Flavone derivatives and uses in targeting inflammatory diseases

Abstract

Disclosed are compounds having a structure according to formula I or a pharmaceutically acceptable salt thereof. The compounds can be used to treat or prevent an inflammatory disease including certain neuroinflammatory diseases, such as Alzheimer's disease. Additionally, the compounds can be used to reduce or inhibit CK2 enzyme activity. Some compounds selectively reduce or inhibit the CK2A2 enzyme subunit over the CK2A1 enzyme subunit.

Description

[0001] 7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0002] FLAVONE DERIVATIVES AND USES IN TARGETING INFLAMMATORY DISEASES

[0003] CROSS REFERENCE TO RELATED APPLICATION

[0004] This application claims the benefit of and priority to the earlier filing date of U.S. Provisional Patent Application Nos. 63 / 789,886, filed April 16, 2025, and 63 / 841,695, filed July 10, 2025, each of which is incorporated herein by reference in its entirety.

[0005] FIELD

[0006] Disclosed aspects herein are directed to a compound useful to treat or prevent an inflammatory disease and / or to reduce or inhibit CK2 enzyme activity, along with methods of making and using the compound.

[0007] BACKGROUND

[0008] The protein kinase casein kinase 2 (CK2) has been a target of interest for therapeutic modalities to address a wide range of disorders over the last few decades. The CK2 holoenzyme (CK2(h)) is a tetramer comprised of two catalytic (CK2A1 and / or CK2A2) and regulatory (CK2B) subunits. The crystal structures of the CK2Ah / CK2B2 tetramer, CK2A1 subunit, and CK2A2 subunit have been solved, revealing key aspects of the interaction of these subunits with one another. Notable features of CK2 activity relative to other kinases include the use of both adenosine triphosphate (ATP) and guanosine triphosphate (GTP) as sources for phosphoryl transfer and the catalysis of an array phosphorylation events by the alpha subunit alone. Under cell type and disease-context dependent conditions, CK2 has been reported to phosphorylate a variety of different substrates within the PI3K / Akt, IKK / NFKB, JAK2 / STAT3, Wnt / β-catenin, DNA damage response, and androgen receptor pathways, among many others. However, recent studies have challenged the pleiotropy of CK2, suggesting its substrate scope could be more limited than previously described.

[0009] SUMMARY

[0010] Disclosed herein are aspects of a compound having a structure according to Formula I7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0011]

[0012] Formula I

[0013] or a pharmaceutically acceptable salt thereof. With respect to Formula I, each of R1and R3independently is H or F. R2is Br, CN, CON(Ra)2, -CH2N(Ra)2, CONHCH2CF3, or heteroaryl optionally substituted with Ci-ealkyl, where each Raindependently is H or C1-6alkyl. R4is H or halo, R5is H, halo, O(Ci-6alkyl), or CF3, R6is OH, CO2H, CH2CO2H, or NHC(O)C1-6alkyl, and R7is H or halo. Also, X is N or O, Y is NH or CR8where R8is H or OH, and Z is N or CH. Additionally with respect to Formula I, if R2is Br, then one or more of the following conditions may apply: R1and / or R3are other than H; or X is O, Y is CR8where R8is OH; or Z is N, R5is OMe, R6is OH, and R7is H; or R5is OMe, R6is CO2H, and R7is H; or R5is Br, R6is CO2H, and R7is H; or R5is H, R6is CH2CO2H, and R7is H.

[0014] Also disclosed herein are aspects of a method for using the compounds. In some aspects, the method comprises contacting a cell that expresses CK2 enzyme with an effective amount of one or more of the compounds, thereby reducing activity of the CK2 enzyme. And in some aspects, the method comprises administering an effective amount of one or more of the compounds, or a pharmaceutically acceptable composition thereof, to a subject in need thereof. In some aspects the method treats a disease or condition characterized at least in part by dysregulated CK2 enzyme activity, such as an inflammatory disease or a disease that causes undesired inflammation, such as cancer, cardiac hypertrophy, cystic fibrosis, a neurodegenerative disease, bipolar disorder, depression, a viral infection (such as SARS-CoV-2), obesity, diabetes mellitus, atherosclerosis, or epilepsy.

[0015] The foregoing and other objects and features of the disclosure will become more apparent from the following detailed description, which proceeds with reference to the accompanying figures.

[0016] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 provides representative top small molecule CK2 Inhibitors and standardization of measurements. The first inhibitory constant for CX-4945 for CK2(h) comes from Pierre et al. Inhibitory constants for SGC-CK2-1 for both CK2 catalytic subunit paralogs come from Wells et al. The first inhibitory constant listed for KN2 comes from Lindenblatt et al. The first7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0017] inhibitory values listed for API and CHR come from Baier et al. The first inhibitory constants listed for FLC-26 and FNH-79 come from Golub et al. All other values are as according to the present disclosure.

[0018] FIGS. 2 A and 2B provide images illustrating the rationale for development of a C6-Lewis base-projecting chromenone inhibitor was explored using the crystal structure 5M4U, wherein FIG. 2A shows the predicted C6-nitrile interaction with Tyrl 16 sidechain in magenta and FIG. 2B shows the predicted C6-benzamide interactions with Tyrl 16 sidechain and He 117 backbone in magenta.

[0019] DETAILED DESCRIPTION

[0020] I. Terms

[0021] The following explanations of terms and abbreviations are provided to better describe the present disclosure and to guide those of ordinary skill in the art in the practice of the present disclosure. As used herein, “comprising” means “including” and the singular forms “a” or “an” or “the” include plural references unless the context clearly dictates otherwise. The term “or" refers to a single element of stated alternative elements or a combination of two or more elements, unless the context clearly indicates otherwise.

[0022] Unless explained otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and not intended to be limiting. Other features of the disclosure are apparent from the following detailed description and the claims.

[0023] The disclosure of numerical ranges should be understood as referring to each discrete point within the range, inclusive of endpoints, unless otherwise noted. Unless otherwise indicated, all numbers expressing quantities of components, molecular weights, percentages, temperatures, times, and so forth, as used in the specification or claims are to be understood as being modified by the term “about.” Accordingly, unless otherwise implicitly or explicitly indicated, or unless the context is properly understood by a person of ordinary skill in the art to have a more definitive construction, the numerical parameters set forth are approximations that may depend on the desired properties sought and / or limits of detection under standard test conditions / methods as known to those of ordinary skill in the art. When directly and explicitly7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0024] distinguishing embodiments from discussed prior art, the embodiment numbers are not approximates unless the word “about” is recited.

[0025] Although there are alternatives for various components, parameters, operating conditions, etc. set forth herein, that does not mean that those alternatives are necessarily equivalent and / or perform equally well. Nor does it mean that the alternatives are listed in a preferred order unless stated otherwise.

[0026] Definitions of common terms in chemistry may be found in Richard J. Lewis, Sr. (ed.), Hawley’s Condensed Chemical Dictionary, published by John Wiley & Sons, Inc., 2016 (ISBN 978-1-118-13515-0). The presently disclosed compounds also include all isotopes of atoms present in the compounds, which can include, but are not limited to, deuterium, tritium,18F,14C, etc. Definitions of common terms in molecular biology may be found in Benjamin Lewin, Genes VII, published by Oxford University Press, 2000 (ISBN 019879276X); Kendrew et al. (eds.), The Encyclopedia of Molecular Biology, published by Blackwell Publishers, 1994 (ISBN 0632021829); and Robert A. Meyers (ed.), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, published by Wiley, John & Sons, Inc., 1995 (ISBN 0471186341); and other similar references.

[0027] In order to facilitate review of the various aspects of the disclosure, the following explanations of specific terms are provided:

[0028] Administration: To provide or give a subject an agent, such as one or more compounds according to Formulas I-IV provided herein, by any effective route. Exemplary routes of administration include, but are not limited to, oral, injection (such as subcutaneous, intramuscular, intradermal, intraperitoneal, intravenous, intraosseous, intracerebroventricular, intrathecal, intraprostatic, and intratumoral), sublingual, rectal, transdermal, intranasal, vaginal and inhalation routes.

[0029] Aliphatic: A substantially hydrocarbon-based compound, or a radical thereof (e.g., C6H 13, for a hexane radical), including alkanes, alkenes, alkynes, including cyclic versions thereof, and further including straight- and branched-chain arrangements, and all stereo and position isomers as well. Cyclic versions are commonly referred to as cycloaliphatic. Unless expressly stated otherwise, an aliphatic group contains from one to twenty-five carbon atoms; for example, from one to fifteen, from one to ten, from one to six, or from one to four carbon atoms. An aliphatic chain may be substituted or unsubstituted. Unless expressly referred to as an “unsubstituted aliphatic,” an aliphatic group can either be unsubstituted or substituted. An aliphatic group can be substituted with one or more substituents (up to two substituents for each methylene carbon in an aliphatic chain, or up to one substituent for each carbon of7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0030] a -C=C- double bond in an aliphatic chain, or up to one substituent for a carbon of a terminal methine group). A substituted aliphatic group includes at least one sp3-hybridized carbon or two sp2-hybridized carbons bonded with a double bond or at least two sp-hybridized carbons bonded with a triple bond. Exemplary substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, alkylthio, acyl, aldehyde, amide, amino, aminoalkyl, aryl, arylalkyl, carboxyl, cyano, cycloalkyl, dialkylamino, halo, haloaliphatic, heteroaliphatic, heteroaryl, heterocycloaliphatic, hydroxyl, oxo, sulfonamide, sulfhydryl, thioalkoxy, or other functionality.

[0031] Alkoxy: A radical (or substituent) having the structure -OR, where R is a substituted or unsubstituted alkyl. Methoxy (-OCH3) is an exemplary alkoxy group.

[0032] Alkyl: A hydrocarbon group having a saturated carbon chain. The chain may be cyclic, branched or unbranched. Examples, without limitation, of alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl. The terms alkenyl and alkynyl refer to hydrocarbon groups having carbon chains containing one or more double or triple bonds, respectively.

[0033] Analog or Derivative: An analog is a molecule that differs in chemical structure from a parent compound, for example a homolog (differing by an increment in the chemical structure, such as a difference in the length of an alkyl chain), a molecular fragment, a structure that differs by one or more functional groups, a change in ionization. Structural analogs are often found using quantitative structure activity relationships (QSAR), with techniques such as those disclosed in Remington (The Science and Practice of Pharmacology, 19th Edition (1995), chapter 28). A derivative is a compound that is derived from a similar compound or a compound that can be imagined to arise from another compound, for example, if one atom is replaced with another atom or group of atoms. The latter definition is common in organic chemistry. In biochemistry, the word is used for compounds that at least theoretically can be formed from the precursor compound.

[0034] Casein kinase 2 (CK2): (e.g., OMIM: 115440 and 115441) A serine / threonine-selective protein kinase responsible for phosphorylation of substrates in various pathways within a cell, and has been implicated in cell cycle control, DNA repair, regulation of the circadian rhythm, and other cellular processes. A member of enzyme class EC 2.7.11.1. CK2 typically appears as a tetramer of two a subunits and two |3 subunits. The terms CK2A, CK2a, and CK2a as used herein are interchangeable. Similarly, the terms CK2B, CK2b, and CK2β are interchangeable.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0035] COVID-19: A contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Symptoms of COVID-19 are variable, but often include fever, cough, fatigue, breathing difficulties, and loss of smell and taste. Symptoms can begin one to fourteen days after exposure to the virus. Around one in five infected individuals do not develop any symptoms. While most people have mild symptoms, some people develop acute respiratory distress syndrome (ARDS). ARDS can be precipitated by cytokine storms, multi-organ failure, septic shock, and blood clots. Longer-term damage to organs (in particular, the lungs and heart) has been observed. There is concern about a significant number of patients who have recovered from the acute phase of the disease but continue to experience a range of effects — known as long COVID — for months afterwards. These effects include severe fatigue, memory loss and other cognitive issues, low-grade fever, muscle weakness, and breathlessness. In some examples, one or more of the compounds disclosed herein are used to treat COVID-19.

[0036] Excipient: A physiologically inert substance that is used as an additive in a pharmaceutical composition. As used herein, an excipient may be incorporated within particles of a pharmaceutical composition, or it may be physically mixed with particles of a pharmaceutical composition. An excipient can be used, for example, to dilute an active agent and / or to modify properties of a pharmaceutical composition. Examples of excipients include but are not limited to polyvinylpyrrolidone (PVP), tocopheryl polyethylene glycol 1000 succinate (also known as vitamin E TPGS, or TPGS), dipalmitoyl phosphatidyl choline (DPPC), trehalose, sodium bicarbonate, glycine, sodium citrate, and lactose.

[0037] Pharmaceutically acceptable: A substance that can be taken into a subject without significant adverse toxicological effects on the subject. The term "pharmaceutically acceptable form" means any pharmaceutically acceptable derivative or variation, such as stereoisomers, stereoisomer mixtures, enantiomers, solvates, hydrates, isomorphs, polymorphs, pseudomorphs, neutral forms, salt forms, and prodrug agents.

[0038] SARS-CoV-2: SARS-CoV-2 is a positive-sense, single stranded RNA virus of the genus betacoronavirus. The term SARS-CoV-2 includes the original SARS-Cov-2 virus or variants thereof (such as the UK variant Bl.1.17, the South Africa variant B.1.351, the Brazil variant P.l, the BAA (delta) variant, and the BA.5 (omicron) variants). The viral genome is capped, polyadenylated, and covered with nucleocapsid proteins. The SARS-CoV-2 virion includes a viral envelope with large spike glycoproteins. The SARS-CoV-2 genome, like most coronaviruses, has a common genome organization with the replicase gene included in the 5'-two thirds of the genome, and structural genes included in the 3'-third of the genome. The SARS-CoV-2 genome encodes the canonical set of structural protein genes in the order 5' -7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0039] spike (S) - envelope (E) - membrane (M) and nucleocapsid (N) - 3'. Symptoms of SARS-CoV-2 infection include fever and respiratory illness, such as dry cough and shortness of breath. Cases of severe infection can progress to severe pneumonia, multi-organ failure, and death. The time from exposure to onset of symptoms is approximately 2 to 14 days. In some examples, one or more of the compounds disclosed herein are used to treat SARS-CoV-2 infections.

[0040] Stereoisomers: Isomers that have the same molecular formula and sequence of bonded atoms, but which differ only in the three-dimensional orientation of the atoms in space.

[0041] Subject: An animal (human or non-human) subjected to a treatment, observation or experiment. Includes both human and veterinary subjects, including human and non-human mammals, such as rats, mice, cats, dogs, pigs, horses, cows, and non-human primates. In some examples, the treated subject has an inflammatory disease or a disease that causes undesired inflammation, such as cancer, cardiac hypertrophy, cystic fibrosis, a neurodegenerative disease, bipolar disorder, depression, a viral infection (such as SARS-CoV-2), obesity, diabetes mellitus, atherosclerosis, epilepsy, or any combination thereof.

[0042] Substituent: An atom or group of atoms that replaces another atom in a molecule as the result of a reaction. The term "substituent" typically refers to an atom or group of atoms that replaces a hydrogen atom, or two hydrogen atoms if the substituent is attached via a double bond, on a parent hydrocarbon chain or ring. The term “substituent” may also cover groups of atoms having multiple points of attachment to the molecule, e.g., the substituent replaces two or more hydrogen atoms on a parent hydrocarbon chain or ring. In such instances, the substituent, unless otherwise specified, may be attached in any spatial orientation to the parent hydrocarbon chain or ring. Exemplary substituents include, for instance, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, alkylthio, acyl, aldehyde, amido, amino, aminoalkyl, aryl, arylalkyl, arylamino, carbonate, carboxyl, cyano, cycloalkyl, dialkylamino, halo, haloaliphatic (e.g., haloalky 1), haloalkoxy, heteroaliphatic, heteroaryl, heterocycloaliphatic, hydroxyl, oxo, sulfonamide, sulfhydryl, thio, and thioalkoxy groups.

[0043] Substituted: A fundamental compound, such as an aryl or aliphatic compound, or a radical thereof, having coupled thereto one or more substituents, each substituent typically replacing a hydrogen atom on the fundamental compound. A person of ordinary skill in the art will recognize that compounds disclosed herein may be described with reference to particular structures and substituents coupled to such structures, and that such structures and / or substituents also can be further substituted, unless expressly stated otherwise or context dictates otherwise. Solely by way of example and without limitation, a substituted aryl compound may have an aliphatic group coupled to the closed ring of the aryl base, such as with toluene. Solely by way7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0044] of example and without limitation, a long-chain hydrocarbon may have a hydroxyl group bonded thereto.

[0045] Tautomers: Constitutional isomers of organic compounds that differ only in the position of the protons and electrons, and are interconvertible by migration of a hydrogen atom. Tautomers ordinarily exist together in equilibrium.

[0046] Therapeutically effective amount or dose: An amount sufficient to provide a beneficial, or therapeutic, effect to a subject or a given percentage of subjects.

[0047] Treating or treatment: With respect to disease, either term includes (1) preventing the disease, e.g., causing the clinical symptoms of the disease not to develop in an animal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease, (2) inhibiting the disease, e.g., arresting or reducing the development of the disease or its clinical symptoms, or (3) relieving the disease, e.g., causing regression of the disease or its clinical symptoms.

[0048] II. Overview

[0049] CK2 overexpression and / or overactivation has been characterized in many cancers. Oncogenic pathways in which CK2 is implicated include prevention of caspase activation, reduction of tumor suppression functions, and promotion of multi -drug resistance. The two candidates targeting CK2 inhibition in the clinic, CX-4945 (ATP-competitive benzonapthyridine scaffold, FIG. 1 top left panel) and CIGB-300 (cyclic peptide), are under investigation for oncological indications. Both therapeutic modalities have reached Phase II in the clinic, offering evidence of a window of safety for the systemic inhibition of CK2 despite the reported pleiotropic nature of its function.

[0050] Additionally, CK2 is implicated in the progression of multiple central nervous system (CNS) disorders. CK2 phosphorylates alpha-synuclein in the context of Parkinson’s disease (PD), contributing to the formation of toxic fibrils. In Alzheimer’s disease (AD), CK2 is involved in pathways leading to tau hyperphosphorylation, elevation of amyloid-P, promotion of synaptic pathology via N-methyl D-aspartate receptor subtype 2B (NR2B), and neuroinflammation. Studies have also indicated a role for CK2 in Huntington’s disease, with evidence for the CK2A2 catalytic paralog playing a more significant role in disease progression than CK2A1. A feature of CK2A2 is its preferential expression in the mammalian brain and testes relative to other tissues, whereas CK2A1 is expressed at high levels in most tissues. Furthermore, CK2A2 exhibits a differentiated and narrower substrate scope from that of CK2A1, suggesting that these catalytic paralogs serve different roles. Despite their different7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0051] substrate scopes, CK2A1 and CK2A2 share near 100% homology at the ATP binding site. Selective study of the substrates of CK2A2 has been a challenge — no potent, paralog-selective inhibitors have been identified to date. A further challenge to in vivo study of CK2A2 in CNS disorders is the presence of the blood-brain-barrier (BBB).

[0052] The top CK2 inhibitors in the clinic fall short of addressing the above issues of selectivity and CNS permeability. CX-4945 shows dual inhibition of both CK2 catalytic paralogs (FIG. 1, panel labeled (i)) and multiple kinome off-targets (Table 1). Furthermore, this stmcture may be vulnerable to P-glycoprotein (Pgp) efflux given the presence of a carboxylic acid moiety, undesirable for addressing CK2 -mediated CNS conditions in vivo. The cyclic peptide CIGB-300 is unlikely to possess the necessary physical properties to be CNS-active. To define the role of CK2A2 with greater clarity and address the pathologies CK2A1 and CK2A2 may mediate in the CNS, novel inhibitors are warranted.

[0053]

[0054] In the small molecule inhibitor space, several other classes of structures merit discussion in addition to CX-4945. The pyrazolopyrimidine scaffold SGC-CK2-1 (FIG. 1, panel labeled (i)) is one of the most potent and selective compounds for competitive CK2 inhibition known, improving on the selectivity index of CX-4945 in the kinome by an order of magnitude (Table 1). This scaffold draws inspiration from classes of similar pyrazolopyrimidine CK2 inhibitors developed at AstraZeneca. However, SGC-CK2-1 and its precursors suffer from poor pharmacokinetics (PK). Despite multiple rounds of analogue syntheses to solve these issues, a convergence between excellent potency and selectivity for CK2 and acceptable properties for in vivo efficacy has yet to be achieved for this scaffold. Bivalent inhibition of CK2, specifically via the aD pocket in immediate adjacency to the ATP binding pocket, has been the subject of multiple studies. One of the most potent and selective structures designed for this inhibitory paradigm is KN2 (FIG. 1, panel labeled (ii)). It is shown herein that this compound exhibits7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0055] modest potencies for CK2A1 and CK2A2; furthermore, the high molecular weight and myriad rotatable bonds of the KN2 scaffold make it a poor candidate for CNS activity in vivo.

[0056] An intriguing class of natural products for CK2 inhibition is comprised of flavones, representative examples of which are apigenin (API) and chrysoeriol (CHR) (FIG. 1, panel labeled (iii)). Natural products, semisynthetic derivatives thereof, and fully synthetic compounds containing this chromenone core are implicated in a wide variety of therapeutic avenues, including anticancer, anti-oxidant, anti-inflammatory, and neuroprotective effects. The mechanisms through which these natural products elicit these effects have been difficult to tease out, but a growing body of evidence supports CK2 inhibition as a major contributing mechanism. API inhibits both catalytic paralogs of CK2 with IC50 values in the μM range; CHR, the most potent flavonoid known for this mode of inhibition, possesses IC50 values in the sub 0.5 pM range. Measurements for CK2 inhibition were standardized against each catalytic paralog in isolation using readily-available radiometric kinase assays from Eurofins. General good agreement between measurements and those made in Baier et al, were observed, with the CK2A2 potency for CHR being the largest discrepancy. In addition, CHR was more kinome-selective than CX-4945 in the Eurofins scanMAX assay (Table 1), bolstering the argument for development of this scaffold. As such, the binding mode of CHR to either of the CK2 catalytic paralogs was investigated. The crystal structure for CHR with either paralog has not been solved; however, that of the closely related compound luteolin (LUT) has with the active site of CK2A1, offering evidence for the possibility of CHR binding CK2 at the ATP active site.

[0057] In the realm of synthetic flavones, the work of Golub et al. stands out, culminating in the discovery of potent compounds flavonol FLC-26 and flavone FNH-79 (FIG. 1, panel labeled (iii)). The crystal structures of closely-related FLC-26 analogue FLC-21 with both CK2A1 and CK2A2 were solved, showing the cognate bound to the ATP active site of each paralog. Key features of the binding of FLC-21 with both paralogs include an interaction between the C4’ carboxylate with the conserved lysine (Lys68 of CK2A1 and Lys69 of CK2A2) and the flat nature of the inhibitor allowing it to fit into the relatively small ATP binding pocket. No crystal structure of FNH-79 with either CK2 catalytic subunit paralog exists, but in silico modelling suggests a similar binding mode to FLC-21 with the C4’ hydroxyl group picking up the key interaction with the conserved lysine. This would be similar to the binding mode observed for LUT with CK2A1. Decreased inhibitory efficiency of both CK2A1 and CK2A2 alone was observed relative to that observed of the holoenzyme by FLC-26 and FNH-79; this is consistent with results observed for flavone natural products. An explanation for this phenomenon may be the presence of the CK2B subunits in the holoenzyme increasing the catalytic activity of the7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0058] CK2A subunits, thus rendering the holoenzyme more sensitive to inhibition. In this process, FLC-26 was determined to have single-digit nanomolar potency for CK2A2 and a tenfold window of paralog selectivity (FIG. 1, panel labeled (iii)). In addition, limited kinome selectivity profiling has been done for FLC-26 and FNH-79.

[0059] II. Compounds

[0060] Disclosed herein are compounds according to Formula I

[0061]

[0062] or a pharmaceutically acceptable salt thereof.

[0063] With respect to Formula I, each of R1and R3independently is H or F.

[0064] R2is Br, -CN, -C(O)N(Ra)2, -CH2N(Ra)2, -C(O)NHCH2CF3, or heteroaryl optionally substituted with Ci-ealkyl, such as methyl.

[0065] In some aspects, R2is -CN, -C(O)N(Ra)2, -CH2N(Ra)2, -C(O)NHCH2CF3, such as -CN, -C(O)NH2, -C(O)NHMe, or -C(O)N(Me)2.

[0066] Each Raindependently is H or Ci-ealkyl, such as H or methyl.

[0067] In some aspects, R2is heteroaryl, such as oxazolyl, isoxazolyl, pyrazolyl, imidazolyl,

[0068] optionally substituted with Ci-6alkyl, such as methyl. In some aspects, R2is O 0 F,

[0069]

[0070]

[0071] R4is H or halo, such as H or Br.

[0072] R5is H, halo, O(C1-6alkyl), or CF3, such as H, Br, Cl, F, OMe, or CF3.

[0073] R6is OH, CO2H, CH2CO2H, or NHC(O)C1-6alkyl, such as OH, CO2H, CH2CO2H, NHC(O)CH3, or NHC(O)CH2CH3.

[0074] R7is H or halo, such as H, Cl or F.

[0075] X is N or O.

[0076] Y is NH or CR8, where R8is H or OH.

[0077] Z is N or CH.7158- 113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0078] Also with respect to Formula I, if R2is Br, then one or more of the following provisos may apply:

[0079] R1and / or R3are other than H; or

[0080] X is O, Y is CR8where R8is OH; or

[0081] Z is N, R5is OMe, R6is OH, and R7is H; or

[0082] R5is OMe, R6is CO2H, and R7is H; or

[0083] R5is Br, R6is CO2H, and R7is H; or

[0084] R5is H, R6is CH2CO2H, and R7is H.

[0085] In some aspects, X is O and Y is CR8. In some aspects, the compound has a structure according to Formula II.

[0086]

[0087] Formula II

[0088] In some aspects, X is N and Y is NH. In some aspects, the compound has a structure according to Formula III.

[0089]

[0090] Formula III

[0091] Exemplary compounds according to Formulas I, II and / or III include, but are not limited to:

[0092]

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[0094]

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[0096]

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[0098]

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[0100]

[0101] Additional exemplary compounds according to Formulas I, II and / or III include, but are not

[0102]

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[0104]

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[0106]

[0107] IV. Pharmaceutical Compositions

[0108] The disclosure also encompasses pharmaceutical compositions comprising one or more of the disclosed compounds. A pharmaceutical composition comprises a compound as disclosed herein and a pharmaceutically acceptable excipient.

[0109] The compounds described herein can be used to prepare therapeutic pharmaceutical compositions. The compounds may be added to the compositions in the form of a salt or solvate. For example, in cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compounds as salts may be appropriate.

[0110] Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, a-ketoglutarate, and b-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, halide, sulfate, nitrate, bicarbonate, and carbonate salts.

[0111] Pharmaceutically acceptable salts may be obtained using procedures known to persons of ordinary skill in the art, for example by reacting a sufficiently basic compound, such as an amine, with a suitable acid to provide a physiologically acceptable ionic compound. Alkali7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0112] metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example, calcium) salts of carboxylic acids can also be prepared by analogous methods.

[0113] The compounds of the formulas described herein can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human or veterinary patient, in a variety of forms. The forms can be specifically adapted to a chosen route of administration, e.g., oral or parenteral administration, by intravenous, intramuscular, topical or subcutaneous routes.

[0114] The compounds described herein may be systemically administered in combination with a pharmaceutically acceptable vehicle, such as an inert diluent or an assimilable edible carrier. For oral administration, compounds can be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into the food of a patient's diet. Compounds may also be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations typically contain at least 0.1% of active compound. The percentage of the compositions and preparations can vary and may conveniently be from about 2% to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level can be obtained.

[0115] The tablets, troches, pills, capsules, and the like may also contain one or more of the following excipients: binders such as gum tragacanth, acacia, cornstarch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; and a lubricant such as magnesium stearate. A sweetening agent such as sucrose, fructose, lactose or aspartame; or a flavoring agent such as peppermint, oil of Wintergreen, or cherry flavoring, may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid earner, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and flavoring such as cherry or orange flavor. Any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially nontoxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices.

[0116] The active compound may be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can be prepared in glycerol, liquid polyethylene7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0117] glycols, triacetin, or mixtures thereof, or in a pharmaceutically acceptable oil. Under ordinary conditions of storage and use, preparations may contain a preservative to prevent the growth of microorganisms.

[0118] Pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions, dispersions, or sterile powders comprising the active ingredient adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. The ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions, or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thiomersal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers, or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by agents delaying absorption, for example, aluminum monostearate and / or gelatin.

[0119] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation can include vacuum drying and freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.

[0120] Useful dosages of the compounds described herein can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U. S. Patent No. 4,938,949 (Borch et al.). The amount of a compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will be ultimately at the discretion of an attendant physician or clinician.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0121] V. Methods of Use

[0122] Casein kinase 2 (CK2) is a potent driver of inflammation, such as neuroinflammation. CK2, primarily isoform CK2A2, is a potent driver of glial inflammation, especially in Alzheimer’s disease (AD), and pharmacological inhibition or genetic perturbation of CK2 reduces biochemical and transcriptional programs driving inflammation in glia. NF-KB is a major transcriptional driver of inflammation. CK2 modulates NF-KB activity via phosphorylation of NF-KB S529 and IκBα S32 and downregulates NF-KB transcriptional signatures. Isoform CK2A2 specifically phosphorylates AKT1 S129. CK2 activity is upregulated in AD, Huntington's disease (HD), and Parkinson's disease (PD) patients in part through CK2A2 upregulation at the transcript and protein level or post-translational modification (such as, but not limited to, S-nitrosylation, phosphorylation, and sulfation). In AD patient-derived astrocytes, this correlates with higher secretion of alarmin HMGB1, which can be blocked by CK2 inhibition. AD patient-derived neurons also have overactivated CK2 signaling and mitochondrial dysfunction. CK2 inhibition reduces tau phosphorylation (at PHF-1, or Ser396 / 404), amyloid-β levels (Bettegazzi, et al., Cell Death Dis 12, 769 (2021)), and mutant huntingtin aggregates (Yu et al., Acta Neuropathologica Commun 10, 83 (2022); Gomez-Pastor et al., Nature Communications 8, 14405 (2017)). CK2 thus may play a multi-pathogenic role in certain neuroinflammatory diseases, such as AD, by blocking mitophagy and autophagy, sustaining chronic inflammation, and leading to toxic protein aggregation.

[0123] In some aspects, the disclosed compounds are inhibitors of CK2 enzyme activity.

[0124] Inhibiting, or reducing, CK2 kinase activity reduces or blocks inflammatory signaling and or improves mitochondrial phenotypes, for example a reduction of inflammatory signaling and / or CK2 kinase activity of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or even 100%, and / or an increase in mitochondrial phenotypes of at least 25%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 100%, at least 200%, at least 300%, at least 400%, or at least 500%, for example as compared to such activity in the absence of a compound according to formulas I-IV. Thus, in some examples, reducing CK2 kinase activity does not require 100% reduction in CK2 kinase activity. In any of the foregoing or following aspects, the compound may be a targeted degrader where R is -L-Q, and inhibiting, or reducing, CK2 activity further comprises degrading the CK2 enzyme. Exemplary methods of measuring CK2 kinase activity are provided herein.

[0125] A method of reducing CK2 activity is disclosed, which includes contacting a cell that expresses CK2 enzyme with an effective amount of one or more compounds as disclosed herein, thereby reducing activity of the CK2 enzyme. Contacting may be performed in vitro, in vivo, or7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0126] ex vivo. In some aspects, the cell is an astrocyte, a microglia, a neuron, a white blood cell, an adipocyte, a myocyte, or an epithelial cell. The white blood cell may be a granulocyte (neutrophil, eosinophil, or basophil), a phagocyte (dendritic cell, monocyte, macrophage), a lymphocyte (T cell, B cell, natural killer (NK) cell)).

[0127] In any of the foregoing or following aspects, reducing activity of the CK2 enzyme may reduce phosphorylation of one or more biomarkers, increase mitophagy, decrease mitochondrial fission, increase mitochondrial function, or any combination thereof, for example increase or decrease by at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, at least 100%, at least 200%, at least 300%, at least 400%, or at least 500%, for example as compared to such activity in the absence of a compound according to formulas I-IV. In some aspects, the one or more biomarkers are AKT1 (pS129), HMGB1, S100A9, SORCS1, IFI16, ILF2, IFNL1, ARFGAP1, RL6IP4, DTD1, SQSTM1, FERMT2, HDLBP, MAP4K4, NAVI, PNPLA6, SMC3, TMX2, IMMT, NF-KB, IκBa, FUNDC1, CK2 (pY255), or any combination thereof.

[0128] In any of the foregoing or following aspects, contacting the cell with the compound may include administering a therapeutically effective amount of the compound, or a therapeutically effective amount of a pharmaceutical composition comprising the compound, to a subject. The subject may be an animal, such as a mammal. In some examples, the subject is a human. In some aspects, the subject has a disease or condition characterized at least in part by dysregulated CK2 activity. The subject may be identified as having such a disease or condition by any suitable means as understood by a person skilled in the art, such as a physician or diagnostician. Suitable means for identifying the subject as having such a disease or condition may include laboratory tests, imaging, physical evaluation, and the like.

[0129] In some aspects, administering the therapeutically effective amount of the compound or the therapeutically effective amount of the pharmaceutical composition comprising the compound to the subject ameliorates at least one sign or symptom of the disease or condition. “Ameliorate” means that at least one sign or symptom is reduced. In certain aspects, the sign or symptom may be eliminated. Thus, administration of the compound may reduce severity of the disease or condition, slow progression of the disease or condition, or treat the disease or condition. In some aspects, the compound may be administered on a prophylactic basis to prevent a disease or condition characterized at least in part by dysregulated CK2 activity.

[0130] In some aspects, the disease or condition is characterized at least in part by inflammation, and administering the therapeutically effective amount of the compound or the therapeutically effective amount of the pharmaceutical composition comprising the compound to7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0131] the subject may reduce the inflammation. In certain aspects, the inflammation is neuroinflammation. In some examples inflammation or neuroinflammation is reduced by at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or even 100%, for example as compared to such activity in the absence of a compound according to formulas I-IV.

[0132] In any of the foregoing or following aspects, the disease or condition may be cancer (e.g., cancers with mutated CSNK2A1 genotype or upregulated CK2 levels, such as cancers of the breast, lung, colon, and prostate), cardiac hypertrophy, cystic fibrosis, a neurodegenerative disease, bipolar disorder, depression, a viral infection, obesity, diabetes mellitus, atherosclerosis, epilepsy, or any combination thereof. Exemplary neurodegenerative diseases include, but are not limited to, Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, multiple sclerosis, and amyotrophic lateral sclerosis. Exemplary viral infections include, but are not limited to, coronavirus infections, such as SARS-CoV-2 infections. Advantageously, some aspects of the disclosed compounds may be multi-targeting compounds, e.g., reducing neuroinflammation, mitochondrial defects, and / or toxic protein aggregation in central nervous system diseases.

[0133] In some examples, the disease or condition is a viral infection, such as a positive-strand RNA viral infection or negative-strand RNA viral infection. Exemplary positive-strand RNA viral infection includes, but are not limited to, infection with one or more of: Picornaviruses (such as Aphthoviridae [for example foot-and-mouth-disease virus (FMDV)]), Cardioviridae; Enteroviridae (such as Coxsackie viruses, Echoviruses, Enteroviruses, and Polioviruses);

[0134] Rhinoviridae (Rhinoviruses)); Hepataviridae (Hepatitis A viruses); Togaviruses (examples of which include rubella; alphaviruses (such as Western equine encephalitis virus, Eastern equine encephalitis virus, and Venezuelan equine encephalitis virus)); Flaviviruses (examples of which include Dengue virus, West Nile virus, and Japanese encephalitis virus); Caliciviridae (which includes Norovirus and Sapovirus); and Coronaviruses (examples of which include SARS coronavimses, such as the Urbani strain and SARS-CoV-2). Exemplary negative-strand RNA viral infections include, but are not limited to infection with one or more of: Orthomyxoviruses (such as the influenza virus), Rhabdoviruses (such as Rabies virus), and Paramyxoviruses (examples of which include measles virus, respiratory syncytial virus, and parainfluenza viruses). In some examples, the disease or condition is a DNA viral infection, such as:

[0135] Herpesviruses (such as Varicella-zoster virus, for example the Oka strain; cytomegalovirus; and Herpes simplex virus (HSV) types 1 and 2), Adenoviruses (such as Adenovirus type 1 and Adenovirus type 41), Poxviruses (such as Vaccinia virus), and Parvoviruses (such as Parvovirus7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0136] Bl 9). In some examples, the disease or condition is a Retrovirus infection, such as human immunodeficiency virus type 1 (HIV-1), such as subtype C; HIV-2; equine infectious anemia virus; feline immunodeficiency virus (FIV); feline leukemia viruses (FeLV); simian immunodeficiency virus (SIV); and avian sarcoma virus.

[0137] In some examples, the disease or condition is a cancer, such as a solid tumors such as breast carcinomas (e.g. lobular and duct carcinomas), sarcomas, carcinomas of the lung (e.g., non-small cell carcinoma, large cell carcinoma, squamous carcinoma, and adenocarcinoma), mesothelioma of the lung, colorectal adenocarcinoma, stomach carcinoma, prostatic adenocarcinoma, ovarian carcinoma (such as serous cystadenocarcinoma and mucinous cystadenocarcinoma), ovarian germ cell tumors, testicular carcinomas and germ cell tumors, pancreatic adenocarcinoma, biliary adenocarcinoma, hepatocellular carcinoma, bladder carcinoma (including, for instance, transitional cell carcinoma, adenocarcinoma, and squamous carcinoma), renal cell adenocarcinoma, endometrial carcinomas (including, e.g., adenocarcinomas and mixed Mullerian tumors (carcinosarcomas)), carcinomas of the endocervix, ectocervix, and vagina (such as adenocarcinoma and squamous carcinoma of each of same), tumors of the skin (e.g., squamous cell carcinoma, basal cell carcinoma, malignant melanoma, skin appendage tumors, Kaposi sarcoma, cutaneous lymphoma, skin adnexal tumors and various types of sarcomas and Merkel cell carcinoma), esophageal carcinoma, carcinomas of the nasopharynx and oropharynx (including squamous carcinoma and adenocarcinomas of same), salivary gland carcinomas, brain and central nervous system tumors (including, for example, tumors of glial, neuronal, and meningeal origin), tumors of peripheral nerve, soft tissue sarcomas and sarcomas of bone and cartilage, and lymphatic tumors (including B-cell and T-cell malignant lymphoma). In one example, the cancer is an adenocarcinoma, such as prostate adenocarcinoma. In some examples, the disease or condition is a liquid tumor, such as a lymphatic, white blood cell, or other type of leukemia. In a specific example, the cancer is a tumor of the blood, such as a leukemia (for example acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), hairy cell leukemia (HCL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, and adult T-cell leukemia), lymphomas (such as Hodgkin’s lymphoma and non-Hodgkin’s lymphoma), and myelomas).

[0138] The compound or pharmaceutical composition may be administered to the subject through any suitable route, and may be local or systemic. In some aspects, the compound or pharmaceutical composition is administered to the subject by the oral route or in a single bolus delivery, via continuous delivery (for example, continuous transdermal, mucosal or intravenous7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0139] delivery) over an extended time period, or in a repeated administration protocol (for example, by an hourly, daily or weekly, repeated administration protocol). In some aspects, the compound or pharmaceutical composition is administered to the subject by injection. The therapeutically effective dosages of the agents can be provided as repeated doses within a prolonged prophylaxis or treatment regimen that will yield clinically significant results to alleviate one or more symptoms or detectable conditions associated with a targeted condition as set forth herein. Determination of effective dosages in this context is typically based on animal model studies followed up by human clinical trials and is guided by administration protocols that significantly reduce the occurrence or severity of targeted disease symptoms or conditions in the subject. Suitable models in this regard include, for example, murine, rat, avian, porcine, feline, nonhuman primate, and other accepted animal model subjects known in the art. Alternatively, effective dosages can be determined using in vitro models. Using such models, only ordinary calculations and adjustments are required to determine an appropriate concentration and dose to administer a therapeutically effective amount of the compound (for example, amounts that are effective to elicit a desired immune response or alleviate one or more symptoms of a targeted disease). In alternative aspects, an effective amount or effective dose of the agents may simply inhibit or enhance one or more selected biological activities correlated with a disease or condition, as set forth herein, for either therapeutic or diagnostic purposes.

