Autophagy inhibitor that targets the ATG14l-beclin1 protein-protein interaction

Abstract

Disclosed herein are aspects of a compound that targets the ATG14L-BECLIN1 protein-protein interaction. Some aspects the compound may inhibit autophagy. In some aspects, the compound has a structure according to Formula I or Formula II. Also disclosed are aspects of a method for making the compound, and aspects of a method for using the compound. The compounds may be useful for treating certain viral infections.

Description

[0001] 4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0002] AUTOPHAGY INHIBITOR THAT TARGETS THE ATG14L-BECLIN1 PROTEINPROTEIN INTERACTION

[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 No. 63 / 705,241, filed October 9, 2024, which is incorporated herein by reference in its entirety.

[0005] ACKNOWLEDGMENT OF GOVERNMENT SUPPORT

[0006] This invention was made with government support under grant number UL1 TR002003 awarded by National Institutes of Health and grant number F31CA265072 awarded by the National Cancer Institute. The government has certain rights in the invention.

[0007] FIELD

[0008] This disclosure relates to Beclinl inhibitors and compositions and methods of treating diseases or disorders where inhibition of autophagy would provide a benefit.

[0009] BACKGROUND

[0010] Autophagy is the primary eukaryotic homeostasis mechanism in which cellular components, such as long-lived proteins and organelles, undergo catabolic degradation and recycling. Under normal conditions, basal autophagy ensures cellular health and maintenance of key biological functions, and dysregulation of autophagy has been implicated in a variety of diseases. The study of autophagy in cancer has proven especially challenging due to the dual role of this pathway in cancer development and progression. Beclinl can function as a tumor suppressor and positively regulates autophagy. Monoallelic deletion of the BECN1 gene in mice led to increased tumor formation, and in human subjects, deletion of the BECN1 gene was observed in 94% of ovarian cancer cases. This same deletion is also observed in breast and prostate cancer, leading to the conclusion that BECN1 acts as a haploinsufficient tumor suppressor gene. However, when cells are subjected to intrinsic or metabolic stress, such as hypoxia or nutrient deprivation, autophagy is significantly upregulated to enable cell survival. Although autophagy has a preventative role in early tumor formation, if cancerous cells develop, these cells can hijack the pathway to promote tumor proliferation and4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0011] progression by supporting cell survival in stressful environments. Furthermore, autophagy upregulation contributes to chemotherapeutic resistance by alleviating DNA damage and mitochondrial-induced apoptosis induced by anticancer drugs. These observations have led to the hypothesis that autophagy inhibition could potentially provide a way to selectively target autophagy-dependent tumors and spare healthy cells.

[0012] The FDA-approved antimalarial drug chloroquine (CQ) and its analogue hydroxychloroquine (HCQ) are known to inhibit the autophagy pathway and have been explored extensively as potential drug candidates. CQ and HCQ are lysosomotropic molecules that accumulate in lysosomes and alkalize the internal pH, resulting in decreased fusion of autophagosomes with lysosomes and late-stage inhibition of autophagy. Treatment with CQ or HCQ in both cell and mouse models revealed significantly reduced tumor cell growth and proliferation rates. In addition, treatment with CQ or HCQ in combination with other anticancer agents or radiation significantly reduced tumor growth and enhanced the therapeutic effects of these anticancer drugs when they were previously ineffective, suggesting autophagy inhibition as a potential strategy to overcome chemoresistance. Despite these successes, CQ and HCQ have been shown to enhance tumor growth in some cases, and their use in clinical trials remains largely ineffective.11Both CQ and HCQ cause adverse effects with long-term use, including cardiac disorders, renal toxicity, and adverse neuronal effects, and the narrow therapeutic windows and poor membrane permeability in acidic environments limit the efficacy of these treatments. Furthermore, disruption of lysosome function is not specific for the autophagy pathway, as lysosomes are involved in multiple cellular pathways. Therefore, more selective inhibitors of autophagy are necessary to fully assess the efficacy of autophagy inhibition in cancer.

[0013] To overcome the limitations of late-stage inhibitors, more recent attempts have focused on inhibition at an early-stage by targeting key kinases involved in autophagy initiation, specifically the ULK1 serine / threonine kinase and the VPS34 lipid kinase.

[0014] However, ULK1 / 2 have been implicated in other cellular processes, such as stress granule disassembly and glucose flux and glycolysis, and VPS34 associates with two multi-protein complexes: the autophagy initiation complex (Complex I) and the endosomal trafficking complex (Complex II), so direct kinase inhibition results in undesirable side effects. While these molecules are more selective for the autophagy pathway than late-stage inhibitors, small molecules that inhibit autophagy without impacting off-target cellular processes are4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0015] still required and will be important to clarify the role of selective autophagy inhibition in cancer.

[0016] SUMMARY

[0017] Previous work by the inventors evaluated a novel target for selective autophagy inhibition, the ATG14L-Beclinl protein-protein interaction (PPI). ATG14L is only found in the autophagy initiation Complex I and is known to bind to Beclinl through an interaction with its coiled-coil domain. Disruption of this interaction prevents the recruitment of VPS34-VPS15 to the autophagosome, thus inhibiting autophagy. ATG14L is replaced by UVRAG in Complex II, and deletion of the ATG14 gene in yeast does not affect vacuole protein sorting, and conversely, disruption of the UVRAG homolog VPS38 does not suppress autophagy, thus highlighting the ATG14L-Beclinl PPI as potential target for selective autophagy inhibition.

[0018] A high-throughput assay was developed using bioluminescence resonance energy transfer (NanoBRET) to measure the interaction of Beclinl with ATG14L or UVRAG proteins. This approach led to the discovery of Compound 19, which selectively inhibits the Beclinl -ATG14L PPI and autophagy without inhibiting the UVRAG-Beclinl PPI or affecting vesicle trafficking. Subsequent development of synthetic strategies to access a variety of Compound 19 analogues has enabled evaluation of structure-activity relationships to reveal key regions, moieties, and functional groups that impact the potency and physicochemical properties of Compound 19 and impart selectivity for VPS34 Complex I over Complex II.

[0019] Disclosed herein are aspects of a compound according to Formula I or Formula II

[0020]

[0021] 4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0022]

[0023] or a pharmaceutically acceptable salt thereof. With respect to Formulas I and II, L is a bond, -N(R9)-, -C(O)N(R9)-, -N(R9)C(O)-, -S(O)2N(R9)- or -N(R9)S(O)2-, and R9is H or Ci-6alkyl. Ri is substituted or unsubstituted phenyl, substituted or unsubstituted phenyl-Ci-6alkyl, substituted or unsubstituted 5- or 6-membered cycloalkyl, substituted or unsubstituted 5- or 6-membered cycloalkylalkyl, substituted or unsubstituted 5- or 6-membered heterocyclyl, substituted or unsubstituted 5- or 6-membered heterocyclylalkyl, or substituted or unsubstituted 5- to 6-membered heteroaryl, or R9and Ri together with the atom to which they are attached forms a substituted or unsubstituted 5- or 6-membered heterocyclyl.

[0024] R2 is selected from H, alkyl, alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted 5- or 6-membered heteroaryl, substituted or unsubstituted 5- or 6-membered heteroaryl-Ci-6alkyl, substituted or unsubstituted C3-6cycloalkyl-Ci-6alkyl, substituted or unsubstituted 5- or 6-membered heterocyclyl, and substituted or unsubstituted 5- or 6-membered heterocyclyl-Ci-ealkyl. R3 and Re are independently selected from H, halo, alkyl, haloalkyl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted arylalkyl. And R4 and R5 independently are selected from H, hydroxy, Ci-e lkoxy, halo, Ci-ealkyl, Ci-ehaloalkyl or cyano.

[0025] N-°..

[0026] II ■■ / ■ —( >r NH3C / \H

[0027]

[0028] - CH O Additionally, in some aspects, the compound is not3Additionally disclosed herein are aspects of a method for using the compounds. The compounds may be useful for inhibiting autophagy, and / or treating viral infections, such as Machupo virus, Influenza A virus, HIV-1, Ebola virus, SARS-CoV-2, or Lassa virus.

[0029] The foregoing and other objects, features, and advantages of the disclosure will become more apparent from the following detailed description, which proceeds with reference to the accompanying figures.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0030] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 A is a graph of normalized average puncta per cell for various compounds, illustrating the results from eGFP-LC3 HeLa cells that were treated with compounds at 100 |iM for 20 hours before adding CQ (20 M) co-treatment for 4 hours. Data are normalized to the DMSO controls are presented as a mean ± SEM of three independent experiments in duplicate.

[0031] FIG. IB provides representative images from the eGFP-LC3 assay.

[0032] FIG. 1C is a representative CETSA western blots from three independent experiments assessing thermal stability of ATG14L following compound treatment.

[0033] FIG. ID is a graph illustrating the results from A549 cells treated with DQ-BSA for 1 hour and then exposed to compounds (100 pM), CQ (20 pM), BafAl (100 nM), PIKIII (12.5 pM), or SAR405 (12.5 pM) for 4 hours. Data are presented as a mean ± SEM of three independent experiments in duplicate.

[0034] FIG. IE is a representative phase contrast image of A549 cells treated with lb (100 pM), or VPS34 inhibitors, PIKIII and SAR405, (12.5 pM) for 4 hours.

[0035] FIG. 2A is a graph of corrected BRET ratio versus concentration, illustrating dose response curves for the most potent compounds in ATG14L-Beclinl NanoBRET assay.

[0036] FIG. 2B is a dose response curve for analogue 4j in UVRAG-Beclinl NanoBRET assay.

[0037] FIG. 2C is a graph illustrating the normalized DQ-BSA Puncta per cell for then exposed to compounds (100 pM), CQ (20 pM), BafAl (100 nM), PIKIII (12.5 pM), or SAR405 (12.5 pM) for 4 h. Significance is noted as not significant (ns), p < 0.05 (*), p < 0.01 (**), p < 0.001 (***), or p < 0.0001 (****).

[0038] FIG. 2D provides graphs illustrating the improved cell viability observed in the biaryl series with re-incorporation of oxadiazole moiety. The nuclear counts were conducted using images acquired from the eGFP-LC3 assays. Nuclear counts in compound treated wells were divided by the average of the DMSO control wells and multiplied by 100% to generate normalized percent nuclear count or percent viability.

[0039] FIG. 3 provides activity data for synthetic Compound 19. Top left are results from ATG14L-Beclinl NanoBRET assay for synthetic Compound 19 at 100 pM concentration. Top right provides dose response data for synthetic Compound 19 in ATG14L-Beclinl4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0040] NanoBRET assay. IC50 value was confirmed to be similar to the value for the initial hit (35.2 |iM) purchased from ChemDiv. Bottom left provides results from UVRAG-Beclinl NanoBRET assay for synthetic Compound 19 at 100 |iM concentration. And bottom right provides dose response data for synthetic Compound 19 in UVRAG-Beclinl NanoBRET assay.

[0041] FIG. 4 is a graph of corrected BRET ratio versus concentration, illustrating a dose response curve for analogue 4k in ATG14L-Beclinl NanoBRET assay.

[0042] FIG. 5 is a graph of corrected BRET ratio versus concentration, illustrating a dose response curve for analogue 4k in a UVRAG-Beclinl NanoBRET assay.

[0043] FIG. 6 provides the results from eGFP-LC3 HeLa cells treated with compounds at 50 pM for 20 hours before adding CQ (20 pM) co-treatment for 4 hours. Data are normalized to the DMSO controls. Unless denoted as not significant (ns), p values for all comparisons to the CQ control are < 0.01.

[0044] FIG. 7 provides graphical representations of NanoBRET assay data in Table 5 highlighting significant differences between Beclinl / ATG14L PPI and Beclinl / UVRAG PPI induced by compound treatment at 100 pM. Normalized % NanoBRET Ratio represents the normalized NanoBRET signal for each compound normalized to DMSO (100%) and no ligand (0%) control wells.

[0045] FIG. 8 provides graphical representations of NanoBRET assay data in Table 6 highlighting significant differences between Beclinl / ATG14L PPI and Beclinl / UVRAG PPI induced by compound treatment at 100 |iM. Normalized % NanoBRET Ratio represents the normalized NanoBRET signal for each compound normalized to DMSO (100%) and no ligand (0%) control wells.

[0046] FIG. 9 provides graphical representations of NanoBRET assay data in Table 7 highlighting significant differences between Beclinl / ATG14L PPI and Beclinl / UVRAG PPI induced by compound treatment at 100 p M. Normalized % NanoBRET Ratio represents the normalized NanoBRET signal for each compound normalized to DMSO (100%) and no ligand (0%) control wells.

[0047] FIG. 10 provides graphical representations of NanoBRET assay data in Table 8 highlighting significant differences between Beclinl / ATG14L PPI and Beclinl / UVRAG PPI induced by compound treatment at 100 p M. Normalized % NanoBRET Ratio represents the4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0048] normalized NanoBRET signal for each compound normalized to DMSO (100%) and no ligand (0%) control wells.

[0049] FIG. 11 is a graph illustrating the improved solubility in kinetic aqueous solubility assay of the compounds shown in Table 1. Optical density readings were collected at 620 nm to measure precipitate formation. Compounds were considered insoluble at concentrations where the OD reading was more than triple the signal to noise (S / N) ratio of the background.

[0050] FIG. 12 is a graph illustrating the improved solubility in kinetic aqueous solubility assay of the compounds shown in Table 2. Optical density readings were collected at 620 nm to measure precipitate formation. Compounds were considered insoluble at concentrations where the OD reading was more than triple the signal to noise (S / N) ratio of the background.

[0051] FIG. 13 is a graph illustrating the improved solubility in kinetic aqueous solubility assay of the compounds shown in Table 3. Optical density readings were collected at 620 nm to measure precipitate formation. Compounds were considered insoluble at concentrations where the OD reading was more than triple the signal to noise (S / N) ratio of the background.

[0052] FIG. 14 is a graph illustrating the improved solubility in kinetic aqueous solubility assay of the compounds shown in Table 4. Optical density readings were collected at 620 nm to measure precipitate formation. Compounds were considered insoluble at concentrations where the OD reading was more than triple the signal to noise (S / N) ratio of the background.

[0053] FIG. 15 is a graph illustrating the improved solubility in kinetic aqueous solubility assay of the compounds shown in Table 5. Optical density readings were collected at 620 nm to measure precipitate formation. Compounds were considered insoluble at concentrations where the OD reading was more than triple the signal to noise (S / N) ratio of the background.

[0054] FIG. 16 is a graph illustrating the improved solubility in kinetic aqueous solubility assay of the compounds shown in Table 6. Optical density readings were collected at 620 nm to measure precipitate formation. Compounds were considered insoluble at concentrations where the OD reading was more than triple the signal to noise (S / N) ratio of the background.

[0055] FIG. 17 is a graph illustrating the improved solubility in kinetic aqueous solubility assay of the compounds shown in Table 7. Optical density readings were collected at 620 nm to measure precipitate formation. Compounds were considered insoluble at concentrations where the OD reading was more than triple the signal to noise (S / N) ratio of the background.

[0056] FIG. 18 is a graph illustrating the improved solubility in kinetic aqueous solubility assay of the compounds shown in Table 8. Optical density readings were collected at 620 nm4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0057] to measure precipitate formation. Compounds were considered insoluble at concentrations where the OD reading was more than triple the signal to noise (S / N) ratio of the background.

[0058] FIG. 19 is a table providing EC50values from Beclin1-ATG14LPPI NanoBRET Assay and half-life times from mouse liver microsomes for certain exemplary compounds.

[0059] FIG. 20 is a graph illustrating the dose-dependent inhibition of MACV GP-mediated transduction by C19 and its derivatives in HeLa.

[0060] FIG. 21 are graphs illustrating dose-dependent inhibition of replication-competent MACV by C19 and its derivatives in HeLa.

[0061] DETAILED DESCRIPTION

[0062] I. Terms and Definitions

[0063] 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.

[0064] 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.” Unless context indicated otherwise, “about” refers to plus or minus 5% of a reference value. For example, “about” 100 refers to 95 to 105.

[0065] 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 explicitly distinguishing aspects from discussed prior art, the aspect numbers are not approximates unless the word “about” is recited.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0066] 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.

[0067] The following terns and expressions used herein have the indicated meanings.

[0068] Terms used herein may be preceded and / or followed by a single dash,

[0069]

[0070] or a double dash, to indicate the bond order of the bond between the named substituent and its parent moiety; a single dash indicates a single bond and a double dash indicates a double bond. In the absence of a single or double dash it is understood that a single bond is formed between the substituent and its parent moiety; further, substituents are intended to be read “left to right” unless a dash indicates otherwise. For example, Ci-Cealkoxycarbonyloxy

[0071] and -OC(O)Ci-Ce alkyl indicate the same functionality; similarly arylalkyl and -alkylaryl indicate the same functionality.

[0072] “Alkenyl” means a straight or branched chain hydrocarbon containing from 2 to 10 carbons, unless otherwise specified, and containing at least one carbon-carbon double bond.

[0073] Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l -heptenyl, 3-decenyl, and 3, 7-dimethylocta-2, 6-dienyl.

[0074] “Alkoxy” means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0075] “Alkyl” means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms unless otherwise specified. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec -butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3 -methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. When an “alkyl” group is a linking group between4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0076] two other moieties, then it may also be a straight or branched chain; examples include, but are not limited to -CH2-, -CH2CH2-, -CH2CH2CHC(CH3)-, and -CH2CH(CH2CH3)CH2-.

[0077] “Alkynyl” means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

[0078] “Aryl” means a phenyl (i.e., monocyclic aryl), or a bicyclic ring system containing at least one phenyl ring or an aromatic bicyclic ring containing only carbon atoms in the aromatic bicyclic ring system. The bicyclic aryl can be azulenyl, naphthyl, or a phenyl fused to a monocyclic cycloalkyl, a monocyclic cycloalkenyl, or a monocyclic heterocyclyl. The bicyclic aryl is attached to the parent molecular moiety through any carbon atom contained within the phenyl portion of the bicyclic system, or any carbon atom with the napthyl or azulenyl ring. The fused monocyclic cycloalkyl or monocyclic heterocyclyl portions of the bicyclic aryl are optionally substituted with one or two oxo and / or thia groups. Representative examples of the bicyclic aryls include, but are not limited to, azulenyl, naphthyl, dihydroinden-l-yl, dihydroinden-2-yl, dihydroinden-3-yl, dihydroinden-4-yl, 2,3-dihydroindol-4-yl, 2,3-dihydroindol-5-yl, 2,3-dihydroindol-6-yl, 2,3-dihydroindol-7-yl, inden- 1-yl, inden-2-yl, inden-3-yl, inden-4-yl, dihydronaphthalen-2-yl, dihydronaphthalen-3-yl, dihydronaphthalen-4-yl, dihydronaphthalen-l-yl, 5,6,7,8-tetrahydronaphthalen-l-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, 2,3-dihydrobenzofuran-4-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, 2,3-dihydrobenzofuran-7-yl, benzo [d] [ 1,3]dioxol-4-yl, benzo[d][l,3]dioxol-5-yl, 2H-chromen-2-on-5-yl, 2H-chromen-2-on-6-yl, 2H-chromen-2-on-7-yl, 2H-chromen-2-on-8-yl, isoindo line- l,3-dion-4-yl, isoindoline- l,3-dion-5-yl, inden- 1-on-4-yl, inden- l-on-5-yl, inden- l-on-6-yl, inden- l-on-7-yl, 2,3-dihydrobenzo[b][l,4]dioxan-5-yl, 2,3-dihydrobenzo[b][l,4]dioxan-6-yl, 2H-benzo[b][l,4]oxazin3(4H)-on-5-yl, 2H-benzo [b] [ 1,4]oxazin3(4H)-on-6-yl, 2H-benzo [b] [ 1,4]oxazin3(4H)-on-7-yl, 2H-benzo[b][l,4]oxazin3(4H)-on-8-yl, benzo[d]oxazin-2(3H)-on-5-yl, benzo[d]oxazin-2(3H)-on-6-yl, benzo[d]oxazin-2(3H)-on-7-yl, benzo[d]oxazin-2(3H)-on-8-yl, quinazolin-4(3H)-on-5-yl, quinazolin-4(3H)-on-6-yl, quinazolin-4(3H)-on-7-yl, quinazolin-4(3H)-on-8-yl, quinoxalin-2(lH)-on-5-yl, quinoxalin-2(lH)-on-6-yl, quinoxalin-2(lH)-on-7-yl, quinoxalin-4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0079] 2(lH)-on-8-yl, benzo[d]thiazol-2(3H)-on-4-yl, benzo[d]thiazol-2(3H)-on-5-yl,

[0080] benzo [d]thiazol-2(3H)-on-6-yl, and, benzo[d]thiazol-2(3H)-on-7-yl. In certain aspects, the bicyclic aryl is (i) naphthyl or (ii) a phenyl ring fused to either a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, or a 5 or 6 membered monocyclic heterocyclyl, wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia. In certain aspects of the disclosure, the aryl group is phenyl.

[0081] “Cyano” and “nitrile” as used herein, mean a -CN group.

[0082] “Cycloalkyl” means a monocyclic cycloalkyl ring system. Monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic. In certain aspects, cycloalkyl groups are fully saturated. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. In certain aspects of the disclosure, the cycloalkyl is cyclopentyl, cyclohexyl, or cycloheptyl.

[0083] “Halo” or “halogen” means -Cl, -Br, -I or -F. In certain aspects, “halo” or “halogen” refers to -Cl or -F.

[0084] “Haloalkyl” means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl. In certain aspects, each “haloalkyl” is a fluoroalkyl, for example, a polyfluoroalkyl such as a substantially perfluorinated alkyl.

[0085] “Haloalkyloxy means a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

[0086] “Heteroaryl” means a monocyclic heteroaromatic ring. The monocyclic heteroaryl can be a 5 or 6 membered ring. The 5 membered ring consists of two double bonds and one, two, three or four nitrogen atoms and optionally one oxygen or sulfur atom. The 6 membered ring4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0087] consists of three double bonds and one, two, three or four nitrogen atoms. The 5 or 6 membered heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heteroaryl. Representative examples of monocyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl. In certain aspects of the disclosure, the heteroaryl group is furyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, thiazolyl, thienyl, or triazolyl.

[0088] “Heterocyclyl” means a monocyclic heterocycle. The monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S where the ring is saturated or unsaturated, but not aromatic. The 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N and S. The 5 membered ring can contain zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. The monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle. Representative examples of monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl.

[0089] “Saturated” means the referenced chemical structure does not contain any multiple carboncarbon bonds. For example, a saturated cycloalkyl group as defined herein includes cyclohexyl, cyclopropyl, and the like.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0090] “Unsaturated” means the referenced chemical structure contains at least one multiple carboncarbon bond, but is not aromatic. For example, a unsaturated cycloalkyl group as defined herein includes cyclohexenyl, cyclopentenyl, cyclohexadienyl, and the like.

[0091] “Pharmaceutically acceptable salt” refers to both acid and base addition salts.

