crude material was purified by flash column chromatography (0%-10% EA in Hex) 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 (EtOAc / cyclohexane 10%). 1 H NMR (400 MHz, CDCl 3 )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).

[1116] Step 4: Synthesis of 4,4′-bis((tert-butyldimethylsilyl)oxy)-2′-(2-hydroxypropan-2-yl)-5,5′-dimethyl-[1,1′-biphenyl]-2-ol

[1117]

[1118] 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. MeMgBr (0.60 mL, 1.79 mmol, 3.00 equiv) (3 M in EtOH) was then added in one portion. 2 O). The reaction was stirred at 0 °C for 10 minutes and then warmed to room temperature. Stirring was continued at room temperature for 1 hour, after which the reaction was quenched with water and extracted with EtOAc (3x). The combined organic layers were washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated under vacuum. The crude material was purified by flash column chromatography (0%-20% EA in Hex) 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 although it was an inseparable mixture with the undesired product.

[1119] Step 5: Synthesis of ((2,6,6,9-tetramethyl-6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane)

[1120]

[1121] 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 minutes after which the starting material was completely converted. The mixture was concentrated under reduced pressure and the residue was directly subjected to 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 light yellow solid. f =0.4 (EtOAc / cyclohexane 10%). 1 H NMR (400 MHz, CDCl 3)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).

[1122] Step 6: Synthesis of 2,6,6,9-tetramethyl-6H-benzo[c]chromene-3,8-diol

[1123]

[1124] ((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...

Claims

1. 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, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (Ia), in A is 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 NR 11 C(O)R 12 、C(O)NR 11 R 12 and NR 11 S02R 12 ; Each occurrence of R9 is independently selected from OH, NH2, O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH3)C(O)-alkyl, NHSO2-alkyl, N(CH3)SO2-alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; R 10 Selected from C2-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, SO3H, SO2-alkyl and SO2-haloalkyl; Each occurrence of R 11 is selected from H and alkyl; and Each occurrence of R 12 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl and alkyl-heterocycloalkyl; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein A is 3. The method of claim 1 or 2, wherein R2 is H.

4. The method of claim 1 or 2, wherein R2 is OH.

5. The method of claim 1 or 2, wherein R2 is OAc.

6. The method of claim 1 or 2, wherein R2 is selected from 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 the group consisting of alkyl, substituted cycloalkyl, heterocycloalkyl, and alkylheterocycloalkyl; and R 11 is H and R 12 is alkyl-heterocycloalkyl.

7. The method of any one of claims 1-6, wherein R7 is H.

8. The method of any one of claims 1 to 6, wherein R7 is OH.

9. The method of any one of claims 1-6, wherein R7 is OAc.

10. The method of any one of claims 1 to 5, wherein R7 is selected from 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 the group consisting of alkyl, substituted cycloalkyl, heterocycloalkyl, and alkylheterocycloalkyl; and R 11 is H and R 12 is alkyl-heterocycloalkyl.

11. The method of claim 6 or 10, wherein each occurrence of substituted cycloalkyl is independently substituted with OH, halogen or hydroxyalkyl.

12. The method of any one of claims 1-11, wherein R1, R3, R4, R5, R6 and R8 are each H.

13. The method of any one of claims 1-11, wherein one of R1, R3, R4, R5, R6 and R8 is not H.

14. The method of any one of claims 1-11, wherein two of R1, R3, R4, R5, R6 and R8 are not H.

15. The method of claim 13, wherein one of R1, R3, R4, R5, R6 and R8 is alkyl or halogen.

16. The method of claim 14, wherein two of R1, R3, R4, R5, R6 and R8 are independently alkyl or halogen.

17. The method of claim 15 or 16, wherein the compound is selected from:

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

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

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

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

22. A method of 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, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (Ic), in A is 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 independently selected from 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 NR 11 C(O)R 12 、C(O)NR 11 R 12 and NR 11 S02R 12 ; R4 and R5 are independently selected from H, halogen and alkyl; Each occurrence of R9 is independently selected from OH, NH2, O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH3)C(O)-alkyl, NHSO2-alkyl, N(CH3)SO2-alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; R 10 Selected from C2-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, SO3H, SO2-alkyl and SO2-haloalkyl; Each occurrence of R 11 is selected from H and alkyl; and Each occurrence of R 12 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl and alkyl-heterocycloalkyl, or a pharmaceutically acceptable salt thereof.

23. The compound of claim 39, wherein A is selected from 24. The compound of claim 22 or 23, wherein R2 and R7 are each OH.