[0140] The actual dosages of the agents may vary according to factors such as the disease indication and particular status of the subject (for example, the subject’s age, size, fitness, extent of symptoms, susceptibility factors, and the like), time and route of administration, other drugs or treatments being administered concurrently, as well as the specific pharmacology of the agent for eliciting the desired activity or biological response in the subject. Dosage regimens can be adjusted to provide an optimum prophylactic or therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental side effects of the agent are outweighed in clinical terms by therapeutically beneficial effects. A non-limiting range for a therapeutically effective amount of a compound according to any one of formulas I-IV within the methods and formulations of the disclosure is 0.001 mg / kg body weight to 100 mg / kg body weight, such as 0.01 mg / kg body weight to 20 mg / kg body weight, 0.01 mg / kg body weight to 10 mg / kg body weight 0.05 mg / kg to 5 mg / kg body weight, or 0.1 mg / kg to 2 mg / kg body weight. Dosage can be varied by the attending clinician to maintain a desired concentration at a target site (for example, systemic circulation). Higher or lower concentrations can be selected based on the mode of delivery, for example, trans-epidermal or oral delivery versus intravenous or subcutaneous delivery. Dosage can also be adjusted based on the release rate of the7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0141] administered formulation, for example, of sustained release oral versus injected particulate or transdermal delivery formulations, and so forth.

[0142] In any of the foregoing or following aspects, the therapeutically effective amount may be administered at intervals for a period of time effective to provide a therapeutic effect, e.g., amelioration of at least one sign or symptom of a disease or condition characterized at least in part by dysregulated CK2 activity. In some aspects, the intervals are once daily. In other aspects, the therapeutically effective amount may be divided into two or more doses administered at intervals in a 24-hour period. In some aspects, the effective period of time is from one day to several months, such as from one day to 12 months, three days to six months, seven days to three months, 7-30 days, or 7-14 days. In certain aspects, where the disease or condition is chronic, the effective period of time may be even longer than 12 months, such as a period of years.

[0143] In some examples, a subject treated one or more compounds provided herein to reduce CK2 enzyme activity can receive additional treatment with other compounds, such as one or more antiviral compounds (such as molnupiravir or remdesivir), one or more anti-inflammatory agents (such as a steroid, such as a corticosteroid), one or more chemotherapeutic agents, and one or more biologies (such as a monoclonal antibody used to treat cancer, such as one specific for PD1, EGFR (e.g., cetuximab), VEGF (e.g., bevacizumab), CD25, CTLA4, or a tumorspecific antigen such as HER2 (e.g., trastuzumab), CD52 (e.g., alemtuzumab), CD20, or CD19).

[0144] VI. Overview of Several Aspects

[0145] Disclosed herein is a compound having a structure according to Formula I

[0146]

[0147] Formula I

[0148] or a pharmaceutically acceptable salt thereof, wherein:

[0149] each of R1and R3independently is H or F;

[0150] R2is Br, CN, CON(Ra)2, -CH2N(Ra)2, CONHCH2CF3, or heteroaryl optionally substituted with C1-6alkyl;

[0151] each Raindependently is H or C1-6alkyl;

[0152] R4is H or halo;7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0153] R5is H, halo, O(C1-6alkyl), or CF3;

[0154] R6is OH, CO2H, CH2CO2H, or NHC(O)C1-6alkyl;

[0155] R7is H or halo;

[0156] X is N or O;

[0157] Y is NH or CR8;

[0158] R8is H or OH;

[0159] Z is N or CH; and

[0160] if R2is Br, then:

[0161] R1and / or R3are other than H; or

[0162] X is O, Y is CR8where R8is OH; or

[0163] Z is N, R5is OMe, R6is OH, and R7is H; or

[0164] R5is OMe, R6is CO2H, and R7is H; or

[0165] R5is Br, R6is CO2H, and R7is H; or

[0166] R5is H, R6is CH2CO2H, and R7is H.

[0167] In any or all aspects, the compound has a structure according to Formula II or Formula III

[0168]

[0169] Formula II Formula III

[0170] or a pharmaceutically acceptable salt thereof.

[0171] In any or all aspects, R2is -CN, -C(O)N(Ra)2, -CH2N(Ra)2, -C(O)NHCH2CF3.

[0172] In any or all aspects, R2is -CN, -C(O)NH2, -C(O)NHMe, or -C(O)N(Me)2.

[0173] In any or all aspects, R2is oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, optionally substituted with C1-6alkyl.

[0174] In any or all aspects, R5is H or OMe.

[0175] In any or all aspects, R6is OH or CO2H.

[0176] In any or all aspects, Z is N.

[0177] In any or all aspects, Z is CH.

[0178] Also disclosed is a pharmaceutical composition, comprising a compound according to any or all aspects of the disclosure, and a pharmaceutically acceptable excipient.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0179] Also disclosed is a method for reducing CK2 enzyme activity, comprising: contacting a cell that expresses CK2 enzyme with an effective amount of one or more compounds according to any or all aspects of the disclosure, thereby reducing activity of the CK2 enzyme.

[0180] Also disclosed is a method comprising administering an effective amount of one or more compounds according to any or all aspects of the disclosure, or a pharmaceutically acceptable composition thereof, to a subject in need thereof.

[0181] In any or all aspects, the subject has a disease or condition characterized at least in part by dysregulated CK2 enzyme activity.

[0182] In any or all aspects, the disease or condition is characterized at least in part by dysregulated CK2 enzyme activity.

[0183] In any or all aspects, the disease or condition is an inflammatory disease or a disease that causes undesired inflammation.

[0184] In any or all aspects, the disease or condition is cancer, cardiac hypertrophy, cystic fibrosis, a neurodegenerative disease, bipolar disorder, depression, a viral infection (such as SARS-CoV-2), obesity, diabetes mellitus, atherosclerosis, or epilepsy.

[0185] Also disclosed is a compound, or composition thereof, for use in reducing CK2 enzyme activity, wherein the compound has a structure according to any or all aspects of the disclosure.

[0186] Also disclosed is a compound, or composition thereof, for use in treating a disease or condition that is characterized at least in part by dysregulated CK2 enzyme activity, wherein the compound has a structure according to any or all aspects of the disclosure.

[0187] In any or all aspects, the disease or condition is an inflammatory disease or a disease that causes undesired inflammation.

[0188] In any or all aspects, the disease or condition is cancer, cardiac hypertrophy, cystic fibrosis, a neurodegenerative disease, bipolar disorder, depression, a viral infection (such as SARS-CoV-2), obesity, diabetes mellitus, atherosclerosis, or epilepsy.

[0189] VII. Examples

[0190] General Procedures. All reactions were performed in glassware without oven-drying or inert atmosphere unless otherwise noted. Flash-column chromatography (FCC) was performed employing silica gel 60 (40-63 μm, SiliCycle). Analytical thin-layer chromatography (TLC) was performed using 0.25 mm silica gel 60 F254 plates (Merck).

[0191] Materials. Starting materials Sl-la-b, Sl-ld-h, SI-2a-h, SI-7a-c, SI-9b, Sl-lOa-b, SI-llc, SI-17c, SI-17f, SI-30, SI-31, SI-32, SI-35, SI-37. SI-46, SI-56, SI-57, SI-58, SI-59, SI-62, SI-63,7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0192] SI-64, SI-70, triisopropylsilylalkyne (TIPS-alkyne), sodium azide, 3-oxo-oxetane and 3-oxo-thietane were purchased from commercial sources and used without further purification. Starting material SI-67 was generated from the requisite benzylic alcohol.

[0193] Reagent-grade solvents. Dichloromethane (CH2Cl2), dimethylsulfoxide (DMSO), methanol (MeOH), ethanol (EtOH), 1, 4-dioxane, acetonitrile (ACN), isopropanol (IP A), acetone, N, N-dimethylformamide (DMF), ethyl acetate (EtOAc), diethyl ether (Et20) and hexanes were purchased from commercial sources and used as received. Solvents tetrahydrofuran (THF) and toluene (PhMe) were sourced from sureseal bottles.

[0194] Bases. Sodium hydroxide (NaOH) and potassium hydroxide (KOH) were purchased from commercial sources and solvated in deionized (DI) water or EtOH as indicated. Phosphobuffered saline (PBS-lx) was diluted from commercial sources. Bases sodium bicarbonate (NaHCOs), potassium carbonate (K2CO3), sodium methoxide in MeOH (NaOMe, 25 wt% in MeOH), ammonium hydroxide (NH4OH, 50% aqueous) and potassium fluoride (KF) were obtained from commercial sources. Amines ethyldiisopropylamine (EtN(iPr)2), triethylamine (EtsN), N-methylmorpholine (NMM), hydroxylamine (HONH2, 50 wt% aqueous), methylamine (MeNH2, 40 wt% aqueous), tert-butylamine and 2,2,2-trifhioroethylamine were obtained from commercial sources and used as received. Dimethylamine (HNMe2, 2M THF) was sourced from sureseal bottles and used without titration or further modification.

[0195] Acids. 70% Aqueous perchloric acid (HCIO4), tosic acid monohydrate, 88% aqueous formic acid, glacial acetic acid (AcOH), ammonium chloride (NH4CI) concentrated hydrochloric acid (HC1, 12M) and sulfuric acid (H2SO4) were obtained from commercial sources and used as received or diluted as indicated prior to use.

[0196] Oxidants. Hydrogen peroxide (H2O2, 30% aqueous), molecular iodine (I2), molecular bromine (Br2), N-bromosuccinimide (NBS), meta-chloroperbenzoic acid (mCPBA, 70 wt%, wetted with water), 2,3-dichloro-5,6-dicyanoquinone (DDQ), Dess-Martin periodinane (DMP), and sodium nitrite (NaNO2) were purchased from commercial sources and used as received.

[0197] Reductants. Ammonium formate and sodium thiosulfate (Na2S2O3) were purchased from commercial sources and used as received.

[0198] Electrophiles. Allyl bromide, benzyl bromide, methyl iodide (Mel), and acetic anhydride (AC2O) were purchased from commercial sources and used as received.

[0199] Nucleophiles. Potassium iodide (KI) and triphenylphosphine (PPh3) were purchased from commercial sources and used as received.

[0200] Peptide coupling reagents. 1 -Hydroxybenzotriazole monohydrate (HOBt H2O), l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI HC1), and hexafluorophosphate7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0201] azabenzotri azole tetramethyl uranium (HATU) were sourced from commercial vendors and used as received.

[0202] Transition metal sources. Cuprous iodide (CuI), tetrakis(triphenylphosphine)palladium(0) ((Ph3P)4Pd0), bis(acetonitrile)palladium dichloride (PdCl2(ACN)2), and palladium diacetate (Pd(OAc)2) were sourced from commercial vendors and used as received.

[0203] Miscellaneous. Diisobutylaluminum hydride (DIBAL-H, IM in THF) and n-butyllithium (n-BuLi, 1.6 M in hexanes) were sourced from sureseal bottles and used without titration. Boron tribromide (BBr3, 1M in CH2Cl2) was obtained from a commercial source and used without titration or further modification. Triethyl orthoformate (HC(OEt)3) was sourced from sureseal bottles. Morpholinium acetate was generated from the addition of an equimolar component of AcOH to a stirring solution of morpholine in Et2O followed by filtration of the mixture.

[0204] Instrumentation. Proton magnetic resonance

[0205]

[0206] NMR) spectra were recorded at the University of California, San Diego (UCSD) Chemistry and Biochemistry NMR Facility with Varian INOVA-500, JEOL-400, or JEOL-500 spectrometers, are reported in parts per million (δ) and are calibrated using residual non-deuterated solvent as an internal reference: CDCl3, δ7.26 (CHCl3); (CD3)2SO, δ2.50 (CD3(CD2H)SO). Data for

[0207]

[0208] NMR spectra are reported as follows: chemical shift (multiplicity, coupling constants, integration). Multiplicities are reported as follows: s = singlet; d = doublet; t = triplet; q = quartet; p = pentet; sx = sextet, m = multiplet; br = broad, or combinations thereof. Carbon magnetic resonance (13C NMR) spectra were recorded with a Bruker Ascend 800 or JEOL-400 spectrometer, are reported in parts per million (δ) and are referenced from the central peak of the carbon resonance of the solvent: CDCl3, δ77.16; (CD3)2SO, δ39.52. Fluorine magnetic resonance (19F NMR) spectra were recorded with a JEOL-400 spectrometer, are reported in parts per million (δ) and are unreferenced. Mass spectrometry (MS) analysis was performed by the Molecular MS Facility at UCSD. A Thermo LCQdeca mass spectrometer was employed for low resolution MS (LRMS) analysis using electrospray ionization source (ESI) or atmospheric pressure chemical ionization (APCI) as the ion source. An Agilent 6230A time-of-flight mass spectrometer (TOFMS) with Jet Stream ESI source was employed for high resolution MS (HRMS) analysis.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0209] Example 1

[0210] C4’-hydroxy Flavonoids — Compounds 1, 7, 8, 10-15, & 17

[0211]

[0212] Scheme SI-1: C4’ hydroxy flavonoids via perchloric acid route General Procedure 1: A mixture of acetophenone SI-1 (1 equiv.) and benzaldehyde SI-2 (3 equiv.) in HC(OEt)3 was treated with 70% aqueous HCIO4 and stirred at room temperature, producing a thick suspension after a few hours. The mixture was then filtered, and the resultant solid was isolated and dried. The solid was then taken up as a suspension in DI water, and the resultant mixture was heated at reflux for a given time. The suspension was then cooled to room temperature and filtered once more to give the title compound as a solid.

[0213]

[0214] Compound 1: Acetophenone: SI-1a (441 mg, 1.5 mmol, 1 equiv.). Aldehyde: SI-2a (550 mg, 4.5 mmol, 3 equiv.). 70% aqueous HCIO4: 0.15 mL. HC(OEt)3: 2.1 mL. Reaction time to first filtration: 4.5 hours. DI water quantity: 20 mL. Reaction time to second filtration: 15h. Yield: 261 mg (0.66 mmol, 44%) as a tan solid. ’H NMR (500 MHz, DMSO-d6) δ: 10.47(s, 1H), 8.38 (d, J = 2 Hz, 1H), 8.07 (d, J = 2 Hz, 1H), 8.00 (d, J = 9 Hz, 2H), 7.01 (s, 1H), 6.96 (d, J = 9 Hz, 2H).13C NMR (100 MHz, DMSO-d6) δ: 175.17, 163.25, 161.48, 151.32, 138.72, 128.57, 126.69, 125.63, 120.96, 117.69, 116.15, 113.11, 104.67. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C15H8Br2O3, 394.8913: found, 394.8912. The purity of Compound 1 was judged to be >95% by 'H NMR.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0215]

[0216] Compound 7: Acetophenone: SI-1a (147 mg, 0.5 mmol, 1 equiv.). Aldehyde: SI-2b (285 mg, 1.5 mmol, 3 equiv.). 70% aqueous HCIO4: 0.05 mL. HC(OEt)3: 0.7 mL. Reaction time to first filtration: 20 hours. DI water quantity: 7 mL. Reaction time to second filtration: 23h. Yield: 27 mg (0.058 mmol, 12%) as an off-white solid. ’H NMR (400 MHz, DMSO-d6) δ: 11.66 (s, 1H), 8.38 (d, J = 2 Hz, 1H), 8.26 (d, J = 2 Hz, 1H), 8.22 (dd, J = 9, 2 Hz, 1H), 8.06 (d, J = 2 Hz, 1H), 7.20 (d, J = 9 Hz, 1H), 7.15 (s, 1H).13C NMR (201 MHz, DMSO-d6) δ: 175.29, 161.77, 159.29, 151.29, 138.92, 132.15, 126.72, 125.56, 125.36 (app. d, JC-F= 4 Hz), 123.52 (q, JC-F= 273 Hz), 120.96, 117.90 (app. d, JC-F= 4 Hz), 116.28 (q, JC-F = 30 Hz) 113.14, 105.74.19F NMR (376 MHz, DMSO-D6) 8: -61.42. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C16H7Br2F3O3, 462.8787; found, 462.8784. The purity of Compound 7 was judged to be ca 90% by 'H NMR.

[0217]

[0218] Compound 8: Acetophenone: SI-1a (147 mg, 0.5 mmol, 1 equiv.). Aldehyde: SI-2c (204 mg, 1.5 mmol, 3 equiv.). 70% aqueous HCIO4: 0.05 mL. HC(OEt)3: 0.7 mL. Reaction time to first filtration: 3 hours. DI water quantity: 7 mL. Reaction time to second filtration: 19 hours. Yield: 46 mg (0.112 mmol, 22%) as a yellow solid. ’H NMR (500 MHz, DMSO-d6) δ: 10.38 (s, 1H), 8.38 (m, 1H), 8.07 (m, 1H), 7.91 (m, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.00 (s, 1H), 6.96 (d, J = 8.5 Hz, 1H), 2.21 (s, 3H).13C NMR (101 MHz, DMSO-d6) δ: 175.14, 163.44, 159.76, 151.31, 138.69, 129.22, 126.68, 125.98, 125.64, 125.16, 120.70, 117.69, 115.17, 113.15, 104.52, 16.14. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C16H10Br2O3, 408.9069; found, 408.9068. The purity of Compound 8 was judged to be >95% by1H NMR.

[0219]

[0220] 7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0221] Compound 10: Acetophenone: SI-1a (294 mg, 1 mmol, 1 equiv.). Aldehyde: SI-2d (470 mg, 3 mmol, 3 equiv.). 70% aqueous HCIO4: 0.1 mL. HC(OEt)3: 1.4 mL. Reaction time to first filtration: 4 hours. DI water quantity: 8 mL. Reaction time to second filtration: 19 hours. Yield: 139 mg (0.323 mmol, 32%) as an off-white solid.XH NMR (500 MHz, DMSO-d6) δ: 11.26 (s, 1H), 8.39 (m, 1H), 8.13 (m, 1H), 8.07 (m, 1H), 7.96 (d, J = 9 Hz, 1H), 7.16 (d, J = 9 Hz, 1H), 7.11 (s, 1H).13C NMR (101 MHz, DMSO-d6) δ: 175.12, 161.70, 156.84, 151.18, 138.80, 128.17, 126.79, 126.65, 125.48, 122.13, 120.77, 117.82, 117.03, 113.14, 105.45. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C15H7Br2ClO3, 428.8523; found, 428.8520. The purity of Compound 10 was judged to be >95% by ’H NMR.

[0222]

[0223] Compound 11: Acetophenone: SI-1a (294 mg, 1 mmol, 1 equiv.). Aldehyde: SI-2e (573 mg, 3 mmol, 3 equiv.). 70% aqueous HCIO4: 0.1 mL. HC(OEt)3: 1.4 mL. Reaction time to first filtration: 3 hours. DI water quantity: 14 mL. Reaction time to second filtration: 22 hours. Yield: 296 mg (0.64 mmol, 64%) as an off-white solid. 'H NMR (500 MHz, DMSO-d6) δ: 11.28 (br, s, 1H), 8.40 (m, 1H), 8.14 (s, 2H), 8.07 (m, 1H), 7.24 (s, 1H).13C NMR (101 MHz, DMSO-d6) δ: 175.29, 160.35, 152.50, 151.23, 139.01, 126.74, 126.69, 125.48, 123.04, 122.91, 118.00, 113.27, 106.51. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C15H6Br2Cl2O3, 462.8134; found, 462.8130. The purity of Compound 11 was judged to be ca 90% by1H NMR.

[0224]

[0225] Compound 12: Acetophenone: SI-1a (147 mg, 0.5 mmol, 1 equiv.). Aldehyde: SI-2f (237 mg, 1.5 mmol, 3 equiv.). 70% aqueous HCIO4: 0.05 mL. HC(OEt)3: 0.7 mL. Reaction time to first filtration: 3 hours. DI water quantity: 7 mL. Reaction time to second filtration: 19 hours. Yield: 135 mg (0.313 mmol, 63%) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ: 11.39 (br s, 1H), 8.40 (m, 1H), 8.07 (m 1H), 7.85 (d, JH-F = 9 Hz, 2H), 7.21 (s, 1H).13C NMR (101 MHz,7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0226] DMSO-d6) δ: 175.32, 160.72, 152.28 (dd, JC-F = 243, 8 Hz), 151.22, 138.99, 137.75 (t, JC-F = 17 Hz), 126.69, 125.48, 120.54 (t, JC-F = 9 Hz), 118.00, 113.28, 110.45 (dd, JC-F = 16. 8 Hz), 106.38.19F NMR (376 MHz, DMSO-d6) δ: -130.44 (d, JH-F = 9 Hz). HRMS-ESI-TOFMS (m / z):

[0227] [M+H]+calculated for Ci5HeBr2F2O3, 430.8725; found, 430.8724. The purity of Compound 12 was judged to be ca 95% by1H NMR.

[0228]

[0229] Compound 13: Acetophenone: SI-1a (294 mg, 1 mmol, 1 equiv.). Aldehyde: SI-2g (603 mg, 3 mmol, 3 equiv.). 70% aqueous HCIO4: 0.1 mL. HC(OEt)3: 1.4 mL. Reaction time to first filtration: 3 hours. DI water quantity: 14 mL. Reaction time to second filtration: 22 hours. Yield: 116 mg (0.312 mmol, 31%) as an off-white solid. ’H NMR (500 MHz, DMSO-d6) δ: 11.34 (s, 1H), 8.39 (m, 1H), 8.28 (m, 1H), 8.07 (m, 1H), 8.00 (d, J = 9 Hz, 1H), 7.14 (d, J = 9 Hz, 1H), 7.11 (s, 1H).13C NMR (101 MHz, DMSO-d6) δ: 175.19, 161.68, 157.89, 151.24, 138.84, 131.22, 127.51, 126.68, 125.54, 122.57, 117.84, 116.71, 113.16, 110.29, 105.48. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C15H7Br3O3, 472.8018; found, 472.8013. The purity of Compound 13 was judged to be >95% by 'H NMR.

[0230]

[0231] Compound 14: Acetophenone: SI-1a (98 mg, 0.33 mmol, 1 equiv.). Aldehyde: SI-2h (248 mg, 1 mmol, 3 equiv.). 70% aqueous HCIO4: 0.04 mL. HC(OEt)3: 0.5 mL. Reaction time to first filtration: 4 hours. DI water quantity: 8 mL. Reaction time to second filtration: 18 hours. Yield: 17 mg (0.033 mmol, 10%) as an off-white solid. ’H NMR (500 MHz, DMSO-d6) δ: 11.35 (s, 1H), 8.45 (m, 1H), 8.40 (m, 1H), 8.07 (m, 1H), 8.01 (m, 1H), 7.08 (s, 1H), 7.05 (m, 1H).13C NMR (101 MHz, DMSO-d6) δ: 175.17, 161.68, 160.47, 151.29, 138.81, 137.23, 128.32, 126.68, 125.60, 123.02, 117.77, 115.20, 113.12, 105.36, 85.57. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C15H7Br2IO3, 520.7879; found, 520.7871. The purity of Compound 14 was judged to be ca 95% by ’H NMR.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0232]

[0233] Compound 15: Acetophenone: Sl-lb (215 mg, 1 mmol, 1 equiv.). Aldehyde: SI-2g (603 mg, 3 mmol, 3 equiv.). 70% aqueous HCIO4: 0.1 mL. HC(OEt)3: 1.4 mL. Reaction time to first filtration: 22 hours. DI water quantity: 8 mL. Reaction time to second filtration: 21 hours. Yield: 255 mg (0.64 mmol, 64%) as an off-white solid.rH NMR (500 MHz, DMSO-d6) δ: 11.29 (s, 1H), 8.29 (m, 1H), 8.13 (d, J = 8 Hz, 1H), 8.01 (m, 2H), 7.42 (m, 1H), 7.14 (d, J = 8 Hz, 1H), 7.07 (s, 1H).13C NMR (101 MHz, DMSO-d6) δ: 176.41, 161.40, 157.71, 151.87, 137.23, 131.16, 127.43, 126.38, 124.71, 124.52, 122.87, 116.71, 111.36, 110.25, 105.54. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C15H8Br2O3, 394.8913; found, 394.8911. The purity of Compound 15 was judged to be >95% by 'H NMR.

[0234]

[0235] Compound 17: Acetophenone: SI-lc (147 mg, 0.5 mmol, 1 equiv.). Aldehyde: SI-2g (301 mg, 1.5 mmol, 3 equiv.). 70% aqueous HCIO4: 0.05 mL. HC(OEt)3: 0.7 mL. Reaction time to first filtration: 20 hours. Note: solid crashed out with ca 8 mL Et20 before first filtration. DI water quantity: 7 mL. Reaction time to second filtration: 22 hours. Yield: 11 mg (0.023 mmol, 5%) as a tan solid. 'H NMR (400 MHz, DMSO-d6) δ: 11.45 (s, 1H), 8.29 (m, 1H), 8.02 (m, 1H), 8.00 (m, 1H), 7.23 (s, 1H), 7.15 (d, J = 9 Hz, 1H).13C NMR (101 MHz, DMSO-d6) δ: 174.50, 162.36, 158.25, 148.75, 132.98, 132.53, 131.79, 131.53, 127.81, 122.21, 121.70, 116.81, 110.39, 106.44. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C14H6Br3NO3, 473.7971: found, 473.7965. The purity of Compound 17 was judged to be ca 95% by ’H NMR.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0236] Example 2

[0237] C4’-hydroxy Flavonoid-Like Compounds via a Chalcone-mediated Route — Compounds 9,

[0238] 16, 18-29, 65-67, & 70

[0239]

[0240] 7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0241]

[0242] Scheme SI-2: C4’ hydroxy Flavonoid-Like Compounds Via a Chalcone-Mediated Route General Procedure 2:

[0243] Step 1: A mixture of acetophenone SI-1 (1 equiv.) and aldehyde SI-3 (1 equiv.) in EtOH was treated with KOH (3M in 96% EtOH) and stirred at room temperature for a given time. The reaction was then quenched with excess 6M HC1, and the resultant precipitate was isolated and dried by suction filtration. The crude material was triturated in boiling MeOH if necessary and filtered to give the chalcone intermediate SI-4.

[0244] Step 2: A solution of chalcone intermediate SI-4 (1 equiv.) in DMSO was treated with h (0.1 equiv.). The reaction was capped, sealed, and heated with stirring to 140 °C for a given time. The reaction was then cooled to room temperature and quenched with saturated aqueous Na2S2O3, diluted with DI water, and the resultant precipitate was isolated and dried by suction filtration to give pure chromenone intermediate SI-5.

[0245] Step 3: A suspension of chomenone intermediate SI-5 (1 equiv.), K2CO3 (4 equiv.) and (Ph3P)4Pd° (0.05 equiv.) in MeOH was sparged with argon for one minute. The reaction vessel was then capped, sealed, and heated a reflux for a given time. The reaction was then cooled to room temperature and quenched with saturated aqueous NH4CI, and the resultant precipitate was isolated and dried by suction filtration. Recrystallization of the precipitate from MeOH followed by filtration gave the title compound.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0246]

[0247] Compound 9:

[0248] Step 1: Acetophenone SI-1a (517 mg, 1.76 mmol, 1 eq) and aldehyde SI-3a (602 mg, 1.76 mmol, 1 equiv.) were reacted with 3 mL (9 mmol, 5.1 equiv.) 3M KOH in 96% EtOH in 3 mL EtOH. Reaction time: 16h. After trituration in boiling MeOH, 725 mg (1.17 mmol, 66%) of compound SI-4a were obtained as a yellow solid. ’H NMR (500 MHz, DMSO-d6) δ: 13.67 (s, 1H), 8.65 (m, 1H), 8.13 (m, 1H), 8.10 (m, 1H), 8.05 (d, J = 15 Hz, 1H), 8.00 (d, J = 8.5 Hz), 7.90 (d, J = 15 Hz), 7.18 (d, J = 8.5 Hz, 1H), 6.04 (m, 1H), 5.49 (d, J = 18 Hz, 1H), 5.28 (d, J = 11 Hz, 1H), 4.71 (m, 2H), 1.11 (m, 21H).13C NMR (101 MHz, DMSO-d6) δ: 192.88, 161.79.

[0249] 158.27, 146.44, 140.74, 134.20, 132.95, 132.94, 132.40, 126.97, 122.19, 118.93, 117.55, 112.83, 112.62, 112.34, 110.51, 102.45, 95.22, 69.01, 18.61, 10.83. LRMS-ESI-MS (m / z): [M-H]’ calculated for C29H34Br20sSi, 615.06; found, 615.16.

[0250] Step 2: Chalcone: SI-4a (31 mg, 0.05 mmol, 1 equiv.). I2: 1.5 mg, 0.005 mmol 0.1 equiv.

[0251] DMSO: 1 mL. Reaction time: 1 hour. Compound SI-5a (14 mg, 0.022 mmol, 44%) was obtained in acceptable purity as an off-white solid.1H NMR (400 MHz, CDCI3) 8: 8.28 (d, J = 2 Hz, 1H). 8.06 (d, J = 2 Hz, 1H), 8.02 (d, J = 2 Hz, 1H), 7.92 (dd, J = 9, 2 Hz), 6.99 (d, J = 9 Hz, 1H). 6.78 (s, 1H), 6.06 (ddt, J = 18, 11, 5 Hz, 1H), 5.52 (dd, J = 18, 2 Hz, 1H), 5.32 (dd, J = 11 Hz, 2 Hz, 1H), 4.67 (d, J = 5 Hz, 2H), 1.16 (m, 21H).13C NMR (101 MHz, CDCI3) 8: 176.79, 163.32, 162.92, 152.16, 139.71, 132.83, 132.57, 128.45, 128.28, 126.46, 123.41, 118.94, 118.48, 114.96, 113.41, 112.88, 106.42, 102.05, 97.50, 69.92, 19.17, 11.79. LRMS-ESI-MS (m / z): [M+H]+calculated for C29H32Br2C>3Si, 615.06; found, 615.34. Step 2.2 (only en route to compound 9): Compound SI-5a (10 mg, 0.016 mmol, 1 equiv.) was solvated in dry DMF (1 mL) and treated with dry CsF (24 mg, 0.16 mmol, 10 equiv.). The reaction mixture was stirred at room temperature for 18 hours and then crashed out with the addition of saturated aqueous NaHCCh. The precipitate formed was isolated on a filter frit, washed with DI water, and dried to give 5 mg (0.011 mmol, 69%) of SI-5b as a white solid.1H NMR (400 MHz, CDCI3) 8: 8.29 (d, J = 2 Hz, 1H), 8.09 (d, J = 2 Hz, 1H), 8.03 (d, J = 2 Hz, 1H), 7.94 (dd, J = 9, 2 Hz, 1H), 7.03 (d, J = 9 Hz, 1H), 6.77 (s, 1H), 6.08 (ddt, J = 16, 10, 5 Hz, 1H), 5.51 (d, J = 16 Hz, 1H), 5.36 (d, J = 10 Hz, 1H), 4.74 (d, J = 5 Hz, 1H), 3.39 (s, 3H).7158- 113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0252] 13C NMR (101 MHz, CDCh) 5: 176.74, 163.12, 162.95, 152.16, 139.76, 132.94, 132.41, 129.04, 128.29, 126.46, 123.68, 119.02, 118.83, 113.46, 113.42, 113.03. 106.60, 83.14, 79.17, 70.04. LRMS-ESI-MS (m / z): [M+Na]+calculated for C20Hi2Br2O3, 480.91; found, 481.18.

[0253] Step 3: 125 mg (0.272 mmol, 1 equiv.) of SI-5b in 2.7 mL MeOH was treated with equivalencies of other reagents described in general procedure 2. Reaction time: 3.5 hours. Yield of 9: 72 mg (0.17 mmol, 63%) as a tan solid.1H NMR (500 MHz, DMSO-d6) δ: 8.33 (m, 1H), 8.04 (m, 1H), 8.01 (m, 1H), 7.85 (d, J = 9 Hz, 1H), 6.87 (s, 1H), 6.75 (d, J = 9 Hz, 1H), 4.11 (s, 1H).13C NMR (101 MHz, DMSO-d6) δ: 174.69, 168.51, 163.15, 151.24, 138.44, 132.21, 128.89, 126.61, 125.75, 118.00, 117.49, 116.25, 113.00, 111.05, 103.22, 83.34, 81.92. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C17H8Br2O3, 418.8913; found, 418.8912. The purity of Compound 9 was judged to be ca 95% by1H NMR.

[0254]

[0255] Compound 16:

[0256] Step 1: Acetophenone SI-1a (147 mg, 0.5 mmol, 1 equiv.) and aldehyde SI-3b (121 mg, 0.5 mmol, 1 equiv.) were reacted with 0.8 mL (2.7 mmol, 5.4 equiv) 3M KOH in 96% EtOH in 6.2 mL EtOH. Reaction time: 15 hours. After trituration in boiling MeOH, 163 mg (0.315 mmol, 63%) of compound SI-4b were obtained as a yellow solid. ’H NMR (500 MHz, DMSO-d6) δ: 12.99 (s, 1H), 8.35 (m, 1H), 8.14 (m, 1H), 8.11 (d, J = 8 Hz, 1H), 8.01 (d, J = 15 Hz, 1H), 7.73 (d, J = 15 Hz, 1H), 7.63 (d, J = 8 Hz, 1H), 6.07 (m, 1H), 5.49 (d, J=17 Hz, 1H), 5.34 (d, J = 10 Hz, 1H), 4.81 (m, 2H).13C NMR (100 MHz, DMSO-d6) δ: 192.48, 157.41, 152.54, 144.96, 143.55, 140.61, 132.26, 132.25, 132.18, 126.31, 122.93, 122.80, 121.17, 118.34, 112.60, 110.58, 69.67. LRMS-ESI-MS (m / z): [M-H]’ calculated for Ci7Hi2Br3NO3, 515.83; found, 515.94. Step 2: Chalcone: SI-4b (104 mg, 0.2 mmol, 1 equiv.). I2: 5 mg, 0.02 mmol 0.1 equiv. DMSO: 5 mL. Reaction time: 3 hours. Compound SI-5c was obtained in acceptable purity as an off-white solid. *H NMR (500 MHz, CDCh) 8: 8.31 (d, J = 3 Hz, 1H), 8.11 (d, J = 8 Hz, 1H), 8.03 (d, J = 3 Hz, 1H) 7.39 (s, 1H), 7.27 (d, J = 8 Hz, 1H), 6.07 (ddt, J = 18, 11, 5 Hz, 1H), 5.53 (dd, J = 18, 2 Hz, 1H), 5.41 (dd. J = 11, 2 Hz, 1H), 4.74 (d, J = 5 Hz, 2H).13C NMR (101 MHz, CDCh) 8: 176.77, 160.99. 154.50. 152.00, 141.03, 139.76, 134.22, 131.49, 128.56, 126.91, 122.24, 119.96, 119.60, 119.14, 113.28, 108.23, 70.55. LRMS-ESI-MS (m / z): [M+H]+calculated for Ci7Hi0Br3NO3, 515.83; found, 516.04.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0257] Step 3: Compound SI-5c (amount assumed from step 2) in 4 mL MeOH was treated with equivalencies of other reagents described in general procedure 2. Reaction time: 3 hours. Yield of 16: 31 mg (0.063 mmol, 32% over 2 steps) as a slightly yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 8.35 (d, J = 2 Hz, 1H), 8.05 (d, J = 2 Hz, 1H), 7.92 (d, J = 8 Hz, 1H), 7.15 (d, J = 8 Hz, 1H), 6.84 (s, 1H).13C NMR (101 MHz, DMSO-d6) δ: 174.46, 161.87, 159.82, 151.14, 138.54, 135.13, 131.51, 126.69, 126.03, 123.18, 122.67, 117.64, 112.87, 103.36. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C14H6Br3NO3, 473.7971; found, 473.7965. The purity of Compound 16 was judged to be ca 90% by1H NMR.

[0258]

[0259] Compound 18:

[0260] Step 1: Acetophenone SI-1a (147 mg, 0.5 mmol, 1 eq) and aldehyde SI-3c (121 mg, 0.5 mmol, 1 equiv) were reacted with 0.8 mL (2.7 mmol, 5.4 equiv) 3M KOH in 96% EtOH in ImL EtOH. Reaction time: 18 hours. 229 mg (0.44 mmol, 88%) of crude compound SI-4c were obtained as a yellow solid at an acceptable level of purity. 'H NMR (500 MHz, DMSO-d6) δ: 13.11 (s, 1H), 8.54 (m, 1H), 8.51 (m, 1H), 8.44 (m, 1H), 8.16 (m, 1H), 8.14 (d, J = 15 Hz, 1H), 7.77 (d, J = 15 Hz, 1H), 6.08 (ddt, J = 17, 11, 4 Hz, 1H), 5.49 (d, J = 17 Hz, 1H), 5.35 (d, J = 11 Hz, 1H), 4.91 (d, J = 4 Hz, 2H).13C NMR (101 MHz, CDC13) 8: 176.85, 161.32, 154.13, 152.02, 142.51, 139.87, 136.06, 131.75, 128.51, 127.00, 126.90, 123.17, 119.66, 119.24, 113.44, 108.34, 70.98. LRMS-ESI-MS (m / z): [M-H]’ calculated for C17H12Br3NO3, 515.83; found, 515.92.

[0261] Step 2: Chalcone: SI-4c (229 mg, 0.44 mmol, 1 equiv.). I2: 12 mg, 0.044 mmol 0.1 equiv.

[0262] DMSO: 35 mL. Reaction time: 2 hours. Compound SI-5d was obtained in acceptable purity as an off-white solid. 'H NMR (500 MHz, CDCI3) 8: 8.38 (s, 1H), 8.33 (s, 1H), 8.32 (m, 1H), 8.05 (m, 1H), 7.37 (s, 1H), 6.09 (ddt, J = 17, 11, 5 Hz, 1H), 5.54 (d, J = 17 Hz, 1H), 5.42 (d, J = 11 Hz, 1H), 4.84 (d, J = 5 Hz, 1H).13C NMR (101 MHz, CDCI3) 8: 176.85, 161.32, 154.13, 152.02, 142.51, 139.87, 136.06, 131.75, 128.51, 127.00, 126.90, 123.17, 119.66, 119.24, 113.44, 108.34, 70.98. LRMS-ESI-MS (m / z): [M+H]+calculated for C17H10Br3NO3, 515.83; found, 516.03. Step 3: Compound SI-5d (amount assumed from step 2) in 8.8 mL MeOH was treated with equivalencies of other reagents described in general procedure 2. Reaction time: 3 hours. Yield of 18: 51 mg (0.107 mmol, 24% over 2 steps) as a slightly yellow solid. ’H NMR (400 MHz, DMSO-d6) δ: 8.40 (m, 1H), 8.19 (m, 2H), 8.08 (m, 1H), 7.00 (s, 1H).13C NMR (101 MHz,7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0263] DMSO-d6) 8: 174.99, 161.11, 155.59, 151.24, 139.58, 138.95, 137.59, 126.74, 125.91, 125.86, 119.15, 117.97, 113.25, 105.56. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C14H6Br3NO3, 473.7971; found, 473.7966. The purity of Compound 18 was judged to be >95% by1H NMR.

[0264]

[0265] Compound 19:

[0266] Step 1: Acetophenone Sl-lb (65 mg, 0.3 mmol, 1 eq) and aldehyde SI-3b (73 mg, 0.3 mmol, 1 equiv) were reacted with 0.5 mL (1.7 mmol, 5.3 equiv) 3M KOH in 96% EtOH in 3.7 mL EtOH. Reaction time: 18 hours. 77 mg (0.175 mmol, 58%) of compound SI-4d were obtained as a yellow solid following recrystallization from MeOH. ’H NMR (500 MHz, DMSO-d6) 8: 13.28 (s, 1H), 8.51 (s, 1H), 8.48 (s, 1H), 8.29 (d, J = 8 Hz, 1H), 8.19 (d, J = 16 Hz, 1H), 7.93 (d, J = 8 Hz, 1H), 7.81 (d, J = 16 Hz, 1H), 7.01 (t, J = 8 Hz, 1H), 6.08 (m, 1H), 5.49 (d, J = 17 Hz, 1H), 5.35 (d, J = 11 Hz, 1H), 4.90 (m, 2H).13C NMR (101 MHz, DMSO-d6) 8: 193.58, 158.70, 152.07, 146.33, 143.57, 139.67, 136.21, 132.53, 130.54, 129.12, 122.95, 121.36, 121.20, 120.47, 118.39, 111.07, 69.91. LRMS-ESI-MS (m / z): [M-H] calculated for Ci7Hi3Br2NO3, 437.92; found, 438.00.