[0092] “Modulating” or “modulate” refers to the treating, prevention, suppression, enhancement or induction of a function, condition or disorder. For example, it is believed that the compounds of the present disclosure can modulate atherosclerosis by stimulating the removal of cholesterol from atherosclerotic lesions in a human.

[0093] “Treating” or “treatment” covers the treatment of a disease or disorder described herein, in a subject, preferably a human, and includes:

[0094] i. inhibiting a disease or disorder, i.e., arresting its development;

[0095] ii. relieving a disease or disorder, i.e., causing regression of the disorder;

[0096] iii. slowing progression of the disorder; and / or

[0097] iv. inhibiting, relieving, or slowing progression of one or more symptoms of the disease or disorder

[0098] “Subject” refers to a warm blooded animal such as a mammal, preferably a human, or a human child, which is afflicted with, or has the potential to be afflicted with one or more diseases and disorders described herein.

[0099] I. Compounds

[0100] This disclosure provides a compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof.

[0101]

[0102] 4239-114920-02 10 / 09 / 25 E-l S6-2025-0 PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0103]

[0104] II

[0105] With respect to Formulas I and II, Ri is phenyl, phenyl-C1-6alkyl (such as phenyl-CFb-), 5- or 6-membered cycloalkyl, 5- or 6-membered cycloalkylalkyl, 5- or 6-membered heterocyclyl, 5- or 6-membered heterocyclylalkyl, or 5- to 6-membered heteroaryl, or Ri and R9 together with the atom to which they are attached form a 5- or 6-membered heterocyclyl. In some aspects, Ri and R9 together with the atom to which they are attached form a piperidinyl, piparizinyl, or morpholinyl ring.

[0106] Ri may be unsubstituted or Ri may be substituted with one or more substituents independently selected from C1-6alkyl, halo, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkyloxy, nitro (NO2), cyano, OH, 5- or 6-membered heterocyclyl, or R7C(O)- groups, where R7 is Ci-ealkyl or Ci-ehaloalkyl. In some aspects, Ri is unsubstituted or is substituted with one or more, such as 1, 2 or 3 substituents, independently selected from C1-6alkyl (for example, methyl, ethyl, or isopropyl), halo (such as Br, Cl, or F), C1-6alkoxy (for example, methoxy, ethoxy, isopropoxy), 5- or 6-membered heterocyclyl (such as morpholinyl, piperidinyl, or piperazinyl), haloalkyl (for example, CF3), NO2, OH, or C1-6haloalkoxy (for example, CF3O-).

[0107] In some aspects, Ri is a substituted phenyl, and may be substituted at the 2-position, 3-position, or 4-position, or disubstituted at the 2- and 3-postions, or the 2- and 4-positions.

[0108]

[0109] CH

[0110] In a particular aspect, Ri is (2,3-dimethylphenyl).

[0111] L is a bond, -N(R9)-, -C(O)N(R9)-, -N(R9)C(O)-, -S(O)2N(R9)- or -N(R9)S(O)2-, where R9is H or Ci-ealkyl, or R9and Ri together with the atom to which they are attached form a 5- or 6-membered heterocyclyl. In some aspects, R9is H.

[0112] In some aspects, L is a bond.

[0113] In some other aspects, L is -NHS(O)2-.

[0114] In some other aspects, L is -NH-.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0115] R2 is selected from H; alkyl, such as Ci-ealkyl; alkenyl, such as C2-6alkenyl; cycloalkyl, such as C3-6cycloalkyl; aryl, such as C6-10aryl; arylalkyl, such as C6-10aryl-Ci-ealkyl-; 5- or 6-membered heteroaryl; 5- or 6-membered heteroaryl-C1-6alkyl-; C3-6cycloalkyl-C1-6alkyl-; 5- or 6-membered heterocyclyl; or 5- or 6-membered heterocyclyl-C1-6alkyl.

[0116] In some aspects when R2 is other than H, R2 is unsubstituted, but in other aspects, R2 may be substituted, such as by one or more substituents independently selected from halo, haloalkyl, alkoxy, haloalkyloxy, nitro, cyano, or 4- to 6-membered cycloalkyl.

[0117] In some aspects, R2 is Ci -ealkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-membered heteroaryl. In some aspects, R2 is substituted or unsubstituted 5-membered heteroaryl, and may be imidazolyl, or oxadiazolyl, such as 1,2,4-oxadiazolyl, or 1,3,4-oxadiazolyl, and optionally may be substituted by Ci-ealkyl, C4-6cycloalkyl, phenyl, or 5- or 6-membered heteroaryl, such as cyclobutyl, cyclopentyl, methyl, ethyl, n-propyl, isopropyl, isobutyl, or sec -butyl. In some aspects, R2 is substituted with isopropyl or cyclobutyl.

[0118] ' R.

[0119] In certain aspects, R2 is 5-membered heteroaryl having a formula Z wherein X and Z are independently CRa, or N, and Y is O, S, or NRa, where each Raindependently is H or Rs, and each Rs independently is Ci-ealkyl, C4-6cycloalkyl, phenyl, or 5- or 6-membered heteroaryl, such as cyclobutyl, cyclopentyl, methyl, ethyl, n-propyl, isopropyl, isobutyl, or sec -butyl. In certain aspects, each Rais H.

[0120] In some aspects, Rs is isopropyl.

[0121] In some aspects, Rs is cyclobutyl.

[0122] N-Q.

[0123] . A~Rs

[0124] In some aspects, R2 has a formulaN

[0125] hrO,

[0126] A V — O

[0127] In some aspects, R

[0128]

[0129] 2 isN.

[0130] R3 and Re are independently selected from H, halo, alkyl, haloalkyl, heteroarylalkyl, or arylalkyl, such as H, halo, Ci-ealkyl, Ci -ehaloalky 1, 5-membered or 6-membered heteroaryl-C1-6alkyl, or C6-10aryl-C1-6alkyl. In some aspects, Re is H, and R3 is H, Ci-ealkyl, CF3, or halo (such as H, methyl, or CF3). In certain aspects, both Re and R3 are H.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0131] R4 and R5 independently are selected from H, hydroxy, Ci-ealkoxy, halo, Ci-ealkyl, Ci-ehaloalkyl or cyano, such as H, halo, or Ci-ealkyl,

[0132] In some aspects, R4 is H.

[0133] In some aspects, R5 is H, halo, Ci-ealkyl, such as H, Cl, F, or Ci-ealkyl, such as methyl, ethyl, or isopropyl.

[0134] In some aspects, the compound has a structure according to Formula IA or Formula

[0135] N

[0136] Y' T

[0137] \^Z

[0138]

[0139] IIA

[0140] wherein X, Y, Z and Rs are as defined herein for Formulas I and II.

[0141] In another aspect, the compound has a structure according to Formula IB or Formula IIB

[0142]

[0143] 4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0144]

[0145] wherein R2, R3, R4, Rs, and Ro are as defined herein for Formulas I and II.

[0146] In some aspects, the compound has a structure according to Formula IC or Formula IIC

[0147] IC

[0148]

[0149] IIC

[0150] wherein L, R2, R3, and R5 are as defined herein for Formulas I and II.

[0151] Each Rio independently is C1-6alkyl (for example, methyl, ethyl, or isopropyl), halo (such as Br, Cl, or F), C1-6alkoxy (for example, methoxy, ethoxy, isopropoxy), 5- or 6-membered heterocyclyl (such as morpholinyl, piperidinyl, or piperazinyl), haloalkyl (for example, CF3), NO2, OH, or Ci-ehaloalkoxy (for example, CF3O-).

[0152] n is 0, 1, 2, 3, 4, or 5, such as 1, 2, or 3. In some aspects, n is 2. In other aspects, n is 1.

[0153] In some aspects, n is 2 and the substituents are at positions 2 and 3 on the phenyl. In some aspects, n is 2 and each Rio is methyl.

[0154] In some aspects, the compound has a structure according to Formula ID or Formula IID4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0155]

[0156] IID

[0157] wherein L and R2 are as defined herein for Formulas I and II.

[0158] In some aspects, the compound has a structure according to Formula IE or Formula IIE

[0159]

[0160] IIE

[0161] wherein Ri, R3, Rs, Rs, L, X, Y and Z are as defined herein for Formulas I and II.

[0162] In some aspects, the compound has a structure according to Formula IF or Formula IIF4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0163]

[0164] IIF

[0165] wherein Ri, Rs and L are as defined herein for Formulas I and II.

[0166] In some aspects, the compound has a structure according to Formula IG or IIG N-O

[0167] IG

[0168]

[0169] IIG

[0170] wherein Rs and L are as defined herein for Formula I and Formula II and Rio and n are as defined herein for Formula IC and Formula IIC.

[0171] In some aspects of the disclosed formulas, the compound is not Compound 19, which

[0172] has a structure

[0173]

[0174] 4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0175] In some aspects, the compound can be selected from compounds provided by any one of Tables 1 (other than “Cpmd 19”) and 2-11.

[0176] Table 1

[0177] 1a 105.5 ± 2.9% >100 μM

[0178] 1b 72.3 ± 4.1% >100

[0179] 1c 106.7 ± 3.9% >100 pM

[0180] 1d 105.5 ± 4.3% >100 pM

[0181] 1e 95.9 ± 4.6% >100 nM

[0182] 1f 109.6 ± 2.5% >100 nM

[0183] 1g 104.7 ± 4.2% 50 pM

[0184] 1h 111.7 ± 2.1% >100 pM

[0185] 1i 103.0 ± 3.0% >100 pM

[0186] 1j 109.3 ± 4.1% >100 pM

[0187]

[0188] 4239-1 14920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0189] Table 2

[0190] Me

[0191] Compound R2Beclin1-ATG14L Solubility NanoBRET 1k 132.5 ± 4.9% >100 uM

[0192] 11 147.4 ± 5.8% >100 uM

[0193] 1m 134.0 ± 5.8% >100 uM

[0194] 1n 145.4 ± 4.1% >100 μM

[0195] 1o 131.2 ± 5.6% >100 μM

[0196] 1p 105.4 ± 2.8% >100 μM

[0197] 1q 106.9 ± 4.6% 100 μM

[0198] 1r 108.0 ± 2.3% >100 μM

[0199] 110.2 ± 2.4% >100 pM 1s 1t 108.8 ± 4.6% >100 μM

[0200] 1u 115.6 ± 5.8% >100 μM

[0201]

[0202] 4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0203] Table 3

[0204] Me

[0205] Compound Beclin1-ATG14L NanoBRET Solubility

[0206] 2a 96.2 ± 3.2% >100 pM

[0207] 2b 89.2 ±4.6% >100 pM

[0208] 2c 83.2 ±4.2% >100 pM

[0209] 80.0 ± 3.5% >100 pM

[0210] 99.8 ± 2.5% >100 pM

[0211] 59.9 ± 2.4% >100 pM

[0212] / Pr

[0213] 101.4 ± 4.4% >100 μM

[0214] 103.3 ± 2.8% >100 μM

[0215] 99.8 ± 2.3% >100 pM

[0216] 100.9 ± 4.9% >100 μM

[0217] 88.1 ± 3.2% >100 pM

[0218]

[0219] 4239-1 14920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0220] Table 4

[0221] Compound R Beclin1-ATG14L

[0222] N.anoBRET Solubility ’

[0223] 118.8 ± 5.8% >100 pM

[0224] 109.3 ± 4.7% 50 pM

[0225] 103.7 ± 5.7% >100 pM

[0226] 126.6 ± 6.0% >100 pM

[0227] 106.3 ± 4.6% >100 pM

[0228] 111.7 ± 3.6% >100 pM

[0229] 92.0 ± 4.6% >100 pM

[0230] Me

[0231]

[0232] 4239-1 14920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0233] Table 5

[0234] Compound Beclin1-ATG14L Solubility Beclin1-UVRAG Selectivity NanoBRET NanoBRET Ratio 4a 63.2 ± 4.0% >100 pM 95.7 ± 3.1 % 1.51

[0235] 4b 57.3 ± 2.1% >100 pM 91.5 ± 2.5% 1.59

[0236] 4c 65.0 ± 4.5% >100 pM 84.6 ± 3.9% 1.30

[0237] 4d 65.8 ± 5.4% >100 pM 82.6 ± 1.9% 1.25

[0238] 4e 82.5 ± 3.8% >100 pM 104.5 ± 3.5% 1.26

[0239] 4f 79.5 ± 2.1% >100 pM 100.2 ± 4.2% 1.26

[0240] 4g 63.8 ± 3.2% >100 pM 84.2 ± 3.9% 1.32

[0241] 4h 105.5 ± 2.6% >100 pM 108.2 ± 5.0% 1.03

[0242] 4i 75.3 ± 2.7% >100 pM 92.4 ± 2.9% 1.22

[0243] 4j 63.0 ± 2.8% >100 pM 77.7 ± 2.9% 1.23

[0244] Me

[0245]

[0246] 4239-1 14920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0247] Table 6

[0248] Compound Beclin1-ATG14L Solubility Beclin1-UVRAG Selectivity NanoBRET NanoBRET Ratio

[0249] 5a 103.8 ± 3.2% >100 pM 107.6 ± 5.1 % 1.04

[0250] 5b 101.1 ± 3.5% 50 pM 103.5± 1.9% 1.02

[0251] 5c 101.4 ± 3.6% 50 pM 116.1 ± 3.1 % 1.14

[0252] 5d 72.9 ± 7.2% >100 pM 108.3 ± 3.6% 1.49

[0253] 5e 75.8 ± 5.0% >100 pM 116.5 ± 4.7% 1.54

[0254]

[0255] 4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0256] Table 7

[0257] Compound Beclin1-ATG14L Solubility Beclin1-UVRAG Selectivity NanoBRET NanoBRET Ratio 4k >100 μM 95.3 ± 2.2% 1.30

[0258] 4l 94.9 ± 2.4% >100 μM 109.0 ± 3.6% 1.15

[0259] 4m 109.2 ± 1.6% >100 μM 110.5 ± 3.5% 1.01

[0260] 4n 105.2 ± 3.4% >100 μM 110.5 ± 2.5% 1.05

[0261] 4o 89.7 ± 1.9% >100 μM 105.3 ± 3.3% 1.17

[0262] 4p 90.8 ± 2.6% >100 μM 102.5 ± 6.0%

[0263] 4q 98.3 ± 3.1% >100 μM 103.9 ± 3.3% 1.06

[0264] 4r 98.7 ± 4.3% >100 μM 105.0 ± 3.3% 1.06

[0265] 4s 87.9 ± 2.5% >100 μM 100.0 ± 3.8% 1.14

[0266]

[0267] 4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0268] Table 7 (continued)

[0269] Compound Beclin1-ATG14L Solubility Beclin1-UVRAG Selectivity NanoBRET NanoBRET Ratio 4u 79.0 ± 5.6% >100 μM 98.0 ± 5.8% 1.24

[0270] 4v 90.3 ± 4.0% 50 μM 100.7 ± 3.0% 1.11

[0271] 4w 77.4 ± 1.6% >100 μM 98.0 ± 3.9% 1.27

[0272] 4x 85.1 ± 2.8% >100 μM 94.8 ± 2.7% 1.11

[0273] 4y 89.9 ± 1.9% >100 μM 105.6 ± 2.5% 1.17

[0274] 4z 85.1 ± 4.2% 100 μM 115.7 ± 3.8% 1.36

[0275] 4aa 79.7 ± 2.1% 100 μM 119.6 ± 13.2% 1.50

[0276] 4bb 80.5 ± 1.1% >100 μM 116.9 ± 7.1% 1.45

[0277] 4cc 71.6 ± 3.2% >100 μM 92.9 ± 2.9% 1.29

[0278] 4dd 81.6 ± 2.7% >100 μM 99.1 ± 3.0% 1.21

[0279]

[0280] 4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0281] Table 8

[0282] Compound Beclin1-ATG14L Solubility Beclin1-UVRAG Selectivity NanoBRET NanoBRET Ratio 5f 79.3 ± 3.1% >100 μM 119.3 ± 6.7% 1.50

[0283] 5g 93.6 ± 2.8% >100 μM 104.3 ± 6.3% 1.11

[0284] 5h 79.1 ± 3.6% 50 μM 102.3 ± 6.3% 1.29

[0285] 5i 82.0 ± 1.7% >100 μM 101.3 ± 3.2% 1.23

[0286] 5j 88.7 ± 3.0% >100 μM 104.8 ± 5.0% 1.18

[0287] 5k 89.8 ± 1.1% 100 μM 101.7 ± 3.2% 1.13

[0288] 5l 86.2 ± 1.1% 25 μM 108.3 ± 2.9% 1.25

[0289] 5m 83.9 ± 3.3% 100 μM 118.0 ± 12.4% 1.40

[0290] 5n 82.4 ± 4.8% >100 μM 105.1 ± 3.5% 1.27

[0291]

[0292] 4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0293] Table 9

[0294]

[0295] 4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0296] Table 10

[0297]

[0298] 4239-114920-02 10 / 09 / 25 E-1S6-2025-0 PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0299] Table 11

[0300]

[0301] 4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0302] III. Pharmaceutical Compositions

[0303] In other aspects, this disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound as described herein, and one or more pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants, excipients, or carriers. The pharmaceutical composition can be used, for example, inhibition of autophagy in a subject.

[0304] In certain aspects, the disclosure provides a pharmaceutical composition comprising the compounds of the disclosure together with one or more pharmaceutically acceptable excipients or vehicles, and optionally other therapeutic and / or prophylactic ingredients. Such excipients include liquids such as water, saline, glycerol, polyethylene glycol, hyaluronic acid, ethanol, and the like.

[0305] The term “pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient or carrier with which a compound of the disclosure is administered. The terms “effective amount” or “pharmaceutically effective amount” refer to a nontoxic but sufficient amount of the agent to provide the desired biological result. That result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate “effective” amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation.

[0306] “Pharmaceutically acceptable carriers” for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington’s Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990). For example, sterile saline and phosphate-buffered saline at physiological pH can be used. Preservatives, stabilizers, dyes and even flavoring agents can be provided in the pharmaceutical composition. For example, sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid can be added as preservatives. Id. at 1449. In addition, antioxidants and suspending agents can be used. Id.

[0307] Suitable excipients for non-liquid formulations are also known to those of skill in the art. A thorough discussion of pharmaceutically acceptable excipients and salts is available in Remington’s Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990).

[0308] Additionally, auxiliary substances, such as wetting or emulsifying agents, biological buffering substances, surfactants, and the like, can be present in such vehicles. A biological4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0309] buffer can be any solution which is pharmacologically acceptable and which provides the formulation with the desired pH, i.e., a pH in the physiologically acceptable range. Examples of buffer solutions include saline, phosphate buffered saline, Tris buffered saline, Hank’ s buffered saline, and the like.

[0310] Depending on the intended mode of administration, the pharmaceutical compositions can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, creams, ointments, lotions or the like, preferably in unit dosage form suitable for single administration of a precise dosage. The compositions will include an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier and, in addition, can include other pharmaceutical agents, adjuvants, diluents, buffers, and the like.

[0311] In general, the compositions of the disclosure will be administered in a therapeutically effective amount by any of the accepted modes of administration. Suitable dosage ranges depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved. One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this application, to ascertain a therapeutically effective amount of the compositions of the disclosure for a given disease.

[0312] Thus, the compositions of the disclosure can be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The preferred manner of administration is intravenous or oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.

[0313] For solid compositions, conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, and the like, an active compound as described herein and optional pharmaceutical adjuvants in an4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0314] excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered can also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and the like. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington’s Pharmaceutical Sciences, referenced above.

[0315] In yet another aspect is the use of permeation enhancer excipients including polymers such as: polycations (chitosan and its quaternary ammonium derivatives, poly-L-arginine, aminated gelatin); polyanions (N-carboxymethyl chitosan, poly-acrylic acid); and, thiolated polymers (carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosanthiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugates).

[0316] For oral administration, the composition will generally take the form of a tablet, capsule, a softgel capsule or can be an aqueous or nonaqueous solution, suspension or syrup. Tablets and capsules are preferred oral administration forms. Tablets and capsules for oral use can include one or more commonly used carriers such as lactose and com starch.

[0317] Lubricating agents, such as magnesium stearate, are also typically added. Typically, the compositions of the disclosure can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

[0318] When liquid suspensions are used, the active agent can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like and with emulsifying and suspending agents. If desired, flavoring, coloring and / or sweetening agents can be added as well. Other optional components for incorporation into an4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0319] oral formulation herein include, but are not limited to, preservatives, suspending agents, thickening agents, and the like.

[0320] Parenteral formulations can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solubilization or suspension in liquid prior to injection, or as emulsions. Preferably, sterile injectable suspensions are formulated according to techniques known in the art using suitable carriers, dispersing or wetting agents and suspending agents. The sterile injectable formulation can also be a sterile injectable solution or a suspension in a nontoxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that can be employed are water, Ringer’ s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media. In addition, parenteral administration can involve the use of a slow release or sustained release system such that a constant level of dosage is maintained.

[0321] Parenteral administration includes intraarticular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. Administration via certain parenteral routes can involve introducing the formulations of the disclosure into the body of a patient through a needle or a catheter, propelled by a sterile syringe or some other mechanical device such as an continuous infusion system. A formulation provided by the disclosure can be administered using a syringe, injector, pump, or any other device recognized in the art for parenteral administration.

[0322] Preferably, sterile injectable suspensions are formulated according to techniques known in the art using suitable carriers, dispersing or wetting agents and suspending agents. The sterile injectable formulation can also be a sterile injectable solution or a suspension in a nontoxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media. In addition, parenteral administration can involve the use of a slow release or sustained release system such that a constant level of dosage is maintained.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0323] Preparations according to the disclosure for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms can also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They can be sterilized by, for example, filtration through a bacteria retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured using sterile water, or some other sterile injectable medium, immediately before use.

[0324] Sterile injectable solutions are prepared by incorporating one or more of the compounds of the disclosure in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.

[0325] Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Thus, for example, a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.

[0326] Alternatively, the pharmaceutical compositions of the disclosure can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable nonirritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0327] The pharmaceutical compositions of the disclosure can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, propellants such as fluorocarbons or nitrogen, and / or other conventional solubilizing or dispersing agents.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0328] Preferred formulations for topical drug delivery are ointments and creams. Ointments are semisolid preparations which are typically based on petrolatum or other petroleum derivatives. Creams containing the selected active agent, are, as known in the art, viscous liquid or semisolid emulsions, either oil-in-water or water-in-oil. Cream bases are water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also sometimes called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. The specific ointment or cream base to be used, as will be appreciated by those skilled in the art, is one that will provide for optimum drug delivery. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and nonsensitizing.

[0329] Formulations for buccal administration include tablets, lozenges, gels and the like. Alternatively, buccal administration can be effected using a transmucosal delivery system as known to those skilled in the art. The compounds of the disclosure can also be delivered through the skin or muscosal tissue using conventional transdermal drug delivery systems, i.e., transdermal “patches” wherein the agent is typically contained within a laminated structure that serves as a drug delivery device to be affixed to the body surface. In such a structure, the drug composition is typically contained in a layer, or “reservoir,” underlying an upper backing layer. The laminated device can contain a single reservoir, or it can contain multiple reservoirs. In one aspect, the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery.