25. The compound of claim 22 or 23, wherein R2 and R7 are each O-alkyl.

26. The compound of claim 22 or 23, wherein R2 is OH; and R7 is H or O-alkyl.

27. The compound of claim 22 or 23, wherein R2 is H or O-alkyl; and R7 is OH.

28. A compound as described in any one of claims 22-27, wherein R1, R3, R4, R5, R6 and R8 are each H.

29. A compound as described in any one of claims 22-27, wherein one of R1, R3, R4, R5, R6 and R8 is not H.

30. A compound as described in any one of claims 22-27, wherein two of R1, R3, R4, R5, R6 and R8 are not H.

31. The compound of claim 29, wherein one of R1, R3, R4, R5, R6 and R8 is alkyl or halogen.

32. The compound of claim 30, wherein two of R1, R3, R4, R5, R6 and R8 are alkyl or halogen.

33. The compound of claim 31 or 32, wherein the compound is selected from:

34. The compound of claim 22, wherein the compound is selected from:

35. The compound of claim 22, wherein the compound is:

36. A method of 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, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (Id), in A is Y2 is O; Y3 and Y4 are independently selected from H, halogen and alkyl; or, together with the carbon to which they are bound, are combined to form a cycloalkyl or heterocycloalkyl group; R1, R4, R5 and R8 are independently selected from H and halogen; R2, R3, R6 and R7 are independently selected from 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 NR 11 C(O)R 12 、C(O)NR 11 R 12 and NR 11 S02R 12 ; Each occurrence of R9 is independently selected from OH, NH2, O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH3)C(O)-alkyl, NHSO2-alkyl, N(CH3)SO2-alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; R 10 Selected from C2-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, SO3H, SO2-alkyl and SO2-haloalkyl; Each occurrence of R 11 is selected from H and alkyl; and Each occurrence of R 12 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl and alkyl-heterocycloalkyl; or a pharmaceutically acceptable salt thereof.

37. The compound of claim 36, wherein A is selected from 38. A compound as claimed in claim 36 or 37, wherein R2 and R7 are each OH.

39. The compound of claim 36 or 37, wherein one of R2 and R7 is OH and the other of R2 and R7 is O-alkyl.

40. A compound as described in any one of claims 36-39, wherein one of R1, R3, R4, R5, R6 and R8 is alkyl or halogen.

41. A compound as described in any one of claims 36-39, wherein two of R1, R3, R4, R5, R6 and R8 are alkyl or halogen.

42. The compound of claim 40 or 41, wherein the compound is selected from:

43. The compound of claim 36, wherein the compound is selected from:

44. The compound of claim 36, wherein the compound is selected from:

45. A method of 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, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (Ie), in A is 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 independently selected from 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 NR 11 C(O)R 12 、C(O)NR 11 R 12 and NR 11 S02R 12 ; R4 and R5 are independently selected from H, alkyl and halogen; Each occurrence of R9 is independently selected from OH, NH2, O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH3)C(O)-alkyl, NHSO2-alkyl, N(CH3)SO2-alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; R 10 Selected from C2-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, SO3H, SO2-alkyl and SO2-haloalkyl; Each occurrence of R 11 is selected from H and alkyl; and Each occurrence of R 12 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl and alkyl-heterocycloalkyl; or a pharmaceutically acceptable salt thereof.

46. ​​The compound of claim 45, wherein n and m are both 0.

47. The compound of claim 46, wherein A is selected from 48. The compound of claim 45, wherein one of n and m is 0, and the other of n and m is 1.

49. The compound of claim 48, wherein A is selected from 50. A compound as described in any one of claims 45-49, wherein R2 and R7 are each OH.

51. A compound as described in any one of claims 45-49, wherein one of R2 and R7 is OH, and the other of R2 and R7 is not OH.

52. A compound as described in any one of claims 45-49, wherein R2 and R7 are each O-alkyl.

53. A compound as described in any one of claims 45-49, wherein R2 is OH and R7 is O-alkyl; or R2 is O-alkyl and R7 is OH.