[0267] Step 2: Chaicone: SI-4d (44 mg, 0.1 mmol, 1 equiv.). E: 3 mg, 0.01 mmol 0.1 equiv. DMSO: 2 mL. Reaction time: 2 hours. Compound SI-5e (35 mg, 0.08 mmol, 80%) was obtained in acceptable purity as an off-white solid.1H NMR (500 MHz, CDC13) 8: 8.42 (s, 1H), 8.33 (s, 1H), 8.19 (d, J = 8 Hz, 1H), 7.94 (d, J = 8 Hz, 1H), 7.37 (s, 1H), 7.32 (t, J = 8 Hz, 1H), 6.09 (m, 1H), 5.54 (d, J = 18 Hz, 1H), 5.42 (d, J = 11 Hz, 1H), 4.83 (m, 2H).13C NMR (101 MHz, CDC13) 8: 178.24, 161.07, 153.99, 152.95, 142.90, 137.68, 136.01, 131.82, 126.97, 126.51, 126.18, 125.79, 123.17, 119.60, 112.35, 108.38, 70.96. LRMS-ESI-MS (m / z): [M+H]+calculated for CnHuB^NCE, 437.92; found, 438.20.

[0268] Step 3: Compound SI-5e (110 mg, 0.25 mmol, 1 equiv.) in 5 mL MeOH was treated with equivalencies of other reagents described in general procedure 2. The reaction was stirred at reflux for 23 hours. The reaction was cooled to room temperature and (Ph3P)4Pd° (15 mg, 0.012 mmol, 0.05 equiv.) was added, and the reaction was then sparged with argon once more, capped, sealed, and heated back to reflux for five hours. The reaction was then worked up and purified as described in general procedure 2 step 3. Yield of 19: 20 mg (0.05 mmol, 20%) as a slightly7158- 113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0269] yellow solid. ’H NMR (400 MHz, DMSO-d6) δ: 8.40 (m, 1H), 8.19 (m, 2H), 8.08 (m, 1H), 7.00 (s, 1H).13C NMR (201 MHz, DMSO-*) 8: 174.99, 161.11, 155.59, 151.24, 139.58, 138.95, 137.59, 126.74, 125.91, 125.86, 119.15, 117.97, 113.25, 105.56. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C14H7Br2NO3, 395.8865; found, 395.8861. The purity of Compound 19 was judged to be >95% by ’H NMR.

[0270]

[0271] Compound 20:

[0272] Step 1: Acetophenone SI-1a (442 mg, 1.5 mmol, 1 eq) and aldehyde SI-3d (290 mg, 1.5 mmol, 1 equiv) were reacted with 2 mL (6 mmol, 4 equiv) 3M KOH in 96% EtOH in 7.2 mL EtOH. Reaction time: 18 hours. Compound SI-4e was obtained as a yellow solid at an acceptable level of purity without recrystallization. ’H NMR (500 MHz, DMSO-*) 8: 8.42 (s, 1H), 8.39 (d, J = 2 Hz, 1H), 8.29 (d, J = 16 Hz, 1H), 8.18 (d, J = 2 Hz, 1H), 8.00 (s, 1H), 7.83 (d, J = 16 Hz, 1H), 6.06 (ddt, J = 17, 11, 6 Hz, 1H), 5.45 (d, J = 17 Hz, 1H), 5.34 (d, J = 11 Hz, 1H), 4.79 (d, J = 6 Hz, 2H), 4.07 (s, 3H).13C NMR (101 MHz, DMSO-*) 8: 192.80, 157.52, 155.26, 146.84, 145.68, 145.37, 140.68. 135.01, 133.09, 132.13, 122.92, 122.75, 118.56, 112.68, 110.59, 108.66, 69.66, 56.21. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for Ci8Hi5Br2NO4, 467.9441; found, 467.9437.

[0273] Step 2: Chaicone: SI-4e (amount assumed from step 1). I2: 39 mg, 0.15 mmol 0.1 equiv.

[0274] DMSO: 60 mL. Reaction time: 2 hours. Compound SI-5f was obtained in acceptable purity as an off-white solid. ‘H NMR (500 MHz, CDCh) 8: 8.32 (m, 1H), 8.27 (m, 1H), 8.05 (m, 1H), 7.81 (m, 1H), 7.40 (s, 1H), 6.09 (m, 1H), 5.48 (d, J = 18 Hz, 1H), 5.39 (d, J = 11 Hz, 1H), 4.77 (m, 2H), 4.06 (s, 3H).13C NMR (101 MHz, DMSO-*) 8: 175.31, 161.42, 155.11, 151.23, 146.10, 141.91, 139.05, 135.58, 132.97, 126.79, 125.86, 118.68. 118.14, 113.39, 106.33, 104.99, 69.67, 55.77. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for Ci8Hi3Br2NO4, 465.9284; found, 465.9278.

[0275] Step 3: Compound SI-5f (amount assumed from steps 1-2) in 30 mL MeOH was treated with equivalencies of other reagents described in general procedure 2. Reaction time: 26 hours. Yield of 20: 204 mg (0.48 mmol, 32% over 3 steps) as a tan solid. ’H NMR (400 MHz, DMSO-*) 8: 10.51 (s, 1H), 8.41 (m, 1H), 8.21 (m„ 1H), 8.09 (m, 1H), 7.76 (m, 1H), 7.10 (s, 1H), 3.99 (s,7158- 113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0276] 1H).,3C NMR (101 MHz, DMSO-*) 8: 175.28, 161.87, 153.70, 151.28, 146.04, 140.20, 138.98, 138.09, 126.82, 125.93, 118.07, 113.36, 105.82, 105.51. 55.61. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C15H9Br2NO4, 425.8971; found, 425.8968. The purity of Compound 20 was judged to be >95% by1H NMR.

[0277]

[0278] Compound 21:

[0279] Step 1: Acetophenone Sl-lb (108 mg, 0.5 mmol, 1 eq) and aldehyde SI-3d (97 mg, 0.3 mmol, 1 equiv) were reacted with 0.8 mL (2.7 mmol, 5.4 equiv) 3M KOH in 96% EtOH in 6.2 mL EtOH. Reaction time: 16 hours. 83 mg (0.212 mmol, 44%) of compound SI-4f were obtained as a yellow solid following recrystallization from MeOH.1H NMR (400 MHz, DMSO-*) 8: 8.63 (d, J = 15 Hz, 1H), 8.45 (s, 1H), 8.43 (d, J = 8 Hz, 1H), 8.19 (s, 1H), 7.97 (d, J = 8 Hz, 1H), 7.95 (d, J = 15 Hz, 1H), 7.05 (t, J = 8 Hz, 1H), 6.08 (ddt, J = 17, 11, 5 Hz, 1H), 5.46 (d, J = 17 Hz, 1H), 5.35 (d, J = 11 Hz, 1H), 4.84 (d, J = 5 Hz, 2H), 4.14 (s, 3H).13C NMR (101 MHz, DMSO-*) 8: 193.03, 158.66, 146.26, 143.94, 140.05, 137.88, 132.34, 130.78, 128.99, 126.94, 121.24, 120.57, 119.08, 112.21, 111.20, 108.77, 70.38, 57.59. LRMS-ESI-MS (m / z): [M+H]+calculated for CisHi6BrNO4. 390.03; found, 390.23.

[0280] Step 2: Chaicone: SI-4f (58 mg, 0.15 mmol, 1 equiv.). H: 4 mg, 0.015 mmol 0.1 equiv. DMSO: 4 mL. Reaction time: 2 hours. Compound SI-5g (33 mg, 0.097 mmol, 65%) was obtained in acceptable purity as an off-white solid. ’H NMR (400 MHz, DMSO-*) 8: 8.36 (s, 1H), 8.12 (d, J = 8 Hz, 1H), 8.00 (d, J = 8 Hz, 1H), 7.74 (s, 1H), 7.41 (t, J = 8 Hz, 1H), 7.08 (s, 1H), 6.08 (ddt, J = 17, 11, 5 Hz, 1H), 5.45 (d, J = 17 Hz, 1H), 5.32 (d, J = 11 Hz, 1H), 4.76 (d, J = 5 Hz, 2H), 3.97 (s, 3H).13C NMR (101 MHz, DMSO-*) 8: 176.48, 161.14, 155.11, 151.82, 145.98, 142.19, 137.39, 135.55, 133.00, 126.63, 125.01, 124.63, 118.65, 111.54, 106.34, 104.89, 69.65.

[0281] 55.71. LRMS-ESI-MS (m / z): [M+H]+calculated for Ci8Hi4BrNO4, 388.02; found, 388.27. Step 3: Compound SI-5g (78 mg, 0.2 mmol, 1 equiv.) in 2 mL MeOH was treated with equivalencies of other reagents described in general procedure 2. Reaction time: 3 hours. Yield of 21: 22 mg (0.063 mmol, 32%) as a tan solid. ’H NMR (500 MHz, DMSO-*) 8: 10.49 (s, 1H), 8.21 (s, 1H), 8.15 (d, J = 8 Hz, 1H), 8.05 (d, J = 8 Hz, 1H), 7.80 (s, 1H), 7.45 (t, J = 8 Hz, 1H), 7.09 (s, 1H), 3.99 (s, 3H).13C NMR (101 MHz, DMSO-*) 8: 176.46, 161.56, 153.69, 151.81, 145.90, 140.41, 138.02, 137.32, 126.58, 125.03, 124.64, 111.49, 105.81, 105.34, 55.55.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0282] HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C15H10BrNO4, 347.9866; found, 347.9867. The purity of Compound 21 was judged to be ca 95% by1H NMR.

[0283]

[0284] Compound 22:

[0285] Step 1: Acetophenone SI-1a (882 mg, 3 mmol, 1 equiv.) and aldehyde SI-3e (580 mg, 3 mmol, 1 equiv) were reacted with 4 mL (12 mmol, 4 equiv) 3M KOH in 96% EtOH in 14 niL EtOH. Reaction time: 16 hours. 905 mg (1.93 mmol, 64%) of compound SI-4g were obtained as a yellow solid following recrystallization from MeOH.1H NMR (400 MHz, DMSO-d6) 5: 8.29 (d, J = 2 Hz, 1H), 8.13 (d, J = 2 Hz, 1H), 7.96 (d, J = 15 Hz, 1H), 7.76 (d, J = 15 Hz, 1H), 7.59 (d, J = 8 Hz, 1H), 7.38 (d, J = 8 Hz, 1H), 6.06 (ddt, J = 18, 11, 5 Hz, 1H), 5.43 (d, J = 18 Hz, 1H), 5.31 (d, J = 11 Hz, 1H), 4.68 (d, J = 5 Hz, 2H), 4.00 (s, 3H).13C NMR (101 MHz, DMSO-d6) 5: 192.69, 157.45, 153.66, 145.48, 145.03, 140.23, 132.78, 131.97, 123.09, 121.47, 120.97, 119.00, 118.62, 118.61, 112.67, 110.50, 69.03, 53.30. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C18H15Br2NO4, 467.9441; found, 467.9439.

[0286] Step 2: Chaicone: SI-4g (905 mg, 1.93 mmol, 1 equiv.). h: 49 mg, 0.19 mmol 0.1 equiv.

[0287] DMSO: 75 mL. Reaction time: 4 hours. Compound SI-5h was obtained in acceptable purity as an off-white solid. ’ll NMR (400 MHz, DMSO-d6) 5: 8.42 (d, J = 2 Hz, 1H), 8.10 (d, J = 2 Hz, 1H), 7.79 (d, J = 8 Hz, 1H). 7.55 (d, J = 8 Hz, 1H), 7.14 (s, 1H), 6.07 (ddt. J = 17, 11, 5 Hz, 1H), 5.46 (d, J = 17 Hz, 1H), 5.33 (d, J = 11 Hz, 1H), 4.72 (d, J = 5 Hz, 2H), 4.00 (s, 3H).13C NMR (101 MHz, CDCh) 5: 177.19, 162.58, 154.75, 152.11, 146.52, 139.61, 136.58, 132.22, 128.43, 126.83, 119.79, 118.86, 118.63, 116.63, 113.29, 107.45, 70.28, 54.58. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for CisHi3Br2NO4, 465.9284; found, 465.9278.

[0288] Step 3: Compound SI-5h (amount assumed from step 2.) in 39 mL MeOH was treated with equivalencies of other reagents described in general procedure 2. Reaction time: 2 hours. Yield of 22: 674 mg (1.58 mmol, 82%) as a slightly yellow solid. ’H NMR (500 MHz, DMSO-d6) 5: 10.71 (s, 1H), 8.41 (d, J = 2 Hz, 1H), 8.10 (d, J = 2 Hz, 1H), 7.73 (d, J = 8 Hz, 1H), 7.31 (d, J = 8 Hz, 1H), 7.11 (s, 1 H), 4.00 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 175.17, 161.73, 153.41, 151.26, 145.43, 138.85, 133.84, 126.79, 125.87, 121.53, 117.82, 116.77, 113.03, 105.41, 53.29. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for Ci5H9Br2NO4, 425.8971; found, 425.8970. The purity of Compound 22 was judged to be >95% by1H NMR.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0289]

[0290] Compound 23:

[0291] Step 1: Acetophenone Sl-lb (323 mg, 1.5 mmol, 1 equiv.) and aldehyde SI-3e (290 mg, 1.5 mmol, 1 equiv) were reacted with 2 mL (6 mmol, 4 equiv) 3M KOH in 96% EtOH in 7 mL EtOH. Reaction time: 14 hours. Compound SI-4h was obtained as a yellow solid in sufficient purity to carry forward crude. ’H NMR (500 MHz, DMSO-d6) 5: 13.49 (s, 1H), 8.20 (d, J = 8 Hz, 1H), 8.03 (d, J = 15 Hz, 1H), 7.92 (d, J = 8 Hz, 1H), 7.81 (d, J = 15 Hz, 1H), 7.49 (d, J = 8 Hz, 1H), 7.37 (d, J = 8 Hz, 1H), 7.01 (t, J = 8 Hz, 1H), 6.05 (m, 1H), 5.43 (d, J = 17 Hz, 1H), 5.31 (d, J = 11 Hz, 1H), 4.68 (d, J = 5 Hz, 1H), 4.02 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 193.58, 158.75, 153.66. 145.08, 144.79, 140.12, 139.42, 132.78, 130.17, 122.12, 121.20, 120.46, 120.31, 118.90, 118.61, 111.08, 69.00, 53.27. LRMS-ESI-MS (m / z): [M+H]+calculated for Ci8Hi6BrNO4, 390.03; found, 390.25.

[0292] Step 2: Chaicone: SI-4h (amount assumed from step 1). I2: 39 mg, 0.15 mmol 0.1 equiv.

[0293] DMSO: 60 mL. Reaction time: 3 hours. Compound SI-5i was obtained in acceptable purity as an off-white solid. ‘H NMR (400 MHz, CDCI3) 8: 8.17 (d, J = 8 Hz, 1H), 7.90 (d, J = 8 Hz, 1H), 7.84 (d, J = 8 Hz, 1H), 7.33 (s, 1H), 7.29 (t, J = 8 Hz, 1H), 7.17 (d, J = 8 Hz, 1H), 6.08 (ddt, J = 17, 11, 6 Hz, 1H), 5.46 (d, J = 17 Hz, 1H), 5.38 (d, J = 11 Hz, 1H), 4.7 (d, J = 6 Hz, 1H), 4.09 (s, 3H).13C NMR (101 MHZ, CDCI3) 8: 178.60, 162.31, 154.65, 153.03, 146.30, 137.44, 136.93, 132.28, 126.21, 126.10, 125.68, 119.74, 118.68, 116.50, 112.23, 107.49, 70.26, 54.56. LRMS-ESI-MS (m / z): [M+H]+calculated for CisHi4BrNO4, 388.02; found, 388.28.

[0294] Step 3: Compound SI-5i (amount assumed from steps 1-2.) in 30 mL MeOH was treated with equivalencies of other reagents described in general procedure 2. Reaction time: 2 hours. Yield of 23: 240 mg (0.6 mmol, 40% over 3 steps) as a tan solid.1H NMR (500 MHz, DMSO-d6) 8: 10.65 (s, 1H), 8.13 (d, J = 8 Hz, 1H), 8.03 (d, J = 8 Hz, 1H), 7.75 (d, J = 8 Hz, 1H), 7.43 (t, J = 8 Hz, 1H), 7.31 (d, J = 8 Hz, 1H), 7.09 (s, 1H), 4.00 (s, 3H).13C NMR (101 MHz. DMSO-d6) 8: 176.49, 161.55, 153.43, 151.93, 145.31, 137.32, 134.16, 126.47, 125.07, 124.67, 121.63, 116.68, 111.30, 105.52, 53.33. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C15H10BrNO4, 347.9866; found, 347.9867. The purity of Compound 23 was judged to be >95% by 'H NMR.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0295]

[0296] Compound 24:

[0297] Step 1: Acetophenone SI-1a (294 mg, 1 mmol, 1 equiv.) and aldehyde SI-3f (196 mg, 1.2 mmol, 1.2 equiv.) were reacted with 1.7 mL (5.1 mmol, 5.1 equiv.) 3M KOH in 96% EtOH in 5.3 mL EtOH. Reaction time: 16 hours. 278 mg (0.63 mmol, 63%) of compound SI-4i were obtained as a yellow solid following recrystallization from MeOH.1H NMR (400 MHz, DMSO-d6) 8: 8.44 (d, J = 3 Hz, 1H), 8.39 (d, J = 2 Hz, 1H), 8.14 (d, J = 2 Hz, 1H), 8.09 (d, J = 16 Hz, 1H), 8.08 (d, J = 9 Hz, 1H), 7.84 (d, J = 16 Hz, 1H), 7.53 (dd, J = 9, 3 Hz), 6.07 (ddt, J = 17, 11, 5 Hz, 1H), 5.45 (d, J = 17 Hz, 1H), 5.32 (d, J = 11 Hz), 4.75 (d, J = 5 Hz).13C NMR (101 MHz, DMSO-d6) 8: 192.73, 157.62, 155.69, 145.36, 144.87, 140.63, 139.08, 132.80, 132.10, 126.56, 122.76, 121.70, 121.35. 118.46, 112.56, 110.56, 68.87. LRMS-ESI-MS (m / z): [M-Hf calculated for Ci7Hi3Br2NO3, 437.92; found, 438.04.

[0298] Step 2: Chaicone: SI-4i (132 mg, 0.3 mmol, 1 equiv.). I2: 8 mg, 0.03 mmol 0.1 equiv. DMSO: 3 mL. Reaction time: 2 hours. Compound SI-5j (55 mg, 0.126 mmol, 42%) was obtained in acceptable purity as an off-white solid.1H NMR (400 MHz, DMSO-d6) 8: 8.53 (d, J = 3 Hz, 1H), 8.43 (d, J = 2 Hz, 1H), 8.15 (d, J = 9 Hz), 8.11 (d, J = 2 Hz), 7.71 (dd, J = 9, 3 Hz, 1H), 7.13 (s, 1H), 6.08 (ddt, J = 17, 11, 5 Hz, 1H), 5.47 (d, J = 17 Hz, 1H), 5.34 (d, J = 11 Hz, 1H), 4.79 (d, J = 5 Hz, 1H).13C NMR (101 MHz, DMSO-d6) 8: 175.29. 161.62, 156.62, 151.35, 139.50, 139.06, 132.62, 126.83, 125.95, 122.48, 121.73, 119.47, 118.72, 118.04, 113.23, 106.01, 69.03. LRMS-ESI-MS (m / z): [M+H]+calculated for Ci7HnBr2NO3, 437.92; found, 438.18. Step 3: Compound SI-5j (44 mg, 0.1 mmol, 1 equiv.) in 2 mL MeOH was treated with equivalencies of other reagents described in general procedure 2. Reaction time: 23 hours. Yield of 24: 15 mg (0.038 mmol, 38%) as a tan solid. ‘H NMR (500 MHz, DMSO-d6) 8: 10.96 (s, 1H), 8.42 (d, J = 2 Hz, 1H), 8.34 (d, J = 3 Hz, 1H), 8.10 (d, J = 2 Hz, 1H), 8.08 (d, J = 9 Hz, 1H), 7.44 (dd, J = 9, 3 Hz, 1H), 7.09 (s, 1H).13C NMR (101 MHz, DMSO-d6) 8: 175.26, 162.06, 156.62, 151.34, 139.49. 139.00, 138.45, 126.84, 125.99, 122.86, 122.76, 118.01, 113.21, 105.47. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C14H7Br2NO3, 395.8865; found, 395.8866. The purity of Compound 24 was judged to be >95% by1H NMR.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0299]

[0300] Compound 25:

[0301] Step 1: Acetophenone Sl-ld (125 mg, 0.5 mmol, 1 equiv.) and aldehyde SI-3e (97 mg, 0.5 mmol, 1 equiv.) were reacted with 0.8 mL (2.4 mmol, 4.8 equiv.) 3M KOH in 96% EtOH in 6.2 mL EtOH. Reaction time: 16 hours. 148 mg (0.35 mmol, 70%) of compound SI-4j were obtained as a yellow solid following recrystallization from MeOH. ’f l NMR (400 MHz, DMSO-d6) 5: 8.19 (m, 1H), 8.04 (m, 1H), 7.96 (d, J = 15 Hz, 1H), 7.76 (d, J = 15 Hz, 1H), 7.58 (d, J = 8 Hz, 1H), 7.38 (d, J = 15 Hz, 1H), 6.06 (ddt, J = 17, 11, 4 Hz, 1H), 5.43 (d, J = 17 Hz, 1H), 5.33 (d, J = 11 Hz, 1H), 4.68 (d, J = 4 Hz, 2H), 4.01 (s, 3H).13C NMR (101 MHz, DMSO-&) 5: 192.75, 157.15, 153.66, 145.52, 145.05, 140.20, 137.93, 132.78, 129.14, 123.34, 122.36, 121.74, 120.84, 118.93, 118.62, 112.30, 69.02, 53.32. LRMS-ESI-MS (m / z): LM-HJ’ calculated for Ci8Hi5BrClNO4, 423.98; found, 424.07.

[0302] Step 2: Chaicone: SI-4j (85 mg, 0.2 mmol, 1 equiv.). E: 5 mg, 0.02 mmol 0.1 equiv. DMSO: 5 mL. Reaction time: 2 hours. Compound SI-5k (51 mg, 0.12 mmol, 60%) was obtained in acceptable purity as an off-white solid. ’H NMR (400 MHz, CDCh) 5: 8.12 (d, J = 2 Hz, 1H), 7.86 (d, J = 2 Hz, 1H), 7.77 (d, J = 8 Hz, 1H), 7.30 (s, 1H), 7.14 (d, J = 8 Hz, 1H), 6.08, 6.07, 5.46 (d, J = 17 Hz, 1H), 5.38 (d, J = 11 Hz, 1H), 4.69 (d, J = 5 Hz, 1H), 4.07 (s, 3H).13C NMR (101 MHz, CDCh) 8: 177.27, 162.51, 154.67, 151.63, 146.48, 137.00. 136.48, 132.20, 131.64, 126.37, 125.21, 119.79, 118.55, 116.58, 113.07, 107.29, 70.27, 54.56. LRMS-ESI-MS (m / z): [M+H]+calculated for CisHnBrClNCU, 423.98; found, 424.24.

[0303] Step 3: Compound SI-5k (47 mg, 0.1 mmol, 1 equiv.) in 2 mL MeOH was treated with equivalencies of other reagents described in general procedure 2. Reaction time: 2 hours. Yield of 25: 24 mg (0.063 mmol, 63%) as a tan solid. ’H NMR (500 MHz, DMSO-d6) 8: 10.69 (s, 1H), 8.28 (d, J = 2 Hz, 1H), 7.94 (d, J = 2 Hz, 1H), 7.70 (d, J = 8 Hz, 1H), 7.29 (d, J = 8 Hz, 1H), 7.06 (s, 1H), 3.99 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 175.38, 161.81, 153.46, 150.98, 145.48, 136.44, 133.88, 130.16, 125.52, 123.75, 121.58, 116.83, 112.91, 105.37, 53.34. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for Ci5H9BrClNO4, 381.9476; found, 381.9475. The purity of Compound 25 was judged to be ca 95% by1H NMR.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0304]

[0305] Compound 26:

[0306] Step 1: Acetophenone Sl-le (82 mg, 0.4 mmol, 1 equiv.) and aldehyde SI-3e (77 mg, 0.4 mmol, 1 equiv.) were reacted with 0.53 mL (1.6 mmol, 4 equiv.) 3M KOH in 96% EtOH in 1.9 mL EtOH. Reaction time: 22 hours. 107 mg (0.28 mmol, 70%) of compound SI-4k were obtained as a yellow solid following recrystallization from MeOH.

[0307]

[0308] (400 MHz, DMSO-7,1 5: 8.11 (m, 1H), 7.92 (m, 2H), 7.74 (d, J = 15 Hz, 1H), 7.56 (m, 1H), 7.39 (m, 1H), 6.05 (m, 1H), 5.43 (d, J = 17 Hz, 1H), 5.31 (d, J = 11 Hz, 1H), 4.68 (m, 2H), 4.00 (s, 3H).13C NMR (101 MHz, DMSO-fc) 8: 192.67, 155.83, 153.66, 145.32, 145.03, 140.21, 134.81, 132.79, 128.50, 123.16, 122.94, 122.76, 121.73, 121.35, 118.95, 118.62, 69.02, 53.31. LRMS-ESI-MS (m / z): [M-H]’ calculated for C18H15Q2NO4, 378.03: found, 378.08.

[0309] Step 2: Chaicone: SI-4k (95 mg, 0.25 mmol, 1 equiv.). I2: 6 mg, 0.025 mmol 0.1 equiv. DMSO: 8 mL. Reaction time: 2 hours. Compound SI-51 (76 mg, 0.2 mmol, 80%) was obtained in acceptable purity as an off-white solid. ’H NMR (400 MHz, CDCh) 8: 8.11 (d, J = 2 Hz, 1H), 7.79 (d, J = 8 Hz, 1H), 7.73 (d, J = 2 Hz, 1H), 7.35 (s, 1H), 7.17 (d, J = 8 Hz, 1H), 6.08 (ddt, J = 17, 11, 6 Hz, 1H), 5.46 (d, J = 17 Hz, 1H), 5.38 (d, J = 11 Hz, 1H), 4.71 (d, J = 6 Hz, 2H), 4.09 (s, 3H).13C NMR (101 MHz, CDCh) 8: 176.89, 162.02, 154.34, 150.39, 146.13, 136.15, 133.70, 131.83, 130.83, 126.15, 124.29, 124.12, 119.42, 118.19, 116.07, 107.08, 69.89, 54.19. LRMS-ESI-MS (m / z): [M+H]+calculated for C18H13CI2NO4, 378.03; found, 378.22.

[0310] Step 3: Compound SI-51 (38 mg, 0.1 mmol, 1 equiv.) in 2 mL MeOH was treated with equivalencies of other reagents described in general procedure 2. Reaction time: 2 hours. Yield of 26: 10 mg (0.03 mmol, 30%) as a tan solid. H NMR (400 MHz, DMSO-d6) 8: 10.70 (s, 1H), 8.21 (d, J = 2Hz, 1H), 7.93 (d, J = 2 Hz, 1H), 7.71 (d, J = 8 Hz, 1H), 7.30 (d, J = 8 Hz, 1H), 7.11 (s, 1H), 3.99 (s, 3H).13C NMR (101 MHz, DMSO-A,) 8: 175.26, 161.69, 153.44, 150.04, 145.43, 133.85, 133.55, 129.67, 125.69, 123.77, 123.15, 121.62, 116.79, 105.52, 53.29. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C15H9Cl2NO4, 337.9981: found, 337.9983. The purity of Compound 26 was judged to be ca 95% by ’H NMR.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0311]

[0312] Compound 27:

[0313] Step 1: Acetophenone Sl-lf (108 mg, 0.5 mmol, 1 equiv.) and aldehyde SI-3e (97 mg, 0.5 mmol, 1 equiv.) were reacted with 0.8 mL (2.4 mmol, 4.8 equiv.) 3M KOH in 96% EtOH in 6.2 mL EtOH. Reaction time: 16 hours. 112 mg (0.287 mmol, 57%) of compound SI-41 were obtained as a yellow solid following recrystallization from MeOH.1H NMR (400 MHz, DMSO-d6) 8: 11.81 (s, 1H), 7.97 (d, J = 2 Hz, 1H), 7.90 (d, J = 15 Hz, 1H), 7.64 (dd, J = 9, 2 Hz, 1H), 7.61 (s, J = 15 Hz, 1H), 7.45 (d, J = 8 Hz, 1H), 7.34 (d, J = 8 Hz, 1H), 6.98 (d, J = 9 Hz, 1H), 6.05 (ddt, J = 17, 11, 6 Hz, 1H), 5.42 (d, J = 17 Hz), 5.30 (d, J = 11 Hz, 1H), 4.66 (d, J = 6 Hz, 1H), 3.97 (s, 3H).13C NMR (101 MHz, DMSO-d6) 5: 191.74, 158.98, 153.57, 144.67, 143.25, 140.49, 137.40, 132.84. 132.17, 124.81, 123.52, 121.24, 119.98, 119.00, 118.54, 110.32, 68.96, 53.08. LRMS-ESI-MS (m / z): [M-H]’ calculated for CisHieBrNC, 388.02; found, 388.08.

[0314] Step 2: Chaicone: SI-41 (69 mg, 0.176 mmol, 1 equiv.). h: 5 mg, 0.02 mmol 0.1 equiv. DMSO: 5 mL. Reaction time: 4 hours. Compound SI-5m was obtained in acceptable purity as an off-white solid. ’H NMR (400 MHz, CDCh) 8: 8.34 (d, J = 2 Hz, 1H), 7.75 (dd, J = 9, 2 Hz, 1H), 7.65 (d, J = 8 Hz, 1H), 7.43 (d, J = 9 Hz, 1H), 7.32 (s, 1H), 7.13 (d, J = 8 Hz, 1H), 6.08 (ddt, J = 17, 11, 6 Hz, 1H), 5.45 (d, J = 17 Hz, 1H), 5.37 (d, J = 11 Hz, 1H), 4.69 (d, J = 6 Hz, 1H), 4.07 (s, 3H).13C NMR (101 MHz, CDCh) 8: 177.83, 162.48, 155.23, 154.67, 146.27, 137.01, 136.87, 132.25, 128.92, 126.08, 120.37, 119.74, 119.00, 118.49, 115.80, 107.69, 70.25, 54.56. LRMS-ESI-MS (m / z): [M+H]+calculated for CisHuBrNCh, 388.02; found, 388.29.

[0315] Step 3: Compound SI-5m (amount assumed from step 2) in 4 mL MeOH was treated with equivalencies of other reagents described in general procedure 2. Reaction time: 2 hours. Yield of 27: 29 mg (0.083 mmol, 50% over 2 steps) as a tan solid.1H NMR (400 MHz, DMSO-d6) 8: 10.63 (s, 1H), 8.11 (s, 1H), 8.00 (d, J = 8 Hz, 1H), 7.77 (m, 1H), 7.26 (d, J = 8 Hz, 1H), 7.09 (s, 1H), 3.99 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 175.68, 161.93, 154.46, 153.32, 145.26, 136.76, 134.08, 126.98. 125.14, 121.43, 121.14, 117.84, 116.68, 105.44, 53.24. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C15H10BrNO4, 347.9866; found, 347.9865. The purity of Compound 27 was judged to be >95% by1H NMR.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0316]

[0317] Compound 28:

[0318] Step 1: Acetophenone Sl-lg (68 mg, 0.4 mmol, 1 equiv.) and aldehyde SI-3e (77 mg, 0.4 mmol, 1 equiv.) were reacted with 0.53 mL (1.6 mmol, 4 equiv.) 3M KOH in 96% EtOH in 1.9 mL EtOH. Reaction time: 22 hours. 92 mg (0.266 mmol, 67%) of compound SI-4m were obtained as a yellow solid following recrystallization from MeOH. 'll NMR (400 MHz, DMSO-cL) 8: 11.86 (s, 1H), 7.93 (d, J = 15 Hz, 1H), 7.86 (d, J = 2 Hz, 1H), 7.62 (d, J = 15 Hz, 1H), 7.53 (dd, J = 9, 2 Hz, 1H), 7.45 (d, J = 8 Hz, 1H), 7.35 (d, J = 8 Hz, 1H), 7.03 (d, J = 9 Hz, 1H), 6.05 (ddt, J = 17, 11, 6 Hz, 1H), 5.42 (d, J = 17 Hz, 1H), 5.30 (d, J = 11 Hz, 1H), 4.66 (d, J = 6 Hz, 1H), 3.97 (s, 3H).13C NMR (101 MHz, DMSO-&) 8: 191.87, 158.64, 153.59, 144.69, 143.30, 140.49, 134.66, 132.84, 129.29. 124.17, 123.49, 122.88, 121.29, 119.58, 119.04, 118.55, 68.97, 53.12. LRMS-ESI-MS (m / z): [M-H]’ calculated for C18H16ClNO4, 344.06; found, 344.11.

[0319] Step 2: Chaicone: SI-4m (87 mg, 0.25 mmol, 1 equiv.). h: 6 mg, 0.025 mmol 0.1 equiv.

[0320] DMSO: 8 mL. Reaction time: 2 hours. Compound SI-5n (70 mg, 0.203 mmol, 81%) was obtained in acceptable purity as an off-white solid. ’H NMR (400 MHz, CDCh) 8: 8.19 (d, J = 2Hz, 1 H), 7.67 (d, J = 8 Hz, 1 H), 7.62 (dd, J = 9, 2 Hz, 1 H), 7.50 (d, J = 9 Hz, 1 H), 7.33 (s, 1 H), 7.13 (d, J = 8 Hz, 1H), 6.08 (ddt, J = 17, 11, 6 Hz, 1H), 5.45 (d, J = 17 Hz, 1H), 5.37 (d, J = 11 Hz, 1H), 4.69 (d, J = 6 Hz, 1H). 4.08 (s, 3H).13C NMR (101 MHz, CDC13) 8: 178.01, 162.51.

[0321] 154.82, 154.70, 146.27, 136.93, 134.27, 132.27, 131.54, 125.76, 125.73, 120.14, 119.74, 118.51, 115.79, 107.63, 70.27, 54.56. LRMS-ESI-MS (m / z): [M+H]+calculated for C18H14CINO4, 344.06; found, 344.24.

[0322] Step 3: Compound SI-5n (52 mg, 0.15 mmol, 1 equiv.) in 3 mL MeOH was treated with equivalencies of other reagents described in general procedure 2. Reaction time: 3 hours. Yield of 28: 23mg (0.075 mmol, 50%) as a tan solid. ‘H NMR (400 MHz, DMSO-d6) 8: 10.62 (s, 1H), 7.97 (d, J = 2 Hz, 1H), 7.89 (dd, J = 9, 2 Hz, 1H), 7.84 (d, J = 8 Hz, 1H), 7.78 (d, J = 7 Hz,lH), 7.27 (d, J = 7 Hz, 1H), 7.09 (s, 1H), 3.99 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 175.90, 162.01, 154.13, 153.37, 145.29, 134.13, 134.11, 129.93, 124.80, 123.91, 121.48, 121.00, 116.74, 105.41, 53.30. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C15H10CINO4, 304.0371; found, 304.0373. The purity of Compound 28 was judged to be >95% by1H NMR.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0323]

[0324] Compound 29:

[0325] Step 1: Acetophenone Sl-lh (60 uL, 0.5 mmol, 1 equiv.) and aldehyde SI-3e (97 mg, 0.5 mmol, 1 equiv.) were reacted with 0.8 mL (2.4 mmol, 4.8 equiv.) 3M KOH in 96% EtOH in 6.2 mL EtOH. Reaction time: 15 hours. 41 mg (0.13 mmol, 26%) of compound SI-4n were obtained as a yellow solid following recrystallization from MeOH.

[0326]

[0327] (400 MHz, DMSO-d6) δ: 12.36 (s. 1H), 8.04 (dd, J = 8, 2 Hz, 1H)), 8.02 (d, J = 15 Hz, 1H), 7.72 (d, J = 15 Hz, 1H), 7.56 (td, J = 8, 2 Hz, 1H), 7.44 (d, J = 8 Hz, 1H), 7.36 (d, J = 8 Hz, 1H), 7.01 (m, 1H), 6.05 (ddt, J = 17, 11, 5 Hz, 1H), 5.43 (d, J = 17 Hz, 1H), 5.31 (d, J = 11 Hz, 1H), 4.66 (d, J = 5 Hz, 1H), 4.01 (s, 3H).

[0328] 13C NMR (101 MHz, DMSO-&) 8: 193.45. 161.50, 153.62, 144.76, 143.24, 140.42, 136.16, 132.84, 130.49, 121.99. 121.54, 121.24, 119.39, 119.03, 118.57, 117.80, 68.97, 53.18. LRMS-ESI-MS (m / z): [M+H]+calculated for C18H17NO4, 312.12; found, 312.35.

[0329] Step 2: Chaicone: SI-4n (31 mg, 0.1 mmol, 1 equiv.). L: 3 mg, 0.01 mmol 0.1 equiv. DMSO: 2 mL. Reaction time: 2 hours. Compound SI-5o (13 mg, 0.042 mmol, 42%) was obtained in acceptable purity as an off-white solid.1H NMR (400 MHz, CDCL) 8: 8.24 (d, J = 8 Hz, 1H), 7.68 (m, 2H), 7.54 (d, J = 8 Hz, 1H), 7.41 (t, J = 8 Hz, 1H), 7.34 (s, 1H), 7.14 (d, J = 8 Hz, 1H), 6.08 (ddt, J = 17, 11, 5 Hz, 1H), 5.45 (d, J = 17 Hz), 5.37 (d, J = 11 Hz, 1H), 4.68 (d, J = 5 Hz, 1H), 4.09 (s, 3H).13C NMR (101 MHz, CDC13) 8: 179.29, 162.23, 156.52, 154.65, 146.06, 137.37, 134.10. 132.36, 126.27, 125.58, 124.79, 119.66, 118.61, 118.42, 115.62, 107.77, 70.24, 54.54. LRMS-ESI-MS (m / z): [M+H]+calculated for C18H15NO4, 310.11; found, 310.27.

[0330] Step 3: Compound SI-5o (46 mg, 0.15 mmol, 1 equiv.) in 3 mL MeOH was treated with equivalencies of other reagents described in general procedure 2. Reaction time: 3 hours. Yield of 29: 14 mg (0.052 mmol, 35%) as a tan solid. ‘H NMR (500 MHz, DMSO-d6) 8: 10.56 (s, 1H), 8.05 (d, J = 8 Hz, 1H), 7.84 (t, J = 8 Hz, 1H), 7.77 (m, 2H), 7.50 (t, J = 8 Hz, 1H), 7.27 (d, J = 8 Hz, 1H), 7.07 (s, 1H), 4.00 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 177.05, 161.69, 155.56, 153.35, 145.07. 134.48, 134.29, 125.52, 124.92, 123.66, 121.54, 118.50, 116.49, 105.57, 53.28. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C15H11NO4, 270.0761; found, 270.0762. The purity of Compound 29 was judged to be >95% by ’H NMR.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0331]

[0332] Compound 65:

[0333] Step 1: Acetophenone Sl-li (120 mg, 0.5 mmol, 1 equiv.) and aldehyde SI-3e (97 mg, 0.5 mmol, 1 equiv.) were reacted with 0.8 mL (2.4 mmol, 4.8 equiv.) 3M KOH in 96% EtOH in 6.2 mL EtOH. Reaction time: 17 hours. 105 mg (0.253 mmol, 51%) of compound SI-4o were obtained as a yellow solid following recrystallization from MeOH.1H NMR (400 MHz, DMSO-d6) 8: 8.72 (d, J = 2 Hz, 1H), 8.43 (d, J = 2 Hz, 1H), 7.99 (d, J = 15 Hz, 1H), 7.79 (d, J = 15 Hz, 1H), 7.59 (d, J = 8 Hz, 1H), 7.39 (d, J = 8 Hz, 1H), 6.06 (ddt, J = 17, 11, 6 Hz, 1H), 5.43 (d, J = 17 Hz, 1H), 5.31 (d, J = 11 Hz), 4.69 (d, J = 6 Hz, 2H), 4.03 (s, 3H).nC NMR (201 MHz, DMSO-d6) 5: 192.80, 161.75, 153.68, 146.03, 145.13, 141.25, 140.17, 134.95, 132.75, 121.83, 120.70, 118.92, 118.62, 112.17, 103.03, 69.03, 53.38. LRMS-ESI-MS (m / z): [M-H]’ calculated for Ci9Hi5BrN2O4, 413.01; found, 413.07.