[0330] Examples of suitable skin contact adhesive materials include, but are not limited to, polyethylenes, poly siloxanes, poly isobutylenes, polyacrylates, polyurethanes, and the like. Alternatively, the drug-containing reservoir and skin contact adhesive are present as separate and distinct layers, with the adhesive underlying the reservoir which, in this case, can be either a polymeric matrix as described above, or it can be a liquid or gel reservoir, or can take some other form. The backing layer in these laminates, which serves as the upper surface of the device, functions as the primary structural element of the laminated structure and provides the device with much of its flexibility. The material selected for the backing layer should be substantially impermeable to the active agent and any other materials that are present.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0331] The compositions of the disclosure can be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compound will generally have a small particle size for example of the order of 5 microns or less. Such a particle size can be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. The aerosol can conveniently also contain a surfactant such as lecithin. The dose of drug can be controlled by a metered valve. Alternatively, the active ingredients can be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and poly vinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition can be presented in unit dose form for example in capsules or cartridges of e.g., gelatin or blister packs from which the powder can be administered by means of an inhaler.

[0332] IV. Administration

[0333] A pharmaceutically or therapeutically effective amount of the composition is delivered to the subject to treat a disease of condition. In some aspects, the subject has a viral infection, or is at risk of getting a viral infection. Exemplary viral infections that can be treated using one or more of the disclosed compounds, or pharmaceutical compositions thereof, include, but are not limited to, Machupo virus, Influenza A virus, HIV-1, Ebola virus, SARS-CoV-2, and Lassa virus.

[0334] The precise effective amount will vary from subject to subject and will depend upon the species, age, the subject’s size and health, the nature and extent of the condition being treated, recommendations of the treating physician, and the therapeutics or combination of therapeutics selected for administration. Thus, the effective amount for a given situation can be determined by routine experimentation. For purposes of the disclosure, generally a therapeutic amount will be in the range of about 0.01 mg / kg to about 250 mg / kg body weight, more preferably about 0.1 mg / kg to about 10 mg / kg, in at least one dose. In larger mammals the indicated daily dosage can be from about 1 mg to 300 mg, one or more times per day, more preferably in the range of about 10 mg to 200 mg. The subject can be administered as many doses as is required to reduce and / or alleviate the signs, symptoms, or causes of the4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0335] disorder in question, or bring about any other desired alteration of a biological system. When desired, formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient. The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

[0336] V. Results and Discussion

[0337] The high-throughput ATG14L-Beclinl NanoBRET assay revealed that the sulfonamide ring system could tolerate multiple substitution patterns, leading to changes in activity and suggesting this as potential site of changes to the molecule. First, it was decided to explore modifications at the oxadiazole position because analogues of this position were not included in commercial chemical library. Initial efforts to alkylate the amide as the last step resulted in regioselectivity issues between the sulfonamide and the amide, and thus we decided to complete this step prior to the formation of the sulfonamide. 2-aminophenol was exposed to chloroacetyl chloride and potassium carbonate under reflux conditions to generate lactam 6 in excellent yield (Scheme 1).4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0338] 67a -f

[0339] 9a -d

[0340]

[0341] 12 1g-j

[0342] (a) K2CO3, Chloroacetyl chloride, MeCN, 75 °C (b) Alkyl halide (Ri-Br), NaH, DMF, 0 °C to rt (c) CISO3H, 0 °C (d) 2,3-dimethyl aniline (R2-NH2), pyridine, CH2CI2, rt (e) EtsN, CH2CI2, 0 °C to rt (f) Mel, DMF, rt, 92% (g) BBr3, CH2CI2, rt (h) 9a-d, Cs2CO3, DMF, 160

[0343]

[0344] Scheme 1

[0345] S obsequent deprotonation using sodium hydride enabled placement of the substituent at the amide position, providing substituted lactams 7a-f. Electrophilic aromatic substitution (EAS) selectively installed the sulfonyl chloride para to the oxygen, thus forming the desired sulfonyl chlorides 8a-f. Finally, the sulfonyl chlorides were treated with 2,3-dimethyl aniline under basic conditions to generate the desired final analogues la-f (Table 1). While this route efficiently provided alkyl analogues, analogues containing aryl or heteroaryl moi eties were also sensitive to the EAS conditions, resulting in over- sulfonation and / or a lack of regioselectivity. Therefore, a slightly modified route was developed that started with 2-4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0346] bromophenol. Methylation of the alcohol with methyl iodide followed by oxy gen-directed EAS and reaction with 2,3-dimethyl aniline to provide sulfonamide 11, and demethylation using boron tribromide produced the desired bromophenol 12. Similar bromophenols have been shown to undergo O-alkylation and nucleophilic aromatic substitution (SNAr) when treated with chloroamides under basic conditions. Chloroamides 9a-d were generated from a reaction between substituted amines and chloroacetyl chloride under basic conditions in good yields and were then reacted with bromophenols 12 to generate aryl-containing analogues 1g-j (Table 1).

[0347] These 10 analogues were compared to Compound 19 for their ability to inhibit the ATG14L-Beclinl PPI using the NanoBRET assay. Initially, compounds were screened at a single dose of 100 M to identify active compounds that would then be tested at multiple doses (Table 1). The BRET ratios for compound treatments were compared to DMSO treatment (negative control) to generate percent signal values relative to the negative control (100%). Only compound lb significantly reduced the BRET ratio, with a percent signal value of 72.3% of the DMSO control and was determined to have an IC50of 62.9 μM, which was a loss of potency compared to Compound 19 (60.6% signal at 100 pM, IC50=33.9 μM). It was also observed that the propyl group appeared to be the ideal length, because both the ethyl analogue (le) and the butyl analogue (If) were completely inactive (Table 1). Despite the decreased potency of compound lb, a significant improvement in solubility was observed with this propyl-substituted analogue by replacing the oxadiazole moiety in Compound 19. The moderate solubility of Compound 19 would likely limit its utility in future in vivo experiments, and so a major focus of these initial SAR studies was to identify changes that could improve this important property. To assess solubility, a kinetic aqueous solubility assay was performed by adding compounds to phosphate buffered saline (pH 7.4) at six concentrations and optical density (OD) readings were collected at 620 nm to determine if compounds were precipitating out of solution. Compounds were considered insoluble at concentrations where the OD reading was more than triple the signal to noise (S / N) ratio of the background. Compounds were compared to diclofenac, a soluble control, and dipyridamole, an insoluble control. At 8 hours, most of the analogues were significantly more soluble than dipyridamole and Compound 19. In fact, all but two alkylated analogues displayed improved solubility compared to Compound 19. To further explore the activity and properties of the propyl-substituted analogues, a series of 11 additional compounds (Ik-u)4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0348] was prepared from sulfonyl chloride 8b through treatment with a variety of substituted anilines and amines (Table 2). Although this series maintained good solubility, none of these compounds inhibited the ATG14L-Beclinl PPI, and so it was decided to further evaluate compound lb to determine if this analogue would be a suitable starting point for additional optimization.

[0349] The formation of LC3-II from LC3-I is a well-known biomarker for autophagy and quantifying LC3-II levels, either by western blotting or florescence microscopy using antibodies, transient transfection, or cell lines stably expressing tagged LC3, provides a measure for autophagosome formation and autophagy modulation. Using HeLa cells stably expressing eGFP-LC3, the autophagy inhibitory effects of compound lb and inactive analogue le were compared. Cells were treated with compounds for 20 hours before a 4 hour co-treatment with CQ, which induces an increase in LC3-II due to the accumulation of the autophagosomes, and an early-stage inhibitor that targets the autophagy initiation complex should prevent the formation of autophagosomes and thus decrease the levels of LC3-II compared to CQ treatment alone. Compound lb significantly decreased the GFP puncta / cell compared to the inactive analogue, le (FIGS. 1A-1B). Significance is noted as not significant (ns), p < 0.05 (*), p < 0.01 (**), p < 0.001 (***), or p < 0.0001 (****). To confirm this inhibition was a result of an interaction of the compound with ATG14L, a cellular thermal shift assay (CETSA) was performed. This method is based on the principle that small molecule-binding to target proteins can have a stabilizing or destabilizing effect on observed melting temperature, and thus, enables target engagement to be assessed in cells. Compound lb increased the melting temperature of ATG14L when compared to the DMSO control in A549 cells, and this stabilization was not observed with the inactive analogue le, further validating the hypothesized mechanism of compound lb (FIG. 1C). However, additional structural and computational studies will be necessary to determine where active compounds are binding and how this affects the structure and confirmation of ATG14L and its interacting partners.

[0350] To confirm that compound lb selectively inhibits autophagy and Complex I without affecting endosomal trafficking and Complex II, processing of dye-quenched bovine serum albumin (DQ-BSA) was first analyzed. This albumin is heavily labeled with BODIPY dye molecules, and under normal conditions, the dye is endocytosed and trafficked to the lysosome where the albumin is degraded and the unquenched dye produces a bright red4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0351] fluorescent signal. The combined use of DQ-BSA and phase contrast imaging enable analysis of lysosomal degradation and vesicle trafficking defects. DQ-BSA has been previously used to monitor lysosome function and its impact on autophagy, and late-stage autophagy inhibitors, such as BafAl and CQ, are known to reduce DQ-BSA cleavage and thus, lower the fluorescence intensity. Early-stage autophagy inhibitors that do not reduce lysosome function or inhibit vesicle trafficking should exhibit phenotypes similar to the vehicle control in the DQ-BSA assay. To exclude the possibly that any of the compounds affect endosomal uptake of the dye, A549 cells were pulsed with DQ-BSA for 1 hour prior to addition of the compounds. As expected, treatment with late-stage inhibitors (CQ, BafAl) or VPS34 kinase inhibitors (PIK-III, SAR405) resulted in decreased fluorescence signal due to lysosomal and trafficking defects. In contrast, lb did not decrease fluorescence, suggesting that lysosomes and endosomal trafficking are functioning normally (FIG. ID). This observation was further validated by phase contrast imaging. VPS34 kinase inhibitors caused massive accumulation of vacuoles due to inhibition of vesicle trafficking, and this phenotype was not observed following treatment with lb (FIG. IE). Due to the favorable activity profile of compound lb, it was decided to move forward with this analogue and to make modifications to a different region of the scaffold by replacing the sulfonamide with different functional groups, including reverse amides and sulfonamides, biaryls, and amines, to determine the critical structural elements required for activity and to improve potency while maintaining favorable solubility.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0352]

[0353] (a) K2CO3, Chloroacetyl chloride, MeCN, 75 °C (b) Propyl bromide, NaH, DMF, 0 °C to rt (k) SnCl2·H2O, EtOH, 70 °C (l) Sulfonyl chloride, pyridine, CH2Cl2, 0 °C to rt (m) Acid chloride, Et3N, CH2Cl2, 0 °C to rt (n) Boronic acid, Pd(PPh3)4, Cs2CO3, 1,4-dioxane: H2O (4:1), 120°C, μW (o) Aniline, Pd2(dba)3, BINAP, Cs2CO3, PhMe, 110 °C Scheme 2

[0354] The synthesis of the reverse sulfonamides began with 2-amino-4-nitrophenol, and the same two-step reaction sequence used for the previous analogues generated the substituted lactam 15 in excellent yield (Scheme 2). Tin (II) chloride-mediated reduction of the nitro group provided the required aniline for subsequent reaction with a variety of sulfonyl chlorides to generate reverse sulfonamide analogues 2a-k in acceptable yields over two steps. Synthesis of the reverse amides proceeded through the same first three steps before reaction with various acid chlorides to provide analogues 3a-g. To access biaryl and amine analogues, 2-amino-4-bromophenol was used as the starting material to provide substituted lactam 16 over two steps. Biaryl analogues were produced using a microwave-assisted Suzuki crosscoupling with a variety of boronic acids to provide analogues 4a-j. Amine analogues 5a-e were synthesized from lactam 16 using a Buchwald-Hartwig amination for the final step. These routes provided 33 total analogues for evaluation.

[0355] Initial single-dose experiments were performed in the ATG14L-Beclin 1 NanoBRET assay to determine the effect of replacing the sulfonamide. The cut-off for being considered4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0356] active was set as a BRET ratio <80% of the DMSO control and determined that 11 out of the 33 compounds were active. Reverse sulfonamides (Table 3) and reverse amides (Table 4) were generally not well tolerated, as these series only contained one active analogue, reverse sulfonamide 2f. The other 10 active compounds came from the biaryl (Table 5) and amine (Table 6) series. Results for Table 5 compounds are shown in FIG. 7 and results for Table 6 compounds are shown in FIG. 8. The only example where a biaryl analogue completely lost activity was when the aryl ring was replaced with a 4-pyridyl group in 4h. Active compounds were tested at seven doses to compare potency with Compound 19 and lb. Analogues 4a-d, 4i, and 4j all reduced the BRET ratio to a similar level as lb and Compound 19, and these analogues had similar or improved potency, up to a 2 to 3-fold improvement compared to lb (FIG. 2A). All active biaryl and amine analogues also had improved solubility compared to Compound 19.

[0357] For the biaryl and amine series, these compounds were also evaluated in the UVRAG-Beclinl NanoBRET assay to assess selectivity. The selectivity ratio (UVRAG-Beclinl / ATG14L-Beclinl) was calculated, and a ratio of >1.25 was considered selective. Although none of the active compounds had a selectivity ratio that was significantly less than the established cut-off, biaryl compounds, 4c, 4d, 4i, and 4j, reduced the BRET signal in the UVRAG-Beclinl assay to <90% of the DMSO control, indicating that some of the most active compounds in the ATG14L-Beclinl assay had reduced selectivity and were partially inhibiting the UVRAG-Beclinl PPI. When tested at multiple doses, compound 4j was the most potent inhibitor of the UVRAG-Beclinl PPI with an IC50of 42.2 μM (FIG. 2B). The biaryl series was also significantly cytotoxic in the eGFP-LC3 puncta formation assay at 100 pM concentration (FIG. 2D left), which could potentially be due to reduced selectivity for inhibition of the autophagy pathway. The DQ-BSA assay was performed to further evaluate the effect of this change in selectivity; however, a signal reduction was not induced by these compounds compared to the DMSO control (FIG. 2C). Due to the difference in potency between the VPS34 inhibitors and these compounds, it is possible that a more complete inhibition of Complex II activity is required to observe a significant signal reduction in this assay. Interestingly, some compounds, such as 4d and 4i, significantly increased the DQ-BSA fluorescence signal relative to the DMSO control. This increase may be explained by the selective inhibition of the ATG14L-Beclinl complex, which exists in equilibrium with the UVRAG-Beclinl complex and the Beclinl homodimer. Wu and coworkers have shown that4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0358] inhibition of homodimer formation of Beclinl results in upregulation of autophagy and endolysosomal trafficking. Similarly, selective autophagy inhibition by an ATG14L-Beclin 1 PPI inhibitor could increase levels of UVRAG-Beclinl formation as well as homodimer formation of Beclinl. An increase in UVRAG-Beclinl would increase endosomal trafficking, thus increasing the fluorescence signal in the DQ-BSA assay, and it is possible that 4d and 4i have this effect. Even though these compounds show some inhibition of the UVRAG-Beclinl interaction in the NanoBRET assay, their potency is greater for disruption of the ATG14L-Beclin 1 interaction, so when they inhibit this PPI in cells expressing endogenous Beclinl complexes, this could cause an increase in UVRAG-Beclinl complex formation and thus an increase in endosomal trafficking. Future work to quantify the amount of different Beclinl complexes formed following compound treatment will be important to provide a better understanding of these effects and could potentially provide biomarkers for measuring in vivo target engagement and ATG14L-Beclin 1 PPI inhibition.

[0359] Although the activity within the biaryl series was promising, it was hypothesized that the observed decrease in selectivity may be due to the replacement of the oxadiazole moiety with the greatly simplified propyl group. The significant cytotoxicity among compounds in this series also indicated that these compounds could potentially have a variety of other off-target effects. To evaluate this hypothesis, additional biaryl and amine series were prepared and the oxadiazole moiety was reintroduced. A synthetic route to access Compound 19 would also enable preparation of a variety of analogues containing the oxadiazole moiety to assess the importance of this region. Although small amounts of commercial hit compounds, including Compound 19, were useful for preliminary studies, it was also necessary to establish methods to efficiently produce gram-scale quantities of compounds for in vivo studies. Preparation of the 5-cyclobutyl-l,2,4-oxadiazole from acyclic precursors proved challenging and prohibitively expensive for large scale synthesis, and thus the same synthetic route that was successful for generating alkylated analogues Ig-m was attempted using a commercially available primary amine that contained the desired substituted oxadiazole ($79 / g). Reaction of [(5-cyclobutyl-l,2,4-oxadiazol-3-yl)methyl]amine hydrochloride with chloroacetyl chloride resulted in generation of the necessary amide 9e in excellent yields (>90%) (Scheme 3).4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0360] e decomposition 92%

[0361] 17

[0362]

[0363] 7g Compound 19 (e) Chloroacetyl chloride, (5-cyclobutyl-1,2,4-oxadiazol-3-yl)methanamine, Et3N, CH2Cl2, 0 °C to rt (h) 12, Cs2CO3, DMF, 160 °C (i) PPh3, CCl4, DCE, rt (j) 17, NaH, TBAI, THF, 65 °C (c) ClSO3H, CH2Cl2, 0 °C (d) 2,3-dimethylaniline, pyridine, CH2Cl2, 0 °C to rt Scheme 3. Synthesis of Compound 19

[0364] However, attempts to couple a-chloroamide 9e with bromophenol 12 using the previously optimized methods were not successful. Both conventional and microwave heating led to decomposition without any desired product formation. LCMS analysis revealed the presence of the O-alkylated intermediate that would degrade over time without producing any of the lactam product. This suggests that the oxadiazole may be sensitive to the high temperature required for this reaction or that it may interfere with the intramolecular cyclization reaction. Based on these observations, an alternative strategy was implemented to incorporate the oxadiazole prior to sulfonation and sulfonamide formation. Due to the lack of free protons on the oxadiazole system, issues with regioselective installation of the sulfonyl chloride were not anticipated. Commercially available 3-(chloromethyl)-5-cyclobutyl- 1,2,4-oxadiazole (>$250 / g) was used to alkylate lactam 6 in low yield using the same conditions used to access alkylated analogues la-f. While this worked as a proof of concept, a strategy was still required that could provide grams of the desired products with higher efficiency and lower overall cost. Alternative electrophiles were explored using (5-cyclobutyl- 1,2,4-oxadiazol-3-yl)methanol ($27 / g) as an affordable starting material. Although both the tosylate and mesylate electrophiles were evaluated, the most efficient and high yielding reaction used the chloride electrophile and Finkelstein conditions. In light of this observation, an Appel reaction was optimized to enable gram-scale preparation of the required chloride 174239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0365] from the more affordable alcohol precursor in excellent yield and purity. Addition of tetrabutylammonium iodide to the reaction mixture of the synthetic chloride, lactam, and sodium hydride provided the desired product in excellent yield. Subsequent sulfonation and sulfonamide formation provided Compound 19 with an overall yield of 77% over four steps (Scheme 3). This synthetic Compound 19 was evaluated in the ATG14L-Beclinl and UVRAG-Beclinl NanoBRET assays and both activity and selectivity were confirmed (FIG.

[0366] 3).

[0367] Although an efficient strategy had been identified to prepare Compound 19, analogue synthesis provided new challenges. To access the biaryl analogues, the oxadiazole-substituted lactam 18 was prepared from 2-amino-4-bromophenol using the same protocol used to prepare Compound 19 (Scheme 4).

[0368]

[0369] (j) 17, NaH, TBAI, THF, 65 °C, 30min (n) Boronic Acid, Pd(PPh3)4, Cs2CO3, 1,4-dioxane: H2O (4:1), 120 °C, μW (p) Aniline (R-NH2), Pd(OAc)2, Xantphos, NaOtBu, 1,4-dioxane, 100 °C

[0370] Scheme 4

[0371] Unfortunately, exposure to cross-coupling conditions caused degradation of the starting material. The approach was modified to perform the Suzuki coupling prior to the alkylation and were able to successfully access 20 additional biaryl analogues 4k-dd (Scheme 4, Table 7, results summarized in FIG. 9). For the amine series, it was also necessary to perform the Buchwald-Hartwig coupling prior to the alkylation step. Although this cross-4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0372] coupling reaction required considerable optimization with the unsubstituted lactam, 9 additional amine analogues 5f-n (Scheme 4, Table 8, result summarized in FIG. 10) were successfully prepared. These analogues were then evaluated in the ATG14L-Beclinl NanoBRET assay. While this set of analogues did not have the same percentage of active compounds as the previous generation, several emerging trends were observed. Compounds with a methyl at the ortho position, along with an additional substituent at the neighboring meta position were consistently active and selective. Compound 4cc, which only has an ortho isopropyl substituent was also active and possessed good selectivity. Like compound 4j from the previous biaryl series, compound 4k contains a 2,3-dimethyl aryl group, but reincorporation of the oxadiazole restored selectivity. Compound 4k selectively inhibited the ATG14L-Beclin 1 PPI to the same level as Compound 19 with an IC50of 12.5 μM, approximately 3-fold more potent than Compound 19 and 5-fold more potent than lb (FIGS.

[0373] 4 and 5). These SAR trends were also consistently observed for autophagy inhibition in the eGFP-LC3 puncta formation assay (FIG. 6). In addition to compound 4k (mint), compounds with an ortho-Cl (navy) or 0 / 7 / 70-alkyl (teal) inhibited autophagy at the 50,11 M concentration. Compounds 4o (o-Cl, / / -Cl) and 4z (m-Cl) (green) did not significantly inhibit autophagy. Furthermore, even at the 100 pM concentration, this series was significantly less cytotoxic in this assay than the previous biaryl series (FIG. 2D right), which could be due to the restored selectivity. Solubility studies were also conducted on this set of 29 analogues. Overall, these analogues had lower solubility than the propyl analogues, likely due to the reintroduction of the oxadiazole system, but 26 analogues, including 4k, had improved solubility compared to Compound 19, providing several promising molecules as starting points for additional optimization using our new knowledge of the SAR of this scaffold.

[0374] Compound 19 is a promising starting point for developing selective autophagy inhibitors to study the role of autophagy in cancer and to identify new targets and therapeutic strategies. Efficient synthetic routes were developed to access this hit compound and to prepare iterative analogue libraries to produce 83 new compounds to study the structureactivity relationships of the Compound 19 scaffold. Within these libraries, the propylsubstituted lactam was the only tolerated modification at this position, and the original oxadiazole imparted better selectivity for the ATG14L-Beclinl PPI over the UVRAG-Beclinl PPI. Replacement of the sulfonamide with both amine and biaryl linkages provided additional active analogues, and several aryl group substitutions were tolerated, with the most4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0375] notable observation being that aryl rings with lipophilic groups at the ortho position typically had the best potency while modification of the aryl ring to a pyridine completely abolished activity. In addition, analogues were successfully generated with improved solubility that maintain or improve potency and selectivity for the ATG14L-Beclinl PPI. The information obtained through these SAR studies provided valuable insight into which regions of Compound 19 are most amenable to structural changes to enhance potency and solubility without negatively impacting selectivity.