54. A compound as described in any one of claims 45-53, wherein R1, R3, R4, R5, R6 and R8 are each H.

55. A compound as described in any one of claims 45-53, wherein one of R1, R3, R4, R5, R6 and R8 is not H.

56. A compound as described in any one of claims 45-53, wherein two of R1, R3, R4, R5, R6 and R8 are not H.

57. A compound as described in any one of claims 45-53, wherein one of R1, R3, R4, R5, R6 and R8 is alkyl or halogen.

58. A compound as described in any one of claims 45-53, wherein two of R1, R3, R4, R5, R6 and R8 are alkyl or halogen.

59. The compound of claim 57 or 58, wherein the compound is selected from:

60. The compound of claim 45, wherein the compound is selected from:

61. The compound of claim 45, wherein the compound is selected from:

62. The compound of claim 45, wherein the compound is selected from:

63. A method of 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, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (If), in A 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; Y3 and Y4 are independently selected from H, halogen, OH and alkyl, or are combined with the carbon to which they are bound to form a cycloalkyl or cycloheteroalkyl group; Y5 is selected from CH2, NH, N-alkyl, N-arylalkyl, 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 independently selected from 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 NR 11 C(O)R 12 、C(O)NR 11 R 12 and NR 11 S02R 12 , R4 and R5 are independently selected from H, alkyl and halogen; Each occurrence of R9 is independently selected from OH, NH2, O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH3)C(O)-alkyl, NHSO2-alkyl, N(CH3)SO2-alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; R 10 Selected from C2-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, SO3H, SO2-alkyl and SO2-haloalkyl; Each occurrence of R 11 is selected from H and alkyl; and Each occurrence of R 12 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl and alkyl-heterocycloalkyl; or a pharmaceutically acceptable salt thereof.

64. The compound of claim 63, wherein A is And n and m are both 0.

65. The compound of claim 64, wherein A is 66. The compound of claim 63, wherein A is 67. The compound of claim 66, wherein A is selected from 68. The compound of claim 63, wherein A is 69. The compound of claim 68, wherein A is selected from 70. The compound of claim 63, wherein A is selected from 71. The compound of claim 70, wherein A is selected from 72. A compound as described in any one of claims 63-71, wherein R2 and R7 are each OH.

73. A compound as described in any one of claims 63-71, wherein one of R2 and R7 is OH, and the other of R2 and R7 is not OH.

74. A compound as described in any one of claims 63-71, wherein R2 and R7 are each O-alkyl.

75. A compound as described in any one of claims 63-71, wherein R2 is OH and R7 is O-alkyl; or R2 is O-alkyl and R7 is OH.

76. A compound as described in any one of claims 63-71, wherein R1, R3, R4, R5, R6 and R8 are each H.

77. A compound as described in any one of claims 63-71, wherein one of R1, R3, R4, R5, R6 and R8 is not H.

78. A compound as described in any one of claims 63-71, wherein two of R1, R3, R4, R5, R6 and R8 are not H.

79. A compound as described in any one of claims 63-71, wherein one of R1, R3, R4, R5, R6 and R8 is alkyl or halogen.

80. The compound of any one of claims 63-71, wherein two of R1, R3, R4, R5, R6, and R8 are alkyl or halogen.

81. The compound of claim 79 or 80, wherein the compound is selected from:

82. The compound of claim 63, wherein the compound is selected from:

83. The compound of claim 63, wherein the compound is selected from:

84. A method of 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, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (Ih), in A 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; Y3 and Y4 are independently selected from H, halogen and alkyl, or are combined with the carbon to which they are bound to form a cycloalkyl or cycloheteroalkyl group; 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 selected from NH2, NHCH3 and N(CH3)2, and the other of R2 and R7 is selected from 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 NR 11 C(O)R 12 、C(O)NR 11 R 12 and NR 11 S02R 12 ; Each occurrence of R9 is independently selected from OH, NH2, O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH3)C(O)-alkyl, NHSO2-alkyl, N(CH3)SO2-alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; R 10 Selected from H, C2-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, SO3H, SO2-alkyl and SO2-haloalkyl; Each occurrence of R 11 is selected from H and alkyl; and Each occurrence of R 12 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl and alkyl-heterocycloalkyl; or a pharmaceutically acceptable salt thereof.

85. The compound of claim 84, wherein Y1 is selected from O, NH and N-alkyl.

86. A compound as described in claim 84 or 85, wherein A is And n and m are both 0.

87. A compound as described in claim 84 or 85, wherein A is 88. A compound as described in claim 84 or 85, wherein A is 89. The compound of claim 84 or 85, wherein A is And one of n or m is 0, and the other of n or m is 1.

90. The compound of claim 89, wherein A is 91. The compound of claim 89, wherein A is selected from 92. The compound of claim 84, wherein A is And r and s are both 0.