[0334] Step 2: Chaicone: SI-4o (42 mg, 0.1 mmol, 1 equiv.). h: 3 mg, 0.01 mmol 0.1 equiv. DMSO: 1 mL. Reaction time: 1 hour. Compound SI-5p (29 mg, 0.07 mmol, 70%) was obtained in acceptable purity as an off-white solid.1H NMR (400 MHz, DMSO-d6) 8: 8.70 (d, J = 2 Hz, 1H), 8.43 (d, J = 2 Hz, 1H), 7.80 (d, J = 8 Hz, 1H), 7.55 (d, J = 8 Hz, 1H), 7.17 (s, 1H), 6.07 (ddt, J = 17, 11, 6 Hz, 1H), 5.46 (d, J = 17 Hz, 1H), 5.33 (d, J = 11 Hz, 1H), 4.72 (d, J = 6 Hz, 2H), 4.01 (s, 3H).13C NMR (101 MHz, CDCI3) 8: 176.51, 162.87, 155.34, 154.91, 146.86, 139.20, 136.05, 132.13, 130.90, 126.15, 119.88, 118.57, 116.94, 116.91, 113.69, 110.53, 107.91, 70.33, 54.63. LRMS-ESI-MS (m / z): [M+H]+calculated for Ci9Hi3BrN2O4, 413.01; found, 413.16.

[0335] Step 3: Compound SI-5p (84 mg, 0.2 mmol, 1 equiv.) in 8 mL ACN was treated with PdC12(ACN)2 (14 mg, 0.02 mmol, 0.1 equiv.) and 50 mg (0.8 mmol, 4 equiv.) ammonium formate. The resultant mixture was sparged with argon, capped, sealed, and heated to 55 °C for 17 hours. Following cooling to room temperature, the mixture was crashed out with saturated NH4C1, and the resultant precipitate was isolated on a filter frit, washed with DI water, and dried. The precipitate was then recrystallized from MeOH. Yield of 65: 40 mg (0.107 mmol, 52%) as a tan solid.1H NMR (500 MHz, DMSO-d6) 8: 10.75 (s, 1H), 8.70 (d, J = 2 Hz, 1H), 8.43 (d, J = 2 Hz, 1H), 7.75 (d, J = 8 Hz, 1H), 7.32 (d, J = 8 Hz, 1H), 7.14 (s, 1H), 4.00 (s, 3H).

[0336] 13C NMR (101 MHz, DMSO-d6) 8: 175.07, 161.80, 154.47, 153.44, 145.63, 139.30, 133.49, 129.78, 124.95, 121.45, 116.96, 116.78, 112.86, 109.15, 105.79, 53.33. HRMS-ESI-TOFMS7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0337] (m / z): [M-H]’ calculated for C16H9BrN2O4, 370.9673; found, 370.9676. The purity of Compound 65 was judged to be >95% by!H NMR.

[0338]

[0339] Compound 66:

[0340] Step 1: Acetophenone Sl-li (360 mg, 1.5 mmol, 1 equiv.) and aldehyde SI-3g (362 mg, 1.5 mmol, 1 equiv.) were reacted with 2.5 mL (7.5 mmol, 5 equiv.) 3M KOH in 96% EtOH in 8 mL EtOH. Reaction time: 16 hours. 402 mg (0.87 mmol, 58%) of compound SI-4p were obtained as a yellow solid following recrystallization from MeOH.1H NMR (500 MHz, DMSO-&) 5: 8.99 (m, 1H), 8.45 (m, 1H), 8.38 (m, 1H), 8.08 (d, J = 16 Hz, 1H), 7.94 (m, 1H), 7.93 (d, J = 16 Hz, 1H), 7.23 (d, J = 8 Hz, 1H), 6.07 (m, 1H), 5.48 (d, J = 17 Hz, 1H), 5.32 (d, J = 11 Hz, 1H), 4.77 (m, 2H).13C NMR (101 MHz, DMSO-d6) 5: 192.65, 162.48, 156.87, 146.19, 141.40, 135.30, 133.50, 132.76, 131.89, 128.40, 120.93, 118.76, 117.90, 117.48, 113.84, 112.06, 111.95, 102.93, 69.34. LRMS-ESI-MS (m / z): [M-H]’ calculated for Ci9Hi3Br2NO3, 461.92; found, 461.97. Step 2: Chaicone: SI-4p (348 mg, 0.75 mmol, 1 equiv.). I2: 19 mg, 0.075 mmol 0.1 equiv. DMSO: 6 mL. Reaction time: 2 hours. Compound SI-5q (325 mg, 0.705 mmol, 94%) was obtained in acceptable purity as an off-white solid.1H NMR (400 MHz, CDCI3) 5: 8.48 (m, 1H), 8.20 (m, 1H), 8.14 (m, 1H), 7.92 (d, J = 8 Hz, 1H), 7.04 (d, J = 8 Hz, 1H), 6.80 (s, 1H), 6.08 (ddt, J = 17, 11, 5 Hz, 1H), 5.53 (d, J = 17 Hz, 1H), 5.39 (d, J = 11 Hz, 1H), 4.73 (d, J = 5 Hz, 2H).13C NMR (101 MHz, CDCI3) 8: 175.97, 164.07, 158.82, 155.33, 139.36, 132.20, 132.07, 130.73, 127.69, 125.73, 124.33, 119.05, 116.86, 113.87, 113.79, 113.74, 110.71, 107.15, 70.37. LRMS-ESI-MS (m / z): [M+H]+calculated for Ci9HnBr2NO3, 461.92; found, 463.13.

[0341] Step 3: Compound SI-5q (69 mg, 0.15 mmol, 1 equiv.) in 3 mL ACN was treated with PdC12(ACN)2 (12 mg, 0.015 mmol, 0.1 equiv.) and 40 mg (0.6 mmol, 4 equiv.) ammonium formate. The resultant mixture was sparged with argon, capped, sealed, and heated to 55 °C for 25 hours. Following cooling to room temperature, the mixture was crashed out with saturated NH4CI, and the resultant precipitate was isolated on a filter frit, washed with DI water, and dried. The precipitate was then recrystallized from MeOH. Yield of 66: 25 mg (0.06 mmol, 40%) as a tan solid. ’H NMR (500 MHz, DMSO-d6) 8: 11.35 (s, 1H), 8.68 (m, 1H), 8.40 (m, 1H), 8.29 (m, 1H), 8.01 (d, J = 8 Hz, 1H), 7.16 (s, 1H). 7.13 (d, J = 8 Hz, 1H).13C NMR (201 MHz, DMSO-d6) 8: 175.22, 161.91, 158.04, 154.59, 139.32, 131.38, 129.79, 127.67, 124.73,7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0342] 122.40, 116.83, 116.78, 113.00, 110.34, 109.14, 105.99. HRMS-ESI-TOFMS (m / z): [M-H]' calculated for C16H7Br2NO3, 427.8720; found, 427.8719. The purity of Compound 66 was judged to be >95% by ‘H NMR.

[0343]

[0344] Compound 67:

[0345] Step 1: Acetophenone Sl-lj (258 mg, 1 mmol, 1 equiv.) and aldehyde SI-3e (193 mg, 1 mmol, 1 equiv.) were reacted with 1.7 mL (5.1 mmol, 5.1 equiv.) 3M KOH in 96% EtOH in 12.3 mL EtOH. Reaction time: 19 hours. 173 mg (0.4 mmol, 40%) of compound SI-4q were obtained as a yellow solid following recrystallization from MeOH.1H NMR (400 MHz, DMSO- / L) 5: 8.59 (d, J = 2 Hz, 1H), 8.38 (d, J = 2 Hz, 1H), 8.20 (s, 1H), 8.04 (d, J = 15 Hz, 1H), 7.81 (d, J = 15 Hz, 1H), 7.51 (d, J = 8 Hz, 1H), 7.50 (s, 1H), 7.38 (d, J = 8 Hz, 1H), 6.06 (ddt, J = 17, 11, 6 Hz, 1H), 5.43 (d, J = 17 Hz, 1H), 5.31 (d, J = 11 Hz, 1H), 4.68 (d, J = 6 Hz, 2H), 4.02 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 193.54, 165.43, 160.59, 153.70, 145.17, 145.12, 140.13, 137.88, 132.74, 129.25, 126.13, 122.09, 120.68, 120.60, 118.96, 118.58, 111.13, 69.01, 53.17. LRMS-ESI-MS (m / z): [M-H]' calculated for Ci9Hi7BrN2O5, 431.02; found, 431.03.

[0346] Step 2: Chaicone: SI-4q (44 mg, 0.1 mmol, 1 equiv.). h: 3 mg, 0.01 mmol 0.1 equiv. DMSO: 1 mL. Reaction time: 1 hour. Compound SI-5r (25 mg, 0.058 mmol, 58%) was obtained in acceptable purity as an off-white solid.1H NMR (400 MHz, DMSO-d6) 8: 8.57 (d, J = 2Hz, 1H), 8.54 (d, J = 2Hz, 1H), 8.36 (s, 1H), 7.78 (d, J = 8 Hz, 1H), 7.68 (s, 1H), 7.54 (d, J = 8 Hz, 1H), 7.13 (s, 1H), 6.08 (ddt, J = 17, 11, 6 Hz, 1H), 5.46 (d, J = 17 Hz, 1H), 5.33 (d, J = 11 Hz, 1H), 4.71 (d, J = 6 Hz, 1H), 4.00 (s, 3H).13C NMR (101 MHz, DMSO-(Z6) 8: 176.41, 165.24, 161.32, 153.81, 153.56, 145.75, 135.87, 135.12, 132.57, 131.85, 124.51, 124.19, 119.25, 118.84, 116.17, 111.51, 106.22, 69.18, 53.51. LRMS-ESI-MS (m / z): [M+H]+calculated for C19H15BrN2O5, 431.02; found, 431.15.

[0347] Step 3: Compound SI-5r (77 mg, 0.18 mmol, 1 equiv.) in 3.6 mL MeOH was treated with equivalencies of other reagents described in general procedure 2. Reaction time: 24 hours. Yield of 67: 34 mg (0.087 mmol, 48%) as a tan solid. ’H NMR (400 MHz, DMSO-d6) 8: 10.71 (s, 1H), 8.57 (d, J = 2 Hz, 1H), 8.54 (d, J = 2 Hz, 1H), 8.37 (s, 1H), 7.76 (d, J = 8 Hz, 1H), 7.69 (s, 1H), 7.32 (d, J = 8 Hz, 1H), 7.13 (s, 1H), 4.00 (s. 3H).13C NMR (101 MHz, DMSO-d6) 8:

[0348] 176.29, 165.28, 161.59, 153.48, 153.41, 145.41, 135.76, 133.89, 131.77, 124.47, 124.18, 121.53,7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0349] 116.75, 111.43, 105.61, 53.28. HRMS-ESI-TOFMS (m / z): [M-H]’ calculated for Ci6HiiBrN2O5, 388.9779; found, 388.9781. The purity of Compound 67 was judged to be >95% by ’H NMR.

[0350]

[0351] Compound 69:

[0352] Step 1: Acetophenone Sl-lj (126 mg, 0.5 mmol, 1 equiv.) and aldehyde SI-3h (193 mg, 1 mmol, 2 equiv.) were reacted with 0.9 mL (2.7 mmol, 5.4 equiv.) 3M KOH in 96% EtOH in 3.1 mL EtOH. Reaction time: 44 hours. 104 mg (0.25 mmol, 50%) of compound SI-4r were obtained as a yellow solid following recrystallization from MeOH.1H NMR (400 MHz, DMSO-d6) 8: 8.70 (m, 1H), 8.35 (m, 1H), 8.16 (s, 1H), 7.94 (m, 2H), 7.60 (s, 1H), 7.57 (m, 1H), 7.50 (d, J = 8 Hz, 1H), 7.08 (d, J = 8 Hz, 1H), 6.06 (ddt, J = 17, 11, 5 Hz, 1H), 5.42 (d, J = 17 Hz, 1H), 5.28 (d, J = 11 Hz, 1H), 4.65 (d, J = 5 Hz, 2H), 3.88 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 193.46, 165.53, 161.09, 151.00, 149.21, 147.55, 138.06, 133.36, 129.23, 127.25, 125.99, 124.51, 120.30, 118.15, 117.97, 113.00, 112.21, 111.15, 68.94, 55.91. LRMS-ESI-MS (m / z): [M-H]’ calculated for C2oHi8BrNOs, 430.03; found, 430.06.

[0353] Step 2: Chaicone: SI-4r (87 mg, 0.2 mmol, 1 equiv.). I2: 5 mg, 0.01 mmol 0.1 equiv. DMSO: 2 mL. Reaction time: 2 hours. Compound SI-5s (76 mg, 0.177 mmol, 87%) was obtained in acceptable purity as an off-white solid.1H NMR (400 MHz, DMSO-d6) 8: 8.56 (d, J = 2 Hz, 1H), 8.53 (d, J = 2 Hz, 1H), 8.36 (s, 1H), 7.76 (dd, J = 8, 2 Hz, 1H), 7.69 (m, 2H), 7.21 (s, 1H), 7.19 (d, J = 8 Hz, 1H), 6.07 (ddt, J = 17, 11, 6 Hz, 1H), 5.43 (d, J = 17 Hz, 1H), 5.29 (d, J =11 Hz, 1H), 4.68 (d, J = 6 Hz, 2H), 3.90 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 176.56, 165.41, 162.63, 153.65. 151.17, 149.30, 135.74, 133.30, 131.77, 124.23, 124.17, 122.91, 120.04, 118.31, 113.19, 111.65, 109.58, 105.85, 69.01, 55.88. LRMS-APCI-MS (m / z): [M+H]+calculated for C2oHi6BrNOs, 430.03; found, 430.08.

[0354] Step 3: Compound SI-5s (65 mg, 0.15 mmol, 1 equiv.) in 3 mL MeOH was treated with equivalencies of other reagents described in general procedure 2. Reaction time: 1.5 hours. Yield of 69: 35 mg (0.09 mmol, 60%) as a tan solid. H NMR (400 MHz, DMSO-d6) 8: 10.10 (s, 1H), 8.55 (d, J = 2 Hz, 1H), 8.52 (d, J = 2 Hz, 1H), 8.35 (s, 1H), 7.68 (m, 3H), 7.15 (s, 1H), 6.98 (d, J = 8 Hz, 1H), 3.90 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 176.31, 165.33, 162.89, 153.52, 150.97, 148.11, 135.57, 131.68, 124.16, 124.07, 121.27, 120.44, 115.94, 111.48, 110.09, 105.10,7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0355] 55.85. HRMS-ESI-TOFMS (m / z): [M-H]’ calculated for C17H12BrNO5, 387.9826; found, 387.9826. The purity of Compound 69 was judged to be >95% by1H NMR.

[0356]

[0357] Compound 70:

[0358] Step 1: Acetophenone Sl-lk (286 mg, 1 mmol, 1 equiv.) and aldehyde SI-3e (193 mg, 1 mmol, 1 equiv.) were reacted with 1.7 mL (5.1 mmol, 5.1 equiv.) 3M KOH in 96% EtOH in 10 mL EtOH. Reaction time: 14 hours. 265 mg (0.576 mmol, 58%) of compound SI-4s were obtained as a yellow solid following recrystallization from MeOH.1H NMR (400 MHz, DMSO-d6) 8: 8.21 (d, J = 2 Hz, 1H), 8.01 (d, J = 15 Hz, 1H), 7.96 (d, J = 2 Hz, 1H), 7.80 (d, J = 15 Hz, 1H), 7.58 (d, J = 8 Hz, 1H), 7.38 (d, J = 8 Hz, 1H), 6.06 (ddt, J = 17, 11, 6 Hz, 1H). 5.43 (d, J = 17 Hz, 1H), 5.31 (d, J = 11 Hz, 1H), 4.68 (d, J = 6 Hz, 2H), 4.00 (s, 3H), 2.99 (m, 6H).13C NMR (101 MHz, DMSO-d6) 8: 193.43, 167.70, 159.20, 153.66, 145.32, 145.07, 140.20, 137.74, 132.79, 129.01, 128.37, 121.83, 120.79, 120.56, 118.93, 118.65, 111.03, 69.04, 53.27, 35.18. LRMS-ESI-MS (m / z): [M-H] calculated for C2iH2iBrN2O5, 459.06; found, 459.06.

[0359] Step 2: Chaicone: SI-4s (139 mg, 0.3 mmol, 1 equiv.). I2: 8 mg, 0.03 mmol 0.1 equiv. DMSO: 3 mL. Reaction time: 2 hours. Compound SI-5t (100 mg, 0.218 mmol, 73%) was obtained in acceptable purity as an off-white solid.JH NMR (400 MHz, DMSO-d6) 8: 8.18 (m, 1H), 7.98 (m, 1H), 7.78 (d, J = 8 Hz, 1H), 7.53 (d, J = 8 Hz, 1H). 7.12 (s, 1H), 6.07 (ddt, J = 17, 11, 5 Hz, 1H), 5.46 (d, J = 17 Hz, 1H), 5.33 (d, J = 11 Hz, 1H), 4.71 (d, J = 5 Hz, 2H), 3.99 (s, 3H), 3.01 (s, 3H), 2.96 (s, 3H).13C NMR (201 MHz, DMSO-d6) δ: 176.21, 167.39, 161.39, 153.82, 152.26, 145.75, 135.69, 135.16, 134.37, 132.57, 124.49, 123.04, 119.28, 118.81, 116.17, 111.62, 106.11, 69.18, 53.50, 39.10, 34.98. LRMS-ESI-MS (m / z): [M+H]+calculated for C2iHi9BrN2O5, 459.06; found, 459.16.

[0360] Step 3: Compound SI-5t (69 mg, 0.15 mmol, 1 equiv.) in 3 mL MeOH was treated with equivalencies of other reagents described in general procedure 2. Reaction time: 16 hours at room temperature. Yield of 70: 23 mg (0.055 mmol, 37%) as a tan solid. ’H NMR (400 MHz, DMSO- / / 6) 8: 10.70 (s, 1H), 8.18 (m, 1H), 7.99 (m, 1H), 7.76 (d, J = 8 Hz, 1H), 7.32 (d, J = 8 Hz, 1H), 7.12 (s, 1H), 4.00 (s, 3H), 3.01 (s, 3H), 2.95 (s, 3H).13C NMR (101 MHz, DMSO-rir,) 8: 176.14, 167.43, 161.73, 153.46, 152.23, 145.41, 135.61, 134.29, 133.99, 124.49, 123.02, 121.61, 116.80, 111.56, 105.56, 53.32, 39.99, 34.98. HRMS-ESI-TOFMS (m / z): [M-H]’7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0361] calculated for C18H15BrN2O5, 417.0092; found, 417.0096. The purity of Compound 70 was judged to be ca 90% by1H NMR.

[0362] Example 3

[0363] C4’-hydroxy C3-flavonols via the Algar-Flynn-Oyamada Oxidation — Compounds 6, 30,

[0364] 68, & 71

[0365]

[0366] Scheme SI-3: C4’ hydroxy flavonols via the Algar-Flynn-Oyamada Oxidation General Procedure 3:

[0367] Step 1: A stirring suspension of chaicone SI-4 in 3:1 MeOH: THF (0.03 M solution) was cooled in an ice-water bath. A solution of 4M aqueous NaOH (5 equiv.) was added followed by an aqueous solution of 15% H2O2 (3.2 equiv.). The ice-water bath was allowed to expire with stirring over the course of the reaction, which was run from afternoon to morning. The reaction was quenched with saturated aqueous NH4CI, and the resultant precipitate was isolated on a filter frit, washed with DI water, and dried to give the pure 3-flavonol intermediate SI-6.

[0368] Step 2: Refer to step 3 of general procedure 2 in Example 2.

[0369]

[0370] Compound 6:

[0371] Step 1: Compound SI-4t (70 mg, 0.15 mmol, 1 equiv.) was treated according to step 1, giving SI-6a (52 mg, 0.108 mmol, 72%) as an off-white solid. ’H NMR (400 MHz, DMSO-d6) 8: 9.97 (s, 1H), 8.36 (d, J = 2 Hz, 1H), 8.16 (d, J = 2 Hz, 1H), 7.94 (dd, J = 9, 2 Hz, 1H), 7.89 (d, J = 2 Hz, 1H), 7.20 (d, J = 9 Hz, 1H), 6.08 (ddt, J = 17, 11, 5 Hz, 1H), 5.43 (d, J = 17 Hz, 1H), 5.30 (d, J = 11 Hz, 1H), 4.67 (d, J = 5 Hz, 2H), 3.86 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 171.15, 149.86, 149.45. 148.71, 145.97, 138.79, 138.12, 133.40, 126.61, 123.62, 123.47, 121.65, 118.14, 116.72, 113.14, 113.04, 110.68, 68.90, 55.58. LRMS-ESI-MS (m / z): [M-H]’ calculated for C20H18BrNO5, 480.91; found, 480.92.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0372] Step 2: Compound SI-6a (48 mg, 0.1 mmol, 1 equiv.) was treated according to step 2, apart from the reaction being conducted at room temperature. Reaction time: 17 hours. Yield of 6: 15 mg (0.034 mmol, 34%) as a tan solid. ’H NMR (400 MHz, DMSO-d6) 8: 9.87 (s, 1H), 9.86 (s, 1H), 8.34 (d, J = 2 Hz, 1H), 8.15 (d, J = 2 Hz, 1H), 7.88 (d, J = 2 Hz, 1H), 7.86 (dd, J = 8, 2 Hz, 1H), 6.98 (d, J = 8 Hz, 1H), 3.86 (s. 3H).13C NMR (101 MHz, DMSO-d6) 8: 170.96, 149.79, 149.14, 147.57, 146.46, 138.38, 137.98, 126.57, 123.63, 122.11, 121.91, 116.65, 115.75, 113.07, 111.23, 55.64. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for Ci6Hi0Br2O5, 440.8968; found, 440.8963. The purity of Compound 6 was judged to be >95% by1H NMR.

[0373]

[0374] Compound 30:

[0375] Step 1: Compound SI-4g (140 mg, 0.3 mmol, 1 equiv.) was treated according to step 1, giving SI-6b (41 mg, 0.085 mmol, 28%) as an off-white solid. ’H NMR (400 MHz, DMSO-d6) 8: 11.25 (s, 1H), 8.37 (d, J = 2 Hz, 1H), 8.15 (d, J = 2 Hz, 1H), 7.84 (d, J = 8 Hz, 1H), 7.65 (d, J = 8 Hz, 1H), 6.08 (ddt, J = 17, 11, 5 Hz, 1H), 5.46 (d, J = 17 Hz, 1H), 5.33 (d, J = 11 Hz, 1H), 4.73 (d, J = 5 Hz, 2H), 4.03 (s, 3H).13C NMR (101 MHz, CDC13) 8: 172.11, 153.71, 150.40, 144.79, 141.97, 141.34, 139.49, 139.17, 132.00, 128.56, 125.63, 120.54, 120.05, 117.86, 115.51, 113.04, 70.47, 55.02. LRMS-ESI-MS (m / z): [M-H]’ calculated for Ci8Hi3Br2NO5, 481.91: found, 481.85.

[0376] Step 2: Compound SI-6b (72 mg, 0.15 mmol, 1 equiv.) was treated according to step 2 for 6 hours. It was then cooled to RT, and (PhsP^Pd0(another 0.05 equiv.) was added, and the reaction was sparged with argon, capped, sealed, and heated reflux for another 16 hours before workup. Yield of 30: 15 mg (0.034 mmol, 23%) as a tan solid.1H NMR (400 MHz, DMSO-d6) 8: 11.49 (s, 1H), 10.75 (s, 1H), 8.37 (d, J = 2 Hz, 1H), 8.15 (d, J = 2 Hz, 1H), 7.76 (d, J = 8 Hz, 1H), 7.43 (d, J = 8 Hz, 1H), 4.02 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 170.51, 152.38, 149.64, 143.57, 142.37. 139.73, 138.28, 136.37, 126.83, 124.67, 123.00. 116.77, 116.62, 112.94, 53.80. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for Ci5H9Br2NO5, 441.8920; found, 441.8914. The purity of Compound 30 was judged to be >95% by1H NMR.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0377]

[0378] Compound 68:

[0379] Step 1: Compound SI-4q (130 mg, 0.3 mmol, 1 equiv.) was treated according to step 1, giving SI-6c (31 mg, 0.069 mmol, 23%) as an off-white solid.XH NMR (400 MHz, DMSO-d6) 5: 11.26 (s, 1H), 8.64 (d, J = 2 Hz, 1H), 8.52 (d, J = 2 Hz, 1H), 8.37 (s, 1H), 7.85 (d, J = 8 Hz), 7.67 (s, 1H), 7.66 (d, J = 8 Hz, 1H), 6.08 (ddt, J = 17, 11, 6 Hz, 1H), 5.46 (d, J = 17 Hz, 1H), 5.33 (d, J = 11 Hz, 1H), 4.73 (d, J = 6 Hz, 1H), 4.04 (s, 3H).13C NMR (201 MHz, DMSO-d6) 8: 171.88, 165.29, 152.95, 151.97, 143.80, 142.18, 140.08, 137.37, 135.23, 132.59, 130.91, 124.45, 123.03, 120.56, 118.78, 116.48, 111.32, 69.20, 53.85. LRMS-APCI-MS (m / z): [M+H]+calculated for Ci9Hi5BrN2O6, 447.02; found, 447.18.

[0380] Step 2: Compound SI-6c (45 mg, 0.1 mmol, 1 equiv.) was treated according to step 2. Reaction time: 3 hours. Yield of 68: 15 mg (0.037 mmol, 37%) as a tan solid.1H NMR (400 MHz, DMSO-d6) 8: 11.50 (s, 1H), 10.74 (s, 1H), 8.63 (d, J = 2 Hz, 1H), 8.51 (d, J = 2 Hz, 1H), 8.36 (s, 1H), 7.78 (d, J = 8 Hz, 1H), 7.67 (s, 1H), 7.44 (d, J = 8 Hz, 1H), 4.03 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 171.57, 165.31, 152.35, 151.80, 143.47, 142.09, 139.73, 136.40, 135.10, 130.85, 124.44, 123.15, 122.99, 116.46, 111.20, 53.72. HRMS-ESI-TOFMS (m / z): [M-H]’ calculated for Ci6HnBrN2O6, 404.9728; found, 404.9726. The purity of Compound 68 was judged to be >95% by ‘H NMR.

[0381]

[0382] Compound 71:

[0383] Step 1: Compound SI-4s (139 mg, 0.3 mmol, 1 equiv.) was treated according to step 1, giving SI-6d (23 mg, 0.048 mmol, 16%) as an off-white solid. 'H NMR (400 MHz, DMSO-d6) 8: 11.25 (s, 1H), 8.16 (d, J = 2 Hz, 1H), 8.04 (d, J = 2 Hz, 1H), 7.85 (d, J = 8 Hz, 1H), 7.66 (d, J = 8 Hz, 1H), 6.08 (ddt, J = 17, 11, 6 Hz. 1H), 5.46 (d, J = 17 Hz, 1H), 5.33 (d, J = 11 Hz, 1H), 4.73 (d, J = 6 Hz, 2H), 4.04 (s, 3H), 3.01 (s, 3H), 2.96 (s. 3H).13C NMR (201 MHz. DMSO-d6) 8: 171.60, 167.46, 152.91, 150.67, 143.80, 142.15, 140.05, 137.43, 135.13, 133.32, 132.58, 123.20, 123.01,7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0384] 120.55, 118.79, 116.33, 111.42, 69.22, 53.87, 34.99, 29.01. LRMS-ESI-MS (m / z): [M+H]+calculated for C2iHi9BrN20e, 475.05: found, 475.12.

[0385] Step 2: Compound SI-6d (48 mg, 0.1 mmol, 1 equiv.) was treated according to step 2. Reaction time: 1.5 hours. Yield of 71: 16 mg (0.037 mmol, 37%) as a tan solid.!H NMR (400 MHz, DMSO-d6) 8: 11.50 (s, 1H), 8.15 (d, J = 2 Hz, 1H), 8.04 (d, J = 2 Hz, 1H), 7.77 (d, J = 8 Hz, 1H), 7.42 (d, J = 8 Hz, 1H), 4.02 (s, 3H), 3.01 (s, 3H), 2.96 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 171.38, 167.48, 152.39, 150.57, 143.54, 142.23, 139.70, 136.43, 135.02, 133.28, 123.19, 123.15, 123.03, 116.51, 111.34, 53.75, 34.98. HRMS-ESI-TOFMS (m / z): [M-H]’ calculated for C18H15BrN2O6, 433.0041; found, 433.0043. The purity of Compound 71 was judged to be ca 90% by1H NMR.

[0386] Example 4

[0387] C4’-carboxy Flavonoids and Flavonols — Compounds 2-5

[0388]

[0389] Scheme SI-4: C4’ carboxy flavonoids and flavanols

[0390] General Procedure 4: For the syntheses of Compounds 2 and 5, refer to steps 1-2 of general procedure 2 in Example 2. For the syntheses of Compounds 3 and 4, refer to step 1 of general procedure 3 in Example 3.

[0391]

[0392] Compound 2:

[0393] Step 1: Acetophenone SI-1a (476 mg, 1.62 mmol, 1 equiv.) and aldehyde SI-7a (329 mg, 1.62 mmol, 1 equiv.) were reacted with 3.3 mL (9.9 mmol, 6.1 equiv.) 3M KOH in 96% EtOH in 11 mL EtOH in accordance with step 1 of general procedure 2. Reaction time: 14 hours. 440 mg (0.96 mmol, 57%) of compound SI-8a were obtained as a yellow solid following7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0394] recrystallization from MeOH. 'H NMR (400 MHz, DMSO-d6) 8: 8.54 (m, 1H), 8.12 (m, 2H), 7.89 (d, J = 15 Hz, 1H), 7.62 (m, 3H), 3.88 (s, 3H).

[0395] 13C NMR (101 MHz, DMSO-d6) 8: 193.42, 167.50, 158.76, 158.48, 146.37, 141.42, 138.97, 132.95, 131.35, 124.15, 123.16, 122.92, 121.69, 114.04, 112.99, 111.12, 56.71. LRMS-ESI-MS (m / z): [M-H]’ calculated for C17H12BrO5, 455.06; found, 454.90.

[0396] Step 2: Chaicone: SI-8a (92 mg, 0.2 mmol, 1 equiv.). h: 6 mg, 0.02 mmol 0.1 equiv. DMSO: 5 mL. Reaction time: 1 hour. Compound 2 (81 mg, 0.18 mmol, 90%) was obtained as an off-white solid. 'H NMR (400 MHz, DMSO-d6) 8: 8.41 (m, 1H), 8.09 (m, 1H), 7.71 (m, 2H), 7.64 (d, J = 8 Hz, 1H), 7.33 (s, 1H). 3.92 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 175.68, 167.07, 161.62, 157.90, 151.44, 139.14, 133.96, 130.80, 126.75, 126.14, 125.61, 118.11, 118.07, 113.43, 110.01, 107.92, 56.10. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C17H10Br2O5, 452.8968; found, 452.8964. The purity of Compound 2 was judged to be ca 95% by1H NMR.

[0397]

[0398] Compound 3: Compound SI-8a (278 mg, 0.6 mmol, 1 equiv.) was treated according to step 1 of general procedure 3, giving compound 3 (74 mg, 0.157 mmol, 28%) as an off-white solid. ’H NMR (400 MHz, DMSO-d6) 8: 10.44 (s, 1H), 8.40 (d, J = 2 Hz, 1H), 8.18 (d, J = 2 Hz, 1H), 7.98 (m, 1H), 7.97 (d, J = 8 Hz, 1H), 7.83 (d, J = 8 Hz, 1H), 3.91 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 171.79, 166.82, 157.91, 150.01, 144.15, 140.48, 138.54, 135.15, 131.04, 126.70, 123.43, 122.43, 119.64, 116.87, 113.28, 110.63, 55.80. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C17H10Br2O6, 468.8917; found, 468.8913. The purity of Compound 3 was judged to be >95% by 1H NMR.

[0399]

[0400] Compound 4:

[0401] Step 1: Acetophenone SI-1a (476 mg, 1.62 mmol, 1 equiv.) and aldehyde SI-7c (329 mg, 1.62 mmol, 1 equiv.) were reacted with 4 mL (12 mmol, 6 equiv.) 3M KOH in 96% EtOH in 4 mL7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0402] EtOH in accordance with step 1 of general procedure 2. Reaction time: 14 hours. 817 mg (0.96 mmol, 57%) of compound SI-8c were obtained as a yellow solid free from major impurities. ’H NMR (400 MHz, DMSO-d6) 8: 12.44 (s, 1H), 8.63 (d, J = 2 Hz, 1H), 8.14 (d, J = 2 Hz, 1H), 8.11 (d, J = 15 Hz, 1H), 7.95 (d, J = 8 Hz, 2H), 7.92 (d, J = 15 Hz, 1H), 7.39 (d, J = 8 Hz, 1H), 3.66 (s, 2H).13C NMR (101 MHz, DMSO-d6) 8: 192.92, 172.34, 158.15, 146.98, 140.79, 138.91, 132.69, 132.38, 130.14, 129.72, 122.24, 120.16, 112.38, 110.56, 40.59. LRMS-ES1-MS (m / z): [M-H]’ calculated for C17H12Br2O4, 438.90; found, 438.97.

[0403] Step 2: Compound SI-8c (88 mg, 0.2 mmol, 1 equiv.) was treated according to step 1 of general procedure 3, giving compound 4 (41 mg, 0.09 mmol, 45%) as an off-white solid. ’H NMR (400 MHz, DMSO-d6) 8: 12.45 (s, 1H), 10.08 (s, 1H), 8.38 (d, J = 2 Hz, 1H). 8.21 (d, J = 8 Hz, 2H), 8.18 (d, J = 2 Hz, 1H), 7.49 (d, J = 8 Hz, 2H), 3.69 (s, 2H).13C NMR (101 MHz, DMSO-d6) 8: 172.38, 171.50, 150.05, 145.85, 139.42, 138.30, 137.53, 129.89, 129.35, 127.56, 126.67, 123.64, 116.76, 113.18, 40.53. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C17H10Br2O5, 452.8968; found, 452.8965. The purity of Compound 4 was judged to be ca 95% by 'H NMR.

[0404]

[0405] Compound 5:

[0406] Step 1: Acetophenone SI-1a (588 mg, 2 mmol, 1 equiv.) and aldehyde SI-7b (300 mg, 2 mmol, 1 equiv.) were reacted with 3.3 mL (9.9 mmol, 5 equiv.) 3M KOH in 96% EtOH in 10 mL EtOH in accordance with step 1 of general procedure 2. Reaction time: 50 hours. 535 mg (1.21 mmol, 62%) of compound SI-8b were obtained as a yellow solid following recrystallization from MeOH. ‘H NMR (500 MHz, DMSO-d6) 8: 13.33 (s, 1H), 13.22 (s, 1H), 8.65 (m, 1H), 8.23 (d, J = 15 Hz, 1H), 8.16 (m, 1H), 8.11 (d, J = 8 Hz, 2H), 8.01 (d, J = 8 Hz, 2H), 7.96 (d, J = 15 Hz, 1H).13C NMR (101 MHz, DMSO-d6) 8: 192.86, 166.83, 164.73, 161.49, 158.05, 145.34, 140.97, 138.27, 132.75, 132.54, 129.71, 122.93, 122.33, 110.65. LRMS-ESI-MS (m / z): [M-H]’ calculated for C16H10Br2O4, 425.09; found, 424.88.

[0407] Step 2: Chaicone: SI-8b (86 mg, 0.2 mmol, 1 equiv.). E: 6 mg, 0.02 mmol 0.1 equiv. DMSO: 5 mL. Reaction time: 3 hours. Compound 5 (70 mg, 0.165 mmol, 83%) was obtained as an off-white solid. ‘H NMR (400 MHz, DMSO-d6) 8: 8.44 (d, J = 2 Hz, 1H), 8.26 (d, J = 8 Hz, 2H), 8.12 (m, 3H), 7.31 (s, 1H).13C NMR (101 MHz, DMSO-d6) 8: 175.64, 166.57, 161.65, 151.54, 139.25, 134.48, 133.77, 130.00, 126.71, 126.79, 125.69, 118.13, 113.42, 108.25. HRMS-ESI-7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0408] TOFMS (m / z): [M+H]+calculated for C16H8Br2O4, 422.8862; found, 422.8859. The purity of Compound 5 was judged to be ca >95% by ’H NMR.

[0409] Example 5

[0410] Benzofuranone Syntheses — Compounds 31-42

[0411]

[0412] Scheme SI-5: Benzofuranone syntheses

[0413] General Procedure 5: An equimolar mixture of compounds SI-9 and SI-10, SI-2, or SI-7 in IPA with either i) one drop concentrated HC1 or ii) 20 mol% morpholinium acetate was heated at reflux for a given time. The reaction was then cooled to room temperature and diluted with DI water. The precipitate formed was isolated on a filter frit, washed with DI water, and dried to give the title compound.

[0414]

[0415] Compound 31: Compounds SI-9a (87 mg, 0.3 mmol, 1 equiv.) and Sl-lOa (46 mg, 0.3 mmol, 1 equiv.) were reacted with one drop concentrated HO in 1 mL IPA according to general procedure 5 for 4 hours. Compound 31 (93 mg, 0.218 mmol, 73%) was obtained as a yellow solid. ’H NMR (500 MHz, DMSO-d6) 5: 10.07 (s, 1H), 8.28 (m, 1H), 7.97 (m, 1H), 7.80 (m, 1H), 7.47 (d, J = 8 Hz, 1H), 7.07 (s, 1H), 6.92 (d, J = 8 Hz, 1H), 3.88 (s. 3H).13C NMR (101 MHz, DMSO-d6) 8: 181.00, 160.70, 150.12, 147.95, 144.70, 140.32, 127.29, 125.87, 124.51, 122.92, 116.06, 116.04, 116.01, 114.59, 106.96, 55.50. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C16H10Br2O4, 424.9019; found, 424.9015. The purity of Compound 31 was judged to be >95% by ’H NMR.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0416]

[0417] Compound 32: Compounds SI-9a (87 mg, 0.3 mmol, 1 equiv.) and SI-2a (37 mg, 0.3 mmol, 1 equiv.) were reacted with one drop concentrated HC1 in 1 mL IPA according to general procedure 5 for 4 hours. Compound 32 (84 mg, 0.212 mmol, 71%) was obtained as an orange solid. ’H NMR (500 MHz, DMSO-d6) 8: 10.42 (s, 1H), 8.29 (m, 1H), 7.98 (m, 1H), 7.91 (d, J = 8 Hz, 2H), 7.06 (s, 1H), 6.93 (d, J = 8 Hz, 2H).13C NMR (201 MHz, DMSO-d6) 8: 181.09, 160.81, 160.41, 144.63, 140.39, 134.22, 125.83, 124.51, 122.46, 116.34, 115.96, 115.66, 106.87. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C15H8Br2O3, 394.8913; found, 394.8909. The purity of Compound 32 was judged to be >95% by ’H NMR.