[0376] VI. Example Aspects

[0377] The following numbered paragraphs illustrate exemplary aspects of the disclosed technology.

[0378] Paragraph 1. A compound according to Formula I or Formula II

[0379]

[0380] or a pharmaceutically acceptable salt thereof, wherein:

[0381] L is a bond, -N(R9)-, -C(O)N(R9)-, -N(R9)C(O)-, -S(O)2N(R9)- or -N(R9)S(O)2-; R9is H or C1-6alkyl;

[0382] Ri is substituted or unsubstituted phenyl, substituted or unsubstituted phenyl-C1-6alkyl, substituted or unsubstituted 5- or 6-membered cycloalkyl, substituted or unsubstituted 5- or 6-membered cycloalkylalkyl, substituted or unsubstituted 5- or 6-membered heterocyclyl, substituted or unsubstituted 5- or 6-membered heterocyclylalkyl, or substituted or unsubstituted 5- to 6-membered heteroaryl, or R9and Ri together with the atom to which they are attached forms a substituted or unsubstituted 5- or 6-membered heterocyclyl;

[0383] R2is selected from H, alkyl, alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0384] unsubstituted 5- or 6-membered heteroaryl, substituted or unsubstituted 5- or 6-membered heteroaryl-Ci-ealkyl, substituted or unsubstituted C3-6cycloalkyl-Ci-6alkyl, substituted or unsubstituted 5- or 6-membered heterocyclyl, and substituted or unsubstituted 5- or 6-membered heterocyclyl-C1-6alkyl;

[0385] R3 and Re are independently selected from H, halo, alkyl, haloalkyl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted arylalkyl; and

[0386] R4 and R5 independently are selected from H, hydroxy, Ci-ealkoxy, halo, Ci-ealkyl, Ci-ehaloalkyl or cyano;

[0387] O. P

[0388] U=: / '~'N I

[0389] z"\ H

[0390] CH

[0391] and wherein the compound is not

[0392]

[0393] 3

[0394] Paragraph 2. The compound of paragraph 1, wherein L is a bond.

[0395] Paragraph 3. The compound of paragraph 1, wherein L is -NHS(O)2-.

[0396] Paragraph 4. The compound of paragraph 1, wherein L is -NH-.

[0397] Paragraph 5. The compound of any one of paragraphs 1-4, wherein Ri is substituted or unsubstituted phenyl.

[0398] Paragraph 6. The compound of paragraph 5, wherein Ri is phenyl substituted with 1, 2, 3, 4 or 5 substituents.

[0399] Paragraph 7. The compound of paragraph 5, wherein Ri is phenyl substituted with 1 or 2 substituents.

[0400] Paragraph 8. The compound of any one of paragraphs 1-7, wherein Ri is substituted with one or more substituents selected from Ci-ealkyl, halo, Ci-ehaloalkyl, Ci-ealkoxy, Ci-ehaloalkyloxy, nitro (NO2), cyano, OH, 5- or 6-membered heterocyclyl, or R7C(O)- groups, where R7 is Ci-ealkyl or Ci-6haloalkyl.

[0401] Paragraph 9. The compound of any one of paragraphs 1-8, wherein Ri is substituted with one or more substituents selected from Ci-ealkyl, halo, Ci-ealkoxy, 5- or 6-membered heterocyclyl, haloalky], NO2, OH, or Ci-ehaloalkoxy.

[0402] Paragraph 10. The compound of any one of paragraphs 1-9, wherein Ri is substituted with one or more substituents selected from methyl, ethyl, isopropyl, Cl, Br, F, methoxy, ethoxy, isopropoxy, morpholinyl, piperidinyl, piperazinyl, CF3, or CF3O-.4239-114920-02 10 / 09 / 25 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0403] Paragraph 11. The compound of any one of paragraphs 1-10, wherein Ri is

[0404]

[0405] CH3Paragraph 12. The compound of any one of paragraphs 1-11, wherein R2 is H, Ci-ealkyl, C2-ealkenyl, Cs ecycloalkyl, substituted or unsubstituted C6-10aryl, substituted or unsubstituted C6-10aryl-Ci-ealkyl-, substituted or unsubstituted 5- or 6-membered heteroaryl, substituted or unsubstituted 5- or 6-membered heteroaryl-Ci-ealkyl-, substituted or unsubstituted C ecycloalkyl-Ci -ealkyl-, substituted or unsubstituted 5- or 6-membered heterocyclyl, or substituted or unsubstituted 5- or 6-membered heterocyclyl-Ci-ealkyl.

[0406] Paragraph 13. The compound of any one of paragraphs 1-12, wherein R2 is substituted or unsubstituted 5- or 6-membered heteroaryl.

[0407] Paragraph 14. The compound of any one of paragraphs 1-13, wherein R2 is substituted by one or more substituents independently selected from halo, haloalkyl, alkoxy, haloalkyloxy, nitro, cyano, or 4- to 6-membered cycloalkyl.

[0408] Paragraph 15. The compound of any one of paragraphs 1-14, wherein R2 is optionally substituted imidazolyl or optionally substituted oxadiazolyl.

[0409] Paragraph 16. The compound of any one of paragraphs 1-15, wherein R2 is 5- X'\

[0410] membered heteroaryl having a formula

[0411]

[0412] ' A- Z wherein

[0413] X and Z are independently CRa, or N, and Y is O, S, or NRa;

[0414] each Raindependently is H or Rs; and

[0415] each Rg independently is Ci-6alkyl, C4-6cycloalkyl, phenyl, or 5- or 6-membered heteroaryl.

[0416] Paragraph 17. The compound of paragraph 16, wherein Rg is cyclobutyl, cyclopentyl, methyl, ethyl, n-propyl, isopropyl, isobutyl, or sec -butyl.

[0417] Paragraph 18. The compound of any one of paragraphs 16-17, wherein R2 has a

[0418] formula

[0419]

[0420] Paragraph 19. The compound of paragraph 18, wherein R2 is

[0421]

[0422] 4239-114920-02 10 / 09 / 25

[0423]

[0424] FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0425] Paragraph 20. The compound of any one of paragraphs 1-19, wherein Re is H. Paragraph 21. The compound of any one of paragraphs 1-20, wherein R3 is H, methyl, or CF3.

[0426] Paragraph 22. The compound of any one of paragraphs 1-21, wherein R4 and Rs independently are selected from H, hydroxy, Ci-ealkoxy, halo, Ci-ealkyl, Ci-ehaloalkyl or cyano;

[0427] Paragraph 23. The compound of any one of paragraphs 1-22, wherein R4 is H. Paragraph 24. The compound of any one of paragraphs 1-23, wherein Rs is H, halo, Ci-ealkyl.

[0428] Paragraph 25. The compound of paragraph 24, wherein Rs is H, Cl, F, methyl, ethyl, or isopropyl.

[0429] Paragraph 26. The compound of paragraph 25, wherein Rs is H.

[0430] Paragraph 27. The compound of paragraph 16 or paragraph 17, wherein the compound has a Formula IA or IIA

[0431] IA

[0432]

[0433] R8

[0434] IIA.

[0435] Paragraph 28. The compound of paragraph 27, wherein Rs is cyclobutyl.

[0436] Paragraph 29. The compound of paragraph 1, wherein the compound has a Formula IB or Formula IIB4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0437]

[0438] IIB.

[0439] Paragraph 30. The compound of any one of paragraphs 1-11, wherein the compound has a formula selected from:

[0440]

[0441] 4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0442] or a pharmaceutically acceptable salt thereof, wherein:

[0443] each Rio independently is Ci-ealkyl, halo, Ci-ealkoxy, 5- or 6-membered heterocyclyl, haloalkyl, NO2, OH, or Ci -ehaloalkoxy;

[0444] n is 0, 1, 2, 3, 4, or 5;

[0445] X and Z are independently CRa, or N, and Y is O, S, or NRa;

[0446] each Raindependently is H or Rs; and

[0447] each Rs independently is Ci-ealkyl, C4-6cycloalkyl, phenyl, or 5- or 6-membered heteroaryl.

[0448] Paragraph 31. The compound of paragraph 30, wherein each Rio independently is methyl, ethyl, isopropyl, Br, Cl, F, methoxy, ethoxy, isopropoxy, morpholinyl, piperidinyl, piperazinyl, CF3, OH, CF3O-.

[0449] Paragraph 32. The compound of paragraph 31, wherein each Rio independently is methyl, CF3, or Cl.

[0450] Paragraph 33. The compound of any one of paragraphs 30-32, wherein n is 1, 2 or 3. Paragraph 34. The compound of paragraph 33, wherein n is 1.

[0451] Paragraph 35. The compound of paragraph 33, wherein n is 2.

[0452] Paragraph 36. The compound of paragraph 35, wherein each Rio is methyl.

[0453] Paragraph 37. The compound of paragraph 35 or paragraph 26, wherein Rio is located at the 2- and 3-positions on the phenyl.

[0454] Paragraph 38. The compound of paragraph 1, wherein the compound is

[0455] Paragraph 39. The compound of paragraph 1, wherein the compound is

[0456]

[0457] Paragraph 40. The compound of paragraph 1, wherein the compound is selected from the compounds shown in Tables 1-11 as disclosed herein.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0458] Paragraph 41. A pharmaceutial composition comprisng a compound according to any one of paragraphs 1 -40 and a pharmaceutially accetpable excipient.

[0459] Paragraph 42. A method, comprising adminsitering an effective amount of a compound according to any one of paragraphs 1-40, or a pharmaceutial composition thereof, to a subject in need thereof.

[0460] Paragraph 43. The method of paragraph 42, wherein the subject has Machupo virus, Influenza A virus, HIV-1, Ebola virus, SARS-CoV-2, or Lassa virus.

[0461] Paragraph 44. A method of treating a disease or disorder where inhibition of autophagy could provide a benefit comprising administering to a subject an effective amount of a compound according to any one of paragraphs 1 -40.

[0462] Paragraph 45. A method of inhibiting autophagy, comprising contacting a cell with an effective amount of a compound according to any one of paragraphs 1 -40.

[0463] Paragraph 46. The method of paragraph 45, wherein the cell is infected with Machupo virus, Influenza A virus, HIV-1, Ebola virus, SARS-CoV-2, or Lassa virus.

[0464] Paragraph 47. A use of a compound in the preparation of a medicament for the treatment of Machupo virus, Influenza A virus, HIV-1, Ebola virus, SARS-CoV-2, or Lassa virus.

[0465] Paragraph 48. A use of a compound in the preparation of a medicament to inhibit autophagy.

[0466] Paragraph 49. A compound according to any one of paragraphs 1-40 for use in a method of administration to a subject in need thereof.

[0467] Paragraph 50. The compound of paragraph 49, wherein the subject has Machupo virus, Influenza A virus, HIV-1, Ebola virus, SARS-CoV-2, or Lassa virus.

[0468] Paragraph 51. A compound according to any one of paragraphs 1-40 for use in a method of inhibiting autophagy.

[0469] VII. Examples

[0470] General Methods

[0471] All chemicals for synthetic methods were purchased from Sigma-Aldrich, Alfa-Aesar, Acros Organics, TCI America, Oakwood Chemicals, Aurum Pharmatech, or Chem Impex and were used without further purification unless otherwise noted. Reaction mixtures were purified on a Biotage Isolera One automated chromatography system with silica gel columns.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0472] Microwave reactions utilized the Biotage Initiator + microwave reactor. Reactions were monitored by TLC (Silica gel 60 F254 Glass Backed plates) and mass spectrometry using LCMS (Agilent 1260 Series automated chromatographic system outfitted with a Thermo Scientific Accucore column (2.1 mm x 50 mm, 2.6 pm particle size)) and an Agilent 6120 quadrupole MS, utilizing a gradient elution mobile phase of 25% ACN / H2O to 95% ACN / H2O over 3 min, then holding at 95% ACN / H2O for 2 min (0.200 mL / min flow rate, 30 °C column compartment, detection modes: wavelengths of 254 and 280 nm). NMR data were collected on a Bruker AV 500 MHz spectrometer outfitted with a Bruker 5 mm 1H19F / BBO S2 Z-gradient probe, and spectra were processed utilizing Mestrenova (Mestrelab Research). Data were recorded at ambient temperature and are reported as chemical shift (ppm) relative to solvent peak (1H NMR: CDCl3= 7.26 ppm, MeOD = 3.31 ppm, D2O = 4.65 ppm; C NMR: CDCl3= 77.16 ppm, MeOD = 49.00 ppm). IR data were collected on a Thermo Scientific Nicolet IS 5 spectrometer outfitted with a Thermo Fisher Scientific iD5 ATR. HRMS data were collected using Waters Q-TOF Ultima ESI.

[0473] Example 1

[0474] Experimental Protocols

[0475] Compounds and Reagents: For biochemical assays, compounds that were purchased include PIK-III and SAR405 (Selleck Chemical), chloroquine diphosphate (Sigma Aldrich), and Compound 19 (ChemDiv). All antibodies were purchased from Cell Signaling technologies. The nanoBRET Nano-Gio Detection System was utilized in the nanoBRET assay. Data analysis and statistics were performed in GraphPad Prism (10.1.2).

[0476] Cell Culture: Hek293T cells were a gift Stephanie Cologna at the University of Illinois at Chicago, Chicago, IL. HeLa cells stably expressing eGFP-LC3 were a gift from Ramnik Xavier at Massachusetts General Hospital, Boston, MA. HeLa and A549 cells were purchased from Sigma Aldrich. All cells were cultured in DMEM (Coming) with 8.8% FBS (Gemini Bio), 3.6 mM L-glutamine (Corning), and lx penicillin / streptomycin (Coming). Cultured cells were maintained in a humidified incubator at 37 °C with 5% CO2. NanoBRET assays were performed using Opti-MEM (Thermo) with 4% FBS.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0477] NanoBRET Assays: Hek293T cells were plated in a 10 cm dish at a density of 8.0 x 106cells and incubated for 4 hour at RT before being transfected with a 1: 1 ratio of NanoLuc donor and HaloTag vectors (12 L total) and a 30 uL of Lipofectamine 2000 (1:2.5 ratio). For the ATG14L-Beclin 1 nanoBRET assay, a C-terminal ATG14L NanoLuc and a C-terminal Beclin 1 HaloTag vectors were used. For the UVRAG nanoBRET, N-terminal UVRAG NanoLuc and N-terminal Beclin 1 HaloTag vectors were used. Cells were incubated for 20 hour before being replated into 384- well white plates (Corning) at a density of 1.1 x 104cells / well. HaloTag ligand was added to each well except the negative control wells, and the plate was incubated for 1 hour at room temperature. Compounds were added into the plate using a 96-well pin tool (V& P Scientific) attached to a BioMek NXP Liquid Handler (Beckman Coulter). For single point experiments, cells were treated at 100 pM. For dose response curves, cells were treated in 7- or 8-point dose (200 pM to 3.13 or 1.56 pM, respectively) Cells were incubated for 24 hours in an incubator before all wells were treatment with NanoLuc substrate. The plate was incubated for 5 minutes before being analyzed with a Victor V3 plate reader (PerkinElmer) using F460 and a 632 / 645 nm filter for 1 second.

[0478] eGFP-LC3 Assay: HeLa cells stably expressing eGFP-LC3 were plated at a density of 1.25 x 103cells / well in a 384 well black plate (Coming) and incubated at RT for 1 hour before a 24 hour incubation in an incubator. Cells were treated with hits six -point dose of compounds (100 pM to 3.125 pM) or DMSO as a control. Following a 20 hour growth in an incubator, CQ (20 pM) was cotreated in each compound well and allowed to incubate for 4 h. Cells were fixed with 4% paraformaldehyde (Electron Microscopy Sciences) for 15 min RT, and nuclei were stained with Hoechst 33342 (Thermo Fisher) form 20 min at RT. lx PBS was added to each well before the plate was sealed and imaged using an ImageXpress XLS automated fluorescent microscope (Molecular Devices). Images were analyzed to quantify cell and GFP-puncta amounts using MetaXpress software.

[0479] Cellular Thermal Shift Assay: A549 cells were plated in a 10 cm dish as a density of 2.5 x 106cells and grown for 24 h. Cells were treated with compound (100 pM) or DMSO and incubated for an additional 24 h. Trypsinized cells were pelleted and washed with lx PBS before being resuspended in lx PBS supplemented with a Pierce Protease and Phosphatase4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0480] Inhibitor tablet (Thermo Fisher) at a density of 1.0 x 107cells / mL. 50 pL aliquots were dispensed into PCR tubes (BioRad) and heated to temperatures of 48 - 56 °C (increasing 2-degree increments) for 3 min using a BioRad T100 thermal cycler. A sample of 25 °C was also taken as a negative control. Cells were lysed by freeze-thaw before cells were transferred to Eppendorf tubes. Cellular debris was removed by centrifugation at 18,000 g for 30 min at 4 °C. Supernatant was transferred to separate Eppendorf tubes and then underwent western blotting to determine protein concentrations at each temperature. In brief, 12 µL of each sample were loaded onto a 10% acrylamide gel before exposure to 120 V for 1 h. Proteins were transferred from the gel to PVDF transfer paper at 25 V for 1 h. Blots were then washed with 5% Blocking Buffer (nonfat dried milk in TBS buffer spiked with 0.1% Tween 20) and incubated for 1 hour on an orbital shaker set to 140 RPMs. Blots were cut and incubated with primary antibodies in 5% Blocking buffer overnight at 4 °C A 1:1000 dilution was used for ATG14L antibody, and a 1:2000 dilution was used for β-Actin. Blots were washed in triplicate with TBS-T and incubated with secondary antibody for 1 hour at RT. A 1:5000 dilution of Anti-Rabbit IgG, HRP-linked secondary antibody was used. Membranes were washed with TBS-T in triplicate and incubated with SuperSignal West Pico PLUS Chemiluminescent Substrate (Thermo Fisher) for 3 min at room temperature. Blots were visualized using the c Series Capture Software on the Azure Imaging System. Images were quantified using ImageJ.

[0481] DQ-BSA Assay: A549 cells were plated at a density of 2.5 x 103cells / well in a 384-well black plate (Perkin Elmer). The plate was incubated for 1 hour at RT before being placed in an incubator for 24 h. A 50 pg / mL solution of DQ-BSA Red (Thermo Fisher) was prepared and 10 pL was added to each well. Plates were incubated for 1 hour before media was removed by aspiration. Cells were washed in triplicate with lx PBS and fresh DMEM media was added. Cells were then treated with compounds in 4-point dose (100 pM to 12.5 pM) before a 4 hour incubation. After this time, nuclei were stained with Hoechst 33342 and incubated for an additional 30 minutes. The plate was sealed and imaged using the ImageXpress XLS automated fluorescent microscope (Molecular Devices). Images were analyzed to quantify cell and DQ-BSA puncta counts using MetaXpress software.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0482] Phase Contrast Evaluation: A549 cells were plated at a density of 2.5 x 103cells / well in a 384-well black plate and grown for 24 h. Cells were treated in 4-point dose (100 pM to 12.5 pM) for 4 h before nuclear staining using Hoechst 33342. Plates were imaged using ImageXpress XLS phase-contrast addition.

[0483] Kinetic Aqueous Solubility Assay: Compounds were diluted with lx PBS (Ph 7.4) to concentrations between 100 pM to 3.13 pM (6-point dose) in a 96-well clear assay plate (Corning). Diclofenac was used as a soluble control, while dipyridamole was used as an insoluble control. Optical density readings at 620 nm were taken on a SpectraMax i3x (Molecular Devices) using the Softmax Pro 6.5.1 software.

[0484] Cell Viability Calculations: Following the procedure of the eGFP-LC3 assay, the nuclear count was measured in the acquired images. These counts in compound treated wells were divided by the average of the DMSO control wells and multiplied by 100% to generate percent viability. These calculations were performed to provide the average across three independent experiments in duplicate.

[0485] Example 2

[0486] Synthetic Protocols

[0487]

[0488] 2H-benzo[b][1,4]oxazin-3(4H)-one (6): To a flame dried flask was added 2-aminophenol (1.00 g, 9.16 mmol, 1.0 eq) and potassium carbonate (2.53 g, 18.33 mmol, 2.0 eq) in anhydrous MeCN (15 ml, 0.61 M). The resulting mixture was allowed to stir at room temperature for 10 min before the slowly addition of chloroacetyl chloride (730 pL, 9.16 mmol, 1.0 eq). The mixture was then heated to reflux (75 °C) for 3 hours until completion. After cooling down to room temperature, the resulting mixture was quenched with water and extracted with EtOAc in triplicate. The organic phase was concentrated in vacuo and used without further purification as an orange powder.1H NMR (500 MHz, MeOD) δ 6.92 (s, 3H), 6.88 (d, J = 4.4 Hz, 1H), 4.53 (s, 2H).13C NMR (125 MHz, MeOD) δ 166.3, 143.8, 126.7, 123.5, 122.3, 116.1, 115.7, 66.8.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0489]

[0490] 4-methyl-2H-benzo[Z>][l,4]oxazin-3(4H)-one (7a) To a flame dried flask was added 2H-benzo[b][1,4]oxazin-3(4H)-one (200.0 mg, 1.34 mmol, 1.0 eq.) in anhydrous DMF (5.36 ml, 0.25 M). The mixture was cooled down to 0 °C and sodium hydride (107.3 mg, 2.68 mmol, 2.0 eq., 60% dispersion in mineral oil) was slowly added into the reaction vessel. Then iodomethane (0.1 ml, 1.61 mmol, 1.2 eq.) was added into the reaction mixture at 0 °C. The resulting solution was warmed to room temperature and stirred overnight until completion. The organic layer was concentrated in vacuo and purified via column chromatography (0 to 20% EtOAc in Hex) to yield the desired product (173.4 mg, 79%). ’H NMR (500 MHz, CDCh) 57.03 - 6.81 (m, 4H), 4.51 (s, 2H), 3.27 (s, 3H).13C NMR (125 MHz, CDCh) 5 164.4, 145.0, 129.5, 123.8, 122.7, 116.7, 114.7, 67.5, 27.9.