93. The compound of claim 92, wherein A is selected from, 94. The compound of claim 93, wherein A is selected from 95. A compound as described in any one of claims 84-94, wherein R2 is selected from NH2, NHCH3 and N(CH3)2.

96. A compound as described in any one of claims 84-94, wherein R7 is selected from H, OH, halogen, O-alkyl and haloalkyl.

97. A compound as described in any one of claims 84-94, wherein R7 is selected from alkynyl-R9 and OR 10 ; R9 is OH; and R 10 is alkyl-heterocycloalkyl.

98. A compound as described in any one of claims 84-97, wherein R1, R3, R4, R5, R6 and R8 are each H.

99. The compound of any one of claims 84-97, wherein one of R1, R3, R4, R5, R6, and R8 is not H.

100. The compound of any one of claims 84-97, wherein two of R1, R3, R4, R5, R6, and R8 are not H.

101. The compound of any one of claims 84-97, wherein one of R1, R3, R4, R5, R6 and R8 is alkyl or halogen.

102. The compound of any one of claims 84-97, wherein two of R1, R3, R4, R5, R6 and R8 are independently alkyl or halogen.

103. The compound of claim 101 or 102, wherein the compound is selected from:

104. The compound of claim 84, wherein the compound is selected from:

105. The compound of claim 84, wherein the compound is selected from:

106. The compound of claim 84, wherein the compound is selected from: or a pharmaceutically acceptable salt thereof.

107. The method of any one of claims 1, 22, 36, 45, 63, and 83, wherein the compound is a compound selected from Table A.

108. The method of any one of claims 1-107, wherein a neuromuscular disorder is treated in the subject.

109. The method of claim 108, wherein the neuromuscular disorder is Chuck-Marie-Doo disease.

110. The method of any one of claims 1-107, wherein a muscle disorder is treated in the subject.

111. The method of claim 110, wherein the muscle disorder is hereditary inclusion body myositis, oculopharyngeal muscular dystrophy, inclusion body myopathy, Paget's disease of bone, frontotemporal dementia, or Duchenne muscular disorder.

112. The method of any one of claims 1-107, wherein pulmonary fibrosis is treated in the subject.

113. The method of claim 112, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.

114. The method of any one of claims 1-107, wherein liver disease is treated in the subject.

115. The method of claim 114, wherein the liver disease is non-alcoholic steatohepatitis.

116. The method of any one of claims 1-107, wherein inflammatory bowel disease is treated in the subject.

117. The method of claim 116, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

118. The method of any one of claims 1-107, wherein cancer is treated in the subject.

119. The method of claim 118, wherein the cancer is responsive to immunotherapy.

120. The method of claim 118 or 119, wherein the compound inhibits tumor growth.

121. The method of any one of claims 118-120, wherein the subject is concurrently treated with cancer immunotherapy.

122. The method of claim 121, wherein the compound enhances the effectiveness of the cancer immunotherapy.

123. The method of claim 121, wherein the compound enhances the anti-tumor response of the cancer immunotherapy in the subject.

124. The method of claim 121, wherein the compound enhances the immune response to tumor cells in the subject.

125. The method of any one of claims 118-125, wherein the compound promotes T memory stem cells (T SCM )’s formation.

126. The method of any one of claims 118-125, wherein the compound promotes chimeric antigen receptor (CAR) T memory stem cells (T SCM )’s formation.

127. The method of any one of claims 118-125, wherein the compound promotes anti-tumor CD8+ T cell immunity.

128. The method of any one of claims 118-125, wherein the compound promotes anti-tumor function following adoptive cell transfer.

129. The method of any one of claims 118-128, 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.

130. The method of claim 129, wherein the cancer is colorectal cancer.

131. The method of any one of claims 121-130, wherein the subject is concurrently treated with an immune checkpoint inhibitor.

132. The method of claim 130 or 131, wherein the subject is concurrently treated with pembrolizumab, nivolumab, or ipilimumab.

133. The method of any one of claims 1-107, wherein a heart disease is treated in the subject.

134. The method of claim 133, wherein the heart disease is heart failure.

135. The method of claim 133 or 134, wherein the compound reduces heart failure when administered to the subject following a myocardial infarction in the subject.

136. The method of claim 133 or 134, wherein the compound reduces left ventricular systolic dysfunction following myocardial infarction in the subject.

137. The method of any one of claims 133-136, wherein the subject has an increase in ejection fraction and / or fractional shortening.

138. The method of any one of claims 1-107, wherein cognitive impairment is treated in the subject.

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