[0418]

[0419] Compound 33: Compounds SI-9a (87 mg, 0.3 mmol, 1 equiv.) and SI-2g (60 mg, 0.3 mmol, 1 equiv.) were reacted with one drop concentrated HC1 in 1 mL IPA according to general procedure 5 for 4 hours. Compound 33 (107 mg, 0.225 mmol, 75%) was obtained as a yellow solid. 'H NMR (500 MHz, DMSO-d6) 8: 11.24 (s, 1H), 8.30 (d, J = 2 Hz, 1H), 8.26 (d, J = 2 Hz, 1H), 7.98 (d, J = 2 Hz, 1H), 7.88 (dd, J = 8, 2 Hz, 1H), 7.09 (d, J = 8 Hz, 1H), 7.06 (s, 1H).I3C NMR (101 MHz, DMSO-d6) 8: 181.26, 160.96, 156.69, 145.15, 140.64, 136.66, 132.92, 125.95, 124.36, 124.15, 116.84, 116.16, 113.88, 110.21, 106.87. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C15H7Br3O3, 472.8018; found, 472.8013. The purity of Compound 33 was judged to be ca 90% by ’H NMR.

[0420]

[0421] 7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0422] Compound 34: Compounds SI-9a (87 mg, 0.3 mmol, 1 equiv.) and Sl-lOb (60 mg, 0.3 mmol, 1 equiv.) were reacted with one drop concentrated HC1 in 1 mL IPA according to general procedure 5 for 4 hours. Compound 34 (90 mg, 0.19 mmol, 63%) was obtained as an orange solid. 'H NMR (500 MHz, DMSO-d6) 8: 10.87 (s, 1H), 8.32 (m, 1H), 8.23 (d, J = 8 Hz, 1H), 8.02 (m, 1H), 7.21 (m, 1H), 7.15 (s, 1H), 7.00 (d, J = 8 Hz, 1H).13C NMR (101 MHz, DMSO-d6) 8: 181.42, 161.10. 160.64, 145.45, 140.80, 133.32, 127.79, 126.05, 124.20, 121.30, 120.29, 116.33, 116.17, 111.66, 106.94. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for Ci5H7Br3O3, 472.8018; found, 472.8011. The purity of Compound 34 was judged to be ca 90% by ’H NMR.

[0423]

[0424] Compound 35: Compounds SI-9a (87 mg, 0.3 mmol, 1 equiv.) and SI-2d (47 mg, 0.3 mmol, 1 equiv.) were reacted with one drop concentrated HC1 in 1 mL IPA according to general procedure 5 for 4 hours. Compound 35 (81 mg, 0.188 mmol, 63%) was obtained as a yellow solid. ‘H NMR (500 MHz, DMSO-d6) 8: 11.18 (s, 1H), 8.31 (m, 1H), 8.10 (m, 1H), 7.99 (m, 1H), 7.85 (d, J = 8 Hz, 1H), 7.11 (d, J = 8 Hz, 1H), 7.07 (s, 1H).13C NMR (101 MHz, DMSO-d6) 8: 181.30, 160.98, 155.69, 145.19, 140.66, 133.52, 132.37, 125.96, 124.36, 123.72, 120.61, 117.20, 116.17, 113.97, 106.91. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for Ci5H7ClBr2O3, 428.8523; found, 428.8519. The purity of Compound 35 was judged to be >95% by1H NMR.

[0425]

[0426] Compound 36: Compounds SI-9a (87 mg, 0.3 mmol, 1 equiv.) and SI-2h (75 mg, 0.3 mmol, 1 equiv.) were reacted with one drop concentrated HC1 in 1 mL IPA according to general procedure 5 for 4 hours. Compound 36 (103 mg, 0.197 mmol, 66%) was obtained as a yellow solid. 'H NMR (500 MHz, DMSO-d6) 8: 11.28 (s, 1H), 8.47 (m, 1H), 8.30 (m. 1H), 7.99 (m, 1H), 7.90 (d, J = 8 Hz, 1H), 7.04 (s, 1H), 7.02 (d, J = 8 Hz, 1H).13C NMR (101 MHz, DMSO-d6) 8: 181.20, 160.90, 159.29, 145.01, 142.92, 140.59, 133.70, 125.95, 124.63, 124.41, 116.12,7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0427] 115.39, 113.87, 106.83, 85.74. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for Ci5H7Br2IO3, 520.7879; found, 520.7870. The purity of Compound 36 was judged to be >95% by ’H NMR.

[0428]

[0429] Compound 37: Compounds SI-9a (43 mg, 0.15 mmol, 1 equiv.) and SI-lOc (23 mg, 0.15 mmol, 1 equiv.) were reacted with morpholinium acetate (5 mg, 0.03 mmol, 0.2 equiv. in 1.5 mL IPA according to general procedure 5 for 16 hours. Compound 37 (39 mg, 0.091 mmol, 60%) was obtained as a yellow solid. 'H NMR (400 MHz, DMSO-d6) 8: 10.49 (s, 1H), 8.24 (d, J = 2 Hz, 1H), 7.93 (d, J = 2 Hz, 1H), 7.58 (d, J = 8 Hz, Ih), 7.18 (d, J = 8 Hz, 1H), 6.84 (s, 1H), 4.03 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 181.91, 161.47, 153.25, 145.36, 143.56, 140.73, 137.24, 125.92, 124.27, 123.77, 121.57, 116.00, 114.13, 106.92, 53.37. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C15H9Br2NO4 425.8971; found, 425.8968. The purity of Compound 37 was judged to be ca 95% by1H NMR.

[0430]

[0431] Compound 38: Compounds SI-9b (32 mg, 0.15 mmol, 1 equiv.) and SI-lOc (23 mg, 0.15 mmol, 1 equiv.) were reacted with morpholinium acetate (5 mg, 0.03 mmol, 0.2 equiv. in 1.5 mL IPA according to general procedure 5 for 17 hours. Compound 38 (18 mg, 0.051 mmol, 33%) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-d6) 8: 10.45 (s, IH), 8.02 (d, J = 8 Hz, IH), 7.78 (d, J = 8 Hz, IH), 7.62 (d, J = 8 Hz, IH), 7.25 (t, J = 8 Hz, IH), 7.20 (d, J = 8 Hz, IH), 6.84 (s, IH), 4.04 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 183.18, 162.26, 153.24, 145.38, 143.35, 139.56, 137.42, 125.32, 123.57, 123.37, 122.98, 121.67, 113.43, 105.37, 53.33. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C15H10BrNO4, 347.9866; found, 347.9865. The purity of Compound 38 was judged to be ca 95% by1H NMR.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0432]

[0433] Compound 39: Compounds SI-9a (43 mg, 0.15 mmol, 1 equiv.) and Sl-lOd (30 mg, 0.15 mmol, 1 equiv.) were reacted with morpholinium acetate (5 mg, 0.03 mmol, 0.2 equiv. in 1.5 mL IPA according to general procedure 5 for 15 hours. Compound 39 (51 mg, 0.107 mmol, 71%) was obtained as a brown-yellow solid. 'H NMR (400 MHz, DMSO-d6) 5: 11.69 (s, 1H), 8.40 (s, 1H), 8.36 (s, 1H), 8.34 (m, 1H), 8.02 (m, 1H), 6.84 (s, 1H).13C NMR (101 MHz, DMSO-d6) 8: 181.84, 161.41, 152.13, 146.06, 142.27, 141.13, 138.97, 131.06, 126.13, 124.04, 118.71, 116.47, 112.72, 106.89. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C14H6Br2NO5, 473.7971; found, 473.7965. The purity of Compound 39 was judged to be ca 95% by1H NMR.

[0434]

[0435] Compound 40: Compounds SI-9b (21 mg, 0.1 mmol, 1 equiv.) and Sl-lOd (20 mg, 0.1 mmol, 1 equiv.) were reacted with morpholinium acetate (3 mg, 0.02 mmol, 0.2 equiv. in 1.5 mL IPA according to general procedure 5 for 15 hours. Compound 40 (26 mg, 0.065 mmol, 65%) was obtained as a brown solid. ’H NMR (400 MHz, DMSO-d6) 8: 11.64 (s, 1H), 8.43 (s, 1H), 8.36 (s, 1H), 8.08 (d, J = 8 Hz, 1H), 7.82 (d, J = 8 Hz, 1H), 7.29 (t, J = 8 Hz, 1H), 6.81 (s, 1H).13C NMR (101 MHz, DMSO-d6) 8: 183.09, 162.19, 151.99, 146.13, 142.53, 139.95, 138.92, 130.92, 125.73, 123.79, 122.78, 118.75, 112.06, 105.35. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C14H7Br2NO5, 395.8865; found, 395.8863. The purity of Compound 40 was judged to be ca 90% by1H NMR.

[0436]

[0437] 7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0438] Compound 41: Compounds SI-9a (87 mg, 0.3 mmol, 1 equiv.) and SI-7b (45 mg, 0.3 mmol, 1 equiv.) were reacted with one drop concentrated HC1 in 1 mL IPA according to general procedure 5 for 4 hours. Compound 41 (95 mg, 0.224 mmol, 75%) was obtained as a tan solid. 'H NMR (400 MHz, DMSO-d6) 8: 8.31 (d, J = 2 Hz, 1H), 8.09 (d, J = 9 Hz, 2H), 8.03 (d, J = 9 Hz, 2H), 7.99 (d, J = 2 Hz, 1H), 7.12 (s, 1H).13C NMR (101 MHz, DMSO-d6) 8: 182.07, 166.77, 161.61, 147.06, 141.21, 135.70, 131.88, 131.56, 129.86, 126.24, 124.04, 116.52, 112.59, 106.97. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C16H6Br2O4, 420.8717; found, 420.8716. The purity of Compound 41 was judged to be ca 90% by1H NMR.

[0439]

[0440] Compound 42: Compounds SI-9b (43 mg, 0.2 mmol, 1 equiv.) and SI-7b (30 mg, 0.2 mmol, 1 equiv.) were reacted with morpholinium acetate (6 mg, 0.04 mmol, 0.2 equiv. in 2 mL IPA according to general procedure 5 for 22 hours. Compound 42 (35 mg, 0.1 mmol, 50%) was obtained as a tan solid.1H NMR (400 MHz, DMSO-d6) 8: 8.14 (d, J = 8 Hz, 2H), 8.09 (dd, J = 8, 1 Hz, 1H), 8.06 (d, J = 8 Hz, 2H), 7.84 (dd, J = 8, 1 Hz, 1H), 7.30 (t, J = 8 Hz, 1H), 7.13 (s, 1H).13C NMR (101 MHz, DMSO-d6) 8: 183.21, 166.77, 162.34, 147.03, 139.98, 135.87, 131.72, 131.46, 129.83, 125.75, 123.82, 122.69, 111.90, 105.39. HRMS-ESI-TOFMS (m / z): [M-H]' calculated for Ci6H9BrO4, 342.9611; found, 342.9609. The purity of Compound 2 was judged to be >95% by1H NMR.

[0441] Example 6

[0442] Quinazolinone Syntheses — Compounds 43, 45-49, & 51-64

[0443]

[0444] 7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0445] Scheme SI-6: Quinazolinone syntheses

[0446] General Procedure 6: A mixture of compounds SI-11 and SI-10, SI-2, or SI-7 in IPA or DMSO in the presence of I2 was heated at reflux for a given time. The reaction was cooled to room temperature, quenched with saturated aqueous Na2S2Ch and diluted with DI water. The precipitate formed was isolated on a filter frit, washed with DI water, and dried to give the title compound.

[0447]

[0448] Compound 43: Compounds Sl-lla (117 mg, 0.4 mmol, 1 equiv.) and SI-2g (81 mg, 0.4 mmol, 1 equiv.) were reacted with I2 (508 mg, 2 mmol, 5 equiv.) in 4 mL IPA according to general procedure 6 for 42 hours. Compound 43 (168 mg, 0.354 mmol, 89%) was obtained as a white solid. 'H NMR (400 MHz, DMSO-d6) 5: 11.18 (s, 1H), 8.47 (m, 1H), 8.36 (m, 1H), 8.19 (m, 1H), 8.15 (d, J = 8 Hz, 1H), 7.10 (d, J = 8 Hz, 1H).13C NMR (201 MHz, DMSO-d6) 5: 160.85, 157.64, 151.93, 145.45, 139.63, 132.83, 128.91, 127.83, 124.16, 123.38, 123.26, 118.15, 116.15, 109.64. HRMS-ESI-TOFMS (m / z): [M-H]-calculated for C14H7Br3N2O2, 470.7985; found, 470.7985. The purity of Compound 43 was judged to be ca 95% byTH NMR.

[0449]

[0450] Compound 45: Compounds Sl-lla (117 mg, 0.4 mmol, 1 equiv.) and Sl-lOa (61 mg, 0.4 mmol, 1 equiv.) were reacted with I2 (508 mg, 2 mmol, 5 equiv.) in 4 mL IPA according to general procedure 6 for 42 hours. Compound 45 (141 mg, 0.33 mmol, 82%) was obtained as a white solid. NMR (400 MHz, DMSO-d6) 8: 9.91 (s, 1H), 8.33 (m, 1H), 8.18 (m, 1H), 7.88 (m, 1H). 7.85 (d, J = 8 Hz, 1H), 6.93 (d, J = 8 Hz, 1H), 3.89 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 161.05, 153.03, 150.63, 147.52, 145.67, 139.58, 127.84, 123.30, 123.06, 122.73, 122.12, 117.75, 115.58, 111.56, 55.77. HRMS-ESI-TOFMS (m / z): [M-H]’ calculated for C15H10Br2N2O3, 422.8975; found, 422.8976. The purity of Compound 45 was judged to be >95% by ’H NMR.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0451]

[0452] Compound 46: Compounds Sl-lla (59 mg, 0.2 mmol, 1 equiv.) and SI-2d (32 mg, 0.2 mmol, 1 equiv.) were reacted with I2 (151 mg, 0.6 mmol, 3 equiv.) in 1 mL IPA according to general procedure 6 for 41 hours. Compound 46 (60 mg, 0.139 mmol, 70%) was obtained as a white solid. ’H NMR (400 MHz, DMSO-d6) 8: 12.76 (s, 1H), 11.14 (s, 1H), 8.35 (m, 1H), 8.31 (m, 1H), 8.18 (m, 1H), 8.11 (d, J = 8 Hz, 1H), 7.12 (d, J = 8 Hz, 1H).13C NMR (101 MHz, DMSO-d6) 8: 161.02, 156.79, 152.20, 145.49, 139.52, 129.78, 128.24, 127.82, 123.73, 123.34, 123.21, 120.20, 118.01, 116.54. HRMS-ESI-TOFMS (m / z): [M-H]' calculated for C14H7Br2ClN2O2, 426.8490; found, 426.8491. The purity of Compound 46 was judged to be >95% by 'H NMR.

[0453]

[0454] Compound 47: Compounds Sl-lla (59 mg, 0.2 mmol, 1 equiv.) and SI-7b (30 mg, 0.2 mmol, 1 equiv.) were reacted with I2 (6 mg, 0.02 mmol, 0.1 equiv.) in 2 mL DMSO according to general procedure 6 at 120 °C for 40 hours. Compound 47 (68 mg, 0.16 mmol, 80%) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) 8: 8.40 (d, J = 2 Hz, 1H), 8.33 (d, J = 8 Hz, 2H), 8.23 (d, J = 2 Hz, 1H), 8.10 (d, J = 8 Hz, 2H).13C NMR (101 MHz, DMSO-d6) 8: 166.83, 160.97, 152.80, 145.30, 139.73, 135.98, 133.83, 129.48, 128.27, 127.93, 123.84, 123.78, 119.05. HRMS-ESI-TOFMS (m / z): [M-H]’ calculated for C15H8Br2N2O3, 420.8829; found, 420.8827. The purity of Compound 47 was judged to be ca 90% by1H NMR.

[0455]

[0456] Compound 48: Compounds Sl-llb (30 mg, 0.1 mmol, 1 equiv.) and SI-2g (20 mg, 0.1 mmol, 1 equiv.) were reacted with I2 (253 mg, 1 mmol, 10 equiv.) in 1 mL IPA according to general7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0457] procedure 6 for 91 hours. Compound 48 (11 mg, 0.023 mmol, 23%) was obtained as a gray solid following recrystallization from MeOH. ’H NMR (400 MHz, DMSO-d6) 8: 11.31 (s, 1H), 8.46 (d, J = 2 Hz, 1H), 8.15 (dd, J = 9, 2 Hz, 1H), 8.09 (s, 1H), 7.1 1 (d, J = 9 Hz, 1H).13C NMR (101 MHz, DMSO-d6) 8: 160.19, 158.09, 153.62, 142.70, 142.58, 133.08, 132.96, 129.80, 129.23, 123.82, 122.64, 116.32, 109.79. HRMS-ESI-TOFMS (m / z): [M-H]’ calculated for C13H6Br3N3O2, 471.7937: found, 471.7936. The purity of Compound 48 was judged to be ca 85% by1H NMR.

[0458]

[0459] Compound 49: Compounds Sl-lla (22 mg, 0.075 mmol, 1 equiv.) and SI-lOc (15 mg, 0.1 mmol, 1.3 equiv.) were reacted with h (95 mg, 0.375 mmol, 5 equiv.) in 1 mL IPA according to general procedure 6 for 67 hours. Compound 49 (22 mg, 0.052 mmol, 69%) was obtained as a gray solid. ‘H NMR (400 MHz, DMSO-d6) 8: 12.04 (s, 1H), 10.57 (s, 1H), 8.37 (d, J = 2 Hz, 1H), 8.22 (d, J = 2 Hz, 1H), 8.03 (d, J = 8 Hz, 1H), 7.32 (d, J = 8 Hz, 1H), 4.11 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 159.98, 152.97, 151.19, 145.67, 145.36, 139.73, 134.89, 128.10, 123.89, 123.31, 122.20, 118.41, 118.27, 54.06. HRMS-ESI-TOFMS (m / z): [M-H]’ calculated for C14H8Br2N3O3, 423.8938; found, 423.8938. The purity of Compound 49 was judged to be >95% by ’H NMR.

[0460]

[0461] Compound 51: Compounds SI-llc (16.5 mg, 0.075 mmol, 1 equiv.) and SI- 10c (15 mg, 0.1 mmol, 1.3 equiv.) were reacted with I2 (95 mg, 0.375 mmol, 5 equiv.) in 1 mL IPA according to general procedure 6 for 67 hours. Compound 51 (10 mg, 0.029 mmol, 38%) was obtained as a gray solid. ‘H NMR (400 MHz, DMSO-d6) 8: 11.86 (s, 1H), 10.53 (s, 1H), 8.15 (m, 2H), 8.05 (d. J = 8 Hz, 1H), 7.40 (t, J = 8 Hz, 1H), 7.32 (d, J = 8 Hz, 1H), 4.12 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 160.94, 152.94, 150.76, 146.37, 145.20, 138.06, 135.10, 127.22, 125.98, 122.96, 122.27, 121.91, 118.06, 54.02. HRMS-ESI-TOFMS (m / z): [M-H]’ calculated for7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0462] C14H10BrN3O3, 345.9833; found, 345.9836. The purity of Compound 51 was judged to be >95% by ’H NMR.

[0463]

[0464] Compound 52: Compounds Sl-lla (22 mg, 0.075 mmol, 1 equiv.) and Sl-lOd (20 mg, 0.1 mmol, 1.3 equiv.) were reacted with I2(95 mg, 0.375 mmol, 5 equiv.) in 1 mL IPA according to general procedure 6 for 66 hours. Compound 52 (27 mg, 0.056 mmol, 76%) was obtained as an off-white solid. ‘H NMR (400 MHz, DMSO-d6) 8: 12.28 (s, IH), 11.85 (s, IH), 8.55 (s, IH), 8.39 (d, J = 2 Hz, IH), 8.33 (s, IH), 8.21 (d, J = 2 Hz, IH).13C NMR (101 MHz, DMSO-d6) 8: 159.57, 154.28, 150.19. 145.24, 140.18, 139.72, 137.04, 128.02, 127.16, 124.28, 123.52, 119.75, 118.99. HRMS-ESI-TOFMS (m / z): [M-H]- calculated for C13H6Br3N3O2, 471.7937; found, 471.7934. The purity of Compound 52 was judged to be ca >95% by ’H NMR.

[0465]

[0466] Compound 53: Compounds SI-llc (16.5 mg, 0.075 mmol, 1 equiv.) and Sl-lOd (20 mg, 0.1 mmol, 1.3 equiv.) were reacted with h (95 mg, 0.375 mmol, 5 equiv.) in 1 mL IPA according to general procedure 6 for 62 hours. Compound 53 (20 mg, 0.05 mmol, 67%) was obtained as a gray solid. ’H NMR (400 MHz, DMSO-d6) 5: 12.07 (s, IH), 11.81 (s, 1H), 8.56 (s, IH), 8.32 (s, Ih), 8.15 (app. t, J = 8 Hz, 2H), 7.42 (t, J = 8 Hz, 1H).13C NMR (101 MHz, DMSO-d6) δ:

[0467] 160.64, 154.23, 149.79, 145.98, 140.42, 138.09, 137.02, 127.75, 127.09, 125.96, 123.38, 122.16, 119.84. HRMS-ESI-TOFMS (m / z): [M-H]’ calculated for Ci3H7Br2N3O2, 393.8832; found, 393.8834. The purity of Compound 53 was judged to be >95% by ’H NMR.

[0468]

[0469] 7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0470] Compound 54: Compounds Sl-lld (48 mg, 0.2 mmol, 1 equiv.) and Sl-lOa (31 mg, 0.2 mmol, 1 equiv.) were reacted with I2 (254 mg, 1 mmol, 5 equiv.) in 1.5 mL IPA according to general procedure 6 for 40 hours. Compound 54 (43 mg, 0.116 mmol, 58%) was obtained as a white solid. 'H NMR (500 MHz, DMSO-d6) 8: 12.90 (s, 1H), 10.06 (s, 1H), 8.58 (m, 1H), 8.48 (m, 1H), 7.92 (m, 2H), 6.96 (d, J = 8 Hz, 1H), 3.89 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 161.10, 155.14, 151.25, 149.53, 147.59, 139.25, 130.88, 122.75, 122.68, 122.30, 122.02, 117.32, 115.66, 111.77, 108.27, 55.80. HRMS-ESI-TOFMS (m / z): [M-H]’ calculated for C16H10BrN3O3, 369.9833; found, 369.9833. The purity of Compound 54 was judged to be ca 90% by1H NMR.

[0471]

[0472] Compound 55: Compounds Sl-lld (48 mg, 0.2 mmol, 1 equiv.) and SI-2g (40 mg, 0.2 mmol, 1 equiv.) were reacted with I2 (508 mg, 2 mmol, 10 equiv.) in 1.5 mL IPA according to general procedure 6 for 66 hours. Compound 55 (16 mg, 0.038 mmol, 19%) was obtained as a white solid following trituration in boiling MeOH.rH NMR (500 MHz, DMSO-d6) δ: 12.94 (s, 1H), 11.32 (s, 1H), 8.60 (m, 1H), 8.52 (m, 1H), 8.48 (m, 1H), 8.19 (d, J = 8 Hz, 1H), 7.11 (d, J = 8 Hz, 1H).13C NMR (101 MHz, DMSO-d6) δ: 160.96, 158.20, 154.13, 149.36, 139.40, 133.28, 130.90, 129.38, 123.80, 122.82, 122.32, 117.27, 116.25, 109.78, 108.69. HRMS-ESI-TOFMS (m / z): [M-H]‘ calculated for C15H7Br2N3O2, 417.8832; found, 417.8829. The purity of Compound 55 was judged to be >95% by 'H NMR.

[0473]

[0474] Compound 56: Compounds Sl-lld (48 mg, 0.2 mmol, 1 equiv.) and SI-lOc (37 mg, 0.24 mmol, 1.2 equiv.) were reacted with I2 (254 mg, 1 mmol, 5 equiv.) in 1.5 mL IPA according to general procedure 6 for 41 hours. Compound 56 (34 mg, 0.091 mmol, 46%) was obtained as a white solid. 'll NMR (500 MHz, DMSO-d6) 8: 12.24 (s, 1H), 10.69 (s, 1H), 8.60 (m, 1H), 8.52 (m, 1H), 8.09 (d, J = 8 Hz, 1H), 7.33 (d, J = 8 Hz, 1H), 4.12 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 160.01, 153.22, 153.05, 149.55, 145.89, 139.39, 134.47, 131.04, 122.87, 122.67, 122.07, 119.10, 117.24, 108.81, 54.14. HRMS-ESI-TOFMS (m / z): [M-H]’ calculated for7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0475] C15H9BrN4O3, 370.9785; found, 370.9787. The purity of Compound 56 was judged to be >95% by1H NMR.

[0476]

[0477] Compound 57: Compounds Sl-lle (33 mg, 0.2 mmol, 1 equiv.) and SI-lOc (37 mg, 0.24 mmol, 1.2 equiv.) were reacted with I2 (254 mg, 1 mmol, 5 equiv.) in 1.5 mL IPA according to general procedure 6 for 41 hours. Compound 57 (18 mg, 0.061 mmol, 31%) was obtained as a white solid. ‘H NMR (500 MHz, DMSO-d6) 8: 11.99 (s, 1H), 10.62 (s, 1H), 8.53 (m, 1H), 8.17 (d, J = 8 Hz, 1H), 8.02 (d, J = 8 Hz, 1H), 7.82 (d, J = 8 Hz, 1H), 7.28 (d, J = 8 Hz, 1H), 4.12 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 160.31, 152.99, 152.76, 145.58, 136.76, 134.68, 131.60, 128.51, 122.08, 121.80, 118.50, 118.41, 108.30, 54.06. HRMS-ESI-TOFMS (m / z): [M-H]- calculated for C15H10N4O3, 293.0680; found, 293.0681. The purity of Compound 57 was judged to be ca 95% by1H NMR.

[0478]

[0479] Compound 58: Compounds Sl-llf (39 mg, 0.15 mmol, 1 equiv.) and Sl-lOa (23 mg, 0.15 mmol, 1 equiv.) were reacted with I2 (190 mg, 0.75 mmol, 5 equiv.) in 2mL IPA according to general procedure 6 for 37 hours. Compound 58 (38 mg, 0.097 mmol, 65%) was obtained as a white solid. ’H NMR (500 MHz, DMSO-d6) 8: 9.98 (s, 1H), 8.66 (d, J = 2 Hz, 1H), 8.54 (d, J = 2 Hz, 1H), 8.32 (s, 1H), 7.90 (m, 2H), 7.89, 7.61 (s, 1H), 6.95 (d, J = 8 Hz, 1H), 3.89 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 165.61, 162.10, 153.86, 150.81, 148.32, 147.57, 136.33, 131.60, 125.39, 122.72, 122.35, 121.83, 121.54, 115.65, 111.63, 55.81. HRMS-ESI-TOFMS (m / z): [M-H]- calculated for Ci6Hi2BrN3O4, 387.9938; found, 387.9940. The purity of Compound 58 was judged to be ca 90% by1H NMR.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0480]

[0481] Compound 59: Compounds Sl-llf (39 mg, 0.15 mmol, 1 equiv.) and SI-2g (30 mg, 0.15 mmol, 1 equiv.) were reacted with I2 (190 mg, 0.75 mmol, 5 equiv.) in 2mL IPA according to general procedure 6 for 37 hours. Compound 59 (50 mg, 0.114 mmol, 76%) was obtained as a white solid. ’H NMR (500 MHz, DMSO-d6) 5: 11.25 (s, 1H), 8.66 (d, J = 2 Hz, 1H), 8.55 (d, J = 2 Hz, 1H), 8.50 (d, J = 2 Hz, 1H), 8.33 (s, 1H), 8.18 (dd, J = 9. 2 Hz, 1H), 7.63 (s, 1H), 7.11 (d, J = 9 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ: 165.56, 161.91, 157.82, 152.78, 148.10, 136.36, 133.02, 131.92, 129.11, 125.37, 124.18, 121.93, 121.78, 116.23, 109.71. HRMS-ESI-TOFMS (m / z): [M-H]' calculated for C15H9Br2N3O3, 435.8938; found, 435.8938. The purity of Compound 59 was judged to be ca 90% by1H NMR.

[0482]

[0483] Compound 60: Compounds Sl-llf (155 mg, 0.6 mmol, 1 equiv.) and SI-lOc (92 mg, 0.6 mmol, 1 equiv.) were reacted with I2 (761 mg, 3 mmol, 5 equiv.) in 8 mL IPA according to general procedure 6 for 66 hours. Compound 60 (214 mg, 0.547 mmol, 91%) was obtained as a tan solid. 'H NMR (400 MHz, DMSO-d6) 5: 12.04 (s, 1H), 10.61 (s, 1H), 8.69 (d, J = 2 Hz, 1H), 8.56 (d, J = 2 Hz, 1H), 8.35 (s, 1H), 8.08 (d, J = 8 Hz, 1H), 7.63 (s, 1H), 7.33 (d, J = 8 Hz, 1H), 4.12 (s, 3H).13C NMR (101 MHz, DMSO-d6) 5: 165.54, 160.95, 153.00, 151.98, 148.30, 145.52, 136.42, 134.85, 132.06, 125.52, 122.37, 122.21, 121.83, 118.54, 54.07. HRMS-ESI-TOFMS (m / z): [M-H]' calculated for C15H11BrN4O4, 388.9891; found, 388.9896. The purity of Compound 60 was judged to be >95% by1H NMR.

[0484]

[0485] Compound 61: Compounds Sl-llg (27 mg, 0.1 mmol, 1 equiv.) and SI-lOc (15 mg, 0.1 mmol, 1 equiv.) were reacted with I2 (126 mg, 0.5 mmol, 5 equiv.) in 1.5 mL IPA according to general7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0486] procedure 6 for 66 hours. Compound 61 (13 mg, 0.032 mmol, 32%) was obtained as a tan solid. 'H NMR (400 MHz, DMSO-d6) 8: 12.04 (s, 1H), 10.61 (s, 1H), 8.84 (m, 1H), 8.66 (d, J = 2Hz, 1H), 8.53 (d, J = 2 Hz, 1H), 8.08 (d, J = 8 Hz, 1H), 7.33 (d, J = 8 Hz, 1H), 4.12 (s, 3H), 2.82 (d, 3H).13C NMR (101 MHz, DMSO-d6) 8: 164.19, 160.94, 152.99, 151.93, 148.16, 145.51, 136.06, 134.84, 132.11, 124.92, 122.40, 122.20, 121.91, 118.53, 54.07, 26.52. HRMS-ESI-TOFMS (m / z): [M-H]- calculated for C16H13BrN4O4, 403.0047; found, 403.0052. The purity of Compound 61 was judged to be ca 90% by1H NMR.

[0487]

[0488] Compound 62: Compounds Sl-llh (29 mg, 0.1 mmol, 1 equiv.) and SI-lOc (20 mg, 0.13 mmol, 1.3 equiv.) were reacted with I2 (64 mg, 0.25 mmol, 2.5 equiv.) in 1 mL IPA according to general procedure 6 for 43 hours. Compound 62 (23 mg, 0.054 mmol, 54%) was obtained as a white solid. 'H NMR (400 MHz, DMSO-d6) 8: 12.02 (s, 1H), 10.59 (s, 1H), 8.16 (d, J = 2 Hz, 1H). 8.11 (d, J = 2 Hz, 1H), 8.07 (d, J = 8 Hz, 1H), 7.33 (d, J = 8 Hz, 1H), 4.12 (s. 3H), 3.01 (s, 3H), 2.99 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 167.69, 160.78, 152.98, 151.58, 146.92, 145.41, 136.33, 134.94, 134.60, 124.43, 122.36, 122.22, 121.91, 118.39, 54.06, 35.01, 29.07. HRMS-ESI-TOFMS (m / z): [M-H]' calculated for Ci7Hi5BrN4O4, 417.0204; found, 417.0210. The purity of Compound 62 was judged to be ca 95% by1H NMR.

[0489]

[0490] Compound 63: Generated over two steps.

[0491] Step 1: Compounds Sl-lli (51 mg, 0.15 mmol, 1 equiv.) and Sl-lOe (37 mg, 0.15 mmol, 1 equiv.) were reacted with I2 (190 mg, 0.75 mmol, 5 equiv.) in 2 mL IPA according to general procedure 6 for 67 hours. Compound SI-12 (72 mg, 0.128 mmol, 85%) was obtained as a white solid. ’H NMR (400 MHz, DMSO-d6) 8: 12.24 (s, 1H), 9.53 (t, J = 6 Hz, 1H), 8.75 (d, J = 2 Hz, 1H), 8.59 (d, J = 2 Hz, 1H), 8.15 (d, J = 8 Hz, 1H). 7.69 (d, J = 8 Hz, 1H), 7.50 (m, 2H), 7.43 (m, 2H), 7.39 (m, 1H), 5.24 (s, 2H), 4.14 (m, 2H), 4.13 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 164.56, 160.84, 153.51, 152.09, 148.56, 146.11, 136.22, 136.02, 135.83, 130.85, 128.55,7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0492] 128.28, 128.20, 124.77 (q, JC-F = 280 Hz), 125.44, 122.52, 122.10, 119.86, 117.96, 70.21, 54.22.

[0493] Note: methylene adjacent to trifluoromethyl under residual.19F NMR (376 MHz, DMSO-d6) 8: -70.25 (t, JH-F= 10 Hz). LRMS-ESI-TOFMS (m / z): [M+H]+calculated for C24H18BrF3N4O4, 563.05; found, 563.23.

[0494] Step 2: Compound SI-12 (42 mg, 0.075 mmol, 1 equiv.) was suspended in 7.5 mL of 1:1 glacial AcOH:12M HCl The resultant mixture was stirred at 55 °C for 16 hours. It was then cooled to room temperature, diluted with DI water, and the solid formed was isolated and dried on a filter frit. Compound 63 (35 mg, 0.074 mmol, 99%) was obtained as a tan solid. 'H NMR (400 MHz, DMSO-d6) 8: 12.12 (s, 1H), 10.64 (s, 1H), 9.52 (t, J = 6 Hz, 1H), 8.74 (d, J = 2 Hz, 1H), 8.57 (d, J = 2 Hz, 1H), 8.09 (d, J = 8 Hz, 1H), 7.34 (d, J = 8 Hz, 1H), 4.14 (m, 2H), 4.13 (s, 3H).13C NMR (100 MHz, DMSO-d6) 8: 164.63, 160.93, 153.03, 152.31, 148.75, 145.62, 136.28, 134.79, 130.67, 125.52, 124.86 (q, JC-F = 281 Hz), 122.46, 122.19, 122.10, 118.69, 54.11. Note:

[0495] methylene adjacent to trifluoromethyl under residual.19F NMR (376 MHz, DMSO-d6) δ: -70.26 (t, JHF = 10 Hz). HRMS-ESI-TOFMS (m / z): [M-H]’ calculated for C17H12BrF3N4O4, 470.9921; found, 470.9928. The purity of Compound 63 was judged to be >95% by1H NMR.

[0496]

[0497] Compound 64: Compounds Sl-llj (47 mg, 0.15 mmol, 1 equiv.) and SI-lOc (31 mg, 0.2 mmol, 1.3 equiv.) were reacted with I2 (190 mg, 0.75 mmol, 5 equiv.) in 1.5 mL IPA according to general procedure 6 for 67 hours. Compound 64 (47 mg, 0.105 mmol, 70%) was obtained as a white solid. ’H NMR (400 MHz, DMSO-d6) 8: 12.03 (s, 1H), 10.62 (s, 1H), 8.62 (d, J = 2 Hz.

[0498] 1H), 8.50 (d, J = 2 Hz, 1H), 8.24 (s, 1H), 8.07 (d, J = 8 Hz, 1H), 7.33 (d, J = 8 Hz, 1H), 4.12 (s, 3H), 1.41 (s, 9H).13C NMR (100 MHz, DMSO-d6) δ: 163.89, 160.93, 153.00, 151.77, 147.94, 145.47, 136.40, 134.87, 133.55, 125.33, 122.21, 122.14, 121.62, 118.45, 54.06, 51.27, 28.55. HRMS-ESI-TOFMS (m / z): [M-H]’ calculated for C19H19BrN4O4, 445.0517; found, 445.0522. The purity of Compound 64 was judged to be ca 95% by1H NMR.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0499] Example 7

[0500] N-methylated Quinazolinone Syntheses from Protected Phenols — Compounds 44 & 50

[0501]

[0502] Scheme SI-7: Synthesis of Compound 44

[0503] Procedure:

[0504] Step 1: Compounds Sl-lla (441 mg, 1.5 mmol, 1 equiv.) and SI-3g (363 mg, 1.5 mmol, 1 equiv.) were reacted with I2 (1140 mg, 4.5 mmol, 3 equiv.) in 15 mL IPA according to general procedure 6 for 68 hours. Compound SI-13 (726 mg, 1.41 mmol, 94%) was obtained as a tan solid. ‘H NMR (500 MHz, DMSO-d6) 8: 12.86 (s, 1H), 8.54 (m, 1H), 8.37 (m, 1H), 8.28 (d, J = 9 Hz, 1H), 8.20 (m, 1H), 7.32 (d, J = 9 Hz, 1H), 6.08 (m, 1H), 5.49 (d, J = 17 Hz, 1H), 5.33 (d, J = 11 Hz, 1H), 4.79 (m, 2H).13C NMR (101 MHz, DMSO-d6) δ: 160.95, 157.20. 151.77, 145.40, 139.69, 132.72, 132.63, 129.00, 127.88, 125.72, 123.52, 123.41, 118.41, 117.93, 113.61, 111.27, 69.36. LRMS-ESI-MS (m / z): [M-H]’ calculated for C17H11Br3N2O2, 512.83; found, 512.91. Step 2: A solution of SI-13 (104 mg, 0.2 mmol, 1 equiv.) in DMF (2 mL) was treated with KI (34 mg, 0.2 mmol, 1 equiv.), K2CO3 (70 mg, 0.5 mmol, 2.5 equiv.) and finally Mel (32 uL, 0.5 mmol, 2.5 equiv.). The reaction was capped, sealed, and heated to 80 °C for 17 hours. The reaction was cooled to room temperature, poured into DI water, and extracted into EtOAc. The combined organic extracts were washed with DI water, dried over sodium sulfate, filtered, and concentrated at reduced pressure. The residue obtained was purified by normal-phase FCC (0-5-10-40% EtOAc / hexanes) to give SI-14 (35 mg, 0.066 mmol, 33%) as a white solid. ’H NMR (400 MHz, CDCI3) 8: 8.39 (d, J = 2 Hz, 1H), 8.13 (d, J = 2 Hz, 1H), 7.87 (d, J = 2 Hz, 1H), 7.56 (dd, J = 9, 2 Hz, 1H), 7.01 (d, J = 9 Hz, 1H), 6.08 (ddt, J = 17, 11, 5 Hz, 1H), 5.52 (d, J = 17 Hz, 1H), 5.37 (d, J = 11 Hz, 1H), 4.71 (d, J = 5 Hz, 2H), 3.56 (s, 3H).13C NMR (101 MHz, CDCh) 8: 161.88, 157.31, 155.89, 144.60, 140.86, 134.29, 132.40, 129.72, 129.37, 128.74, 124.17, 123.00, 120.53, 118.86, 113.47, 113.00, 70.33, 35.61. LRMS-ESI-MS (m / z): [M-H]-calculated for C18H13Br3N2O2, 526.84; found, not found.

[0505] Step 3: Compound SI-14 (35 mg, 0.066 mmol, 1 equiv.) was treated according to step 3 of general procedure 2. The reaction was heated with stirring at reflux for 27 hours. Following trituration in boiling MeOH, compound 44 (13 mg, 0.027 mmol, 41%) was obtained as a gray solid. 'll NMR (500 MHz, DMSO-d6) 8: 10.97 (s, 1H), 8.38 (m, 1H), 8.24 (m, 1H), 7.86 (m,7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0506] 1H), 7.56 (d, J = 9 Hz, 1H), 7.09 (d, J = 9 Hz, 1H), 3.40 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 160.46, 156.52, 156.34, 143.83, 139.46, 133.38, 129.48, 128.05, 126.54, 123.30, 122.40, 118.67, 115.92, 109.27, 34.66. HRMS-ESI-TOFMS (m / z): [M-H]' calculated for C15H9Br3N2O2, 484.8141; found, 484.8137. The purity of Compound 44 was judged to be ca 95% by ’H NMR.