[0491] Me

[0492] or

[0493] 4-propyl-2H-benzo|7>][l,4]oxazin-3(4H)-one (7b) To a flame dried flask was added 2H-benzo[b][1,4]oxazin-3(4H)-one (200.0 mg, 1.34 mmol, 1.0 eq.) in anhydrous DMF (5.36 ml, 0.25 M). The mixture was cooled down to 0 °C and sodium hydride (107.3 mg, 2.68 mmol, 2.0 eq., 60% dispersion in mineral oil) was slowly added into the reaction vessel. Then 1-bromopropane (0.15 ml, 1.61 mmol, 1.2 eq.) was added into the reaction mixture at 0 °C. The resulting solution was warmed to room temperature and stirred overnight until completion. The organic layer was concentrated in vacuo and purified via column chromatography (0 to 20% EtOAc in Hex) to yield the desired product (225.6 mg, 88%). *H NMR (500 MHz, CDCh) 56.97 (d, J= 11.5 Hz, 4H), 4.55 (s, 2H), 3.86 (t, J= 7.5 Hz, 2H), 1.67 (q, J= 7.4 Hz, 2H), 0.95 (t, J= 7.3 Hz, 3H).13C NMR (125 MHz, CDCh) 5 164.2, 145.4, 128.5, 123.7, 122.7, 117.1, 114.9, 67.6, 42.6, 20.4, 11.2.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0494]

[0495] 4-allyl-2H-benzo[Z>][l,4]oxazin-3(4H)-one (7c) To a flame dried flask was added 2H-benzo[b][1,4]oxazin-3(4H)-one (200.0 mg, 1.34 mmol, 1.0 eq.) in anhydrous DMF (5.0 ml, 0.25 M). The mixture was cooled down to 0 °C and sodium hydride (107.3 mg, 2.68 mmol, 2.0 eq., 60% dispersion in mineral oil) was slowly added into the reaction vessel. Then allyl iodide (0.15 ml, 1.61 mmol, 1.2 eq.) was added into the reaction mixture at 0 °C. The resulting solution was warmed to room temperature and stirred overnight until completion. The organic layer was concentrated in vacuo and purified via column chromatography (l:4 / EtOAc: Hex) to yield the desired product (222.1 mg, 87%). ’H NMR (500 MHz, CDCh) 56.98 (s, 4H), 5.87 (ddt, J= 15.5, 10.1, 5.0 Hz, 1H), 5.27 - 5.16 (m,13C NMR (125 MHz, CDCh) 5 164.2, 145.2, 131.6, 128.8, 123.9, 122.7, 117.3, 117.0, 115.5, 67.6, 43.7.

[0496]

[0497] 4-(cyclohexylmethyl)-2H-benzo[Z>][l,4]oxazin-3(4H)-one (7d) To a flame dried flask was added 2H-benzo[b][1,4]oxazin-3(4H)-one (200.0 mg, 1.34 mmol, 1.0 eq.) in anhydrous DMF (5.0 ml, 0.25 M). The mixture was cooled down to 0 °C and sodium hydride (107.3 mg, 2.68 mmol, 2.0 eq., 60% dispersion in mineral oil) was slowly added into the reaction vessel. Then (bromomethyl)cyclohexane (0.17 ml, 1.61 mmol, 1.2 eq.) was added into the reaction mixture at 0 °C. The resulting solution was warmed to room temperature and stirred overnight until completion. The organic layer was concentrated in vacuo and purified via column chromatography (0 to 20% EtOAc in Hex) to yield the desired product (296.7 mg, 90%). 'H NMR (500 MHz, CDCh) 56.99 (dd, J = 12.5, 3.4 Hz, 4H), 4.58 (s, 2H), 3.81 (d, J = 7.2 Hz, 2H), 1.78 - 1.57 (m, 6H), 1.19 - 0.99 (m, 5H).13C NMR (125 MHz, CDCh) 8 164.5, 145.5, 128.8, 123.7, 122.6, 117.2, 115.3, 67.6, 46.5, 35.7, 30.7, 26.3, 25.8.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0498] ^Me

[0499] a

[0500]

[0501] 4-ethyly-2H-benzo[Z>][l,4]oxazin-3(4H)-one (7e) To a flame dried flask was added 2H-benzo[b][1,4]oxazin-3(4H)-one (100.0 mg, 0.67 mmol, 1.0 eq.) in anhydrous DMF (1.34 ml, 0.25 M). The mixture was cooled down to 0 °C and sodium hydride (53.6 mg, 1.34 mmol, 2.0 eq., 60% dispersion in mineral oil) was slowly added into the reaction vessel. Then lodoethane (65.0 pl, 0.804 mmol, 1.2 eq.) was added into the reaction mixture at 0 °C. The resulting solution was warmed to room temperature and stirred overnight until completion. The organic layer was concentrated in vacuo and purified via column chromatography (0 to 10% EtOAc in Hex) to yield the desired product (99.3 mg, 84%).1H NMR (500 MHz, CDCb) 57.07 - 6.88 (m, 4H), 4.55 (s, 2H), 3.96 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H).

[0502] 13C NMR (125 MHz, CDCh) 5 164.0, 145.4, 128.3, 123.7, 122.8, 117.1, 114.7, 67.6, 36.2, 12.5.

[0503]

[0504] 4-butyl-2 / / -benzo[ / >][l,4]oxazin-3(4 / / )-one (7f) To a flame dried flask was added 2H-benzo[b][1,4]oxazin-3(4H)-one (100.0 mg, 0.67 mmol, 1.0 eq.) in anhydrous DMF (1.34 ml, 0.25 M). The mixture was cooled down to 0 °C and sodium hydride (53.6 mg, 1.34 mmol, 2.0 eq., 60% dispersion in mineral oil) was slowly added into the reaction vessel. 1-Iodobutane (91.7 pl, 0.804 mmol, 1.2 eq.) was then added into the reaction mixture at 0 °C. The resulting solution was warmed to room temperature and stirred overnight until completion. The organic layer was concentrated in vacuo and purified via column chromatography (0 to 10% EtOAc in Hex) to yield the desired product (105.1 mg, 76%).XH NMR (500 MHz, CDCI3) 5 7.04 - 6.92 (m, 4H), 4.55 (s, 2H), 3.94 - 3.86 (m, 2H), 1.68 - 1.56 (m, 2H), 1.43 - 1.33 (m, 2H), 0.95 (t, J= 7.3 Hz, 3H).13C NMR (125 MHz, CDCh) 5 164.2, 145.4, 128.5, 123.7, 122.7, 117.1, 114.9, 67.6, 40.9, 29.1, 20.1, 13.8.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0505] Me

[0506]

[0507] 4-methyl-3-oxo-3,4-dihydro-2 / / -benzo[Z>][l,4]oxazine-6-sulfonyl chloride (8a) To a flame dried flask was added 4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (81.6 mg, 0.50 mmol, 1.0 eq.) and the reaction vessel was kept at 0 °C ice bath. Chlorosulfuric acid (2.0 ml, 0.25 M) was then added into the reaction flask dropwise. The resulting mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was poured into the iced water once it went to complete via thin layer chromatography (0 to 20% EtOAc in Hex) and extracted with EtOAc (3x). The organic layer was combined and concentrated in vacuo to yield the desired product. ‘H NMR (500 MHz, CDCh) 57.71 (dd, J = 8.5, 2.1 Hz, 1H), 7.57 (d, J= 2.2 Hz, 1H), 7.15 (d, J= 8.5 Hz, 1H), 4.76 (s, 2H), 3.43 (s, 3H).13C NMR (125 MHz, CDCh) 5 162.9, 150.3, 138.2, 130.2, 123.7, 117.7, 113.6, 67.3, 28.3.

[0508] Me

[0509]

[0510] 3-oxo-4-propyl-3,4-dihydro-2H-benzo[Z>][l,4]oxazine-6-sulfonyl chloride (8b) To a flame dried flask was added 4-propyl-2 / -benzo[£>][l,4]oxazin-3(4H)-one (95.6 mg, 0.50 mmol, 1.0 eq.) and the reaction vessel was kept at 0 °C ice bath. Chlorosulfuric acid (2.0 ml, 0.25 M) was then added into the reaction flask dropwise. The resulting mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was poured into the iced water once it went to complete via thin layer chromatography (0 to 20% EtOAc in Hex) and extracted with EtOAc (3x). The organic layer was combined and concentrated in vacuo to yield the desired product. IR (neat) Umax = 1682, 1505, 1434, 1358, 1178, 1033, 995, 776 cm' ‘HNMR (500 MHz, CDCh) 57.69 (d, J= 8.3 Hz, 1H), 7.56 (s, 1H), 7.15 (d, J= 8.6 Hz, 1H), 4.74 (s, 2H), 3.95 (t, J = 7.5 Hz, 2H), 1.71 (q, J = 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H).

[0511] 13C NMR (125 MHz, CDCI3) 5 162.7, 150.6, 138.3, 129.2, 123.4, 118.0, 113.7, 67.3, 42.9, 20.1, 11.2.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0512]

[0513] 4-allyl-3-oxo-3,4-dihydro-2H-benzo[Z>][l,4]oxazine-6-sulfonyl chloride (8c) To a flame dried flask was added 4-allyl-2H-benzo[b][1,4]oxazin-3(4H)-one (94.6 mg, 0.50 mmol, 1.0 eq.) and the reaction vessel was kept at 0 °C ice bath. Chlorosulfuric acid (2.0 ml, 0.25 M) was then added into the reaction flask dropwise. The resulting mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was poured into the iced water once it went to complete via thin layer chromatography (0 to 20% EtOAc in Hex) and extracted with EtOAc (3x). The organic layer was combined and concentrated in vacuo to yield the desired product.1H NMR (500 MHz, CDCI3) 57.69 (dd, J = 8.6, 2.1 Hz, 1H), 7.59 (d, J= 2.2 Hz, 1H), 7.16 (d, J= 8.5 Hz, 1H), 5.85 (ddt, J= 15.9, 10.2, 5.1 Hz, 1H), 5.31 (dd, 7= 22.4, 13.8 Hz, 2H), 4.79 (s, 2H), 4.63 (d, 7= 5.2 Hz, 2H).13C NMR (125 MHz, CDCI3) 5 162.7, 150.4, 138.2, 130.2, 129.2, 123.6, 118.7, 117.9, 114.5, 67.3, 43.8.

[0514]

[0515] 4-(cyclohexylmethyl)-3-oxo-3,4-dihydro-2H-benzo[Z>][l,4]oxazine-6-sulfonyl chloride (8d) To a flame dried flask was added 4-(cyclohexylmethyl)-277-benzo[£>][ 1,4]oxazin-3(477)-one (122.7 mg, 0.50 mmol, 1.0 eq.) and the reaction vessel was kept at 0 °C ice bath.

[0516] Chlorosulfuric acid (2.0 ml, 0.25 M) was then added into the reaction flask dropwise. The resulting mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was poured into the iced water once it went to complete via thin layer chromatography (0 to 20% EtOAc in Hex) and extracted with EtOAc (3x). The organic layer was combined and concentrated in vacuo to yield the desired product. IR (neat) Umax = 2926, 1670, 1448, 1435, 1335, 1277, 1166, 668 cm1.1H NMR (500 MHz, CDCl3) δ 7.68 (d, 7 = 8.7 Hz, 1H), 7.58 (s, 1H), 7.15 (d, 7 = 8.6 Hz, 1H), 4.74 (s, 2H), 3.86 (d, 7 = 7.2 Hz, 2H), 1.78 - 1.61 (m, 6H), 1.17 (d, 7= 8.1 Hz, 3H), 1.07 (q, 7= 11.9 Hz, 2H).13C NMR (1254239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0517] MHz, CDCI3) 5 163.0, 150.6, 138.2, 129.5, 123.3, 118.0, 114.2, 67.3, 47.0, 35.6, 30.7, 26.1, 25.6.

[0518]

[0519] 4-ethyl-3-oxo-3,4-dihydro-2H-benzo[£>][l,4]oxazine-6-sulfonyl chloride (8e) To a flame dried flask was added 4-ethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (79.7 mg, 0.45 mmol, 1.0 eq.) and the reaction vessel was kept at 0 °C ice bath. Chlorosulfuric acid (89.9 pl, 1.35 mmol, 3.0 eq.) in anhydrous CH2C12(4.5 ml, 0.1 M) was then added into the reaction flask dropwise. The resulting mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was poured into the iced water once it went to complete via thin layer chromatography (0 to 20% EtOAc in Hex) and extracted with EtOAc (3x). The organic layer was combined and concentrated in vacuo to yield the desired product. IR (neat) Umax = 2923, 1685, 1507, 1435, 1380, 1280, 1174, 1040, 834 cm1.1H NMR (500 MHz, CDC13) 5 7.70 (dd, 7= 8.6, 2.2 Hz, 1H), 7.59 (d, 7 = 2.2 Hz, 1H), 7.15 (d, 7= 8.6 Hz, 1H), 4.74 (s, 2H), 4.05 (q, 7 = 7.2 Hz, 2H), 1.32 (t, 7 = 7.2 Hz, 3H).13C NMR (125 MHz, CDCI3) 5 162.4, 150.6, 138.3, 129.0, 123.5, 118.2, 113.4, 67.3, 36.6, 12.2.

[0520]

[0521] 4-butyl-3-oxo-3,4-dihydro-2 / 7-benzo[£>][l,4]oxazine-6-suIfonyl chloride (8f) To a flame dried flask was added 4-butyl-2H-benzo[b][1,4]oxazin-3(4H)-one (82.1 mg, 0.40 mmol, 1.0 eq.) and the reaction vessel was kept at 0 °C ice bath. Chlorosulfuric acid (79.9 pl, 1.20 mmol, 3.0 eq.) in anhydrous CH2CI2 (4.0 ml, 0.1 M) was then added into the reaction flask dropwise. The resulting mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was poured into the iced water once it went to complete via thin layer chromatography (0 to 20% EtOAc in Hex) and extracted with EtOAc (3x). The organic layer was combined and concentrated in vacuo to yield the desired product. IR (neat) Umax =4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0522] 1690, 1504, 1435, 1376, 1174, 1039 cm1. 'H NMR (500 MHz, CDCI3) 87.70 (dd, 7= 8.5, 2.2 Hz, 1H), 7.58 (d, J= 2.2 Hz, 1H), 7.15 (d, J= 8.6 Hz, 1H), 4.74 (s, 2H), 3.99 (t, J= 7.6 Hz, 2H), 1.65 (q, J = 8.0 Hz, 2H), 1.43 (p, J = 7.5 Hz, 2H), 0.98 (t, J = 7.3 Hz, 3H).13C NMR (125 MHz, CDCI3) 8 162.7, 150.6, 138.3, 129.1, 123.4, 118.0, 113.7, 67.3, 41.2, 28.8, 20.0, 13.7.

[0523] O

[0524]

[0525] N-benzyl-2-chloroacetamide (9a) To a flame dried flask was added benzylamine (0.26 ml, 2.4 mmol, 1.2 eq.) in anhydrous CH2CI2 (4.8 ml, 0.5 M). The mixture was cooled down to 0 °C and triethylamine (0.34 ml, 2.40 mmol, 1.2 eq.) was slowly added into the flask. After stirring at 0 °C for 10 min, chloroacetyl chloride (0.16 ml, 2.00 mmol, 1.0 eq.) was slowly added to the reaction vessel. The resulting mixture was allowed to warm to room temperature and stirred overnight. The completed reaction mixture was quenched with water and extracted with CH2CI2 (3x). The organic layer was combined, concentrated, and purified via column chromatography (l:l / EtOAc: Hex) to yield the desired product (304.8 mg, 83%). IR (neat) umax= 3276, 1711, 1363, 1221, 910, 728 cm ’ / H NMR (500 MHz, CDCI357.39 -7.33 (m, 2H), 7.33 - 7.27 (m, 3H), 6.85 (s, 1H), 4.50 (d, J = 5.8 Hz, 2H), 4.11 (s, 2H).13C NMR (125 MHz, CDCI3) 8 165.9, 137.3, 128.9, 127.8, 127.8, 43.9, 42.6.

[0526] O

[0527]

[0528] 2-chloro-N-(pyridin-3-ylmethyl)acetamide (9b) To a flame dried flask was added 3-(aminomethyl)pyridine (0.12 ml, 1.20 mmol, 1.2 eq.) in anhydrous CH2CI2 (2.4 ml, 0.5 M). The mixture was cooled down to 0 °C and triethylamine (0.17 ml, 1.20 mmol, 1.2 eq.) was slowly added into the flask. After stirring at 0 °C for 10 min, chloroacetyl chloride (0.08 ml, 1.00 mmol, 1.0 eq.) was slowly added to the reaction vessel. The resulting mixture was allowed to warm to room temperature and stirred overnight. The completed reaction mixture was quenched with water and extracted with CH2Q2 (3x). The organic layer was combined, concentrated, and purified via column chromatography (l:l / EtOAc: Hex) to yield the desired4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0529] product (124.7 mg, 68%). IR (neat) umax= 3195, 1683, 1329, 1354, 1254, 1024, 771 cm-1.1H NMR (500 MHz, CDC13) 6 8.50 (s, 1H), 7.88 (s, 1H), 7.75 - 7.50 (m, 1H), 7.36 - 7.01 (m, 2H), 4.54 (s, 2H), 4.06 (s, 2H).13C NMR (125 MHz, CDCh) 5 166.2, 155.6, 149.1, 136.9, 122.6, 122.0, 44.6, 42.6.

[0530]

[0531] 2-chloro-N-(3-methylbenzyl)acetamide (9c) To a flame dried flask was added phenethylamine (0.15 ml, 1.20 mmol, 1.2 eq.) in anhydrous CH2CI2 (2.4 ml, 0.5 M). The mixture was cooled down to 0 °C and triethylamine (0.17 ml, 1.20 mmol, 1.2 eq.) was slowly added into the flask. After stirring at 0 °C for 10 min, chloroacetyl chloride (0.08 ml, 1.00 mmol, 1.0 eq.) was slowly added to the reaction vessel. The resulting mixture was allowed to warm to room temperature and stirred overnight. The completed reaction mixture was quenched with water and extracted with CH2CI2 (3x). The organic layer was combined, concentrated, and purified via column chromatography (l:l / EtOAc: Hex) to yield the desired product (187.8 mg, 95%). IR (neat) umax= 3337, 1645, 1539, 1260, 752, 697 cm’1. 'H NMR (500 MHz, CDCh) 57.31 (t, 7 = 7.5 Hz, 2H), 7.22 (dd, J = 22.9, 7.4 Hz, 3H), 6.71 (s, 1H), 3.98 (s, 2H), 3.55 (q, J = 6.7 Hz, 2H), 2.84 (t, J = 7.2 Hz, 2H).13C NMR (125 MHz, CDCh) 5 165.9, 138.4, 128.8, 128.7, 126.7, 42.7, 41.0, 35.5.

[0532] 0

[0533]

[0534] 2-chloro-N-(furan-2-ylmethyl)acetamide (9d) To a flame dried flask was added furfurylamine (0.11 ml, 1.20 mmol, 1.2 eq.) in anhydrous CH2CI2 (2.4 ml, 0.5 M). The mixture was cooled down to 0 °C and triethylamine (0.17 ml, 1.20 mmol, 1.2 eq.) was slowly added into the flask. After stirring at 0 °C for 10 min, chloroacetyl chloride (0.08 ml, 1.00 mmol, 1.0 eq.) was slowly added to the reaction vessel. The resulting mixture was allowed to warm to room temperature and stirred overnight. The completed reaction mixture was quenched with water and extracted with CH2CI2 (3x). The organic layer was combined, concentrated, and purified via column chromatography (l:l / EtOAc: Hex) to yield the desired product (125.0 mg, 72%). IR (neat) umax= 3252, 1644, 1563, 1417, 1326, 1207, 1016, 7294239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0535] cm1.XH NMR (500 MHz, CDCh) 87.35 (d, J= 2.3 Hz, 1H), 6.96 (s, 1H), 6.34 - 6.28 (m, 1H), 6.24 (d, J= 3.2 Hz, 1H), 4.46 (d, J= 5.6 Hz, 2H), 4.04 (s, 2H).13C NMR (125 MHz, CDCh) 5 165.8, 150.4, 142.5, 110.5, 107.9, 42.5, 36.7.

[0536] aBr

[0537] OMe

[0538] 1-bromo-2-methoxybenzene (10): To a flame dried flask was added 2-bromophenol (346 mg, 2 mmol, 1.0 eq) in anhydrous DMF (0.67 M). The mixture was cooled down to 0 °C and potassium carbonate (1.38 g, 10 mmol, 5.0 eq) was added into the reaction vessel. Then the iodomethane (0.31 ml, 5 mmol, 2.5 eq) was added into the reaction mixture at 0 °C. The resulting solution was warmed to room temperature and stirred overnight until completion. The organic layer was concentrated in vacuo and purified via column chromatography (0 to 20% EtOAc in Hex) to yield the desired product (345.0 mg, 92%). IR (neat) Umax = 1586, 1479, 1272, 1248, 1022, 743, 659 cm’1. ‘HNMR (500 MHz, CDCh) 87.54 (d, 7= 7.7 Hz, 1H), 7.28 (t, 7= 7.8 Hz, 1H), 6.91 (d, 7 = 8.2 Hz, 1H), 6.84 (t, 7 = 7.6 Hz, 1H), 3.90 (s, 3H).

[0539] 13C NMR (125 MHz, CDCh) 8 155.9, 133.4, 128.5, 121.8, 112.0, 111.7, 56.2. HRMS (ESI) C7H7OBr. Calculated: [M+2H]+, 186.9759 Found: [M+2H]+, 186.9750.

[0540]

[0541] 3-bromo-4-methoxybenzenesulfonyl chloride (SI): To a flame dried flask was added 1-bromo-2-methoxybenzene (188 mg, 1.01 mmol, 1.0 eq) and the reaction vessel was kept at 0 °C ice bath. Chlorosulfuric acid (202 pL, 3.04 mmol, 3.0 eq) in CH2CI2 (10.1 mL, 0.25 M) was then added into the reaction flask dropwise. The resulting mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was poured into the iced water once it went to complete via thin layer chromatography (20 % EtOAc in Hex) check and extracted with EtOAc in triplicate. The organic layer was combined and concentrated in vacuo to yield the desired product. The crude was carried for the next step without purification. 'H NMR (500 MHz, CDC13) 88.13 (d, J = 2.38 Hz, 1H), 7.93 (dd, J = 8.86, 2.44 Hz, 1H), 7.05 (d, J = 8.84 Hz, 1H), 4.00 (s, 3H).13C NMR (125 MHz, CDCh) 8 161.3, 136.5, 132.24, 132.0, 128.5, 112.6, 111.8, 57.1.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0542]

[0543] 3-bromo-N-(2,3-dimethylphenyl)-4-methoxybenzenesulfonamide (11): To a flame dried flask was added 2,3-dimethylaniline (129 LIL, 1.05 mmol, 1.0 eq) in anhydrous CH2CI2 (10.5 mL, 0.1 M). The mixture was cooled down to 0 °C and pyridine (169 pL, 2.10 mmol, 2.0 eq) was slowly added into the flask. After stirring at 0 °C for 10 min, 3-bromo-4-methoxybenzenesulfonyl chloride (300 mg, 1.05 mmol, 1.05 eq) was added as a solution in anhydrous CH2CI2 (4.6 ml, 0.5 M). The resulting mixture was allowed to warm to room temperature and stirred overnight. The completed reaction mixture was quenched with water and extracted with CH₂Cl₂ in triplicate. The organic layer was combined, concentrated, and purified via column chromatography (0 to 50% EtOAc in Hex) to yield the desired product (296.5 mg, 76%). 'H NMR (500 MHz, CDCh) 57.89 (d, 7= 2.3 Hz, 1H), 7.63 (dd, 7= 8.7, 2.3 Hz, 1H), 7.04 - 6.96 (m, 3H), 6.86 (d, 7= 8.7 Hz, 1H), 6.74 (s, 1H), 3.92 (s, 3H), 2.21 (s, 3H), 2.00 (s, 3H).13C NMR (125 MHz, CDCh) 5 159.3, 138.1, 133.9, 132.6, 132.4, 132.1, 128.6, 128.4, 126.0, 123.6, 112.0, 111.3, 56.6, 21.1, 13.9. HRMS (ESI) C15H16BrNO3S. Calculated: [M+H]+, 370.0113 Found: [M+H]+, 370.0106.

[0544]

[0545] 3-bromo-N-(2,3-dimethylphenyl)-4-hydroxybenzenesulfonamide (12): To a flame dried flask was added 3-bromo-N-(2,3-dimethylphenyl)-4-methoxybenzenesulfonamide (430 mg, 1.16 mmol, 1.0 eq) in anhydrous CH2CI2 (11.6 ml, 0.1 M). The mixture was cooled down to -78 °C and boron tribromide (5.8 ml, 5.81 mmol, 5.0 eq) was slowly added into the reaction mixture. The dry ice bath was then removed, and the resulting mixture was stirred at room temperature overnight. The reaction process was checked via thin-layer chromatography. The reaction mixture was quenched with water, extracted with CH2CI2 in triplicate. The organic layer was combined and concentrated in vacuo to yield the desired product. The crude was carried for the next step without purification.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0546]

[0547] 2V-(2,3-dimethylphenyI)-4-methyl-3-oxo-3,4-dihydro-2H-benzo[Z>][l,4]oxazine-6-sulfonamide (la): To a flame dried flask was added 2,3-Dimethylaniline (30.4 pl, 0.25 mmol, 1.0 eq.) in anhydrous CH2Q2 (2.5 ml, 0.1 M). The mixture was cooled down to 0 °C and Pyridine (40.3 pl, 0.50 mmol, 2.0 eq.) was slowly added into the flask. After stirring at 0 °C for 10 min, 4-methyl-3-oxo-3,4-dihydro-27 / -benzo[Z>][l,4]oxazine-6-sulfonyl chlorides (65.4 mg, 0.25 mmol, 1.0 eq.) was added as a solution in anhydrous CH2Ch(2.5 ml, 0.1 M). The resulting mixture was allowed to warm to room temperature and stirred overnight. The completed reaction mixture was quenched with water and extracted with CH2CI2 (3x). The organic layer was combined, concentrated, and purified via column chromatography (0 to 50% EtOAc in Hex) to yield the desired product (59.9 mg, 69%). IR (neat) umax= 1713, 1422, 1360, 1220, 1094, 826 cm1. ‘H NMR (500 MHz, CDCI3) 57.41 (dd, J = 8.4, 2.0 Hz, 1H), 7.18 (d, 7= 1.9 Hz, 1H), 7.05 - 6.99 (m, 4H), 6.37 (s, 1H), 4.68 (s, 2H), 3.20 (s, 3H), 2.23 (s, 3H), 1.99 (s, 3H).13C NMR (125 MHz, CDCI3) 5 163.4, 148.4, 138.2, 134.0, 133.7, 131.9, 129.5, 128.7, 126.1, 123.5, 123.3, 117.1, 114.1, 67.3, 28.1, 20.6, 13.9. HRMS (ESI) C17H18N2O4S, Calculated: [M-H]+, 345.0909; Found: [M-H]+, 345.0909.

[0548] Me

[0549]

[0550] A'-(2,3-dimethylphenyl)-3-oxo-4-propyl-3,4-dihydro-2 / / -benzo[ / fl[l,4]oxazine-6-sulfonamide (lb): To a flame dried flask was added 2,3-Dimethylaniline (30.4 pl, 0.25 mmol, 1.0 eq.) in anhydrous CH2Q2 (2.5 ml, 0.1 M). The mixture was cooled down to 0 °C and Pyridine (40.3 pl, 0.50 mmol, 2.0 eq.) was slowly added into the flask. After stirring at 0 °C for 10 min, 3-oxo-4-propyl-3,4-dihydro-277-benzo|A][l,4]oxazine-6-sulfonyl chloride (72.4 mg, 0.25 mmol, 1.0 eq.) was added as a solution in anhydrous CH2Ch(2.5 ml, 0.1 M). The resulting mixture was allowed to warm to room temperature and stirred overnight. The completed reaction mixture was quenched with water and extracted with CH2CI2 (3x). The4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0551] organic layer was combined, concentrated, and purified via column chromatography (0 to 50% EtOAc in Hex) to yield the desired product (78.8 mg, 69%). IR (neat) Umax = 1667, 1449, 1394, 1330, 1159, 844 cm1. 'H NMR (500 MHz, CDCh) 57.45 (dd, J = 8.4, 2.0 Hz, 1H), 7.15 (d, 7= 1.9 Hz, 1H), 7.10 (d, 7 = 5.4 Hz, 1H), 7.05 - 6.97 (m, 3H), 6.82 (s, 1H), 4.64 (s, 2H), 3.80 - 3.64 (m, 2H), 2.20 (s, 3H), 1.94 (s, 3H), 1.40 (q, 7= 7.5 Hz, 2H), 0.83 (t, 7 = 7.4 Hz, 3H).13C NMR (125 MHz, CDC13) 5 163.2, 148.6, 138.1, 134.0, 133.7, 131.8, 128.6, 128.4, 126.1, 123.7, 123.0, 117.5, 114.3, 67.3, 42.5, 20.6, 19.9, 13.8, 11.0. HRMS (ESI) C19H22N2O4S, Calculated: [M+H]+, 375.1379; Found: [M+H]+, 375.1367.

[0552] OH

[0553]

[0554] N-(2,3-dimethylphenyI)-4-(2-hydroxypropyl)-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazine-6-sulfonamide (lc): To a flame dried flask was added 2,3-Dimethylaniline (30.4 pl, 0.25 mmol, 1.0 eq.) in anhydrous CH2CI2 (2.5 ml, 0.1 M). The mixture was cooled down to 0 °C and Pyridine (40.3 pl, 0.50 mmol, 2.0 eq.) was slowly added into the flask. After stirring at 0 °C for 10 min, 4-allyl-3-oxo-3,4-dihydro-2 / 7-benzol / ? J[l,4Joxazine-6-sulfonyl chloride (71.9 mg, 0.25 mmol, 1.0 eq.) was added as a solution in anhydrous CH2C12(2.5 ml, 0.1 M). The resulting mixture was allowed to warm to room temperature and stirred overnight. The completed reaction mixture was quenched with water and extracted with CH2CI2 (3x). The organic layer was combined, concentrated, and purified via column chromatography (0 to 50% EtOAc in Hex) to yield the desired product (86.6 mg, 93%). IR (neat) umax= 1669, 1434, 1382, 1326, 1275, 1095, 661 cm1. 'H NMR (500 MHz, CDCh) 57.41 - 7.36 (m, 2H), 7.06 - 6.97 (m, 4H), 6.78 (s, 1H), 4.73 - 4.61 (m, 2H), 3.95 - 3.82 (m, 2H), 3.75 (dd, 7= 14.2, 3.1 Hz, 1H), 2.21 (s, 3H), 1.95 (s, 3H), 1.18 (d, 7= 6.1 Hz, 2H).13C NMR (125 MHz, CDCI3) 5 164.4, 148.6, 138.2, 134.0, 133.6, 132.1, 129.2, 128.6, 126.0, 123.8, 123.4, 117.4, 115.0, 67.4, 65.9, 49.0, 21.3, 20.6, 13.9. HRMS (ESI) C19H20N2O4S, Calculated: [M+H]+, 373.1216; Found: [M+H]+, 373.1222.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0555]

[0556] 4-(cyclohexylmethyl)-N-(2,3-dimethylphenyl)-3-oxo-3,4-dihydro-2H-benzo[Z>][l,4]oxazine-6-sulfonamide (Id): To a flame dried flask was added 2,3-Dimethylaniline (30.4 pl, 0.25 mmol, 1.0 eq.) in anhydrous CH2CI2 (2.5 ml, 0.1 M). The mixture was cooled down to 0 °C and Pyridine (40.3 pl, 0.50 mmol, 2.0 eq.) was slowly added into the flask. After stirring at 0 °C for 10 min, 4-(cyclohexylmethyl)-3-oxo-3,4-dihydro-277-benzo[h][l,4]oxazine-6-sulfonyl chloride (86.0 mg, 0.25 mmol, 1.0 eq.) was added as a solution in anhydrous CH2CI2 (2.5 ml, 0.1 M). The resulting mixture was allowed to warm to room temperature and stirred overnight. The completed reaction mixture was quenched with water and extracted with CH2Q2 (3x). The organic layer was combined, concentrated, and purified via column chromatography (0 to 50% EtOAc in Hex) to yield the desired product (78.8 mg, 69%). IR (neat) umax= 2924, 1672, 1469, 1360, 1336, 1278, 1184, 1046, 740 cm1. 'H NMR (500 MHz, CDCI3) 57.41 (d, 7 = 8.4 Hz, 1H), 7.29 (s, 1H), 7.07 (d, J = 4.8 Hz, 1H), 7.05 - 6.97 (m, 3H), 6.78 (s, 1H), 4.64 (s, 2H), 3.66 (d, J = 6.6 Hz, 2H), 2.21 (s, 3H), 1.99 (s, 3H), 1.72 - 1.58 (m, 3H), 1.53 (d, 7= 10.2 Hz, 3H), 1.10 (t, 7= 9.2 Hz, 3H), 0.94 (d, 7= 11.1 Hz, 2H).13C NMR (125 MHz, CDCI3) 5 163.5, 148.7, 138.0, 134.0, 133.7, 131.5, 128.9, 128.5, 126.0, 123.2, 123.1, 117.6, 114.7, 67.3, 46.7, 35.4, 30.5, 26.1, 25.5, 20.6, 13.8. HRMS (ESI) C23H28N2O4S, Calculated: [M+H]+, 429.1848; Found: [M+H]+, 429.1842.

[0557]

[0558] N-(2,3-dimethylphenyl)-4-ethyl-3-oxo-3,4-dihydro-2 / f-benzo[Z>][l,4]oxazine-6-sulfonamide (le): To a flame dried flask was added 2,3-Dimethylaniline (13.2 pl, 0.11 mmol, 1.0 eq.) in anhydrous CH2CI2 (1.1 ml, 0.1 M). The mixture was cooled down to 0 °C and Pyridine (17.5 pl, 0.22 mmol, 2.0 eq.) was slowly added into the flask. After stirring at 0 °C for 10 min, 4-ethyl-3-oxo-3,4-dihydro-2F / -benzo[b][l,4]oxazine-6-sulfonyl chloride (30.0 mg, 0.11 mmol, 1.0 eq.) was added as a solution in anhydrous CHzChQ.l ml, 0.1 M). The4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0559] resulting mixture was allowed to warm to room temperature and stirred overnight. The completed reaction mixture was quenched with water and extracted with CH2CI2 (3x). The organic layer was combined, concentrated, and purified via column chromatography (0-50% EtOAc in Hex) to yield the desired product (24.5 mg, 69%). IR (neat) Umax = 1738, 1653, 1365, 1059, 968, 762 cm1. ‘H NMR (500 MHz, CDCb) 57.43 (d, J= 8.4 Hz, 1H), 7.22 -7.17 (m, 1H), 7.12 - 7.06 (m, 1H), 7.02 (t, 7 = 6.0 Hz, 3H), 6.31 (s, 1H), 4.65 (d, 7= 4.8 Hz, 2H), 3.84 (q, 7 = 7.2 Hz, 2H), 2.22 (s, 3H), 1.97 (s, 3H), 1.07 (t, 7= 7.2 Hz, 3H).13C NMR (125 MHz, CDCh) 5 162.8, 148.7, 138.2, 134.0, 133.8, 131.6, 128.7, 128.2, 126.1, 123.5, 123.1, 117.5, 114.1, 67.3, 36.2, 20.6, 13.8, 12.1. HRMS (ESI) C18H20N2O4S, Calculated: [M-H]+, 359.1066; Found: [M-H]+, 359.1067.

[0560]

[0561] 4-butyl-N-(2,3-dimethylphenyl)-3-oxo-3,4-dihydro-2H-benzo[ / >][l,4]oxazine-6-sulfonamide (If): To a flame dried flask was added 2,3-Dimethylaniline (14.6 pl, 0.12 mmol, 1.0 eq.) in anhydrous CH2CI2 (1.2 ml, 0.1 M). The mixture was cooled down to 0 °C and Pyridine (19.3 pl, 0.24 mmol, 2.0 eq.) was slowly added into the flask. After stirring at 0 °C for 10 min, 4-butyl-3-oxo-3,4-dihydro-2 / / -benzo[ / ?][l,4]oxazine-6-sulfonyl chloride (36.4 mg, 0.12 mmol, 1.0 eq.) was added as a solution in anhydrous CH2Ch(1.2 ml, 0.1 M). The resulting mixture was allowed to warm to room temperature and stirred overnight. The completed reaction mixture was quenched with water and extracted with CH2CI2 (3x). The organic layer was combined, concentrated, and purified via column chromatography (0 to 50% EtOAc in Hex) to yield the desired product (28.8 mg, 62%). IR (neat) umax= 1683, 1437, 1391, 1339, 1279, 1168, 784, 670 cm. 'H NMR (500 MHz, CDCI3) 87.44 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.18 (d, 7 = 2.1 Hz, 1H), 7.08 (t, 7= 4.8 Hz, 1H), 7.02 (dd, 7= 6.8, 3.9 Hz, 3H), 6.56 (s, 1H), 4.64 (s, 2H), 3.76 (t, 7= 7.6 Hz, 2H), 2.22 (s, 3H), 1.97 (s, 3H), 1.39 (td, 7 = 8.3, 4.1 Hz, 2H), 1.28 (td, 7= 12.9, 11.1, 5.3 Hz, 3H), 0.89 (t, 7 = 7.3 Hz, 3H).13C NMR (125 MHz, CDCl3) δ 163.1, 148.7, 138.1, 134.0, 133.7, 131.7, 128.6, 128.4, 126.1, 123.5, 123.0, 117.5, 114.3, 67.3, 40.9, 28.6, 20.6, 19.9, 13.8, 13.6. LC / MS (ESI) C20H24N2O4S, Calculated: [M+H]+, 389.1535; Found: [M+H]+, 389.1533.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0562]

[0563] 4-benzyl-N-(2,3-dimethylphenyl)-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazine-7-sulfonamide (1g): To a flame dried vial was added 3-bromo-N-(2,3-dimethylphenyl)-4-methoxybenzenesulfonamide (35.5 mg, 0.10 mmol, 1.0 eq.), / V-benzyl-2-chloroacetamide (27.5 mg, 0.15 mmol, 1.5 eq.), cesium carbonate (130.3 mg, 0.40 mmol, 4.0 eq.) and anhydrous DMF (2.0 ml, 0.05 M). The resulting mixture was heated up to 160 °C for 20 hours. After cooling down to room temperature, the reaction was quenched with water, and extracted with EtOAc (3x). The combined organic layer was concentrated and purified via column chromatography (1:1 / EtOAc: Hex) to yield the desired product (20 mg, 50%). IR (neat) umax= 1694, 1499, 1390, 1327, 1252, 1159, 1052, 938, 735 cm1.1H NMR (500 MHz, CDCl3) δ 7.39 - 7.24 (m, 5H), 7.21 (t, J = 9.3 Hz, 3H), 6.99 (d, J = 5.8 Hz, 3H), 6.88 (d, J = 8.5 Hz, 1H), 6.31 (s, 1H), 5.17 (s, 2H), 4.76 (s, 2H), 2.20 (s, 3H), 1.94 (s, 3H).13C NMR (125 MHz, CDCh) 5 164.2, 145.1, 138.0, 134.9, 134.9, 133.8, 132.5, 131.5, 129.1, 128.5, 127.9, 126.6, 126.0, 123.1, 122.2, 116.0, 115.8, 67.5, 45.0, 20.6, 13.8. HRMS (ESI) C23H20N2O4S, Calculated: [M+H]+, 421.1222; Found: [M+H]+, 423.1220.

[0564]

[0565] -(2,3-dimethylphenyl)-3-oxo-4-(pyridin-2-ylmethyl)-3,4-dihydro-2-benzo[][1,4]oxazine-7-sulfonamide (1h): To a flame dried vial was added 3-bromo--(2,3-dimethylphenyl)-4-methoxybenzenesulfonamide (35.5 mg, 0.10 mmol, 1.0 eq.), 2-chloro--(pyridin-3-ylmethyl)acetamide (27.7 mg, 0.15 mmol, 1.5 eq.), cesium carbonate (130.3 mg, 0.40 mmol, 4.0 eq.) and anhydrous DMF (2.0 ml, 0.05 M). The resulting mixture was heated up to 160 °C for 20 hours. After cooling down to room temperature, the reaction was4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0566] quenched with water, and extracted with EtOAc (3x). The combined organic layer was concentrated and purified via column chromatography (1:1 / EtOAc: Hex) to yield the desired product (18 mg, 44%). IR (neat) umax= 1703, 1503, 1467, 1388, 1329, 1254, 1152, 944, 760 cm1. 'H NMR (500 MHz, CDC13) 5 8.55 (d, J= 3.0 Hz, 1H), 7.68 (t, J = 7.3 Hz, 1H), 7.35 (s, 1H), 7.26 (s, 2H), 7.25 - 7.21 (m, 1H), 7.14 (d, J= 8.5 Hz, 1H), 6.98 (s, 3H), 6.49 (s, 1H), 5.29 (s, 2H), 4.75 (s, 2H), 2.21 (s, 3H), 1.98 (s, 3H).13C NMR (125 MHz, CDCI3) 5 164.3, 154.9, 149.1, 144.9, 138.0, 137.6, 135.1, 133.9, 132.6, 131.5, 128.5, 126.0, 123.1, 122.3, 122.1, 116.2, 116.0, 67.5, 46.9, 20.6, 13.9. HRMS (ESI) C22H21N3O4S, Calculated: [M+H]+, 424.1331; Found: [M+H]+, 424.1322.

[0567]

[0568] A-(2,3-dimethylphenyl)-3-oxo-4-phenethyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-7-sulfonamide (li): To a flame dried vial was added 3-bromo--(2,3-dimethylphenyl)-4-methoxybenzenesulfonamide (35.5 mg, 0.10 mmol, 1.0 eq.), 2-chloro-A-(3-methylbenzyl)acetamide (29.6 mg, 0.15 mmol, 1.5 eq.), cesium carbonate (130.3 mg, 0.40 mmol, 4.0 eq.) and anhydrous DMF (2.0 ml, 0.05 M). The resulting mixture was heated up to 160 °C for 20 hours. After cooling down to room temperature, the reaction was quenched with water, and extracted with EtOAc (3x). The combined organic layer was concentrated and purified via column chromatography (1:1 / EtOAc: Hex) to yield the desired product (18.8 mg, 43%). IR (neat) Umax = 3282, 1698, 1456, 1393, 1330, 1256, 1228, 1217, 1160 cm1.1H NMR (500 MHz, MeOD) δ 7.30 (d, 7= 8.6 Hz, 1H), 7.25 - 7.21 (m, 4H), 7.18 (d, 7 = 7.2 Hz, 4H), 7.03 (d, 7 = 7.5 Hz, 1H), 6.95 (t, 7 = 7.8 Hz, 1H), 6.81 (d, 7 = 7.8 Hz, 1H), 4.58 (s, 2H), 4.20 (t, 7 = 7.4 Hz, 2H), 2.93 (t, 7 = 7.3 Hz, 3H), 2.21 (s, 3H), 2.02 (s, 3H).13C NMR (125 MHz, MeOD) 5 164.5, 158.0, 145.2, 137.8, 135.3, 133.8, 132.0, 128.6, 128.2, 126.3, 125.2, 124.9, 121.8, 117.2, 115.4, 115.3, 114.9, 42.2, 38.4, 38.3, 32.6, 13.1. HRMS (ESI) C24H24N2O4S, Calculated: [M-H]+, 435.1379; Found: [M+H]+, 435.1379.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0569]

[0570] A-(2,3-dimethylphenyl)-4-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazine-7-sulfonamide (Ij): To a flame dried vial was added 3-bromo-A-(2,3-dimethylphenyl)-4-methoxybenzenesulfonamide (35.5 mg, 0.10 mmol, 1.0 eq.), 2-chloro-A-(furan-2-ylmethyl)acetamide (26.0 mg, 0.15 mmol, 1.5 eq.), cesium carbonate (130.3 mg, 0.40 mmol, 4.0 eq.) and anhydrous DMF (2.0 ml, 0.05 M). The resulting mixture was heated up to 160 °C for 20 hours. After cooling down to room temperature, the reaction was quenched with water, and extracted with EtOAc (3x). The combined organic layer was concentrated and purified via column chromatography (1:1 / EtOAc: Hex) to yield the desired product (18 mg, 44%). IR (neat) umax= 1697, 1502, 1394, 1325, 1230, 1150, 931, 738 cm’1.

[0571] 1H NMR (500 MHz, CDCl3) δ 7.36 (dd, J = 10.3, 5.3 Hz, 3H), 7.28 (s, 1H), 7.01 (s, 3H), 6.33 (s, 2H), 6.27 (s, 1H), 5.09 (s, 2H), 4.66 (s, 2H), 2.23 (s, 3H), 2.00 (s, 3H).13C NMR (125 MHz, CDCh) 6 163.8, 148.7, 145.0, 142.5, 138.1, 135.0, 133.9, 132.5, 131.4, 128.5, 126.1, 123.0, 122.3, 116.7, 115.5, 110.7, 109.4, 67.5, 38.4, 20.6, 13.9. HRMS (ESI) C21H20N2O5S, Calculated: [M-H]+, 411.1015; Found: [M-H]+, 411.1009.