[0507]

[0508] Scheme SI-8: Synthesis of Compound 50

[0509] Procedure:

[0510] Step 1: Compounds Sl-lla (88 mg, 0.3 mmol, 1 equiv.) and Sl-lOe (73 mg, 0.3 mmol, 1 equiv.) were reacted with I2 (381 mg, 1.5 mmol, 5 equiv.) in 3 mL IPA according to general procedure 6 for 74 hours. Compound SI-15 (146 mg, 0.28 mmol, 93%) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) 5: 12.20 (s, 1H), 8.39 (d, J = 2 Hz, 1H), 8.23 (d, J = 2 Hz, 1H), 8.10 (d, J = 8 Hz, 1H), 7.67 (d, J = 8 Hz, 1H), 7.49 (m, 2H), 7.43 (m, 2H), 7.38 (m, 1H), 5.23 (s, 2H), 4.12 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 160.04, 153.48, 151.06, 145.95, 145.54, 139.75, 136.17, 135.89, 128.63, 128.38, 128.33, 128.12, 124.01, 123.41, 119.85, 118.65, 117.67, 70.21. 54.25. LRMS-ESI-MS (m / z): [M-H]’ calculated for C21H15Br2N3O3, 515.94; found, 515.98.

[0511] Step 2: A solution of SI-15 (52 mg, 0.1 mmol, 1 equiv.) in DMF (2 mL) was treated with KI (17 mg, 0.1 mmol, 1 equiv.), K2CO3 (35 mg, 0.25 mmol, 2.5 equiv.) and finally Mel (16 uL, 0.25 mmol, 2.5 equiv.). The reaction was capped, sealed, and heated to 100 °C for 43 hours. The reaction was cooled to room temperature, diluted with DI water, and the resultant solid was isolated and dried by suction filtration. SI-16 (43 mg, 0.081 mmol, 81%) was obtained as a white solid. Only SI-16 was observed under these conditions; SI-14 had to be separated from its O-methylated isomer by column.1H NMR (400 MHz, DMSO-d6) 8: 8.39 (d, J = 2 Hz, 1H), 8.24 (d, J = 2 Hz, 1H), 7.60 (m, 2H), 7.49 (m, 2H), 7.43 (m, 2H), 7.38 (m, 1H), 5.23 (s, 2H), 3.92 (s, 3H), 3.58 (s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 160.64, 154.43, 152.51, 144.35, 143.68, 139.94, 139.62, 136.05, 128.65, 128.32, 128.23, 128.17, 123.46, 122.63, 119.82, 119.69, 119.20, 70.01, 53.70, 34.18. LRMS-ESI-MS (m / z): [M+H]+calculated for C22H17Br2N3O3, 531.97; found, 532.11.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0512] Step 3: Compound SI-16 (40 mg, 0.075 mmol, 1 equiv.) was suspended in 7.5 mL of 1:1 glacial AcOH: 12M HCL The resultant mixture was stirred at 50 °C for 15 hours. It was then cooled to room temperature, diluted with DI water, and the solid formed was isolated and dried on a filter frit. Compound 50 (22 mg, 0.05 mmol, 67%) was obtained as a gray solid. 'H NMR (400 MHz, DMSO-d6) δ: 10.39 (s, 1H). 8.39 (d, J = 2 Hz, 1H), 8.24 (d, J = 2 Hz, 1H), 7.53 (d, J = 8 Hz, 1H), 7.30 (d, J = 8 Hz, 1H), 3.91 (s, 3H), 3.59 (s, 3H).13C NMR (100 MHz, DMSO-d6) 5:

[0513] 160.68, 154.54, 151.89, 143.67, 143.55, 139.52, 138.67, 128.17, 123.33, 122.47, 121.99, 120.23, 118.96, 53.49, 34.26. HRMS-ESI-TOFMS (m / z): [M-H]' calculated for C15H11Br2N3O3, 437.9094; found, 437.9096. The purity of Compound 50 was judged to be ca 95% by1H NMR.

[0514] Example 8

[0515] Syntheses and Evaluation of Acid Bioisostere Aurones SI-

[0516]

[0517] Scheme SI-9: Convergent Acid Bioisostere Aurone Syntheses.

[0518] Procedure: Refer to general procedure 5.

[0519]

[0520] Compound SI-18: Compounds SI-9a (87 mg, 0.3 mmol, 1 equiv.) and SI-17a (53 mg, 0.3 mmol, 1 equiv.) were reacted with one drop concentrated HC1 in 1 mL IPA according to general procedure 5 for 4 hours. Compound SI-18 (92 mg, 0.205 mmol, 68%) was obtained as a tan solid. ‘H NMR (400 MHz, DMSO-d6) 5: 8.29 (d, J = 2 Hz, 1H), 8.15 (m, 4H), 7.97 (d, J = 2 Hz,7158- 113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0521] 1H), 7.13 (s, 1H).13C NMR (201 MHz, DMSO-d6) 8: 181.89, 161.48, 153.75, 146.89, 141.12, 134.13, 132.28, 127.46, 126.16, 125.27, 124.00, 116.46, 112.68. 106.95. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C₁₆H₈Br₂N₄O₂, 446.9087; found, 446.9081. The purity of Compound SI-18 was judged to be ca 95% by1H NMR.

[0522]

[0523] Compound SI-19: Compounds SI-9a (58 mg, 0.2 mmol, 1 equiv.) and SI-17b (30 mg, 0.2 mmol, 1 equiv.) were reacted with one drop concentrated HC1 in 1 mL IPA according to general procedure 5 for 5 hours. Compound SI-19 (42 mg, 0.1 mmol, 50%) was obtained as a yellow solid. ’H NMR (500 MHz, DMSO-d6) 8: 8.35 (m, 1H), 8.09 (m, 3H), 8.01 (m, 3H), 7.54 (s, 1H), 7.15 (s, 1H).13C NMR (101 MHz, DMSO-&) 8: 181.96, 167.09, 161.52, 146.79, 141.12, 135.48, 134.16, 131.37, 128.14, 126.18, 124.09, 116.43, 112.99, 106.94. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C₁₆H₉Br₂NO₃, 421.9022; found, 421.9018. The purity of Compound SI-19 was judged to be >95% by 'H NMR.

[0524]

[0525] Compound SI-20: Compounds SI-9a (58 mg, 0.2 mmol, 1 equiv.) and SI-17c (30 mg, 0.2 mmol, 1 equiv.) were reacted with one drop concentrated HC1 in 1 mL IPA according to general procedure 5 for 6 hours. Compound SI-20 (39 mg, 0.09 mmol, 45%) was obtained as a yellow solid. ‘H NMR (500 MHz, DMSO-d6) 8: 8.33 (m, 1H), 8.26 (s, 2H), 8.02 (m, 1H), 7.99 (d, J = 8 Hz, 2H), 7.92 (d, J = 8 Hz, 2H), 7.09 (s, 1H).13C NMR (101 MHz, DMSO-d6) 8: 181.91, 161.45, 146.46, 141.00, 134.69, 132.88, 130.61, 126.13, 124.18, 116.30, 114.26, 106.97.

[0526] HRMS-ESI-TOFMS (m / z): [M-H]' calculated for Ci5H9BBr2O4, 420.8891; found, 420.8890. The purity of Compound SI-20 was judged to be ca 95% by1H NMR.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0527]

[0528] Compound SI-21: Compounds SI-9a (58 mg, 0.2 mmol, 1 equiv.) and SI-17d (40 mg, 0.2 mmol, 1 equiv.) were reacted with one drop concentrated HC1 in 1 mL IPA according to general procedure 5 for 5 hours. Compound SI-21 (52 mg, 0.11 mmol, 55%) was obtained as a yellow solid. ‘H NMR (500 MHz, DMSO-d6) 5: 8.36 (m, 1H), 8.20 (m, 2H), 8.05 (m, 1H), 7.90 (m, 2H), 7.59 (m, 1H), 7.18 (s, 1H).13C NMR (101 MHz, DMSO-d6) 8: 182.07, 161.65, 147.26, 141.26, 140.23, 135.39, 131.97, 127.30, 126.28, 124.03, 116.55, 111.93, 106.91, 28.72. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C₁₆H₁₁Br₂NO₄S, 471.8848; found, 471.8841. The purity of Compound SI-21 was judged to be >95% by1H NMR.

[0529]

[0530] Compound SI-22: Compounds SI-9a (58 mg, 0.2 mmol, 1 equiv.) and SI-17e (54 mg, 0.2 mmol, 1 equiv.) were reacted with morpholinium acetate (6 mg, 0.04 mmol, 0.2 equiv.) in 2 mL IPA according to general procedure 5 for 19 hours. Compound SI-22 (37 mg, 0.068 mmol, 34%) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-d6) 8: 8.78 (m, 1H), 8.35 (m, 1H), 8.19 (d, J = 8 Hz, 2H), 8.05 (m, 1H), 7.96 (d, J = 8 Hz, 2H), 7.17 (s, 1H), 3.78 (m, 2H).13C NMR (100 MHz, DMSO-d6) 8: 182.09, 161.66, 147.33, 141.56, 141.29, 135.66, 131.98, 127.01, 126.29, 124.39 (q, Jc-r= 278 Hz), 124.02, 116.57, 111.79, 106.90, 43.40 (q, Jc-r= 34 Hz).19F NMR (376 MHz, DMSO-cfe) 8: -70.93 (t, JH-F = 9 Hz). HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C₁₇H₁₀Br₂F₃NO₄S, 539.8722; found, 539.9719. The purity of Compound SI-22 was judged to be ca 95% by 'H NMR.

[0531]

[0532] 7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0533] Compound SI-23: Compounds SI-9a (44 mg, 0.15 mmol, 1 equiv.) and SI-17f (28 mg, 0.15 mmol, 1 equiv.) were reacted with morpholinium acetate (5 mg, 0.03 mmol, 0.2 equiv.) in 2 mL IPA according to general procedure 5 for 13 hours. Compound SI-23 (37 mg, 0.081 mmol, 54%) was obtained as a yellow solid.JH NMR (500 MHz, DMSO-d6) 8: 8.34 (m, 1H), 8.17 (m, 2H), 8.03 (m, 1H), 7.94 (m, 2H), 7.52 (m, 2H), 7.15 (s. 1H).13C NMR (100 MHz, DMSO-d6) 8: 181.99, 161.60, 147.11, 145.02, 141.21, 134.77, 131.77, 126.24, 124.01, 116.50, 112.11, 106.91. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for Ci5H9Br2NO4S, 457.8692; found, 457.8696. The purity of Compound SI-23 was judged to be ca 95% by1H NMR.

[0534]

[0535] Compound SI-24: Compounds SI-9a (44 mg, 0.15 mmol, 1 equiv.) and SI-17g (25 mg, 0.15 mmol, 1 equiv.) were reacted with morpholinium acetate (5 mg, 0.03 mmol, 0.2 equiv.) in 2 mL IPA according to general procedure 5 for 19 hours. Compound SI-24 (31 mg, 0.071 mmol, 47%) was obtained as a yellow solid. ’H NMR (400 MHz, DMSO-d6) 8: 8.60 (m, 1H), 8.35 (m, 1H), 8.09 (m, 2H), 8.04 (m, 1H), 7.97 (m, 2H), 7.15 (s, 1H), 2.81 (m, 3H).13C NMR (100 MHz, DMSO-d6) 8: 181.96, 165.81, 161.53, 146.79, 141.12, 135.67, 133.99, 131.41, 127.74, 126.19, 124.10, 116.41, 112.97, 106.92, 26.36. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C₁₇H₁₁Br₂NO₃, 435.9178; found, 435.9175. The purity of Compound SI-24 was judged to be ca 95% by1H NMR.

[0536]

[0537] Compound SI-25: Compounds SI-9a (29 mg, 0.1 mmol, 1 equiv.) and SI-17h (23 mg, 0.1 mmol, 1 equiv.) were reacted with morpholinium acetate (3 mg, 0.02 mmol, 0.2 equiv.) in 2 mL IPA according to general procedure 5 for 22 hours. Compound SI-25 (20 mg, 0.04 mmol, 40%) was obtained as a yellow solid. ’H NMR (400 MHz, DMSO-<7(1) 8: 9.24 (m, 1H), 8.35 (m, 1H), 8.13 (d, J = 8 Hz, 2H), 8.03 (m, 3H), 7.16 (s, 1H), 4.12 (m, 2H).13C NMR (100 MHz, DMSO-7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0538] de) 8: 181.94, 166.16, 161.54, 146.94, 141.14, 134.76, 134.24, 131.44, 128.12, 126.19, 124.81 (q, JC-F = 279 HZ), 124.04, 116.42, 112.65, 106.88, 40.26 (q, JC-F = 32 HZ).19F NMR (376 MHZ, DMSO-6?6) 8: -70.28 (t, JHF = 10 Hz). HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C₁₈H₁₀Br₂F₃NO₃, 503.9052; found, 503.9047. The purity of Compound SI-25 was judged to be >95% by ’H NMR.

[0539]

[0540] Compound SI-26: Compounds SI-9a (58 mg, 0.2 mmol, 1 equiv.) and SI-17i (36 mg, 0.2 mmol, 1 equiv.) were reacted with morpholinium acetate (6 mg, 0.04 mmol, 0.2 equiv.) in 2 mL IPA according to general procedure 5 for 15 hours. Compound SI-26 (37 mg, 0.068 mmol, 34%) was obtained as a tan solid.1H NMR (500 MHz, DMSO-zTs) 8: 8.33 (m, 1H), 8.07 (d, J = 8 Hz, 2H), 8.02 (m, 1H), 7.77 (d, J = 8 Hz, 2H), 7.13 (s, 1H), 6.52 (s, 1H), 4.80 (d, J = 7 Hz, 2H), 4.72 (d, J = 7 Hz, 2H).13C NMR (101 MHz, DMSO-d6) 8: 181.78, 161.36, 146.91, 146.21, 140.93, 131.71, 130.38, 126.09, 125.36, 124.21, 116.27, 114.05, 106.93, 85.10, 73.95. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C₁₈H₁₂Br₂O₄, 452.9162; found, not found. The purity of Compound SI-26 was judged to be >95% by 'H NMR.

[0541]

[0542] Compound SI-27: Compounds SI-9a (58 mg, 0.2 mmol, 1 equiv.) and SI-17j (39 mg, 0.2 mmol, 1 equiv.) were reacted with morpholinium acetate (6 mg, 0.04 mmol, 0.2 equiv.) in 2 mL IPA according to general procedure 5 for 15 hours. Compound SI-27 (40 mg, 0.085 mmol, 43%) was obtained as a tan solid.1H NMR (500 MHz, DMSO-ri / ,) 8: 8.33 (m, 1H), 8.06 (m, 2H), 8.02 (m, 1H), 7.88 (m, 2H), 7.13 (s, 1H), 6.56 (s, 1H), 3.64 (m, 2H), 3.42 (m, 2H).13C NMR (101 MHz, DMSO-6fe) 8: 181.79, 161.37, 148.70, 146.21, 140.93, 131.66, 130.53, 126.09, 125.21, 124.21, 116.27, 114.05, 106.94, 76.85, 42.30. HRMS-ESI-TOFMS (m / z): [M+H]+7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0543] calculated for C₁₈H₁₂Br₂O₃S, 468.8933; found, not found. The purity of Compound SI-27 was judged to be ca 95% by1H NMR.

[0544]

[0545] Compound SI-28: Compounds SI-9a (58 mg, 0.2 mmol, 1 equiv.) and SI-17k (55 mg, 0.2 mmol, 1 equiv.) were reacted with morpholinium acetate (6 mg, 0.04 mmol, 0.2 equiv.) in 2 mL IPA according to general procedure 5 for 15 hours. Compound SI-28 (30 mg, 0.055 mmol, 28%) was obtained as a tan solid.JH NMR (400 MHz, DMSO-d6) 5: 8.96 (s, 1H), 8.33 (d, J = 2 Hz, 1H). 8.14 (d, J = 8 Hz, 2H), 8.03 (d, J = 2 Hz, 1H), 7.83 (d, J = 8 Hz, 2H), 7.14 (s, 1H).13C NMR (100 MHz, DMSO-d6) 5: 182.43, 162.04, 147.43, 141.61, 133.83. 132.92, 131.97, 127.95, 126.66, 124.51, 123.27 (q, JC-F = 289 Hz), 116.87, 112.98, 107.37, 77.33 (sept, JC-F = 28 Hz).19F NMR (376 MHz, DMSO-&) 8; -73.66. HRMS-ESI-TOFMS (m / z); [M-H]’ calculated for C₁₈H₈Br₂F₆O₃, 542.8672; found, 542.8669. The purity of Compound SI-28 was judged to be ca 85% by1H NMR.

[0546] Example 9

[0547]

[0548] Scheme SI-10: Late-Stage Acid Bioisostere Aurone SI-29 Synthesis Procedure: To a solution of Compound 41 (42 mg, 0.1 mmol, 1 equiv.) in DMF (2 mL) was added EDCIHC1 (25 mg, 0.13 mmol, 1.3 equiv.), HOBt H2O (20 mg, 0.13 mmol, 1.3 equiv.) and NMM (15 uL, 0.13 mmol, 1.3 equiv.). The resultant mixture was stirred at RT for 50 minutes. HONH2 solution (50 wt% aqueous, 31 uL, 0.5 mmol, 5 equiv.) was then added, and stirring continued for 16 hours at RT. The reaction was then diluted with DI water, and the resultant precipitate was isolated and dried via suction filtration. The solid obtained was recrystallized from MeOH. Compound SI-29 (7 mg, 0.016 mmol, 16%) was obtained as an7158- 113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0549] orange solid. ’H NMR (400 MHz, DMSO-&) 8: 11.39 (s, 1H), 9.20 (s, 1H), 8.33 (m, 1H), 8.08 (d, J = 8 Hz, 2H), 8.02 (m, 1H), 7.88 (d, J = 8 Hz, 2H), 7.13 (s, 1H).13C NMR (100 MHz, DMSO-d6) 8: 181.98, 163.36, 161.55, 146.82, 141.13, 134.11, 134.03, 131.48, 127.56, 126.20, 124.11, 116.41, 112.94, 106.93. HRMS-ESI-TOFMS (m / z): [M-H]’ calculated for Ci6H9Br2NO4, 435.826; found, 435.8827. The purity of Compound SI-29 was judged to be ca 85% by1H NMR.

[0550] Example 10

[0551] Evaluation of Compounds SI- 18 to SI-29

[0552] Compounds SI-18-29 were tested against both CK2A and CK2A2 in the same radiometric kinase assay as Compounds 1-71 and were found to be inactive. (ICso>5 pM for CK2A1 and CK2A2)

[0553] Example 11

[0554]

[0555] Scheme SI-11: Synthesis of compound SI-lc

[0556] Procedure: To a solution of SI-30 (411 mg, 3 mmol, 1 equiv.) in DMF (3 mL) was added NBS (1335 mg, 7.5 mmol, 2 equiv.). The resultant mixture was stirred at room temperature for 21 hours and then quenched with saturated aqueous Na2S2O3, poured into DI water and extracted into EtOAc. The combined organic fractions were washed with copious amount of DI water, dried over sodium sulfate, filtered, and concentrated at reduced pressure to give an oily residue. The residue obtained was recrystallized from CH2C12to give compound SI-lc (464 mg, 1.57 mmol, 52%) as a gray solid. ’H NMR (500 MHz, CDCh) 8: 12.13 (s, 1H), 7.68 (s, 1H). 2.70 (s, 3H).13C NMR (100 MHz, DMSO-d6) 8: 202.36, 150.97, 131.85, 130.59, 127.35, 127.06, 28.44. LRMS-ESI (m / z): [M-H]’ calculated for C7H5Br2NO2, 293.86; found, 294.15.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0557] Example 12

[0558]

[0559] Scheme SI-12: Syntheses of compounds Sl-li and Sl-lj Procedure:

[0560] Step 1: Preparation of compound Sl-li: A solution of SI-31 (1934 mg, 12 mmol, 1 equiv.) in DMF (12 mL) was treated with NBS (2350 mg, 13.2 mmol, 1.1 equiv.). The resultant mixture was stirred at room temperature for 15 hours. It was then quenched with saturated aqueous Na2S2O3, diluted with DI water, and the resultant precipitate was washed with copious amounts of DI water and then dried via suction filtration. Compound Sl-li (1863 mg, 7.76 mmol, 65%) was obtained as a white solid free from major impurities.

[0561]

[0562] NMR (400 MHz, DMSO-i / e) 5: 8.56 (m, 1H), 8.43 (m, 1H), 2.73 (s, 3H).13C NMR (100 MHz, CDC13) 8: 203.91, 162.93, 141.92, 134.91, 120.61, 117.35, 114.00, 104.17, 27.20. LRMS-ESI (m / z): [M-H]’ calculated for C9H6BrNO2, 237.95; found, 238.29.

[0563] Step 2: Preparation of compound Sl-lj: A suspension of compound Sl-li (480 mg, 2 mmol, 1 equiv.) in H2SO4 (4 mL) was stirred at room temperature for 22 hours. The resultant mixture was diluted with 200 mL DI water and the precipitate formed was isolated and dried by suction filtration. Compound Sl-lj (414 mg, 1.61 mmol, 80%) was isolated with sufficient purity as a light blue solid. ‘H NMR (400 MHz, DMSOYL) 8: 8.46 (m, 1H), 8.35 (m, 1H), 8.14 (s, 1H), 7.52 (s, 1H), 2.74 (s, 3H).13C NMR (100 MHz, DMSO-d6) 8: 205.57, 165.34, 159.77. 137.95, 130.61, 126.02, 119.92. 110.69, 27.17. LRMS-ESI (m / z): [M-H]’ calculated for C₉H₈BrNO₃ 255.96; found, 256.27.

[0564] Example 13

[0565]

[0566] Scheme SI-13: Synthesis of compound Sl-lk

[0567] Procedure:

[0568] Step 1: Preparation of compound SI-33: A suspension of compound SI-32 (1.8 g, 10 mmol, 1 equiv.) in CH2CI2 (50 mL) was treated with HNMe2 (2M in THF, 5.4 mL, 10.8 mmol, 1.087158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0569] equiv.) followed by EDCIHCl (2098 mg, 11 mmol, 1.1 equiv.). The resultant mixture was stirred at room temperature for 20 hours. It was then diluted with DI water and extracted into CH2CI2. The combined organic extracts were washed with DI water, dried over sodium sulfate, filtered, and concentrated at reduced pressure to give compound SI-33 as a yellow syrup, which was parlayed into the next step without further purification, 'll NMR (400 MHz, CDCI3) 5: 12.36 (s, 1H), 7.89 (d, J = 2 Hz, 1H), 7.50 (dd, J = 8, 2 Hz, 1H), 6.94 (d, J = 8 Hz, 1H), 3.03 (app. s, 6H), 2.61 (s, 3H).13C NMR (101 MHz, CDCh) 8: 204.91, 170.84, 163.75, 135.57, 131.38, 127.19, 119.75, 118.52, 40.27, 36.12, 27.20. LRMS-ESI (m / z): [M-H]’ calculated for C11H13NO3, 206.89; found, 206.32.

[0570] Step 2: Preparation of compound Sl-lk: A solution of compound SI-33 (2.16 g, 10 mmol assumed, 1 equiv.) in DMF (20 mL) was treated with NBS (1958 mg, 11 mmol, 1.1 equiv.). The resultant mixture was stirred at RT for 24 hours. The reaction was then quenched with saturated Na2. S2Ch aqueous, diluted into DI water, and extracted into EtOAc. The combined organic fractions were washed with DI water, dried over sodium sulfate, filtered, and concentrated at reduced pressure. The resultant brown oil was recrystallized from CH2Q2 to give compound Sl-lk (946 mg, 3.31 mmol, 33% from compound SI-32) as a brown, waxy solid. ’H NMR (400 MHz, CDCI3) 8: 7.90 (m, 1H), 7.82 (m, 1H), 3.08 (app. s, 6H), 2.68 (s, 3H).13C NMR (101 MHz, CDCh) 8: 204.65, 169.40, 160.31, 138.43, 130.30, 128.07, 120.35, 112.17, 40.27, 36.18, 27.23. LRMS-ESI (m / z): [M-H]’ calculated for C₁₁H₁₂BrNO₃, 283.99; found, 284.25.

[0571] Example 14

[0572]

[0573] Scheme SI-14: Synthesis of compound SI-3a

[0574] Procedure:

[0575] Step 1: Preparation of compound SI-34: A solution of compound SI-2g (1206 mg, 6 mmol, 1 equiv.) in DMF (19.2 mL) and EtiN (4.8 mL) was treated with (PUPqPd0(348 mg, 0.3 mmol, 0.05 equiv.), Cui (87 mg, 0.45 mmol, 0.075 equiv.) and TIPS-alkyne (2.1 mL, 9 mmol, 1.5 equiv.). The resultant mixture was sparged with argon for one minute, capped, sealed, and heated to 40 °C with stirring for ten days. Upon cooling to room temperature, the reaction was quenched with saturated NH4CI aqueous, diluted with DI water, and extracted into EtOAc. The combined organic fractions were washed with copious amounts of DI water, dried over sodium7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0576] sulfate, filtered, and concentrated at reduced pressure to give an oil. The crude residue obtained was purified by normal-phase FCC (5-10-15% EtOAc / hexanes) to give compound SI-34 (519 mg, 1.72 mmol, 29%) as an off-white solid. Characterization data matched those reported. Step 2: Preparation of compound SI-3a: A solution of compound SI-34 (302 mg, 1 mmol, 1 equiv.) in acetone (10 mL) was treated with K2CO3 (209 mg, 1.5 mmol, 1.5 equiv.), followed by allyl bromide (0.26 mL, 3 mmol, 3 equiv.). The resultant mixture was stirred at room temperature for 15 hours. It was then filtered and the filtrate was concentrated. The crude residue obtained was purified by normal-phase FCC (5-10% EtOAc / hexanes) to give compound SI-3a (254 mg, 0.74 mmol, 74%) as a yellow oil.1H NMR (400 MHz, CDCI3) 8: 9.86 (s, 1H), 7.97 (m, 1H), 7.79 (d, J = 9 Hz, 1H), 6.96 (d, J = 9 Hz, 1H), 6.05 (ddt, J = 17, 11, 5 Hz, 1H), 5.51 (d, J = 17 Hz, 1H). 5.32 (d, J = 11 Hz, 1H), 4.66 (d, J = 5 Hz, 2H), 1.14 (m, 21H).13C NMR (101 MHz, CDCh) 8: 190.79, 164.68, 136.26, 132.48, 132.03, 129.98, 118.62, 114.74, 112.33, 101.83, 97.35, 70.00, 19.17, 11.81. LRMS-ESI (m / z): [M+H]+calculated for C2iH3o02Si, 343.21; found, 343.34.

[0577] Example 15

[0578]

[0579] Scheme SI- 15: Synthesis of compound SI-3b

[0580] Procedure:

[0581] Step 1: Preparation of compound SI-36: A solution of SI-35 (204 mg, 1 mmol, 1 equiv.) in acetone (5 mL) was treated with K2CO3 (415 mg, 3 mmol, 3 equiv.), followed by allyl bromide (0.19 mL, 2.2 mmol, 3 equiv.). The resultant mixture was stirred at room temperature for 22 hours. It was then filtered, and the filtrate was concentrated to give compound SI-36 (236 mg, 0.968 mmol, 97%) as a clear oil. 'H NMR (400 MHz, CDCI3) 8: 7.22 (d, J = 8 Hz, 1H), 7.14 (d, J = 8 Hz, 1H), 6.04 (ddt, J = 17. 10, 5 Hz. 1H), 5.48 (d, J = 17 Hz, 1H), 5.35 (d, J = 10 Hz, 1H), 4.68 (s, 2H), 4.63 (d, J = 5 Hz, 2H).13C NMR (100 MHz, CDCI3) 8: 152.53, 151.51, 132.77, 132.25, 121.59, 120.82, 119.02, 70.50, 64.50. LRMS-ESI (m / z): [M+H]+calculated for C₉H₁₀BrNO₂, 244.00; found, 244.19.

[0582] Step 2: Preparation of compound SI-3b: A solution of compound SI-36 (236 mg, 0.968 mmol.l equiv.) in DCM (10 mL) was treated with DMP (433 mg, 1.02 mmol. 1.05 equiv.). The resultant mixture was stirred at RT for 17 hours. The reaction was quenched with 1:1 saturated Na2S2O3 aqueous: saturated NaHCOs aqueous, diluted with DI water, and extracted into CH2CI2.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0583] The combined organic fractions were dried over sodium sulfate, filtered, and concentrated at reduced pressure. The residue obtained was purified by normal-phase FCC (5-15% EtOAc / hexanes) to give compound SI-3b (214 mg, 0.88 mmol, 91%) as a clear oil.rH NMR (400 MHz, CDC13) 5: 9.92 (s, 1H), 7.92 (d, J = 8 Hz, 1H), 7.23 (d, J = 8 Hz, 1H), 6.05 (ddt, J = 17, 10, 5 Hz, 1H), 5.52 (d, J = 17 Hz, 1H), 5.40 (d, J = 10 Hz, 1H), 4.73 (d, J = 5 Hz, 2H).13C NMR (101 MHz, CDCh) 8: 191.20, 156.09, 146.27, 133.72. 131.28, 122.92, 119.76, 119.72, 70.63. LRMS-ESI (m / z): [M+H]+calculated for C₉H₈BrNO₂, 241.98; found, 242.25.

[0584] Example 16

[0585]

[0586] Scheme SI-16: Synthesis of compound SI-3c

[0587] Procedure:

[0588] Step 1: Preparation of compound SI-38: A solution of compound SI-37 (940 mg, 5 mmol, 1 equiv.) in acetone (25 mL) was treated with K2CO3 (1037 mg, 7.5 mmol, 1.5 equiv.), followed by allyl bromide (0.95 mL, 11 mmol, 2.2 equiv.). The resultant mixture was stirred at room temperature for 2 hours. It was then filtered, and the filtrate was concentrated to give compound SI-38 (1071 mg, 4.7 mmol, 94%) as a red oil. 'H NMR (400 MHz, CDCI3) 8: 8.09 (s, 1H), 7.37 (s, 1H), 6.05 (ddt, J = 17, 11, 4 Hz, 1H), 5.47 (d, J = 17 Hz, 1H), 5.33 (d, J = 11 Hz, 1H), 4.66 (d, J = 4 Hz, 2H), 2.47 (s, 3H).13C NMR (100 MHz, CDCh) 8: 152.44, 150.47, 135.59, 132.63, 128.18, 123.38, 118.94, 71.04, 23.62. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C9Hi0BrNO, 228.0019; found, 228.0016.

[0589] Step 2: Preparation of compound SI-39: A solution of compound SI-38 (1071 mg, 4.7 mmol, 1 equiv.) in CH2Q2 (47 mL) was treated with mCPBA (70 wt%, 1236 mg, 5.01 mmol, 1.05 equiv.). The resultant mixture was stirred at room temperature for 20 hours. The reaction was quenched with 1:1 saturated Na2S2O3aqueous: saturated NaHCOs aqueous and extracted into CH2Q2. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated at reduced pressure to give compound SI-39 (1130 mg, 4.63 mmol, 98%) as a white solid. ’H NMR (400 MHz, CDCh) 8: 7.98 (s, 1H), 7.41 (s, 1H), 6.01 (ddt, J = 17, 11, 57158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0590] Hz, 1H), 5.49 (d, J = 17 Hz, 1H), 5.38 (d, J = 11 Hz, 1H), 4.59 (d, J = 5 Hz, 2H), 2.43 (s, 3H).

[0591] 13C NMR (101 MHZ, CDCl3) δ: 152.18, 131.42, 129.64, 127.63. 119.74, 119.06, 111.35, 71.14, 17.31. LRMS-ESI (m / z): [M+H]+calculated for C9H10BrNO, 244.00; found, 244.17.

[0592] Step 3: Preparation of compound SI-40: A suspension of compound SI-39 (1130 mg, 4.63 mmol, 1 equiv.) in 1,4-dioxane (9.2 mL) was treated with EtN(iPr)2 (8.9 mL, 50.9 mmol, 11 equiv.) and AC2O (4.4 mL, 46.3 mmol, 10 equiv.). It was then capped, sealed, and heated to 110 °C for 20 hours. The reaction was then cooled to room temperature, diluted with DI water, and extracted into CH2Q2. The combined organic extracts were washed with saturated NH4CI aqueous, dried over sodium sulfate, filtered, and concentrated at reduced pressure. The residue obtained was purified by normal-phase FCC (0-5-10-20% EtOAc / hexanes) to give compound SI-40 (475 mg, 1.66 mmol, 36%) as a slightly brown oil. ’H NMR (400 MHz, CDCI3) 8: 8.19 (s, 1H), 7.57 (s, 1H), 6.05 (ddt, J = 17, 10, 5 Hz, 1H), 5.49 (d, J = 17 Hz, 1H), 5.36 (d, J = 10 Hz, 1H), 5.13 (s, 2H), 4.71 (d, J = 5 Hz, 2H), 2.15 (s, 3H).13C NMR (101 MHz, CDCl3) δ: 171.13, 151.96, 149.55, 135.59, 132.27, 127.54, 123.51, 119.21, 70.94, 66.38, 21.41. LRMS-ESI (m / z):

[0593] [M+H]+calculated for C₁₁H₁₂BrNO₃, 286.01; found, 286.12.

[0594] Step 4: Preparation of compound SI-41: A solution of compound SI-40 (475 mg, 1.66 mmol, 1 equiv.) in MeOH (17 mL) was treated with K2CO3 (241 mg, 1.74 mmol, 1.05 equiv.), and the resultant mixture was stirred at room temperature 15 hours. The reaction was then quenched with saturated aqueous NH4CI and extracted into CH2CI2. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated at reduced pressure to give compound SI-41 (359 mg, 1.47 mmol, 89%) as a brown, oily solid. ’H NMR (400 MHz, CDCI3) 8: 8.14 (s, 1H), 7.51 (s, 1H), 6.06 (ddt, J = 17, 11, 5 Hz, 1H), 5.49 (d, J = 17 Hz, 1H), 5.36 (d, J = 11 Hz, 1H), 4.70 (d, J = 5 Hz, 2H), 4.69 (s, 2H).13C NMR (101 MHz, CDCI3) 8: 153.20, 135.62, 134.82, 132.36, 125.77, 123.92, 119.13, 70.97, 64.10. LRMS-ESI (m / z): [M+H]+calculated for C9H10BrNO2, 244.00; found, 244.15.

[0595] Step 5: Preparation of compound SI-3c: A solution of compound SI-41 (359 mg, 1.47 mmol, 1 equiv.) in DCM (15 mL) was treated with DMP (687 mg, 1.62 mmol, 1.1 equiv.). The resultant mixture was stirred at RT for 15 hours. The reaction was quenched with 1:1 saturated Na2S2O3aqueous: saturated NaHCCL aqueous, diluted with DI water, and extracted into CH2Q2.

[0596] The combined organic fractions were dried over sodium sulfate, filtered, and concentrated at reduced pressure. The residue obtained was purified by normal-phase FCC (5-15% EtOAc / hexanes) to give compound SI-3c (274 mg, 1.13 mmol, 77%) as a tan solid. ’H NMR (400 MHz, CDCh) 8: 9.95 (s, 1H), 8.33 (s, 1H), 8.19 (s, 1H), 6.08 (ddt, J = 17, 11, 5 Hz, 1H).

[0597] 5.54 (d, J = 17 Hz, 1H), 5.42 (d, J = 11 Hz, 1H), 4.84 (d, J = 5 Hz, 2H).13C NMR (101 MHz,7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0598] CDCl3) δ: 191.39, 155.45, 147.36, 135.37, 131.54, 127.56, 123.50, 119.78, 70.99. LRMS-ESI (m / z): [M+H]+calculated for C8H7BrNO2. 241.98; found, 242.23.

[0599] Example 17

[0600]

[0601] Scheme SI-17: Synthesis of compound SI-3d

[0602] Procedure:

[0603] Step 1: Preparation of compound SI-42: A solution of compound SI-38 (912 mg, 4 mmol, 1 equiv.) in DMF (8 mL) was treated with NaOMe (25 wt% in MeOH, 1.8 mL, 8 mmol, 2 equiv.) The resultant mixture was sealed and heated with stirring to 75 °C for 16 hours. The reaction was cooled to room temperature and more NaOMe solution (0.9 mL, 4 mmol, 1 equiv.) was added. The resultant mixture was sealed and heated with stirring to 75 °C for another 6 hours. The reaction was then cooled to room temperature, diluted with DI water, and extracted thrice into EtOAc. The combined organic fractions were washed with copious amounts of DI water, dried over sodium sulfate, filtered, and concentrated at reduced pressure to give an oily liquid. The residue obtained was purified by normal-phase FCC (50-80% EtOAc / hexanes) to give compound SI-42 (382 mg, 2.13 mmol, 53%) as a yellow liquid. 'H NMR (400 MHz, CDCI3) 8: 8.00 (s, 1H), 6.66 (s, 1H), 6.05 (ddt, J = 17, 11, 6 Hz, 1H), 5.39 (d, J = 17 Hz, 1H), 5.29 (d, J = 11 Hz, 1H), 4.60 (d, J = 6 Hz, 2H), 3.88 (s, 3H), 2.47 (s, 3H).13C NMR (101 MHz, CDCh) 8: 156.46, 153.57, 143.34, 135.56, 133.36, 119.08, 106.80, 71.33, 56.07, 24.63. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C10H13NO2, 180.1019; found, 180.1017.

[0604] Step 2: Preparation of compound SI-43: A solution of compound SI-42 (382 mg, 2.13 mmol, 1 equiv.) in CH2Q2 (22 mL) was treated with mCPBA (70 wt%, 552 mg, 2.24 mmol, 1.05 equiv.). The resultant mixture was stirred at room temperature for 20 hours. The reaction was quenched with 1:1 saturated Na2S2O3aqueous: saturated NaHCO3aqueous and extracted into CH2Q2. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated at reduced pressure to give compound SI-43 (390 mg, 2 mmol, 94%) as a white solid. ’H NMR (400 MHz, CDCh) 8: 7.96 (s, 1H), 6.66 (s, 1H), 6.01 (dtt, J = 17, 11, 6 Hz, 1H).

[0605] 5.43 (d, J = 17 Hz, 1H), 5.35 (d, J = 11 Hz, 1H), 4.56 (d, J = 6 Hz, 2H), 3.91 (s, 3H), 2.48 (s,7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0606] 3H).13C NMR (101 MHz, CDCl3) δ: 149.60, 148.01, 145.04, 131.90, 127.75, 120.13, 108.25, 71.28. 56.85, 18.22. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C10H13NO3, 196.0968; found, 196.0967.

[0607] Step 3: Preparation of compound SI-44: A suspension of compound SI-43 (390 mg, 2 mmol, 1 equiv.) in 1,4-dioxane (4 mL) was treated with EtN(iPr)2 (3.8 mL, 22 mmol, 11 equiv.) and AC2O (1.9 mL, 20 mmol, 10 equiv.). It was then capped, sealed, and heated to 110 °C for 16 hours. The reaction was then cooled to room temperature, diluted with DI water, and extracted into CH2Q2. The combined organic extracts were washed with saturated NH4CI aqueous, dried over sodium sulfate, filtered, and concentrated at reduced pressure. The residue obtained was purified by normal-phase FCC (0-20-40-60% EtOAc / hexanes) to give compound SI-44 (462 mg, 1.95 mmol, 98%) as a slightly yellow oil. 'H NMR (400 MHz, CDCI3) 8: 8.12 (s, 1H), 6.89 (s, 1H), 6.05 (ddt, J = 17, 10, 6 Hz, 1H), 5.42 (d, J = 17 Hz, 1H), 5.32 (d, J = 10 Hz, 1H), 5.12 (s, 2H). 4.65 (d, J = 6 Hz, 2H), 3.92 (s, 3H), 2.14 (s, 3H).13C NMR (101 MHz, CDCI3) 8: 171.30, 156.62, 150.50, 144.76, 135.32, 132.94, 119.42, 106.32, 71.11, 67.42, 56.33, 21.48. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C12H15NO4, 238.1074; found, 238.1073.