[0572] Me

[0573]

[0574] A-(2-bromophenyl)-3-oxo-4-propyI-3,4-dihydro-2H-benzo[Z>][l,4]oxazine-6-sulfonamide (Ik): To a flame dried flask was added 2-bromoaniline (43.0 mg, 0.25 mmol, 1.0 eq.) in anhydrous CH2CI2 (2.5 ml, 0.1 M). The mixture was cooled down to 0 °C and Pyridine (40.3 pl, 0.50 mmol, 2.0 eq.) was slowly added into the flask. After stirring at 0 °C for 10 min, 3-oxo-4-propyl-3,4-dihydro-27 / -benzo[ / ?][l,4]oxazine-6-sulfonyl chloride (72.4 mg, 0.25 mmol, 1.0 eq.) was added as a solution in anhydrous CH2CI2 (2.5 ml, 0.1 M). The resulting mixture was allowed to warm to room temperature and stirred overnight. The completed reaction mixture was quenched with water and extracted with CH2Q2 (3x). The organic layer4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0575] was combined, concentrated, and purified via column chromatography (0 to 50% EtOAc in Hex) to yield the desired product (75.0 mg, 71%). IR (neat) umax= 1683, 1503, 1386, 1277, 1217, 1043, 715 cm’1.1H NMR (500 MHz, CDCl3) δ 7.73 - 7.67 (m, 1H), 7.41 (dt, J = 8.0, 2.2 Hz, 2H), 7.29 (t, J = 7.7 Hz, 1H), 7.19 (d, 7= 2.3 Hz, 1H), 7.05 (s, 1H), 7.04 - 6.95 (m, 2H), 4.61 (s, 2H), 3.74 (d, J= 8.2 Hz, 2H), 1.45 (p, 7= 7.4, 6.8 Hz, 2H), 0.86 (t, J = 7.3 Hz, 3H).13C NMR (125 MHz, CDC13) 5 163.0, 149.0, 134.6, 132.8, 132.7, 128.6, 126.9, 123.9, 123.4, 117.5, 116.6, 114.0, 67.3, 42.6, 20.0, 11.1. HRMS (ESI) C17H17BrN2O4S, Calculated:

[0576] [M+H]+, 425.0171; Found: [M+H]+, 425.0164.

[0577] Me

[0578]

[0579] 2V-(2-fluorophenyl)-3-oxo-4-propyl-3,4-dihydro-2H-benzo|7>][l,4]oxazine-6-sulfonamide (11): To a flame dried flask was added 2-fluoroaniline (24.0 pl, 0.25 mmol, 1.0 eq.) in anhydrous CH2CI2 (2.5 ml, 0.1 M). The mixture was cooled down to 0 °C and Pyridine (40.3 pl, 0.50 mmol, 2.0 eq.) was slowly added into the flask. After stirring at 0 °C for 10 min, 3-oxo-4-propyl-3,4-dihydro-2W-benzo| / fl| 1,4|oxazine-6-siill'onyl chloride (72.4 mg, 0.25 mmol, 1.0 eq.) was added as a solution in anhydrous CH2Q2 (2.5 ml, 0.1 M). The resulting mixture was allowed to warm to room temperature and stirred overnight. The completed reaction mixture was quenched with water and extracted with CH2CI2 (3x). The organic layer was combined, concentrated, and purified via column chromatography (0 to 50% EtOAc in Hex) to yield the desired product (68.0 mg, 75%). IR (neat) Umax = 1698, 1497, 1378, 1336, 1273, 1166, 1100, 753 cm1. 'H NMR (500 MHz, CDCh) 57.60 (td, J = 7.6, 3.4 Hz, 1H), 7.44 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.30 (d, 7 = 2.6 Hz, 2H), 7.09 (dt, 7 = 6.7, 3.1 Hz, 2H), 6.99 -6.93 (m, 2H), 4.62 (s, 2H), 3.77 (t, 7 = 7.7 Hz, 2H), 1.47 (h, 7 = 7.5 Hz, 2H), 0.87 (t, J = 7.4 Hz, 3H).13C NMR (125 MHz, CDCh) 5 163.2, 155.5, 153.5, 148.9, 132.9, 128.6, 126.8, 126.7, 124.8, 124.8, 124.5, 124.4, 123.3, 117.5, 115.7, 115.6, 114.0, 67.3, 42.6, 20.0, 11.1.

[0580] HRMS (ESI) C17H17FN2O4S, Calculated: [M+H]+, 365.0971; Found: [M+H]+, 365.0966.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0581] Me

[0582]

[0583] 3-oxo--phenyl-4-propyl-3,4-dihydro-2-benzo[][1,4]oxazine-6-sulfonamide (1m): To a flame dried flask was added aniline (22.8 pl, 0.25 mmol, 1.0 eq.) in anhydrous CH2CI2 (2.5 ml, 0.1 M). The mixture was cooled down to 0 °C and Pyridine (40.3 pl, 0.50 mmol, 2.0 eq.) was slowly added into the flask. After stirring at 0 °C for 10 min, 3-oxo-4-propyl-3,4-dihydro-2H-benzo[£>][l,4]oxazine-6-sulfonyl chloride (72.4 mg, 0.25 mmol, 1.0 eq.) was added as a solution in anhydrous CH2O2 (2.5 ml, 0.1 M). The resulting mixture was allowed to warm to room temperature and stirred overnight. The completed reaction mixture was quenched with water and extracted with CH2CI2 (3x). The organic layer was combined, concentrated, and purified via column chromatography (0 to 50% EtOAc in Hex) to yield the desired product (75.2 mg, 87%). IR (neat) umax= 1667, 1600, 1396, 1278, 1179, 1053, 795 cm1, ifl NMR (500 MHz, CDCI3) 57.66 (s, 1H), 7.48 (dd, J= 8.5, 2.2 Hz, 1H), 7.30 (d, J = 2.1 Hz, 1H), 7.24 (t, J = 7.8 Hz, 2H), 7.12 (dd, 7= 15.5, 7.7 Hz, 3H), 6.98 (d, J= 8.6 Hz, 1H), 4.62 (s, 2H), 3.76 (t, J = 7.6 Hz, 2H), 1.44 (q, J = 7.6 Hz, 2H), 0.86 (t, J = 7.4 Hz, 3H).

[0584] 13C NMR (125 MHz, CDCI3) 5 163.27, 148.78, 136.58, 132.92, 129.42, 128.53, 125.64, 123.27, 121.82, 117.53, 114.21, 67.25, 42.63, 19.98, 11.08. HRMS (ESI) C17H18N2O4S, Calculated: [M+H]+, 347.1066; Found: [M+H]+, 347.1063.

[0585] Me

[0586]

[0587] 2V-(3-chlorophenyl)-3-oxo-4-propyl-3,4-dihydro-2H-benzo| >][l,4]oxazine-6-sulfonamide (In): To a flame dried flask was added 3 -chloroaniline (26.1 pl, 0.25 mmol, 1.0 eq.) in anhydrous CH2CI2 (2.5 ml, 0.1 M). The mixture was cooled down to 0 °C and Pyridine (40.3 pl, 0.50 mmol, 2.0 eq.) was slowly added into the flask. After stirring at 0 °C for 10 min, 3-oxo-4-propyl-3,4-dihydro-27 / -benzo[7>][l,4]oxazine-6-sulfonyl chloride (72.4 mg, 0.25 mmol, 1.0 eq.) was added as a solution in anhydrous CH2CI2 (2.5 ml, 0.1 M). The resulting mixture was allowed to warm to room temperature and stirred overnight. The completed4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0588] reaction mixture was quenched with water and extracted with CH2CI2 (3x). The organic layer was combined, concentrated, and purified via column chromatography (0 to 50% EtOAc in Hex) to yield the desired product (31.0 mg, 33%). IR (neat) Umax = 1667, 1584, 1447, 1384, 1332, 1169, 870, 679 cm’1. ‘H NMR (500 MHz, CDCh) 57.51 - 7.47 (m, 2H), 7.32 (d, 7 = 2.2 Hz, 1H), 7.20 - 7.15 (m, 2H), 7.11 - 7.08 (m, 1H), 7.02 (t, 7= 8.5 Hz, 2H), 4.65 (s, 2H), 3.81 (t, 7 = 7.6 Hz, 2H), 1.50 (h, 7 = 7.5 Hz, 2H), 0.91 (t, 7= 7.5 Hz, 3H).13C NMR (125 MHz, CDCI3) 5 163.2, 149.0, 137.8, 135.1, 132.6, 130.5, 128.7, 125.6, 123.2, 121.3, 119.3, 117.8, 114.2, 67.3, 42.7, 20.1, 11.1. HRMS (ESI) C17H17CIN2O4S, Calculated: [M+H]+, 381.0676; Found: [M+H]+, 381.0670.

[0589] Me

[0590]

[0591] A-(3-chloro-2-methylphenyl)-3-oxo-4-propyl-3,4-dihydro-2 / / -benzo[Z»][l,4]oxazine-6-sulfonamide (lo): To a flame dried flask was added 3-chloro-2-methylaniline (29.9 pl, 0.25 mmol, 1.0 eq.) in anhydrous CH2CI2 (2.5 ml, 0.1 M). The mixture was cooled down to 0 °C and Pyridine (40.3 pl, 0.50 mmol, 2.0 eq.) was slowly added into the flask. After stirring at 0 °C for 10 min, 3-oxo-4-propyl-3,4-dihydro-277-benzo[£>][l,4]oxazine-6-sulfonyl chloride (72.4 mg, 0.25 mmol, 1.0 eq.) was added as a solution in anhydrous CH2O2 (2.5 ml, 0.1 M). The resulting mixture was allowed to warm to room temperature and stirred overnight. The completed reaction mixture was quenched with water and extracted with CH2CI2 (3x). The organic layer was combined, concentrated, and purified via column chromatography (0 to 50% EtOAc in Hex) to yield the desired product (73.8 mg, 75%). IR (neat) Umax = 1666, 1450, 1435, 1334, 1281, 1161, 844, 713 cm’1.1H NMR (500 MHz, CDCl3) δ 7.44 (dd, J = 8.4, 2.2 Hz, 1H), 7.23 (dd, 7= 11.9, 8.1 Hz, 2H), 7.17 (s, 2H), 7.07 (t, 7= 8.1 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H), 4.65 (s, 2H), 3.74 (t, 7 = 7.6 Hz, 2H), 2.07 (s, 3H), 1.41 (q, 7 = 7.6 Hz, 2H), 0.84 (t, 7 = 7.4 Hz, 3H).13C NMR (125 MHz, CDCh) 5 163.2, 148.9, 135.6, 135.3, 133.3, 131.2, 128.6, 127.8, 127.0, 124.2, 123.0, 117.7, 114.1, 67.3, 42.5, 19.9, 14.7, 11.1. HRMS (ESI) C18H19CIN2O4S, Calculated: [M-H]+, 393.0676; Found: [M-H]+, 393.0679.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0592] Me

[0593]

[0594] N-(2,6-dimethylphenyl)-3-oxo-4-propyl-3,4-dihydro-2H-benzo[Z>][l,4]oxazine-6-sulfonamide (Ip): To a flame dried flask was added 2,6-dimethylaniline (30.8 pl, 0.25 mmol, 1.0 eq.) in anhydrous CH2CI2 (2.5 ml, 0.1 M). The mixture was cooled down to 0 °C and Pyridine (40.3 pl, 0.50 mmol, 2.0 eq.) was slowly added into the flask. After stirring at 0 °C for 10 min, 3-oxo-4-propyl-3,4-dihydro-277-benzo[Z / ][l,4]oxazine-6-sulfonyl chloride (72.4 mg, 0.25 mmol, 1.0 eq.) was added as a solution in anhydrous CH2Q2 (2.5 ml, 0.1 M). The resulting mixture was allowed to warm to room temperature and stirred overnight. The completed reaction mixture was quenched with water and extracted with CH2CI2 (3x). The organic layer was combined, concentrated, and purified via column chromatography (0 to 50% EtOAc in Hex) to yield the desired product (67.6 mg, 72%). IR (neat) umax= 1658, 1436, 1393, 1266, 1217, 1161, 1047, 776 cm’1.1H NMR (500 MHz, CDCl3) δ 7.44 (dd, J = 8.5, 2.1 Hz, 1H), 7.14 (d, J= 2.2 Hz, 1H), 7.10 - 7.05 (m, 1H), 7.01 (t, J = 9.4 Hz, 3H), 6.54 (s, 1H), 4.65 (s, 2H), 3.72 (t, J = 7.6 Hz, 2H), 2.06 (s, 6H), 1.43 (h, J = 7.5 Hz, 2H), 0.82 (t, J = 7.4 Hz, 4H).13C NMR (125 MHz, CDCl3) δ 163.2, 148.7, 137.6, 134.7, 132.5, 128.9, 128.5, 127.9, 123.0, 117.6, 114.3, 67.4, 42.5, 19.9, 18.7, 11.0. HRMS (ESI) C19H22N2O4S, Calculated: [M-H]+, 373.1222; Found: [M-H]+, 373.1219.

[0595] OMe Me

[0596]

[0597] N-(2,5-dimethoxyphenyl)-3-oxo-4-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonamide (Iq): To a flame dried flask was added 2,5-dimethoxyaniline (35.6 pl, 0.25 mmol, 1.0 eq.) in anhydrous CH2CI2 (2.5 ml, 0.1 M). The mixture was cooled down to 0 °C and Pyridine (40.3 pl, 0.50 mmol, 2.0 eq.) was slowly added into the flask. After stirring at 0 °C for 10 min, 3-oxo-4-propyl-3,4-dihydro-277-benzo[Z?][l,4]oxazine-6-sulfonyl chloride (72.4 mg, 0.25 mmol, 1.0 eq.) was added as a solution in anhydrous CH2Q2 (2.5 ml, 0.1 M). The resulting mixture was allowed to warm to room temperature and stirred overnight. The4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0598] completed reaction mixture was quenched with water and extracted with CH2CI2 (3x). The organic layer was combined, concentrated, and purified via column chromatography (0 to 50% EtOAc in Hex) to yield the desired product (93.9 mg, 83%). IR (neat) Umax = 1693, 1435, 1404, 1239, 1213, 1164, 1029, 675 cm’1.1H NMR (500 MHz, CDCl3) δ 7.43 (d, J = 8.8 Hz, 1H), 7.36 (dd, J= 8.3, 2.1 Hz, 1H), 7.13 (d, J= 2.1 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.76 (s, 1H), 6.42 (dd, J = 8.7, 2.7 Hz, 1H), 6.26 (d, J = 2.7 Hz, 1H), 4.58 (s, 2H), 3.72 (s, 5H), 3.48 (s, 3H), 1.43 (h, J = 7.5 Hz, 2H), 0.86 (t, J = 7.4 Hz, 3H).13C NMR (125 MHz, CDCl3) δ 163.1, 158.7, 152.1, 148.4, 133.3, 128.1, 125.0, 123.3, 118.4, 117.1, 114.3, 104.4, 98.7, 67.3, 55.6, 55.5, 42.5, 19.9, 11.0. HRMS (ESI) C19H22N2O6S, Calculated: [M-H]+, 405.1120; Found: [M-H]+, 405.1113.

[0599] Me

[0600]

[0601] N-(3-morpholinophenyl)-3-oxo-4-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonamide (Ir): To a flame dried flask was added 3 -morpholinoaniline (44.56 mg, 0.25 mmol, 1.0 eq.) in anhydrous CH2Q2 (2.5 ml, 0.1 M). The mixture was cooled down to 0 °C and Pyridine (40.3 pl, 0.50 mmol, 2.0 eq.) was slowly added into the flask. After stirring at 0 °C for 10 min, 3-oxo-4-propyl-3,4-dihydro-277-benzo[ / j][l,4]oxazine-6-sulfonyl chloride (72.4 mg, 0.25 mmol, 1.0 eq.) was added as a solution in anhydrous CH2Q2 (2.5 ml, 0.1 M). The resulting mixture was allowed to warm to room temperature and stirred overnight. The completed reaction mixture was quenched with water and extracted with CH2CI2 (3x). The organic layer was combined, concentrated, and purified via column chromatography (0 to 50% EtOAc in Hex) to yield the desired product (88.4 mg, 82%). IR (neat) Umax = 1690, 1502, 1435, 1192, 1121, 997, 841, 692 cm1. > HNMR (500 MHz, CDCh) 87.60 (s, 1H), 7.47 (dd, J = 8.4, 2.1 Hz, 1H), 7.31 (d, J = 2.1 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 6.98 (d, J = 8.5 Hz, 1H), 6.75 - 6.71 (m, 1H), 6.64 (dd, J = 8.4, 2.5 Hz, 1H), 6.55 (dd, J = 8.0, 2.1 Hz, 1H), 4.62 (s, 2H), 3.82 - 3.78 (m, 4H), 3.78 - 3.74 (m, 2H), 3.07 (dd, J = 5.8, 3.7 Hz, 4H), 1.47 (h, J = 7.6 Hz, 2H), 0.87 (t, J = 7.3 Hz, 3H).13C NMR (125 MHz, CDCl3) δ 163.2, 152.2, 148.7, 137.6, 133.0, 129.9, 128.6, 123.2, 117.5, 114.2, 112.6, 112.4, 108.7, 67.3, 66.7,4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0602] 48.8, 42.6, 20.1, 11.2. HRMS (ESI) C21H25N3O5S, Calculated: [M+H]+, 432.1593; Found:

[0603] [M+H]+, 432.1594.

[0604] Me

[0605]

[0606] 6-(morpholinosulfonyl)-4-propyl-2H-benzo[b][1,4]oxazin-3(4H)-one (Is): To a flame dried flask was added morpholine (21.9 pl, 0.25 mmol, 1.0 eq.) in anhydrous CH2Q2 (2.5 ml, 0.1 M). The mixture was cooled down to 0 °C and Pyridine (40.3 pl, 0.50 mmol, 2.0 eq.) was slowly added into the flask. After stirring at 0 °C for 10 min, 3-oxo-4-propyl-3,4-dihydro-2W- benzo[(>][l,4]oxazine-6-sulfonyl chloride (72.4 mg, 0.25 mmol, 1.0 eq.) was added as a solution in anhydrous CH2Q2 (2.5 ml, 0.1 M). The resulting mixture was allowed to warm to room temperature and stirred overnight. The completed reaction mixture was quenched with water and extracted with CH2CI2 (3x). The organic layer was combined, concentrated, and purified via column chromatography (0 to 50% EtOAc in Hex) to yield the desired product (85.0 mg, 62%). IR (neat) umax= 1690, 1499, 1432, 1296, 1126, 940, 732 cm’1. 'H NMR (500 MHz, CDCl3) δ 7.37 (dd, 7= 8.4, 2.1 Hz, 1H), 7.31 (d, 7= 2.1 Hz, 1H), 7.10 (d, 7= 8.5 Hz, 1H), 4.68 (s, 2H), 3.92 (t, 7 = 7.6 Hz, 2H), 3.73 (t, 7 = 4.7 Hz, 4H), 2.99 (t, 7 = 4.6 Hz, 5H), 1.67 (h, 7 = 7.5 Hz, 2H), 0.97 (t, 7 = 7.4 Hz, 3H).13C NMR (125 MHz, CDCl3) δ 163.2, 148.9, 129.4, 128.9, 123.7, 117.7, 114.6, 67.3, 66.1, 46.0, 42.7, 20.3, 11.2. HRMS (ESI) C15H20N2O5S, Calculated: [M+H]+, 341.1171; Found: [M+H]+, 341.1168.

[0607] Me

[0608]

[0609] 6-(piperidin-1-ylsulfonyl)-4-propyl-2H-benzo[b][1,4]oxazin-3(4H)-one (It): To a flame dried flask was added piperidine (24.7 pl, 0.25 mmol, 1.0 eq.) in anhydrous CH2CI2 (2.5 ml, 0.1 M). The mixture was cooled down to 0 °C and Pyridine (40.3 pl, 0.50 mmol, 2.0 eq.) was slowly added into the flask. After stirring at 0 °C for 10 min, 3-oxo-4-propyl-3,4-dihydro-277-benzo[(>][l,4]oxazine-6-sulfonyl chloride (72.4 mg, 0.25 mmol, 1.0 eq.) was added as a4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0610] solution in anhydrous CH2Q2 (2.5 ml, 0.1 M). The resulting mixture was allowed to warm to room temperature and stirred overnight. The completed reaction mixture was quenched with water and extracted with CH2Cl2(3x). The organic layer was combined, concentrated, and purified via column chromatography (0 to 50% EtOAc in Hex) to yield the desired product (41.4 mg, 49%). IR (neat) Umax = 1683, 1446, 1384, 1279, 1159, 1085, 1035, 749 cm'1.1H NMR (500 MHz, CDCl3) δ 7.37 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 4.67 (s, 2H), 3.92 (t, J = 7.5 Hz, 2H), 2.98 (t, J = 5.2 Hz, 4H), 1.65 (dt, J = 11.7, 6.7 Hz, 7H), 1.43 (t, J = 5.9 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H).13C NMR (125 MHz, CDCl3) δ 163.3, 148.5, 130.7, 128.7, 123.5, 117.5, 114.5, 67.3, 46.9, 42.7, 25.2, 23.5, 20.3, 11.2. HRMS (ESI) C16H22N2O4S, Calculated: [M+H]+, 339.1379; Found: [M+H]+, 339.1378.

[0611] Me

[0612]

[0613] N-benzyl-3-oxo-4-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonamide (1u): To a flame dried flask was added phenylmethanamine (27.3 pl, 0.25 mmol, 1.0 eq.) in anhydrous CH2CI2 (2.5 ml, 0.1 M). The mixture was cooled down to 0 °C and Pyridine (40.3 pl, 0.50 mmol, 2.0 eq.) was slowly added into the flask. After stirring at 0 °C for 10 min, 3-oxo-4-propyl-3,4-dihydro-277-benzo[ / 2][l,4]oxazine-6-sulfonyl chloride (72.4 mg, 0.25 mmol, 1.0 eq.) was added as a solution in anhydrous CH2CI2 (2.5 ml, 0.1 M). The resulting mixture was allowed to warm to room temperature and stirred overnight. The completed reaction mixture was quenched with water and extracted with CH2Q2 (3x). The organic layer was combined, concentrated, and purified via column chromatography (0 to 50% EtOAc in Hex) to yield the desired product (47.2 mg, 52%). IR (neat) umax= 1667, 1455, 1369, 1331, 1205, 1146, 1044, 718 cm1.1H NMR (500 MHz, CDCl3) δ 7.49 (dd, J = 8.4, 2.1 Hz, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.23 (d, J = 7.1 Hz, 3H), 7.19 - 7.14 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 5.36 (t, J = 6.1 Hz, 1H), 4.64 (s, 2H), 4.13 (d, J = 5.5 Hz, 2H), 3.85 (t, J = 7.5 Hz, 2H), 1.62 (h, J = 7.5 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H).13C NMR (125 MHz, CDCl3) δ 163.3, 148.6, 136.1, 134.3, 128.8, 128.7, 127.9, 127.8, 123.2, 117.5, 114.1, 67.3, 47.3, 42.7, 20.2, 11.2. HRMS (ESI) C18H20N2O4S, Calculated: [M+H]+, 361.1222; Found: [M+H]+, 361.1215.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0614] H

[0615]

[0616] 6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (13): To a flame dried flask was added 2-amino-4-nitrophenol (2.00 g, 13.0 mmol, 1.0 eq.) and potassium carbonate (3.59 g, 26.0 mmol, 2.0 eq.) in anhydrous MeCN (50 ml, 0.26 M). The resulting mixture was allowed to stir at room temperature for 10 min before the slowly addition of chloroacetyl chloride (1.23 mL, 15.6 mmol, 1.2 eq.). The mixture was then heated to reflux (75 °C) for 20 hours until completion. After cooling down to room temperature, the resulting mixture was quenched with water and extracted with EtOAc in triplicate. The organic phase was concentrated in vacuo and used without further purification as a brown powder.1H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 7.81 (dd, J = 8.93, 2.60 Hz, 1H), 7.72 (d, J = 2.59 Hz, 1H), 7.12 (d, J = 8.90 Hz, 1H), 4.75 (s, 2H).13C NMR (125 MHz, DMSO) δ 164.2, 149.1, 142.2, 128.1, 119.6, 117.0, 111.2, 67.2.