[0608] Step 4: Preparation of compound SI-45: A solution of compound SI-44 (462 mg, 1.95 mmol, 1 equiv.) in MeOH (20 mL) was treated with K2CO3 (284 mg, 2.05 mmol, 1.05 equiv.), and the resultant mixture was stirred at room temperature 16 hours. The reaction was then quenched with saturated aqueous NH4CI and extracted into CH2CI2. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated at reduced pressure to give compound SI-45 (340 mg, 1.74 mmol, 89%) as a brown solid.1H NMR (400 MHz, CDCI3) 8: 8.06 (s, 1H), 6.79 (s, 1H), 6.06 (ddt, J = 17, 10, 6 Hz, 1H), 5.42 (d, J = 17 Hz, 1H), 5.32 (d, J = 10 Hz, 1H), 4.67 (s, 2H), 4.64 (d, J = 6 Hz, 2H), 3.92 (s, 3H), 2.53 (s, 1H).13C NMR (101 MHz, CDCI3) 8: 156.92, 154.62, 144.37, 134.35, 133.00, 119.27, 104.11, 71.17, 64.65, 56.29. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C10H13NO3, 196.0968: found, 196.0967.

[0609] Step 5: Preparation of compound SI-3d: A solution of compound SI-45 (340 mg, 1.74 mmol, 1 equiv.) in DCM (18 mL) was treated with DMP (810 mg, 1.91 mmol, 1.1 equiv.). The resultant mixture was stirred at RT for 15 hours. The reaction was quenched with 1:1 saturated Na2S2O3aqueous: saturated NaHCO3aqueous, diluted with DI water, and extracted into CH2Q2. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated at reduced pressure. The residue obtained was purified by normal-phase FCC (5-15-25% EtOAc / hexanes) to give compound SI-3d (258 mg, 1.33 mmol, 76%) as an off-white, waxy solid. ’H NMR (500 MHz, CDCI3) 8: 9.94 (s, 1H), 8.28 (s, 1H), 7.52 (s, 1H), 6.08 (ddt, J = 17, 11, 5 Hz, 1H), 5.47 (d, J = 17 Hz, 1H), 5.38 (d, J = 11 Hz, 1H), 4.77 (d, J = 5 Hz, 2H), 3.99 (s,7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0610] 3H).13C NMR (101 MHz, CDCl3) δ: 192.89, 156.20, 148.68, 148.49, 134.95, 132.20, 120.02, 104.85, 70.95, 56.68. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C10H11NO3, 194.0812; found, 194.0810.

[0611] Example 18

[0612]

[0613] Scheme SI-18: Synthesis of compound SI-3e

[0614] Procedure:

[0615] Step 1: Preparation of compound SI-47: A solution of compound SI-46 (3192 mg, 20 mmol, 1 equiv.) in acetone (100 mL) was treated with K2CO3 (8300 mg, 60 mmol, 3 equiv.), followed by allyl bromide (3.8 mL, 44 mmol, 2.2 equiv.). The resultant mixture was stirred at room temperature for 22 hours. It was then filtered, and the filtrate was concentrated to give compound SI-47 as a clear oil. 'H NMR (400 MHz, CDCI3) 8: 7.21 (m, 2H), 6.05 (ddt, J = 17, 11, 5 Hz, 1H), 5.46 (d, J = 17 Hz, 1H), 5.35 (d, J = 11 Hz, 1H), 4.68 (d, J = 6 Hz, 1H), 4.64 (d, J = 5 Hz, 2H), 2.78 (t, J = 6 Hz, 1H).13C NMR (100 MHz, CDCI3) 8: 151.69, 150.20, 140.80, 132.31, 122.23, 120.49, 119.09, 70.48, 64.53. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C9H10CINO2, 200.0473; found, 200.0471.

[0616] Step 2: Preparation of compound SI-48: A solution of compound SI-47 (20 mmol assumed from step 1, 1 equiv.) in DMF (40 mL) was treated with NaOMe (25 wt% in MeOH, 13.8 mL, 60 mmol, 3 equiv.) The resultant mixture was sealed and heated with stirring to 90 °C for 21 hours. The reaction was then cooled to room temperature, quenched with saturated NH4CI aqueous, diluted with DI water, and extracted thrice into EtOAc. The combined organic fractions were washed with copious amounts of DI water, dried over sodium sulfate, filtered, and concentrated at reduced pressure to give an oily liquid. Compound SI-48 (1.94g, 10 mmol, 50% over 2 steps) was obtained as a yellow liquid at ca 90% purity.1H NMR (400 MHz, CDCl3) δ: 7.06 (d, J = 8 Hz, 1H), 6.74 (d, J = 8 Hz, 1H), 6.05 (ddt, J = 17, 11, 5 Hz), 5.40 (d, J = 17 Hz, 1H), 5.31 (d, J = 11 Hz, 1H), 4.61 (m, 4H), 4.03 (s, 3H), 3.06 (s, 1H).13C NMR (101 MHz, CDCl3) δ: 154.78, 147.57, 142.34, 133.11, 120.72, 119.08, 113.22, 70.38, 64.38, 54.16. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C10H13NO3, 196.0968; found, 196.0966. Step 3: Preparation of compound SI-3e: A solution of compound SI-48 (1.94g, 10 mmol, 1 equiv.) in DCM (100 mL) was treated with DMP (4.45g, 10.5 mmol, 1.05 equiv.). The resultant mixture was stirred at RT for 17 hours. The reaction was quenched with 1:1 saturated Na2S2O37158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0617] aqueous: saturated NaHCO3aqueous, diluted with DI water, and extracted into CH2Q2. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated at reduced pressure. The residue obtained was purified by normal-phase FCC (5-15% EtOAc / hexanes) to give compound SI-3e (1663 mg, 8.61 mmol, 43% over 3 steps) as a white, waxy solid. 'H NMR (400 MHz, CDCh) 8: 9.87 (s, 1H), 7.59 (d, J = 8 Hz, 1H), 7.13 (d, J = 8 Hz, 1H), 6.06 (ddt, J = 17, 10, 6 Hz, 1H). 5.44 (d, J = 17 Hz, 1H), 5.36 (d, J = 10 Hz, 1H), 4.69 (d, J = 6 Hz, 2H), 4.10 (s, 3H).13C NMR (100 MHz, CDCh) 8: 192.14, 155.06, 147.87, 142.39, 132.11, 119.83, 118.30, 118.17, 70.30, 54.53. HRMS-ESI-TOFMS (m / z): [M+H]+calculated for C10H11NO3, 194.0812; found, 194.0810.

[0618] Example 19

[0619]

[0620] Figure SI-1: Compounds SI-3f-h

[0621] Procedure: Each of these three compounds was furnished in good yield from the requisite phenol under conditions analogous to those described for the generation of compounds SI-38 and SI-47.

[0622] SI-3f: ‘H NMR (400 MHz, CDCh) 8: 9.99 (s, 1H), 8.44 (d, J = 3 Hz, 1H), 7.95 (d, J = 9 Hz, 1H), 7.30 (dd, J = 9, 3 Hz, 1H), 6.05 (ddt, J = 17, 11, 5, Hz, 1H), 5.45 (d, J = 17 Hz, 1H), 5.37 (d, J = 11 Hz, 1H), 4.68 (d, J = 5 Hz, 2H).

[0623] SI-3g: ’H NMR (400 MHz, CDCh) 8: 9.84 (s, 1H), 8.09 (d, J = 2 Hz, 1H), 7.79 (dd, J = 8, 2 Hz, 1H), 6.99 (d, J = 8 Hz, 1H), 6.07 (ddt, J = 17, 11, 5 Hz, 1H), 5.52 (d, 17 Hz, 1H), 5.37 (d, J = 11 Hz, 1H), 4.71 (d, J = 5 Hz, 2H).

[0624] SI-3h: ’H NMR (400 MHz, CDCh) 8: 9.85 (s, 1H), 7.44 (m. 2H), 6.98 (d. J = 9 Hz, 1H), 6.09 (ddt, J = 17, 10, 6 Hz, 1H), 5.44 (d, J = 17 Hz, 1H), 5.35 (d, J = 10 Hz, 1H), 4.71 (d, J = 6 Hz, 1H), 3.94 (s, 3H).7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0625] Example 20

[0626]

[0627] Scheme SI-19: Synthesis of compound SI-9a

[0628] Procedure: A solution of compound SI-1a (2940 mg, 10 mmol, 1 equiv.) in AcOH (20 mL) was treated with Br2 (0.56 mL, 11 mmol, 1.1 equiv.). The resultant mixture was capped, sealed, and heated with stirring to 80 °C for one hour. The reaction was then cooled to room temperature, poured into DI water, and extracted into CH2CI2. The combined organic fractions were washed with saturated aqueous NaHCO3, dried over sodium sulfate, filtered, and concentrated at reduced pressure to give an unstable mixture of alpha-brominated ketones, which was parlayed into the next step with no purification. The residue obtained was taken up in DMF (20 mL) and treated with KF (1162 mg, 20 mmol, 2 equiv.). The resultant mixture was stirred at room temperature for 15 hours. It was then poured into DI water and extracted into ether. The combined organic extracts were washed with DI water and brine, dried over magnesium sulfate, filtered, and concentrated at reduced pressure to give a crude yellow oil. The crude material was recrystallized from CH2Q2 to give compound SI-9a (900 mg, 3.08 mmol, 31%) as a tan solid. 'H NMR (500 MHz, CDCI3) 5: 7.91 (m, 1H), 7.75 (m, 1H), 4.77 (s, 2H).13C NMR (100 MHz, CDCI3) S: 197.75, 169.83, 142.74, 126.27, 124.32, 115.46, 108.43, 76.33. LRMS-ESI (m / z): [M-H]’ calculated for C8H4Br2O2, 290.85; found, not found.

[0629] Example 21

[0630]

[0631] Sl-3e SI-10c

[0632] Scheme SI-20: Synthesis of compound SI- 10c

[0633] Procedure: A solution of compound SI-3e (387 mg, 2 mmol, 1 equiv.) in MeOH (10 mL) was treated with K2CO3 (1106 mg, 8 mmol, 4 equiv.) and (Ph3P)4Pd0(23 mg, 0.02 mmol, 0.05 equiv.) The resultant mixture was sparged with argon for one minute, capped, sealed, and stirred at RT for one hour. The reaction was quenched with NH4CI (1284 mg, 24 mmol, 12 equiv.), diluted with 10 mL DI water, and extracted five times into EtOAc. The combined organic7158- 113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0634] fractions were dried over sodium sulfate, filtered, and concentrated at reduced pressure. The residue obtained was recrystallized from CH2Q2, and the supernatant was concentrated at reduced pressure to give compound SI-10c (180 mg, 1.18 mmol, 59%) as a white, fluffy solid. 'H NMR (400 MHz, DMSO-&) 8: 10.85 (s, 1H), 9.73 (s, 1H), 7.53 (d, J = 8 Hz, 1H), 7.23 (d, J = 8 Hz, 1H), 3.96 (s, 3H).13C NMR (100 MHz, DMSO-d6) 8: 190.83, 153.56, 146.95, 140.43, 121.08, 119.67, 53.26. LRMS-APCI (m / z): [M+H]+calculated for C7H7NO3, 154.05; found, 154.18.

[0635] Example 22

[0636]

[0637] Scheme SI-21: Synthesis of compound SI-10d

[0638] Procedure:

[0639] Step 1: Preparation of compound SI-49: A solution of compound SI-37 (940 mg, 5 mmol, 1 equiv.) in acetone (25 mL) was treated with K2CO3 (1037 mg, 7.5 mmol, 1.5 equiv.), followed by benzyl bromide (0.67 mL, 5.5 mmol, 1.1 equiv.). The resultant mixture was stirred at room temperature for 2 hours. It was then filtered, and the filtrate was concentrated to give compound SI-49 (1239 mg, 4.45 mmol, 89%) as a slightly red oil.

[0640]

[0641] NMR (400 MHz, CDCI3) 8: 8.12 (s, 1H), 7.46 (m, 2H), 7.39 (m, 2H), 7.38 (s, 1H), 7.33 (m, 1H), 5.20 (s, 2H), 2.47 (s, 3H).13C NMR (100 MHz, CDCI3) 8: 152.50. 150.54, 136.34, 135.68, 129.17, 128.76, 128.25, 127.74, 123.74, 72.19, 23.57. LRMS-ESI (m / z): [M+H]+calculated for C14H12BrNO, 278.02; found, 278.25. Step 2: Preparation of compound SI-50: A solution of compound SI-49 (1239 mg, 4.45 mmol, 1 equiv.) in CH2Q2 (45 mL) was treated with mCPBA (70 wt%, 1151 mg, 4.67 mmol, 1.05 equiv.). The resultant mixture was stirred at room temperature for 20 hours. More mCPBA (70 wt%, 230 mg, 0.93 mmol, 0.21 equiv.) was added, and the reaction was stirred for three more hours. More mCPBA (70 wt%, 230 mg, 0.93 mmol, 0.21 equiv.) was added, and the reaction was stirred for 16 more hours. The reaction was quenched with 1:1 saturated Na2S2O3aqueous: saturated NaHCO3aqueous and extracted into CH2Q2. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated at reduced pressure to give compound SI-50 as a white solid. ‘H NMR (400 MHz, CDCI3) 8: 8.06 (s, 1H), 7.42 (s, 1H), 7.40 (m, 4H), 7.357158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0642] (m, 1H), 5.12 (s, 2H), 2.42 (s, 3H).13C NMR (101 MHz, CDCI3) 8: 152.22, 135.09, 129.63, 129.32, 129.21, 129.12, 127.83, 127.68, 111.71, 72.29, 17.28. LRMS-ESI (m / z): [M+H]+calculated for Cl H12BrNO2, 294.01; found, 294.19.

[0643] Step 3: Preparation of compound SI-51: A suspension of compound SI-50 (4.45 mmol assumed, 1 equiv.) in 1,4-dioxane (8.9 mL) was treated with EtN(iPr)2 (8.5 mL, 48.9 mmol, 11 equiv.) and AC2O (4.2 mL, 44.5 mmol, 10 equiv.). It was then capped, sealed, and heated to 110 °C for 20 hours. The reaction was then cooled to room temperature, diluted with DI water, and extracted into CH2Q2. The combined organic extracts were washed with saturated NH4CI aqueous, dried over sodium sulfate, filtered, and concentrated at reduced pressure. The residue obtained was purified by normal-phase FCC (0-5-10-20% EtOAc / hexanes) to give compound SI-51 (510 mg, 1.52 mmol, 34% over 2 steps) as a clear oil. ’H NMR (400 MHz, CDCI3) 8: 8.23 (s, 1H), 7.59 (s, 1H), 7.46 (m, 2H), 7.40 (m, 2H), 7.35 (m, 1H), 5.25 (s, 2H), 5.12 (s, 2H), 2.15 (s, 3H).13C NMR (101 MHz, CDCI3) 8: 171.12, 152.00, 149.62, 135.99, 135.72, 129.24, 128.89, 127.69, 127.56, 123.75, 72.04, 66.32, 21.39. LRMS-ESI (m / z): [M+H]+calculated for C15H14BrNO3, 336.02; found, 336.19.

[0644] Step 4: Preparation of compound SI-52: A solution of compound SI-51 (510 mg, 1.52 mmol, 1 equiv.) in MeOH (15 mL) was treated with K2CO3 (221 mg, 1.60 mmol, 1.05 equiv.), and the resultant mixture was stirred at room temperature 15 hours. The reaction was then quenched with saturated aqueous NH4CI and extracted into CH2CI2. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated at reduced pressure to give compound SI-52 as a brown solid. ’H NMR (400 MHz, CDCI3) 8: 8.14 (s, 1H), 7.55 (s, 1H), 7.45 (m, 2H), 7.39 (m, 2H), 7.34 (m, 1H), 5.21 (s, 2H), 4.66 (s, 2H), 3.52 (s, 1H).13C NMR (100 MHz, CDCI3) 8: 153.70, 151.53, 136.05, 134.99, 129.16, 128.79, 127.64, 125.96, 124.11, 72.04, 64.14. LRMS-ESI (m / z): [M+H]+calculated for C13H12BrNO2, 294.01; found, 294.22.

[0645] Step 5: Preparation of compound SI-53: A solution of compound SI-52 (1.52 mmol assumed, 1 equiv.) in DCM (15 mL) was treated with DMP (708 mg, 1.67 mmol, 1.1 equiv.). The resultant mixture was stirred at RT for 16 hours. The reaction was quenched with 1:1 saturated Na2S2O3aqueous: saturated NaHCCL aqueous, diluted with DI water, and extracted into CH2Q2. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated at reduced pressure. The residue obtained was purified by normal-phase FCC (5-15% EtOAc / hexanes) to give compound SI-53 (252 mg, 0.86 mmol, 57% over 2 steps) as a white, waxy solid. 'H NMR (400 MHz, CDCI3) 8: 9.92 (s, 1H), 8.37 (s, 1H), 8.19 (s, 1H), 7.47 (m, 2H), 7.42 (m, 2H), 7.37 (m, 1H), 5.37 (s, 2H).13C NMR (100 MHz, CDCI3) 8: 191.40, 155.44,7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0646] 147.49, 135.62, 135.27, 129.37, 129.16, 127.64, 127.48, 123.64, 72.14. LRMS-ESI (m / z):

[0647] [M+H]+calculated for C13H10BrNO2, 292.00; found, not found.

[0648] Step 6: Preparation of compound SI-10d: A solution of compound SI-53 (146 mg, 0.5 mmol, 1 equiv.) in CH2Q2 (5 mL) was treated with BBrs (IM in CH2CI2, 1.05 mL, 1.05 mmol, 2.1 equiv.) at RT. The resultant mixture was stirred at RT for ten minutes and then quenched with DI water and extracted into EtOAc. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated at reduced pressure to give an oily semisolid. The residue obtained was triturated in hexanes, isolated and dried via suction filtration to give compound SI-lOd (98 mg, 0.485 mmol, 97%) as a tan powder.rH NMR (400 MHz, DMSO-d6) 8: 12.05 (s, 1H), 9.81 (s, 1H), 8.37 (s, 1H), 8.08 (s, 1H).13C NMR (100 MHz, DMSO-d6) 8: 190.92, 155.37, 145.14, 138.37, 127.06, 119.24. LRMS-ESI (m / z): [M-H]’ calculated for C6H4BrO3, 199.93; found, 200.24.

[0649] Example 23

[0650]

[0651] Scheme SI-22: Synthesis of compound Sl-lOe

[0652] Procedure:

[0653] Step 1: Preparation of compound SI-54: A solution of compound SI-46 (479 mg, 3 mmol, 1 equiv.) in acetone (15 mL) was treated with K2CO3 (622 mg, 4.5 mmol, 1.5 equiv.), followed by benzyl bromide (0.41 mL, 3.3 mmol, 1.1 equiv.). The resultant mixture was stirred at room temperature for 18 hours. It was then filtered, and the filtrate was concentrated to give compound SI-54 (668 mg, 2.67 mmol, 89%) as a white solid. 'H NMR (400 MHz, CDCh) 8: 7.44 (m, 2H), 7.40 (m, 2H), 7.35 (m, 1H), 7.24 (d, J = 8 Hz, 1H), 7.17 (d, J = 8 Hz, 1H), 5.19 (s, 2H), 4.67 (s, 2H).13C NMR (101 MHz, CDCI3) 8: 151.78, 150.22, 140.99, 135.99, 129.26, 128.85, 127.61, 122.57, 120.49, 71.61, 64.49. LRMS-ESI (m / z): [M+H]+calculated for C14H12ClNO2, 250.06; found, 250.31.

[0654] Step 2: Preparation of compound SI-55: A solution of compound SI-54 (499 mg, 2 mmol, 1 equiv.) in DMF (4 mL) was treated with NaOMe (25 wt% in MeOH, 1.4 mL, 6 mmol, 3 equiv.) The resultant mixture was sealed and heated with stirring to 90 °C for 15 hours. The reaction was then cooled to room temperature, quenched with saturated NH4CI aqueous, diluted with DI water, and extracted thrice into EtOAc. The combined organic fractions were washed with copious amounts of DI water, dried over sodium sulfate, filtered, and concentrated at reduced7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0655] pressure to give an oily liquid. Compound SI- 55 (385 mg, 1.57 mmol, 78%) was obtained as a yellow liquid at ca 80% purity.1H NMR (400 MHz, CDCh) 8: 7.42 (m, 2H), 7.37 (m, 2H), 7.32 (m, 1H), 7.04 (d, J = 8 Hz, 1H), 6.70 (d, J = 8 Hz, 1H), 5.14 (s, 2H), 4.59 (s, 2H), 4.06 (s, 3H).

[0656] 13C NMR (101 MHz, CDCh) 8: 154.94, 147.70, 142.37, 136.79, 129.15, 128.61, 127.81, 121.33, 113.21, 71.50, 64.33, 54.15. LRMS-ESI (m / z): [M+H]+calculated for C14H15NO3. 246.11; found, 246.27.

[0657] Step 3: Preparation of compound Sl-lOe: A solution of compound SI-55 (385 mg, 1.57 mmol, 1 equiv.) in DCM (16 mL) was treated with DMP (734 mg, 1.73 mmol, 1.1 equiv.). The resultant mixture was stirred at RT for 15 hours. The reaction was quenched with 1:1 saturated Na2S2O3aqueous: saturated NaHCO3aqueous, diluted with DI water, and extracted into CH2Q2. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated at reduced pressure. The residue obtained was purified by normal-phase FCC (2-4-6-8% EtOAc / hexanes) to give compound Sl-lOe (264 mg, 1.09 mmol, 55% over 2 steps) as a white, waxy solid. ‘H NMR (400 MHz, CDCh) 8: 9.85 (s, 1H), 7.54 (d, J = 8 Hz, 1H), 7.42 (m, 2H), 7.38 (m, 2H), 7.34 (m, 1H), 7.13 (d, J = 8 Hz, 1H), 5.21 (s, 2H), 4.10 (s, 3H).13C NMR (100 MHz, CDCh) 8: 192.04, 155.11, 147.87, 142.34, 135.70, 129.25, 128.90, 127.77, 118.49, 118.25, 71.30, 54.45. LRMS-ESI (m / z): [M+H]+calculated for C14H13NO3, 244.10; found, 244.27.

[0658] Example 24

[0659]

[0660] Scheme SI-23: Synthesis of compound SI-11a

[0661] Procedure: To a solution of compound SI-56 (1770 mg, 6 mmol, 1 equiv.) in THF (40 mL) was added EDCIHC1 (1495 mg, 7.8 mmol, 1.3 equiv.), HOBt H2O (1194 mg, 7.8 mmol, 1.3 equiv.) and NMM (0.86 mL, 1.3 mmol, 1.3 equiv.). The resultant mixture was stirred at RT for 20 minutes. NH4OH solution (50 wt% aqueous, 2.3 mL, 30 mmol, 5 equiv.) was then added, and stirring continued for 4 hours at RT. The reaction was then diluted with DI water and extracted into CH2Q2. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated at reduced pressure to give a white solid. The crude material obtained was recrystallized from CH2CI2. Compound SI-11a (1325 mg, 4.51 mmol, 75%) was obtained as a white, fluffy solid. ’H NMR (400 MHz, DMSO-d6) 8: 8.05 (s, 1H), 7.77 (d, J = 2 Hz, 1H), 7.737158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0662] (d, J = 2 Hz, 1H), 7.48 (s, 1H), 6.80 (s, 2H).nC NMR (101 MHz, DMSO-d6) 8: 169.27, 146.03, 136.69, 130.70, 116.84, 110.40, 104.95. LRMS-APCI (m / z): [M+H]+calculated for C7H6Br2N2O, 294.89; found, 294.97.

[0663] Example 25

[0664]

[0665] Scheme SI-24: Synthesis of compound Sl-llb

[0666] Procedure: A solution of compound SI-57 (411 mg, 3 mmol, 1 equiv.) in DMF (3 mL) was treated with NBS (1335 mg, 7.5 mmol, 2.5 equiv.). The resultant mixture was stirred at room temperature for 18 hours. It was then quenched with saturated aqueous Na2S2Ch. diluted with DI water, and the resultant precipitate was washed with copious amounts of DI water and then dried via suction filtration. Compound Sl-llb (655 mg, 2.22 mmol, 74%) was obtained as a white solid free from major impurities. ’H NMR (400 MHz, DMSO-6) δ: 8.27 (s, 1H), 7.81 (s, 1H), 7.75 (s, 1H), 6.78 (s, 1H).13C NMR (101 MHz, DMSO-d6) 8: 167.44, 142.76, 128.86, 125.63, 123.36, 121.62. LRMS-ESI (m / z): [M-H]’ calculated for CTHGBLN / O, 293.87; found, not found.

[0667] Example 26

[0668]

[0669] Scheme SI-25: Syntheses of compound Sl-lld-f

[0670] Procedure:

[0671] Step 1: Preparation of compound Sl-lle: To a solution of compound SI-58 (979 mg, 6 mmol, 1 equiv.) in THF (40 mL) was added EDCI HC1 (1495 mg, 7.8 mmol, 1.3 equiv.), HOBtH2O (1194 mg, 7.8 mmol, 1.3 equiv.) and NMM (0.86 mL, 1.3 mmol, 1.3 equiv.). The resultant mixture was stirred at RT for 20 minutes. NH4OH solution (50 wt% aqueous, 2.3 mL, 30 mmol, 5 equiv.) was then added, and stirring continued for 30 minutes at RT. The reaction was then diluted with DI water and extracted into CH2CI2. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated at reduced pressure to give a white solid. The crude material obtained was recrystallized from CH2CI2. Compound Sl-lle (679 mg, 4.217158- 113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0672] mmol, 70%) was obtained as a white solid.]H NMR (400 MHz, DMSO-d6) 8: 8.00 (d, J = 2 Hz, 1), 7.92 (s, 1H). 7.48 (s, 1H), 7.46 (dd, J = 8, 2 Hz. 1H), 7.32 (s, 1H), 6.77 (d, J = 8 Hz, 1H).13C NMR (100 MHz, DMSO-d6) 5: 169.62, 153.61, 134.62, 134.05, 120.04, 116.82, 113.17, 94.94. LRMS-ESI (m / z): [M-H]' calculated for C8H7N3O, 160.05; found, 160.28.

[0673] Step 2: Preparation of compound Sl-lld: A solution of compound Sl-lle (645 mg, 4 mmol, 1 equiv.) in DMF (4 mL) was treated with NBS (854 mg, 4.8 mmol, 1.2 equiv.). The resultant mixture was stirred at room temperature for 15 hours. It was then quenched with saturated aqueous Na2S2Ch, diluted with DI water, and the resultant precipitate was washed with copious amounts of DI water and then dried via suction filtration. Compound Sl-lld (898 mg, 3.74 mmol, 94%) was obtained as a white solid free from major impurities.1H NMR (400 MHz, DMSO-d6) 8: 8.11 (s, 1H), 8.06 (m, 1H), 8.03 (m, 1H), 7.59 (app. s, 3H).13C NMR (101 MHz, DMSO-d6) 8: 169.04, 150.23, 137.76, 133.18, 114.76, 113.62, 109.19, 96.62. LRMS-ESI (m / z):

[0674] [M-H]-calculated for C8H6BrN3O, 237.96; found, not found.

[0675] Step 3: Preparation of compound Sl-llf: A suspension of compound Sl-lle (480 mg, 2 mmol, 1 equiv.) in H2SO4 (8 mL) was stirred at room temperature for 15 hours. The resultant mixture was diluted with 300 mL DI water and the precipitate formed was isolated and dried by suction filtration. Compound Sl-llf (391 mg, 1.52 mmol, 76%) was isolated with sufficient purity as a white solid. 'H NMR (400 MHz, DMSO-6) δ: 8.14 (d, J = 2 Hz, 1H), 8.04 (d, J = 2 Hz, 1H), 7.97 (s, 1H), 7.67 (s, 1H), 7.46 (s, 1H), 7.22 (s, 1H), 7.10 (s, 2H).13C NMR (101 MHz, DMSO-d6) 8: 170.26, 166.30, 148.74, 134.31, 128.42, 121.25, 114.62, 108.90. LRMS-ESI (m / z): [M-H]‘ calculated for C8H8BrN3O2, 257.97; found, 258.20.

[0676] Example 27

[0677]

[0678] Scheme SI-26: Syntheses of compound Sl-llg-j7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0679] Procedure:

[0680] Step 1: Preparation of compound SI-60: A solution of compound SI-59 (1135 mg, 7 mmol, 1 equiv.) in AcOH (14 mL) was treated with Br2(0.4 mL, 7.7 mmol, 1.1 equiv.). The resultant mixture was stirred at RT for 22 hours. The reaction was then quenched with saturated aqueous Na2S2O3, diluted with DI water, and the resultant precipitate was washed with copious amounts of DI water and then dried via suction filtration. Compound SI-60 (1361 mg, 5.65 mmol, 81%) was obtained as a white solid free from major impurities.

[0681]

[0682] NMR (400 MHz, DMSO-d6) 5: 8.08 (d, J = 2 Hz, 1H), 7.97 (d, J = 2 Hz, 1H), 6.90 (s, 2H).13C NMR (101 MHz, DMSO-6) δ: 164.99, 151.11, 137.85, 134.58, 119.24, 116.46, 107.69, 94.70. LRMS-ESI (m / z): [M-H]’ calculated for C8H5BrN2O2, 238.95; found, 239.07.

[0683] Step 2: Preparation of compound SI-61: A suspension of compound SI-60 (1928 mg, 8 mmol, 1 equiv.) in H2SO4 (64 mL) was stirred at 70 °C for 18 hours. The resultant mixture was cooled to RT, diluted with 300 mL DI water and the precipitate formed was isolated and dried by suction filtration. Compound SI-61 (1708 mg, 6.59 mmol, 82%) was isolated with sufficient purity as a white solid. 'H NMR (400 MHz, DMSO-6) δ: 8.21 (s, 1H), 8.19 (d, J = 2 Hz, 1H), 8.00 (d, J = 2 Hz, 1H), 7.45 (s, 1H), 7.33 (d, 2H).13C NMR (101 MHz, DMSO-6) δ: 170.14, 166.14, 150.08, 135.93. 130.49, 117.57, 114.87, 108.78. LRMS-ESI (m / z): [M-H]’ calculated for C8H7BrN2O3, 256.96; found, 257.13.

[0684] Preparation of compound Sl-llh: A suspension of compound SI-61 (259 mg, 1 mmol, 1 equiv.) in THF (10 mL) was treated with HNMe2 (2M in THF, 0.55 mL, 1.1 mmol, 1.1 equiv.) followed by EDCI HC1 (229 mg, 1.2 mmol, 1.2 equiv.). The resultant mixture was stirred at room temperature for 18 hours. Further proportions of HNMe2 (2M in THF, 0.27 mL, 0.54 mmol, 0.54 equiv.) and EDCIHC1 (115 mg, 0.6 mmol, 0.6 equiv.) were added, and stirring continued at room temperature for 19 hours. The reaction was then diluted with DI water and extracted into EtOAc. The combined organic extracts were washed with DI water, dried over sodium sulfate, filtered, and concentrated at reduced pressure to give an oil, which was triturated in CH2CI2 to give compound Sl-llh (206 mg, 0.72 mmol, 72%) as a brown solid.1H NMR (400 MHz, DMSO-d6) 8: 8.04 (s, 1H), 7.72 (d, J = 2 Hz, 1H), 7.61 (d, J = 2 Hz, 1H), 7.42 (s, 1H), 7.04 (s, 2H), 2.96 (app. s, 6H).13C NMR (101 MHz, DMSO-d6) 8: 170.15, 168.67, 147.75, 134.54, 128.14, 123.12, 114.43, 109.00, 35.20, 28.81. LRMS-ESI (m / z): [M+H]+calculated for C10H12BrN3O2, 286.02; found, 286.16.

[0685] Preparation of compound Sl-llg: A solution of compound SI-61 (259 mg, 1 mmol, 1 equiv.) in DMF (5 mL) was treated at RT with HATU (570 mg, 1.5 mmol, 1.5 equiv.), EtN(iPr)2 (0.26 mL, 1.5 mmol, 1.5 equiv.), and finally MeNH2(12M aqueous, 0.1 mL, 1.2 mmol, 1.2 equiv).7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0686] The reaction was stirred at RT for one hour. The reaction was then diluted with DI water and extracted into EtOAc. The combined organic extracts were washed with DI water, dried over sodium sulfate, filtered, and concentrated at reduced pressure to give an oil, which was triturated in CH2CI2 to give compound Sl-llg (134 mg, 0.49 mmol, 49%) as an off-white powder. 'H NMR (400 MHz, DMSO-6) δ: 8.17 (q, J = 5 Hz, 1H), 8.10 (d, J = 2 Hz, 1H), 8.00 (d, J = 2 Hz, 1H). 7.98 (s, 1H), 7.46 (s, 1H), 7.04 (s, 2H), 2.75 (d, J = 5 Hz, 3H).13C NMR (101 MHz, DMSO-6) δ: 170.32, 165.12, 148.52, 133.84, 127.98, 121.64, 114.87, 108.93, 26.24. LRMS-ESI (m / z): [M-H]’ calculated for C9H10BrN3O2, 269.99; found, 270.18.

[0687] Preparation of compound Sl-lli: A solution of compound SI-61 (259 mg, 1 mmol, 1 equiv.) in DMF (5 mL) was treated at RT with HATU (570 mg, 1.5 mmol, 1.5 equiv.), EtN(iPr)2 (0.26 mL, 1.5 mmol, 1.5 equiv.), and finally 2,2,2-trifluoroethylamine (0.1 mL, 1.2 mmol, 1.2 equiv). The reaction was stirred at RT for one hour. The reaction was then diluted with DI water and extracted into EtOAc. The combined organic extracts were washed with DI water, dried over sodium sulfate, filtered, and concentrated at reduced pressure to give an oil, which was triturated in CH2CI2 to give compound Sl-lli (181 mg, 0.53 mmol, 53%) as an off-white powder. ’H NMR (400 MHz, DMSO-6) δ: 8.78 (t, J = 6 Hz, 1H), 8.17 (m, 1H), 8.10 (d, J = 2 Hz, 1H), 8.02 (s, 1H), 7.50 (s, 1H), 7.16 (s, 2H), 4.08 (m, 1H).13C NMR (101 MHz, DMSO-6) δ: 170.20, 165.16, 149.17, 134.14, 128.65, 124.94 (q, JC-F= 281 HZ), 119.97. 114.92, 108.88. Note: methylene alpha to trifluoromethyl obscured by residual. LRMS-ESI (m / z): [M-H]’ calculated for C10H9BrF3N3O2, 337.98; found, 338.13.

[0688] Preparation of compound Sl-llj: A solution of compound SI-61 (259 mg, 1 mmol, 1 equiv.) in DMF (5 mL) was treated at RT with HATU (570 mg, 1.5 mmol, 1.5 equiv.), EtN(iPr)2(0.26 mL, 1.5 mmol, 1.5 equiv.), and finally tert-butylamine (0.13 mL, 1.2 mmol, 1.2 equiv). The reaction was stirred at RT for one hour. The reaction was then diluted with DI water and extracted into EtOAc. The combined organic extracts were washed with DI water, dried over sodium sulfate, filtered, and concentrated at reduced pressure to give an oil, which was triturated in CH2C12to give compound SI-1 Ij (241 mg, 0.77 mmol, 77%) as an off-white powder. ’H NMR (400 MHz, DMSO-6) δ: 8.05 (m, 2H), 8.02 (d, J = 2 Hz, 1H), 7.52 (s, 1H), 7.46 (s, 1H), 7.05 (s, 2H), 1.36 (s, 9H).13C NMR (101 MHz, DMSO-6) δ: 170.34, 164.34, 148.46, 134.23, 127.92, 122.61, 114.51, 108.91, 50.81, 28.74. LRMS-ESI (m / z): [M+H]+calculated for C12H16BrN3O2, 314.05; found, 314.16.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0689] Example 28

[0690]

[0691] Scheme SI-27: Synthesis of compound SI-17a

[0692] Procedure: A solution of compound SI-62 (1310 mg, 10 mmol, 1 equiv.) in DMF (40 mL) was treated with sodium azide (976 mg, 15 mmol, 1.5 equiv.) and Cui (96 mg, 0.5 mmol, 0.05 equiv.). The resultant mixture was capped, sealed, and heated with stirring to 120 °C for 20 hours. The reaction was cooled to room temperature, quenched with 3M HC1 aqueous, and extracted into EtOAc. The combined organic fractions were washed with DI water and brine, dried over sodium sulfate, filtered, and concentrated at reduced pressure to give compound SI-17a (809 mg, 4.65 mmol, 47%) as a gray solid. ’H NMR (500 MHz, DMSO-d6) 3: 10.10 (s, 1H), 8.27 (d, J = 8 Hz, 2H), 8.13 (d, J = 8 Hz, 2H).

[0693] Example 29

[0694]

[0695] SI-17b SI-17g Sl-17h

[0696] Figure SI-2: Compounds SI-17b, SI-17g-h

[0697] Procedure: Each of these compounds was synthesized from compound SI-7b according to the procedure for the generation of compound Sl-lla in good yield.

[0698]

[0699] 10.08 (s, 1H), 8.18 (s, 1H), 8.05 (d, J = 8 Hz, 2H), 7.98 (d, J = 8 Hz, 2H), 7.62 (s, 1H).

[0700] SI-17g: ‘H NMR (500 MHz, DMSO-d6) 5: 10.07 (s, 1H), 8.66 (m, 1H), 8.00 (m, 4H), 2.80 (m, 3H).

[0701] SI-17h: Note: the Schiff base of the desired product was obtained at first; it was then hydrolyzed in MeOH / 4M HC1 aqueous to give the desired adduct.1H NMR (500 MHz, DMSO-d6) 5: 10.10 (s, 1H), 9.33 (m, 1H), 8.07 (d, J = 8 Hz, 2H), 8.03 (d, J = 8 Hz, 2H), 4.12 (m, 2H).7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0702] Example 30

[0703]

[0704] Sl-17d

[0705] SI-63

[0706] Scheme SI-28: Synthesis of compound SI-17d

[0707] Procedure: A solution of compound SI-63 (409 mg, 2 mmol, 1 equiv.) in CH2CI2 (10 mL) was treated with pyridine (0.2 mL, 2.2 mmol, 1.1 equiv.) and MeNH2(12M aqueous, 0.2 mL, 2 mmol, 1 equiv.). The resultant mixture was stirred at RT for 18 hours. It was then washed with DI water, and the aqueous layer was separated and extracted with CH2Q2. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated at reduced pressure to give the crude product. After recrystallization from CH2CI2, compound SI-17d (200 mg, 1 mmol, 50%) as a white solid.

[0708]

[0709] NMR (500 MHz, CDCI3) 5: 10.12 (s, 1H), 8.04 (m, 4H), 4.46 (m, 1H), 2.73 (m, 3H).

[0710] Example 31

[0711]

[0712] Scheme SI-29: Synthesis of compound SI-17e

[0713] Procedure:

[0714] Step 1: Preparation of compound SI-65: A solution of compound SI-64 (1173 mg, 5 mmol, 1 equiv.) in CH2Q2 (25 mL) was treated with pyridine (0.44 mL, 5.5 mmol, 1.1 equiv.) and 2,2,2-trifluoroethylamine (0.41 mL, 5.25 mmol, 1 equiv.). The resultant mixture was stirred at RT for 15 hours. It was then quenched with 2M HC1, diluted with DI water, and the aqueous layer was separated and extracted with CH2Q2. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated at reduced pressure to give compound SI-65 (1214 mg, 4.08 mmol, 82%) as a white solid. ‘H NMR (400 MHz, CDCI3) 8: 8.18 (d, J = 9 Hz, 2H), 7.94 (d, J = 9 Hz, 2H), 5.28 (t, J = 7 Hz, 1H), 3.97 (s, 3H), 3.72 (m, 2H).13C NMR (101 MHz, CDCI3) 8: 165.99, 144.21, 134.77. 130.94, 127.43, 123.83 (q. JC-F= 280 Hz), 53.24, 45.02 (q, JC-F= 35 Hz).

[0715] 19F NMR (376 MHz, CDCI3) 8: -72.33 (t, J = 9 Hz). LRMS-ESI (m / z): [M-H]' calculated for C10H10F3NO4S, 296.02; found, 296.23.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0716] Step 2: Preparation of compound SI-66: A solution of compound SI-65 (595 mg, 2 mmol, 1 equiv.) in THF (10 mL) under balloon pressure of argon was cooled with stirring in an ice-water bath. DIBAL-H (IM in THF, 8 mL, 8 mmol, 4 equiv.) was added dropwise, and the reaction was allowed to warm to RT and stirred for 16 hours. A further portion of DIBAL-H (IM in THF, 4 mL, 4 mmol, 2 equiv.) was added at RT, and stirring under balloon pressure of argon was continued for 6 hours. The reaction was quenched with MeOH, poured into saturated aqueous sodium potassium tartrate, and extracted into EtOAc. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated at reduced pressure to give the crude product. The residue obtained was purified by normal-phase FCC (25-50-75% EtOAc / hexanes) to give Compound SI-66 (463 mg, 1.72 mmol, 86%) as a white solid.1H NMR (400 MHz, DMSO-6) δ: 8.59 (t, J = 7 Hz, 1H), 7.78 (d, J = 8 Hz, 2H), 7.52 (d, J = 8 Hz, 2H), 4.58 (s, 2H), 3.67 (m, 2H).13C NMR (101 MHz, DMSO-6) δ: 147.82, 138.90, 126.79, 126.33, 124.41 (q, JC-F= 280 Hz), 62.18, 43.37 (q, JC-F= 34 Hz).19F NMR (376 MHz, DMSO-6) δ: -70.96 (t, J = 9 Hz). LRMS-ESI (m / z): [M-H calculated for C9H10F3NO3S, 268.03; found, 268.26.

[0717] Step 3: Preparation of compound SI-17e: A solution of compound SI-66 (463 mg, 1.72 mmol, 1 equiv.) in 9:1 DCM: DMSO (17 mL) was treated with DMP (802 mg, 1.89 mmol, 1.1 equiv.). The resultant mixture was stirred at RT for 16 hours. The reaction was quenched with 1:1 saturated NazSzCh aqueous: saturated NaHCCh aqueous, diluted with DI water, and extracted into CH2CI2. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated at reduced pressure. The residue obtained was purified by normal-phase FCC (10-20-30-40% EtOAc / hexanes) to give compound SI-17e (312 mg, 1.17 mmol, 68%) as a white solid. ’H NMR (400 MHz DMSO-d6) 8: 10.11 (s, 1H), 8.92 (s, 1H), 8.12 (d. J = 8 Hz, 2H), 8.04 (d, J = 8 Hz, 2H), 3.78 (q, J = 9 Hz, 2H).13C NMR (101 MHz, DMSO-d6) 8: 192.68, 145.45, 138.67, 130.31, 127.16, 124.34 (q, JC-F= 280 Hz), 43.35 (q, JC-F = 34 Hz).19F NMR (376 MHz, DMSO-6) δ: -70.98 (t, JH-F= 9 Hz). LRMS-ESI (m / z): [M-H] calculated for C9H8F3NO3S, 266.01; found, 266.21.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0718]

[0719] Scheme SI-30: Syntheses of compound SI-17i-j

[0720] Procedure:

[0721] Preparation of compound SI-68: A solution of compound SI-67 (904 mg, 3 mmol, 1 equiv.) in THF (15 mL) under balloon pressure of argon was cooled with stirring in a dry ice / acetone bath. A solution of n-BuLi in hexanes (1.6 M, 2.3 mL, 3.6 mmol, 1.2 equiv.) was then added dropwise. The resultant mixture was stirred in a dry ice / acetone bath for one hour. 3-oxo-oxetane (0.25 mL, 3.9 mmol, 1.3 equiv.) was then added dropwise. The reaction was allowed to warm to RT slowly under balloon pressure of argon and stirred for 16 hours. The mixture was poured into DI water and extracted into EtOAc. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated at reduced pressure. The residue obtained was purified by normal-phase FCC (2-4-8-10% EtOAc / hexanes) to give compound SI-68 (394 mg, 1.34 mmol, 45%) as a white solid.1H NMR (400 MHz, CDCh) 8: 7.55 (d, J = 8 Hz, 2H), 7.38 (d, J = 8 Hz, 2H), 4.91 (m, 4H), 4.76 (s, 2H), 2.69 (s, 1H), 0.95 (s, 9H), 0.11 (s, 6H).13C NMR (101 MHz, CDCh) 8: 141.77, 141.35, 126.81, 124.92, 86.12, 76.25, 65.06, 26.41, 18.90, -4.78.

[0722] LRMS-ESI (m / z): [M-H]‘ calculated for C16H26O2Si, 293.16; found, not found.

[0723] Preparation of compound SI-17i: A solution of compound SI-68 (295 mg, 1 mmol, 1 equiv.) in CH2Q2 (50 mL) was treated with PBS- IX (5 mL), and the resultant biphase was cooled with vigorous stirring in an ice-water bath. DDQ (568 mg, 2.5 mmol, 2.5 equiv.) was added in one portion, and the reaction was allowed to warm slowly to RT and stirred for 42 hours. The reaction was quenched with saturated aqueous NaHCCh and extracted into CH2CI2. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated at reduced pressure. The residue obtained was purified by normal-phase FCC (10-20% EtOAc / hexanes) to give compound SI-17i (108 mg, 0.6 mmol, 60%) as a white solid. ’H NMR (400 MHz, CDCh) 8: 10.03 (s, 1H), 7.94 (d, J = 8 Hz, 2H), 7.83 (d, J = 8 Hz, 2H), 4.95 (d, J = 7 Hz, 2H), 4.89 (d, J7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0724] = 7 Hz, 2H), 3.32 (s, 1H).13C NMR (101 MHz, CDCl3) δ: 192.45, 149.41, 136.24, 130.60, 125.58, 86.47, 75.88. LRMS-ESI (m / z): [M-H]’ calculated for C10H10O3, 177.06; found, 177.16.

[0725] Preparation of compound SI-69: A solution of compound SI-67 (904 mg, 3 mmol, 1 equiv.) in THF (15 mL) under balloon pressure of argon was cooled with stirring in a dry ice / acetone bath. A solution of n-BuLi in hexanes (1.6 M, 2.3 mL, 3.6 mmol, 1.2 equiv.) was then added dropwise. The resultant mixture was stirred in a dry ice / acetone bath for one hour. 3-oxo-thietane (343 mg, 3.9 mmol, 1.3 equiv.) in THF (4 mL) was then added dropwise. The reaction was allowed to warm to RT slowly under balloon pressure of argon and stirred for 16 hours. The mixture was poured into DI water and extracted into EtOAc. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated at reduced pressure. The residue obtained was purified by normal-phase FCC (2-4-8-10% EtOAc / hexanes) to give compound SI-69 (262 mg, 0.84 mmol, 28%) as a white solid.1H NMR (400 MHz, CDCh) 8: 7.62 (d, J = 8 Hz, 2H), 7.37 (d, J = 8 Hz, 2H), 4.76 (s, 2H), 3.65 (d, J = 10 Hz, 2H), 3.58 (d, J = 10 Hz, 2H), 2.78 (s. 1H), 0.95 (s, 9H), 0.11 (s, 6H).13C NMR (101 MHz, CDCh) 8: 143.57, 141.87, 126.72, 124.64, 79.51, 65.07, 42.97, 26.42, 18.91, -4.78. LRMS-ESI (m / z): [M-H]’ calculated for C16H26O2SSi, 309.13; found, not found.

[0726] Preparation of compound SI-17j: A solution of compound SI-69 (317 mg, 1.02 mmol, 1 equiv.) in CH2Q2 (50 mL) was treated with PBS- IX (5 mL), and the resultant biphase was cooled with vigorous stirring in an ice-water bath. DDQ (576 mg, 2.55 mmol, 2.5 equiv.) was added in one portion, and the reaction was allowed to warm slowly to RT and stirred for 17 hours. The reaction was quenched with saturated aqueous NaHCCh and extracted into CH2Q2. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated at reduced pressure. The residue obtained was purified by normal-phase FCC (10-20% EtOAc / hexanes) to give compound SI-17j (117 mg, 0.6 mmol, 59%) as a white solid.1H NMR (400 MHz, CDCh) 8: 10.02 (s, 1H), 7.91 (m, 4H), 3.62 (m, 4H), 3.28 (s, 1H).13C NMR (101 MHz, CDCh) 8: 192.49, 151.43, 136.29, 130.59. 125.45, 79.05, 42.99. LRMS-ESI (m / z): [M-H]’ calculated for C10H10O2S, 193.03; found, not found.

[0727] Example 33

[0728]

[0729] 7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0730] Scheme SI-31: Synthesis of compound SI-17k

[0731] Procedure:

[0732] Step 1: A solution of compound SI-70 (1296 mg, 5 mmol, 1 equiv.) in ACN (20 mL) was cooled with stirring in an ice-water bath. Tosic acid monohydrate (2853 mg, 15 mmol, 3 equiv.) was added, and the resultant mixture was stirred in the ice-water bath for ten minutes. A solution of NaNO2(690 mg, 10 mmol, 2 equiv.) in DI water (2.5 mL) was added, followed by a solution of KI (2075 mg, 12.5 mmol, 2.5 equiv.) in DI water (5 mL). The ice- water bath was removed, and the reaction was allowed to stir at RT for 15 hours. The reaction was quenched with saturated NaHCOi aqueous and extracted into EtOAc. The combined organic fractions were washed with 10% saturated Na2S2O3aqueous, dried over sodium sulfate, filtered, and concentrated at reduced pressure to give the aryl iodide intermediate, which was submitted to the next manipulation without further purification.1H NMR (500 MHz, CDCl3) δ: 7.80 (d, J = 8 Hz, 2H), 7.45 (d, J = 8 Hz, 2H).

[0733] Step 2: A mixture of PPI13 (1575 mg, 6 mmol, 1.2 equiv.) and I2 (1525 mg, 6 mmol, 1.2 equiv.) in PhMe (20 mL) in a pressure vessel was stirred at RT for ten minutes. The iodide intermediate (5 mmol assumed, 1 equiv.) in PhMe (10 mL) was added to this mixture. Then, Pd(OAc)2 (40 mg, 0.15 mmol, 0.03 equiv.) and Et / N (4.2 mL, 30 mmol, 6 equiv.) were added. The mixture formed was sparged with argon for two minutes, formic acid (88% aqueous, 0.75 mL, 20 mmol, 4 equiv.) was added with a quickness immediately after, and the reaction was capped, sealed, and heated to 80 °C for 16 hours. The reaction was filtered through a celite plug, rinsing with EtOAc, and the filtrate was concentrated at reduced pressure. The residue obtained was purified by normal -phase FCC (10-20% EtOAc / hexanes) to give compound SI-17k (385 mg, 1.4 mmol, 28% over 2 steps) as a white solid.1H NMR (400 MHz, CDCL) 8: 10.07 (s, 1H), 7.98 (d, J = 9 Hz, 2H), 7.94 (d, J = 9 Hz, 2H).13C NMR (101 MHz, CDCI3) 8: 192.31, 137.79, 136.03, 130.17, 128.03 (sept, JC-F= 2 Hz), 122.88 (q, JC-F = 290 Hz). Note: methine alpha to both trifluoromethyl groups obscured by residual.19F NMR (376 MHz, CDCL) 8: -75.10. LRMS-ESI (m / z): [M-H]‘ calculated for C10H6F6O2, 271.02; found, 271.10.

[0734] Example 34

[0735] C6-Basic Chromenone Scaffold 5M4U Binding Mode Model in silico

[0736] Docking of compounds FLC-21, 22, 60, 65 and 67 was performed using Schrodinger Maestro version 2025-1, using the Glide module (parameters: precision XP, force field OPLS_2005, restraining docking to the core structure position SMARTS clcccc(cl2)oc(cc2=O)-c3ccccc3 of the reference cognate ligand FLC-21, with inclusion of the7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0737] following settings: for 5M4U, a) halogens as H-bond donors, b) reward intramolecular H-bonds, and c) enhance planarity of conjugated pi groups: for 5M4F: a) halogens as H-bond acceptors and b) H-bond with Val116 amide N-H. Ligands were prepared using the LigPrep using standard parameters. CK2A2 receptor grid was prepared from pdb file 5M4U and the Protein Preparation Wizard module with standard parameters. CK2A1 receptor grid was prepared from pdb file 5M4F and the Protein Preparation Wizard module with the following parameters: a) halogens as H-bond acceptors and b) H-bond with Val116 amide N-H, and c) 4 key waters participating in the binding of FLC-21 to CK2A1 were kept (see Niefind et al, Figure 4b). Visualization of the resulting pose view files was performed in 3D using the Technical Advanced preset of Schrodinger Maestro Viewer (criteria for H bonds: distance <2.8 A, >90° donor and >60° acceptor) and in 2D using the Ligand Interaction Diagram module.

[0738] Example 35

[0739] cLogP Calculations

[0740] Calculated n-octanol / water partition coefficients (log Pow) were generated from the QikProp module of Schrodinger Maestro version 2023-1.

[0741] Example 36

[0742] Radiometric Kinase Assay

[0743] Compounds 1-71 and SI-18-SI-29 were profiled in radiometric kinase assays through use of Eurofins as a contract research organization (CRO). Studies were performed at the Km of ATP in a dose response (9-point curve in duplicate) for both CK2A1 (Eurofins product #14-197KP) and CK2A2 (Eurofins product #14-689KP) with a top testing concentration of 5 pM. The peptide used in both cases was RRRDDDSDDD. Details of both procedures are available.

[0744] Example 37

[0745] Kinome Selectivity Profiling

[0746] CHR and compounds 20, 22, 60 and 65 were evaluated in the scanMAX assay upon submission to Eurofins DiscoverX Corporation as a CRO. Each compound was tested at a concentration of 1 pM against 468 total and 403 non-mutant kinases, leading to a description of percent inhibition of each kinase.

[0747] - Ill -7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0748] Example 38

[0749] MDR1-MDCKII Bidirectional Permeability

[0750] Bidirectional permeability was measured using Chempartner as a CRO. MDR1-MDCKII cells were seeded onto 24-well plates to form monolayers at a cell density of 0.88x105 / well. Transendothelial electrical resistance (TEER) was measured to verify the quality of the monolayers formed prior to measurement. Lucifer yellow (LY) analysis was performed to judge the quality of the monolayers post-experiment. Apical to basolateral (a- b) and (b-> a) measurements were performed using two timepoints (0 and 90 minutes) in duplicate. Selected compounds were tested at 5 pM in Hank’s Balanced Salt Solution (HBSS) in the presence of 2% bovine serum albumin (BSA) at a pH of 7.4 and temperature of 37°C. Reference compounds Atenolol, Metroprolol, and Digoxin were tested at the same concentration in HBSS without BSA. Post-incubation, samples were analyzed by LCMS / MS using imipramine as an internal standard. From this analysis the apparent permeability a- b (Pappa→b) and Pappb- a values for each compound were derived. Pappb- a / Pappa→b gave the efflux ratio.

[0751] Example 39

[0752] Determination of fu, plasma and fu, brain

[0753] The plasma protein binding ratio (fu,piasma) and brain protein binding ratio (fu, brain) were determined in vitro for selected compounds using ChemPartner as a CRO. Equilibrium dialysis against CD-I mouse plasma and brain homogenate was performed using an HTD 96-well Equilibrium Dialysis Device. Compounds were tested at 1 pM total concentration with warfarin and quinidine as reference compounds. The brain homogenate measurement was buffered at pH = 7.4. Measurements of unbound fraction in both brain homogenate and plasma were taken timepoints of 0 and 5 hours in duplicate. Quantification of the unbound fraction in both cases was determined by LCMS / MS using imipramine as an internal standard. These values were used to calculate KP,UU / KPas shown below.

[0754] Cbrain: Total concentration of an analyte in the brain

[0755] Cplasma- Total concentration of an analyte in plasma

[0756] fu, brain- Unbound proportion of an analyte in the brain

[0757] fu, plasma: Unbound proportion of an analyte in plasma

[0758] Cu, brain: Unbound concentration of an analyte in the brain

[0759] Cu, plasma: Unbound concentration of an analyte in plasma

[0760] Derivation of Kp,Uu / Kpand Kp,uu:

[0761] Kp= Cbrain / Cplasma7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0762] Kp,uu= Cu, brain / Cu, plasma= (Cbrain* fu, brain) / (Cplasma* fu, plasma)

[0763] Therefore:

[0764] Kp,uu= Kp* (fu, brain / fu, plasma) and Kp,uu / Kp= (fu, brain / fu,plasma)

[0765] Example 40

[0766] Determination of Total Brain and Plasma Concentration in vivo (Cplasmaand Cbrain) Formulation of Compound 60: All solvents were passed through a 22 pM filter before use. A 5 mL Eppendorf tube was charged with 8 mg of compound 60 and a flea-flicker Teflon stir bar. Tween20 (0.1 mL) and DMSO (0.1 mL) were added, and the resultant mixture was heated to 90°C with stirring for 30 minutes. The now homogeneous solution was cooled to room temperature (RT). Corn oil (1.8 mL) was added, and the resultant mixture was vortexed for 30 seconds to give a formulation that was stable at RT for >lh. The final concentration of compound 60 was 4 mg / mL.

[0767] Formulation of Compound 65: All solvents were passed through a 22 pM filter before use. A 5 mL Eppendorf tube was charged with 8 mg of 65 and a flea-flicker Teflon stir bar. N-methyl pyrrolidinone (0.1 mL) was added, and the resultant mixture was sonicated in a water bath for 30 seconds. Kolliphor (0.2 mL), propylene glycol (0.2 mL), and polyethylene glycol 400 (0.4 mL) were added, and the resultant mixture was heated with stirring to 100°C for two minutes. The now homogeneous solution was cooled to RT, and corn oil (1.1 mL) was added. The resultant mixture was vortexed for 30 seconds to give a formulation that was stable at RT for >24h. The final concentration of compound 65 was 4 mg / mL.

[0768] Experimentation in vivo: ChemPartner was used as a CRO: both compounds 60 and 65 were assayed as follows. Six male CD-I mice aged 6-8 weeks with food and water ad libitum were treated via subcutaneous injection at 20 mg / kg (5 mL / kg) of either formulation. Following one hour, 110 uL blood were collected from each mouse via a facial vein draw. Quantification of both analytes in the blood was performed with LCMS / MS using osalmid as an internal standard. The mice were sacrificed, and the brains were collected. Each brain was weighed and homogenized with phospho-buffered saline (PBS). Following the addition of osalmid as an internal standard, both analytes were quantified in the brain homogenate by LCMS / MS. The values for Cplasmaand Cbrainwere derived from these measurements for both compounds 60 and 65. From these, Kpand Kp,uuwere calculated (Appendix A) for both compounds.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0769] Example 41

[0770] HLM (half-life measurement and intrinsic clearance)

[0771] The half-life and intrinsic clearance values of selected compounds in human liver microsomes (HLM) were determined using ChemPartner as a CRO. Ketanserin was used a reference compound. Incubation times of 0, 5, 15, 30, and 45 minutes at pH 7.4 and temperature = 37 °C were performed with HLM for all test compounds and the reference at 1 pM, in duplicate. The fraction of compound remaining was quantified by LCMS / MS for each timepoint using imipramine as an internal standard, and from these values a determination of half-life and intrinsic clearance for each compound was calculated.

[0772] Example 42

[0773] Results and Discussion concerning Examples 1-41

[0774] Initial studies centered on selective sidechain additions or deletions and hybridization of the FLC-26 / FNH-79 scaffolds to develop a better understanding of their SAR. Noting the profound effect on potency of the deletion of the C3’ -methoxy moiety from CHR to API, the FNH-79 analogue compound 1 was generated and observed a complete loss of potency (Table 2). Hybridization of the two scaffolds generated compounds 2, 3, and 6, which displayed ratios of CK2 catalytic paralog selectivity in between those observed for FNH-79 and FLC-26.

[0775] Extension of the C4’ benzoic acid in FLC-26 by a single methylene in compound 4 decreased inhibition of both CK2 catalytic paralogs, but the paralog selectivity ratio improved. The deletion of the C3 -hydroxy from FLC-26 to form compound 5 led to a similar outcome. Overall, these results indicated the importance of C3’ substitution for CK2 catalytic subunit potency when C4’ is hydroxy as opposed to an acid. For example, C3’ substitution of FLC-26 with a methoxy group (compound 3) led to modest loss of potency.

[0776] Table 2: Early perturbations of top known flavone scaffolds with the numbers indicating scaffold positions

[0777]

[0778]

[0779] 7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0780]

[0781] Despite the strong preference for CK2A2 over CK2A1 observed with the C4’ acids, efforts to steer towards the study of C3’ -substituted, C4’ -hydroxy FNH-79 analogues were taken given the known issues of Pgp-mediated efflux of acids in the CNS. In addition, efforts to steer away from C3-hydroxy compounds (flavonones) were employed to minimize hydrogen bond (H-bond) donors on the scaffold, also to minimize the prospect of efflux. Given the strong impact of halogenation on potency C6, C8-dibromination was maintained for the initial scan of this class of compounds. For compounds 7-14, an array of C3’- and C3’-C5’ -functionalized, C4’ -hydroxy substituted compounds (Table 3) were studied. The rationale for the study of compounds 11 and 12 included the possibility of the C3’-C5’ bis-halogenated, C4’ -hydroxylated motif acting as an acid bioisostere. However, compounds 11 and 12 showed modest potency for both CK2 catalytic subunit paralogs and exhibited limited paralog selectivity. The most active compound from this initial foray was compound 13, with single-digit-nanomolar potency for CK2A2 and a six-fold paralog selectivity window. However, the clogP calculated for compound 13 of 4.1 is likely too high for CNS activity.

[0782] Table 3: Discovery of the C3’-Brominated Flavone Scaffold with numbers indicating scaffold positions without endocyclic variation

[0783]

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[0785]

[0786] Attempts to reduce the lipophilicity of compound 13 were evaluated with the study of compounds 15-19 (Table 3). Deletion of a single bromide (compounds 15 and 19) or incorporation of a pyridyl moiety at various positions (compounds 16-19) produced either a weaker CK2 catalytic subunit inhibitor or a poorer window of catalytic paralog selectivity.

[0787] Table 4: Discovery of the 2-(pyridin-2-yl)-4H-chromen-4-one Scaffold with numbers indicating scaffold positions without endocyclic variation

[0788]

[0789] 7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0790]

[0791] A similar approach to lower the lipophilicity of FNH-79 was employed. Starting with compound 20, a pyridyl moiety was introduced and instead discovered a serendipitous improvement in potency. (Table 4). Compounds 20 and 21 evinced a modest improvement for CK2 catalytic subunit inhibition from FNH-79. Switching from a 4-methoxy pyridine to a 2-methoxy pyridine in compounds 22 and 23 afforded inhibitors with single-digit nanomolar potency with a trend towards desired catalytic paralog selectivity for compound 22. The loss of potency observed for compound 24 highlighted the continued importance of the C3’ methoxy substitution. Continuing the push for lower lipophilicity, various halogen substitutions / deletions were examined for compounds 25-29, but all were inferior to compound 22. Deferring to the importance of C3-hydroxy substitution observed in the FLC series (Table 2), compound 30 was generated but found it to be of inferior potency to compound 22.

[0792] A class of aurones has been disclosed, the most potent of which were single digit nanomolar CK2(h) inhibitors. It has been suggested that the binding mode of the aurone scaffold to CK2A1 might be similar to that observed for FLC-21. However, C5, C7 bis-halogenated aurone analogues were not pursued. Furthermore, the discoveries made from the survey of chromenone cores (Tables 3 and 4) was applied to the aurone scaffold. A small library of benzofuranone analogues was synthesized on this basis (Table 5).7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0793] Table 5: Benzofuranone Scaffolds Analogous to top Chromenone Scaffolds with numbers indicating scaffold positions without endocyclic variation

[0794]

[0795] Compounds 31-42 showed inferior potencies for both CK2 catalytic subunit paralogs (Table 5) relative to the analogous chromenones. The complete abolition of CK2 potency for compound 32 relative to 31 and compound 34 relative to 33 underscored the continued importance of C3’-substitution for any catalytic subunit potency observed. Poorer inhibition of both catalytic subunit paralogs was observed for benzofuranones 37-40 in comparison to their chromenone analogues 22-23 and 18-19 (Tables 3 and 4). An interesting result from this aurone scan was the ten to twenty-five-fold selectivity for CK2A2 over CK2A1 observed for compounds 41-42. To expand on this result, an acid bioisostere scan was performed for compound 41. Twelve acid bioisosteric replacements were constructed (SI-18-SI-29) to generate a benzofuranone with sufficient brain penetration to modulate CNS disorders while maintaining this window of7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0796] CK2A2 selectivity. However, all these compounds were inactive against both catalytic subunit paralogs (IC50 > 5 pM).

[0797] The last core explored for new classes of inhibitors was the quinazolinone scaffold, given its near-identical three-dimensional structure to that of a chromenone. A quinazolinone moiety in a recently disclosed bromodomain-containing protein 4 (BRD4)-CK2 dual inhibitor also was considered. Similar to the approach to the benzofuranone scaffold, the discoveries were mapped from the chromenone scaffold (Tables 3 and 4) to the quinazolinone scaffold (Table 6).

[0798] Table 6: Quinazolinone Scaffolds Analogous to top Chromenone Scaffolds with numbers indicating scaffold positions without endocyclic variation

[0799]

[0800] The initial quinazolinone analogues demonstrated inferior potencies for both CK2 catalytic subunit paralogs (Table 6), but the loss of inhibitory potency of both paralogs for quinazolinone compounds 43, 49, and 51 relative to chromenones 13, 22, and 23 (Tables 3 and 4) was not as dramatic as the loss observed for the analogous benzofuranones 31, 37, and 38 (Table 5). The N-methylated compounds 44 and 50, analogues of compounds 43 and 49 respectively, displayed7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0801] inferior inhibition of both catalytic paralogs. The trend in selectivity towards CK2A1 over CK2A2 was notable for multiple compounds: 43 and 46-48. With lessons learned from the chromenone, benzofuranone, and quinazolinone scaffolds, one final sidechain modification was evaluated to improve CK2A2 potency and perhaps catalytic paralog selectivity.

[0802] The sequence alignment between both CK2 catalytic paralogs was studied with a focus on which residues at the active sites differed. In the interdomain hinge region near the entrance to the ATP binding site of both CK2A1 and CK2A2, there is a tyrosine residue (Tyrl 16) within CK2A2 in the place of a histidine residue (His 115) within CK2A1. An H-bond acceptor from the C6-position on the chromenone / quinazolinone scaffolds was devised to pick up an interaction with Tyrl 16 and thus improve CK2A2 potency. The 5M4U crystal of FLC-21 bound with CK2A2 was selected as the basis for in silico studies. Modelling of the binding mode of two analogues of compound 22, one with a C6-nitrile and another with a C6-benzamide in place of the C6-bromide, suggested such an interaction was possible (FIGS. 2A and 2B). The prospect of paralog selectivity for the C6-nitrile hinged in part on the protonation state of His 115. The acid dissociation constant (pKa) of a histidine sidechain (meaning the deprotonation of the imidazole to imidazolate) is expected to be >14 in water. A typical tyrosine sidechain pKa in water is circa 10. The pKa for benzonitrilium (as a stand-in for a protonated C6-nitrile analogue) has been extrapolated to be circa -10 in water. Thus, if the Hisl 15 imidazole sidechain is not protonated, it is a weaker H-bond donor than the Tyrl 16 sidechain based on its higher pKa. The Schrodinger Maestro Protein Preparation Module predicts Hisl 15 is not protonated upon binding of FLC-21 (PDB: 5M4F). However, a histidine sidechain imidazolium pKa within a protein may vary anywhere in the range of 5-8, dependent upon the environment of the histidine. If the empircal pKa of the Hisl 15 sidechain diverges from prediction to the higher end of this range, it could be protonated to a meaningful extent at physiological pH (7.4). This imidazolium would then be a superior H-bond donor to Tyrl 16 given its lower pKa. The prospect for C6-benzamide substitution leading to paralog selectivity was more complicated to forecast given both benzamides and imidazoles may act as both H-bond donors and acceptors; nonetheless, the prospect of picking up a second interaction with the CK2A2 Ilel 17 backbone carbonyl in addition to an interaction with Tyrl 16 (FIG. 2B) was evaluated. C6-Lewis base modified quinazolinone scaffolds were sought in addition to C6-modified chromenone scaffolds, given that the quinazolinones performed better than analogous benzofuranones.

[0803] Our studies of C6-Lewis base projecting compounds began with the quinazolinone scaffold (Table 7). C6-nitrile compounds 54 and 55 exhibited weak affinities for both CK2 catalytic subunit paralogs and a continued preference for CK2A1 over CK2A2 as observed for7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0804] earlier quinazolinones (Table 6). Hybridization of the 2-methoxypyridine motif discovered in the initial chromenone studies (Table 4) with the C6-nitrile in compound 56 led to a potent inhibitor for both catalytic subunit paralogs; deletion of the C8 bromide from this compound led to inferior inhibitor 57. A pivot to a benzamide at C6 for compounds 58-60 was taken, and it was discovered that, upon hybridization of the C6-benzamide with the 2-methoxypyridine moiety, the sub-nanomolar inhibitor compound 60 with approximately a threefold window of selectivity for CK2A2 over CK2A1. The shift towards CK2A2 selectivity over CK2A1 is notable from C6-cyano compounds 54-56 to analogous C6-benzamidyl compounds 58-60. Given the desire to minimize H-bond donors, capping the benzamide with one or two alkyl groups was evaluated in structures 61-64. However, perturbation of the amide with even a single methyl group as in compound 61 led to reduced CK2A2 potency, and each of compounds 61-64 were inferior inhibitors to compound 60.

[0805] Table 7: C6 Lewis Base-Projecting Quinazolinone Study Leads to the Discovery of Compound 60 with numbers indicating scaffold positions without endocyclic variation

[0806]

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[0808] Attention was then turned to C6-Lewis basic chromenone compounds (Table 8) and found that almost all of these compounds exhibited single-digit nanomolar potency for CK2A2 inhibition. However, the modifications tended to evince marginal discrimination between the two CK2 catalytic subunit paralogs. Nonetheless, compounds 67 and 68 showed one nanomolar potency for CK2A2, making them the most potent chromenone scaffolds discovered for inhibition of this target. It is notable that compound 69 represents a single modification of the FNH-79 scaffold leading to single-digit nanomolar potency CK2A2 inhibition (an approximate 15-fold improvement in potency). As observed with the quinazolinone series, capping of the benzamide moiety (compounds 70 and 71) resulted in reduced potency.

[0809] Table 8: C6 Lewis Base-Projecting Chromenones: Discovery of Compounds 65, 67 and 68 with numbers indicating scaffold positions without endocyclic variation

[0810]

[0811] Given the interest in CNS activity, we performed studies pertinent to the distribution and metabolism of the top compounds, shown below.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0812]

[0813] Selected compounds were profiled for CNS permeability, prospective CNS activity, and metabolic stability (Table 9). The most notable trend in the permeability data was the C6-cyano moiety leading to improved apparent permeability (Pappa->b) values (Table 9, column 2). For example, C6-cyano compounds 56 and 65 showed marked improvement in Pappa→b values relative to analogous C6-benzamide compounds 60 and 67. In addition, compound 65 shows improved permeability over C6-bromide analogue compound 22. All efflux ratios measured were acceptable (Table 9, column 3).

[0814]

[0815] *Not determined (N. D.) because fu,

[0816]

[0817] , values were too low

[0818] In addition to questions regarding CNS -permeability, there was a concern with the CNS tissue and plasma-binding properties of the compounds in accordance with the free-drug7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0819] hypothesis for CNS activity. A favorable ratio (Kp,uu / Kp> 1) of unbound brain fraction / unbound plasma fraction (Table 9, column 5) was observed for compounds 65, 67 and 70 and a borderline acceptable value for compound 60. Measurement of the ratio of the unbound drug candidate concentration in the brain to the concentration unbound in the plasma (Kp,uu) revealed an acceptable value for compound 65, but an unacceptably low value for compound 60 (Table 9, column 7). This property for compound 60 was measured as opposed to compounds 67 and 70 because i) we deemed the quinazolinone to be more druglike and ii) the sub-nanomolar potency of compound 60 for CK2A2. Finally, acceptable half-lives and intrinsic clearance values were observed for all compounds tested in vitro in a human liver microsome (HLM) assay (Table 9, columns 8 and 9). Overall, compound 65 appeared to be a favorable confluence between CK2A2 inhibitory potency and the physical properties assayed.

[0820] Table 10: Compound 20, 22, 60, and 65 scanMAX kinome selectivity results (all tested at 1 pM)

[0821]

[0822] Following the assay of physical properties, a handful of the top inhibitors were profiled in the Eurofins scanMAX assay (Table 10). In addition, compound 20 was profiled during studies directed towards the development of compound 22, finding it to be more selective than CX-4945 and CHR (Table 1). Compound 22 turned out to be a specific inhibitor of only the CK2 catalytic subunit paralogs per its S(10) score upon testing at 1 pM. Because of its excellent CK2A2 potency, compound 60 was profiled as well despite its less favorable physical properties for CNS indications (Table 9). This compound produced two off-targets in its S(10) measurement, serine / threonine-protein kinase 2 (SRPK2) and PIM2. Finally, compound 65 was profiled because of its strong CK2A2 inhibition and more favorable physical properties to address CNS applications (Table 8). Only one off-target for compound 65 was observed in its S( 10) measurement, dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). Overall, compound 65 appears to be the best overlap of CK2A2 potency, kinome selectivity, and CNS-relevant physical properties to address CK2A2 -mediated CNS disorders, though it is a dual inhibitor of both CK2 catalytic subunit paralogs.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0823] Some overlaps and trends in the S(35) scores of compounds 20, 22, 60, and 65 with one another and with SGC-CK2-1 and CX-4945 merit discussion. The pattern that emerged for the lead compounds is inhibition of PIM kinases to varying extents, in particular PIM-2, and DYRK1 A. While less selective overall, compound 20 was not a potent DRYK1A inhibitor. CHR exhibited inhibition of DYRK1 A but no inhibition of PIM 1-3. DRYK1A, PIM-1, and PIM-3 were all >90% inhibited by CX-4945 in the scanMAX assay. Compounds 60 and 65 share dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) as a kinome off- target with SGC-CK2-1 and CX-4945. Characterization of compounds 22, 60 and 65 in enzymatic assays of the protein off-targets observed in the scanMAX assay will help clarify the extent to which these off-targets are relevant. Large differences between scanMAX percent inhibition values and enzymatic assay IC50 values have been noted.

[0824]

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[0840]

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[0842]

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[0844]

[0845]

[0846] MDRl-MDCKII Papp a^b > 2.5 x 10-6cm / s > MDR1-MDCKII Papp a→b > 1 x 10-6cm / s: **0’6cm / s: ***

[0847] 2.5 x 10-6cm / s > MDR1-MDCKII Papp a→b > 1 x 10-6cm / s: **

[0848] MDRl

[0849]

[0850] MDRl-MDCKII ER < 1: ##

[0851] 1 < MDRl-MDCKII ER < 2: #

[0852] Kp,uu / Kp> 1: ^^^

[0853] 1 > Kp,uu / Kp> 0.5: ^^

[0854] KP,uu / KP< 0.5:

[0855] scanMAX S(10) at 1 uM <0.01: &&&

[0856] 0.01 < scanMAX S(10) at 1 uM <0.02: &&7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026

[0857] scanMAX S(10) at 1 uM >0.02: &

[0858] Not assessed: NA

[0859] At the outset of the studies, a potent, kinome-selective inhibitor of CK2A2 that demonstrated evidence of CNS permeability and activity was sought. With the discovery of compound 65, these objectives were achieved with one scaffold. Although none of the lead compounds generated exhibited selectivity greater than threefold for CK2A2 over CK2A1, an intriguing window (ranging from ten to twenty-five-fold) of CK2A2 paralog selectivity for all C4’ -acidic flavones and aurones studied was identified. However, a functional carboxylic acid bioisostere to address cellular and CNS-specific permeability concerns associated with acidic compounds (supplementary data, section 2, subsection 3) was not developed. Notably, compound 60 was both potent for CK2A2 and kinome selective but exhibited poor in vitro CNS permeability and brain-to-plasma ratio profiles. This putative brain-restricted compound may be useful to address peripheral indications driven by CK2 dysfunction when CNS activity is undesired.

[0860] Notwithstanding the ATP -binding pockets of CK2A1 and CK2A2 differing by only two residues, it has been shown herein that the scaffolds studied herein can achieve more than tenfold selectivity for either paralog. The paralog selectivity of FLC-26 demonstrates that ATP-competitive inhibition can be a viable way to achieve kinase paralog selectivity, despite the small ATP-binding pocket of CK2. Although efforts were focused on obtaining CK2A2 selectivity, a CK2A1 -selective inhibitor may be desired for oncological indications. Several of the quinazolinones such as compounds 55 and 63 demonstrate approximately tenfold CK2A1 selectivity over CK2A2 and may serve as starting points for SAR towards CK2A1 paralog selectivity.

[0861] In view of the many possible aspects to which the principles of the disclosure may be applied, it should be recognized that the illustrated aspects are only examples of the disclosure and should not be taken as limiting the scope of the disclosure. Rather, the scope of the disclosure is defined by the following claims. We therefore claim as the disclosure all that comes within the scope and spirit of these claims.

Claims

1. 7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026We claim:

1. A compound having a structure according to Formula IFormula Ior a pharmaceutically acceptable salt thereof, wherein:each of R1and R3independently is H or F;R2is Br, CN, CON(Ra)2, -CH2N(Ra)2, CONHCH2CF3, or heteroaryl optionally substituted with Ci-<, alkyl:each Raindependently is H or C i-ealkyl;R4is H or halo;R5is H, halo, O(Ci-6alkyl), or CF3;R6is OH, CO2H, CH2CO2H, or NHC(O)C1-6alkyl;R7is H or halo;X is N or O;Y is NH or CR8;R8is H or OH;Z is N or CH; andif R2is Br, then:R1and / or R3are other than H; orX is O, Y is CR8where R8is OH; orZ is N, R5is OMe, R6is OH, and R7is H; orR5is OMe, R6is CO2H, and R7is H; orR5is Br, R6is CO2H, and R7is H; orR5is H, R6is CH2CO2H, and R7is H.

2. The compound of claim 1, wherein the compound has a structure according to Formula II or Formula III7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 2026Formula II Formula IIIor a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein R2is -CN, -C(O)N(Ra)2, -CH2N(Ra)2. -C(O)NHCH2CF3.

4. The compound of claim 3, wherein R2is -CN, -C(O)NH2, -C(O)NHMe, or -C(O)N(Me)2.

5. The compound of claim 1, wherein R2is oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, optionally substituted with Ci-6alkyl.

6. The compound of claim 1, wherein R5is H or OMe.

7. The compound of claim 1, wherein R6is OH or CO2H.

8. The compound of claim 1, wherein Z is N.

9. The compound of claim 1, wherein Z is CH.

10. A pharmaceutical composition, comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

11. A method of reducing CK2 enzyme activity, comprising:contacting a cell that expresses CK2 enzyme with an effective amount of one or more compounds according to claim 1, thereby reducing activity of the CK2 enzyme.

12. A method, comprising administering an effective amount of one or more compounds according to claim 1, or a pharmaceutically acceptable composition thereof, to a subject in need thereof.7158-113721-03 04 / 15 / 26 S2020-038A and S2022-023A FILED ELECTRONICALLY ON APRIL 15, 202613. The method of claim 12, wherein the subject has a disease or condition characterized at least in part by dysregulated CK2 enzyme activity.

14. The method of claim 13, wherein the disease or condition is characterized at least in part by dysregulated CK2 enzyme activity.

15. The method of claim 13, wherein the disease or condition is an inflammatory disease or a disease that causes undesired inflammation.

16. The method of claim 15, wherein the disease or condition is cancer, cardiac hypertrophy, cystic fibrosis, a neurodegenerative disease, bipolar disorder, depression, a viral infection (such as SARS-CoV-2), obesity, diabetes mellitus, atherosclerosis, or epilepsy.

17. A compound, or composition thereof, for use in reducing CK2 enzyme activity, wherein the compound has a structure according to claim 1.

18. A compound, or composition thereof, for use in treating a disease or condition that is characterized at least in part by dysregulated CK2 enzyme activity, wherein the compound has a structure according to claim 1.

19. The compound or composition of claim 18, wherein the disease or condition is an inflammatory disease or a disease that causes undesired inflammation.

20. The compound or composition of claim 19, wherein the disease or condition is cancer, cardiac hypertrophy, cystic fibrosis, a neurodegenerative disease, bipolar disorder, depression, a viral infection (such as SARS-CoV-2), obesity, diabetes mellitus, atherosclerosis, or epilepsy.

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