[0617] Me

[0618]

[0619] 6-nitro-4-propyl-2H-benzo[b][1,4]oxazin-3(4H)-one (15): To a flame dried flask was added 6-bromo-2H-benzo[b][l,4]oxazin-3(4H)-one (254.7 mg, 1.31 mmol, 1.0 eq.) in anhydrous DMF (2.6 mL, 0.5 M). The mixture was cooled down to 0 °C and sodium hydride (104.9 mg, 2.62 mmol, 2.0 eq., 60% dispersion in mineral oil) was slowly added into the reaction vessel. Then 1 -bromopropane (127 pL, 1.57 mmol, 1.2 eq.) was added into the reaction mixture at 0 °C. The resulting solution was warmed to room temperature and stirred overnight until completion. The reaction was quenched using H2O and extracted with EtOAc in triplicate. The organic layer was concentrated in vacuo and purified via column chromatography (0 to 15% EtOAc in Hex) to yield the desired product (225.2 mg, 73%).1H NMR (500 MHz, CDCl3) δ 7.88 (dd, J = 8.83, 2.46 Hz, 1H), 7.83 (d, J = 2.46 Hz, 1H), 7.04 (d, J = 8.83 Hz, 1H), 4.69 (s, 2H), 3.93 (t, 2H), 1.70 (h, J = 7.47 Hz, 2H), 0.98 (t, J = 7.44 Hz, 3H).13C NMR (125 MHz, CDCl3) δ 162.8, 150.3, 143.0, 128.7, 119.7, 117.2, 110.5, 67.3, 42.9, 20.1, 11.1.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0620]

[0621] 6-amino-4-propyl-2H-benzo[b][1,4]oxazin-3(4H)-one (S2): To a flame dried flask was added 6-nitro-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (161.1 mg, 0.682 mmol, 1.0 eq.) and tin(II) chloride monohydrate (461.7 mg, 2.05 mmol, 3.0 eq.) in ethanol (6.82 mL, 0.1M) The reaction was stirred at 70 °C for 16 h. The reaction was quenched using IM sodium hydride and extracted with EtOAc in triplicate. The organic layer was concentrated in vacuo and used crude in the next step.

[0622] Me

[0623]

[0624] 3-methyl-N-(3-oxo-4-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)benzenesulfonamide (2a): To a flame dried flask was added 6-amino-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (0.0852 mmol, 1.0 eq.) and pyridine (20.5 |iL, 0.256 mmol, 3.0 eq.) in CH2CI2 (1 mL, 0.09 M). The reaction stirred for 10 minutes at 0 °C before addition of 3-methylbenzenesulfonyl chloride (15.0,uL, 0.112 mmol, 1.2 eq.) dropwise. The resulting solution was warmed to room temperature and stirred for 16 hours until completion. The reaction was quenched using H2O and extracted with EtOAc in triplicate. The organic layer was concentrated in vacuo and purified via column chromatography (0 to 40% EtOAc in Hex) to yield the desired product (8.0 mg, 26% over 2 steps). IR (neat) Umax = 3250, 2963, 1675, 1606, 1512, 1421, 1398, 1336, 1162, 1052, 1006, 925, 786, 708 cm’1.1H NMR (500 MHz, CDCl3) δ 7.57 (s, 1H), 7.52 (d, J = 7.48 Hz, 1H), 7.39 - 7.31 (m, 2H), 6.83 (d, J = 8.51 Hz, 1H), 6.78 (d, J = 2.35 Hz, 1H), 6.56 (dd, J = 8.51, 2.31 Hz, 1H), 6.52 (s, 1H), 4.55 (s, 2H), 3.78 (t, J = 7.68 Hz, 2H), 2.37 (s, 3H), 1.55 (h, J = 7.37 Hz, 2H), 0.92 (t, J = 7.44 Hz, 3H).13C NMR (125 MHz, CDCl3) δ 163.9, 143.6, 139.4, 138.7, 133.9, 131.0, 129.0, 128.9, 127.6, 124.5, 118.7, 117.4, 111.0, 67.5, 42.6, 21.3, 20.1, 11.1. HRMS (ESI) C18H20N2O4S, Calculated: [M+H]+, 361.1222; Found: [M+H]+, 361.1219.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0625] Me

[0626]

[0627] N-(3-oxo-4-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)benzenesulfonamide (2b):

[0628] To a flame dried flask was added 6-amino-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (0.0953 mmol, 1.0 eq.) and pyridine (23.0 pL, 0.286 mmol, 3.0 eq.) in CH2CI2 (1 mL, 0.09 M). The reaction stirred for 10 minutes at 0 °C before addition of benzenesulfonyl chloride (14.6 pL, 0.114 mmol, 1.2 eq.) dropwise. The resulting solution was warmed to room temperature and stirred for 16 hours until completion. The reaction was quenched using H2O and extracted with EtOAc in triplicate. The organic layer was concentrated in vacuo and purified via column chromatography (0 to 55% EtOAc in Hex) to yield the desired product (13.0 mg, 39% over 2 steps). IR (neat) Umax = 3192, 2963, 2932, 1686, 1663, 1511, 1386, 1330, 1163, 1091, 725 cm’1.1H NMR (500 MHz, CDCl3) δ 7.76 - 7.72 (m, 2H), 7.56 (t, J = 7.48 Hz, 1H), 7.46 (t, J = 7.77 Hz, 2H), 6.85 (s, 1H), 6.83 - 6.78 (m, 2H), 6.58 (dd, J = 8.51, 2.36 Hz, 1H), 4.55 (s, 2H), 3.77 (t, 2H), 1.53 (h, J = 14.86, 7.46 Hz, 2H), 0.92 (t, J = 7.48 Hz, 3H).13C NMR (125 MHz, CDCl3) δ 163.9, 143.5, 138.8, 133.1, 131.0, 129.1, 129.0, 127.3, 123.2, 118.7, 117.4, 115.6, 110.9, 77.3, 77.0, 76.8, 67.5, 42.6, 29.7, 20.2, 11.1. HRMS (ESI) C17H18N2O4S, Calculated: [M+H]+, 347.1066; Found: [M+H]+, 347.1059.

[0629] Me

[0630]

[0631] 3,4-dimethyl-N-(3-oxo-4-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)benzene sulfonamide (2c): To a flame dried flask was added 6-amino-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (0.0953 mmol, 1.0 eq.) and pyridine (23.0 pL, 0.286 mmol, 3.0 eq.) in CH2CI2 (1 mL, 0.09 M). The reaction stirred for 10 minutes at 0 °C before addition of 2,3-dimethylbenzenesulfonyl chloride (39.0 mg, 0.191 mmol, 2.0 eq.) dropwise. The resulting solution was warmed to room temperature and stirred for 16 hours until completion. The reaction was quenched using H2O and extracted with EtOAc in triplicate. The organic layer was concentrated in vacuo, and purified via column chromatography (0 to 25% EtOAc in Hex) to yield the desired product (15.3 mg, 43% over 2 steps). IR (neat) Umax = 3089,4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0632] 2981, 2927, 1661, 1602, 1433, 1386, 1336, 1259, 1157, 1091, 1009, 798, 704 cm’1.1H NMR (500 MHz, CDCl3) δ 7.52 (s, 1H), 7.45 (d, J = 7.93 Hz, 1H), 7.19 (d, J = 7.91 Hz, 1H), 6.82 (d, J = 8.46 Hz, 1H), 6.79 (d, J = 2.31 Hz, 1H), 6.70 (s, 1H), 6.58 (dd, J = 8.52, 2.27 Hz, 1H), 4.55 (s, 2H), 3.78 (t, 2H), 2.29 (s, 3H), 2.26 (s, 3H), 1.54 (h, J = 7.33 Hz, 2H), 0.92 (t, J = 7.41 Hz, 3H).13C NMR (125 MHz, CDCl3) δ 164.0, 143.4, 142.7, 137.9, 136.0, 131.2, 130.1, 129.0, 128.1, 124.9, 118.5, 117.4, 110.7, 67.5, 42.6, 20.1, 20.0, 19.8, 11.1. HRMS (ESI) C19H22N2O4S, Calculated: [M+H]+, 375.1379; Found: [M+H]+, 375.1375.

[0633]

[0634] N-(3-oxo-4-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(trifluoromethyl)benzene sulfonamide (2d): To a flame dried flask was added 6-amino-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (0.0953 mmol, 1.0 eq.) and pyridine (23.0 pL, 0.286 mmol, 3.0 eq.) in CH2CI2 (1 mL, 0.09 M). The reaction stirred for 10 minutes at 0 °C before addition of 3-(trifluoromethyl)benzenesulfonyl chloride (28.0 mg, 0.114 mmol, 2.0 eq.) dropwise. The resulting solution was warmed to room temperature and stirred for 16 hours until completion. The reaction was quenched using H2O and extracted with EtOAc in triplicate. The organic layer was concentrated in vacuo, and purified via column chromatography (0 to 100% EtOAc in Hex) to yield the desired product (12.8 mg, 32% over 2 steps). IR (neat) Umax = 3194, 2966, 1662, 1610, 1512, 1430, 1326, 1163, 1132, 1071, 926, 725 cm1. > HNMR (500 MHz, CDCI3) 57.99 (s, 1H), 7.90 (d, J = 7.76 Hz, 1H), 7.82 (d, J = 7.79 Hz, 1H), 7.61 (t, J = 7.76 Hz, 1H), 6.87 - 6.80 (m, 2H), 6.77 (s, 1H), 6.56 (dd, J= 8.54, 2.52 Hz, 1H), 4.56 (d, 7= 3.10 Hz, 2H), 3.80 (t, 7 = 7.65 Hz, 2H), 1.56 (h, 7 = 7.32 Hz, 2H), 0.93 (t, 7 = 7.37 Hz, 3H).13C NMR (125 MHz, CDCl3) δ 163.8, 144.0, 140.0, 132.0, 130.5, 130.2, 129.9, 129.7 (d), 129.3, 124.4, 119.0, 117.6, 111.4, 67.5, 42.6, 20.2, 11.1. HRMS (ESI) C18H17F3N2O4S, Calculated:

[0635] [M+H]+, 415.9039; Found: [M+H]+, 415.9038.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0636] Me

[0637]

[0638] 4-fluoro-2-methyl-N-(3-oxo-4-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)benzene sulfonamide (2e): To a flame dried flask was added 6-amino-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (0.0953 mmol, 1.0 eq.) and pyridine (23.0 pL, 0.286 mmol, 3.0 eq.) in CH2CI2 (1 mL, 0.09 M). The reaction stirred for 10 minutes at 0 °C before addition of 4-fluoro-2-methylbenzenesulfonyl chloride (23.9 mg, 0.114 mmol, 1.2 eq.) dropwise. The resulting solution was warmed to room temperature and stirred for 16 hours until completion. The reaction was quenched using H2O and extracted with EtOAc in triplicate. The organic layer was concentrated in vacuo, and purified via column chromatography (0 to 25% EtOAc in Hex) to yield the desired product (11.4 mg, 31% over 2 steps). IR (neat) Umax = 3227, 2965, 1667, 1604, 1513, 1336, 1171, 1065, 954, 868, 821, 728 cm’1.1H NMR (500 MHz, CDCl3) δ 7.90 (dd, J = 8.83, 5.64 Hz, 1H), 7.02 (dd, J = 9.21, 2.57 Hz, 1H), 6.95 (td, J = 8.31, 2.67 Hz, 1H), 6.82 (d, J = 8.50 Hz, 1H), 6.75 (d, J = 2.31 Hz, 1H), 6.64 (s, 1H), 6.53 (dd, J = 8.49, 2.34 Hz, 1H), 4.54 (s, 2H), 3.77 (t, 2H), 2.65 (s, 3H), 1.55 (h, J = 7.52 Hz, 2H), 0.94 (t, J = 7.40 Hz, 3H).13C NMR (125 MHz, CDCl3) δ 166.1, 163.9, 143.5, 140.7, 133.2, 132.9 (d, 7 = 9.89 Hz), 130.6, 129.2, 119.5 (d, 7= 22.22 Hz), 118.1, 117.6, 113.4 (d, 7 = 21.86 Hz), 110.4, 67.5, 42.7, 20.7, 20.2, 11.1. HRMS (ESI) C18H19F N2O4S, Calculated: [M+H]+, 379.1128; Found: [M+H]+, 379.1122.

[0639] Me

[0640]

[0641] 2,4,6-triisopropyl-N-(3-oxo-4-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)benzene sulfonamide (2f): To a flame dried flask was added 6-amino-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (0.0937 mmol, 1.0 eq.) and pyridine (22.2 pL, 0.281 mmol, 3.0 eq.) in CH2CI2 (1 mL, 0.09 M). The reaction stirred for 10 minutes at 0 °C before addition of 2,4,6-triisopropylbenzenesulfonyl chloride (34.1 mg, 0.112 mmol, 1.2 eq.) dropwise. The resulting solution was warmed to room temperature and stirred for 16 hours until completion. The reaction was quenched using H2O and extracted with EtOAc in triplicate. The organic4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0642] layer was concentrated in vacuo, and purified via column chromatography (0 to 25% EtOAc in Hex) to yield the desired product (7.0 mg, 16% over 2 steps). IR (neat) Umax = 3234, 2960, 2928, 1689, 1668, 1601, 1509, 1461, 1383, 1325, 1262, 1151, 1052, 883, 736 cm’1.1H NMR (500 MHz, CDCl3) δ 7.26 (s, 1H), 7.14 (s, 2H), 6.85 (d, J = 8.40 Hz, 1H), 6.68 - 6.60 (m, 2H), 6.28 (s, 1H), 4.53 (s, 2H), 3.92 (p, J = 6.76 Hz, 2H), 3.73 - 3.63 (m, 2H), 2.89 (p, J = 6.91 Hz, 1H), 1.45 (h, J = 7.41 Hz, 2H), 1.26 - 1.23 (m, 8H), 1.15 (d, J = 6.72 Hz, 10H), 0.86 (t, J = 7.46 Hz, 3H).13C NMR (125 MHz, CDCl3) δ 163.9, 153.3, 150.6, 144.1, 130.5, 128.9, 123.9, 121.2, 117.4, 113.2, 110.0, 67.5, 42.5, 34.1, 30.0, 29.7, 24.7, 23.5, 20.0, 11.1. HRMS (ESI) C26H36N2O4S, Calculated: [M+H]+, 473.2474; Found: [M+H]+, 473.2471.

[0643] Me

[0644]

[0645] 2,4-dichloro-N-(3-oxo-4-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)benzene sulfonamide (2g): To a flame dried flask was added 6-amino-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (0.0937 mmol, 1.0 eq.) and pyridine (22.2 pL, 0.281 mmol, 3.0 eq.) in CH2CI2 (1 mL, 0.09 M). The reaction stirred for 10 minutes at 0 °C before addition of 2,4-dichlorobenzenesulfonyl chloride (27.6 mg, 0.112 mmol, 1.2 eq.) dropwise. The resulting solution was warmed to room temperature and stirred for 16 hours until completion. The reaction was quenched using H2O and extracted with EtOAc in triplicate. The organic layer was concentrated in vacuo and purified via column chromatography (0 to 25% EtOAc in Hex) to yield the desired product (8.0 mg, 21% over 2 steps). IR (neat) Umax = 3216, 3056, 1668, 1614, 1573, 1383, 1333, 1264, 1166, 1102, 1040, 1008, 926, 818, 721 cm’1. ’H NMR (500 MHz, CDCh) 67.86 (d, 7= 8.50 Hz, 1H), 7.55 (d, 7= 1.96 Hz, 1H), 7.31 (dd, 7= 8.51, 1.96 Hz, 1H), 6.96 (s, 1H), 6.85 (d, 7= 2.30 Hz, 1H), 6.81 (d, 7= 8.49 Hz, 1H), 6.64 (dd, 7 = 8.53, 2.25 Hz, 1H), 4.54 (s, 2H), 3.80 (t, 7 = 7.64 Hz, 2H), 1.57 (h, 7= 7.60 Hz, 2H), 0.97 (t, 7= 7.40 Hz, 3H).13C NMR (125 MHz, CDCl3) δ 163.8, 143.9, 140.2, 134.6, 132.9, 132.2, 131.4, 129.9, 129.2, 127.7, 118.4, 117.6, 110.8, 67.5, 42.6, 20.2, 11.2. HRMS (ESI) C17H16Cl2N2O4S, Calculated: [M+H]+, 415.0286; Found: [M+H]+, 415.0282.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0646] Me

[0647]

[0648] 2,5-dimethoxy-N-(3-oxo-4-propyl-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)benzene sulfonamide (2h): To a flame dried flask was added 6-amino-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (0.0937 mmol, 1.0 eq.) and pyridine (22.2 pL, 0.281 mmol, 3.0 eq.) in CH2CI2 (1 mL, 0.09 M). The reaction stirred for 10 minutes at 0 °C before addition of 2,5-dimethoxybenzenesulfonyl chloride (26.6 mg, 0.112 mmol, 1.2 eq.) dropwise. The resulting solution was warmed to room temperature and stirred for 16 hours until completion. The reaction was quenched using H2O and extracted with EtOAc in triplicate. The organic layer was concentrated in vacuo, and purified via column chromatography (0 to 50% EtOAc in Hex) to yield the desired product (10.8 mg, 28% over 2 steps). IR (neat) Umax = 3265, 2952, 2837, 1667, 1608, 1535, 1325, 1221, 1153, 1026, 936, 811, 742 cm’1.1H NMR (500 MHz, CDCI3) 57.27 (d, J= 3.01 Hz, 1H), 7.04 (dd, J= 8.99, 3.10 Hz, 1H), 7.02 - 6.96 (m, 2H), 6.87 (d, J = 2.34 Hz, 1H), 6.77 (d, J = 8.50 Hz, 1H), 6.56 (dd, J = 8.53, 2.26 Hz, 1H), 4.52 (s, 2H), 4.02 (s, 3H), 3.79 (t, J= 7.69 Hz, 2H), 3.75 - 3.67 (m, 3H), 1.57 (h, J = 7.52 Hz, 2H), 0.94 (t, J = 7.46 Hz, 3H).13C NMR (125 MHz, CDCI3) 5 163.9, 153.4, 150.0, 143.4, 131.3, 129.0, 127.0, 120.7, 118.0, 117.3, 115.2, 113.9, 110.6, 67.5, 57.3, 56.0, 42.6, 20.2, 11.2. HRMS (ESI) C19H22N2O6S, Calculated: |M+H]+, 407.1277; Found: |M+H|+, 407.1276.

[0649] Me

[0650]

[0651] 3-methoxy-N-(3-oxo-4-propyl-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)benzene sulfonamide (2i): To a flame dried flask was added 6-amino-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (0.0937 mmol, 1.0 eq.) and pyridine (22.2 pL, 0.281 mmol, 3.0 eq.) in CH2CI2 (1 mL, 0.09 M). The reaction stirred for 10 minutes at 0 °C before addition of 3-methoxybenzenesulfonyl chloride (15.9 pL, 0.112 mmol, 1.2 eq.) dropwise. The resulting solution was warmed to room temperature and stirred for 16 hours until completion. The reaction was quenched using H2O and extracted with EtOAc in triplicate. The organic layer was concentrated in vacuo, and purified via column chromatography (0 to 40% EtOAc4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0652] in Hex) to yield the desired product (9.0 mg, 25% over 2 steps). IR (neat) Umax = 3234, 2957, 1662, 1598, 1512, 1483, 1424, 1323, 1249, 1158, 1043, 924, 698 cm’1.1H NMR (500 MHz, CDCh) 57.36 (t, J = 7.96 Hz, 1H), 7.31 (d, J = 7.69 Hz, 1H), 7.24 (s, 1H), 7.08 (d, 7= 8.07 Hz, 1H), 6.83 (d, 7= 8.51 Hz, 1H), 6.80 (s, 1H), 6.67 (s, 1H), 6.59 (dd, 7= 8.49, 2.27 Hz, 1H), 4.56 (s, 2H), 3.78 (s, 5H), 1.55 (h, 7 = 7.38 Hz, 2H), 0.92 (t, 7 = 7.34 Hz, 3H).13C NMR (125 MHz, CDC13) 5 163.9, 159.9, 143.6, 139.9, 130.9, 130.1, 129.0, 119.4, 118.8, 117.4, 112.0, 111.0, 67.5, 55.6, 42.6, 20.2, 11.1. HRMS (ESI) C18H20N2O5S, Calculated: [M+H]+, 377.1171; Found: [M+H]+, 377.1165.

[0653] Me

[0654]

[0655] 3-bromo-N-(3-oxo-4-propyl-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)benzenesulfonamide (2j): To a flame dried flask was added 6-amino-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (0.0852 mmol, 1.0 eq.) and pyridine (22.2 pL, 0.256 mmol, 3.0 eq.) in CH2CI2 (1 mL, 0.09 M). The reaction stirred for 10 minutes at 0 °C before addition of 3-bromobenzenesulfonyl chloride (23.0 mg, 0.102 mmol, 1.2 eq.) dropwise. The resulting solution was warmed to room temperature and stirred for 16 hours until completion. The reaction was quenched using H2O and extracted with EtOAc in triplicate. The organic layer was concentrated in vacuo, and purified via column chromatography (0 to 40% EtOAc in Hex) to yield the desired product (10.8 mg, 30% over 2 steps). IR (neat) Umax = 3156, 2963, 1927, 1662, 1611, 1511, 1386, 1342, 1269, 1165, 1068, 1008, 924, 773 cm1.1H NMR (501 MHz, CDCI3) 57.89 (s, 1H), 7.69 (d, 7 = 7.98 Hz, 1H), 7.63 (d, 7 = 7.86 Hz, 1H), 7.34 (t, 7 = 7.61 Hz, 1H), 6.86 (d, 7= 8.40 Hz, 1H), 6.79 (s, 1H), 6.57 (d, 7= 8.61 Hz, 1H), 6.48 (s, 1H), 4.59 (d, 7= 16.02 Hz, 2H), 3.81 (t, 7 = 7.60 Hz, 2H), 1.58 (q, 7= 7.53 Hz, 2H), 0.95 (t, 7 = 7.47 Hz, 3H).13C NMR (126 MHz, CDCh) 5 163.8, 136.2, 130.5, 130.3, 130.2, 129.2, 125.8, 123.1, 121.0, 119.1, 117.6, 115.4, 111.4, 67.5, 42.6, 20.2, 11.2.

[0656] HRMS (ESI) C17H17BrN2O4S, Calculated: [M+H]+, 425.0171; Found: [M+H]+, 425.0169.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0657] Me

[0658]

[0659] 2-bromo-N-(3-oxo-4-propyl-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)benzenesulfonamide (2k): To a flame dried flask was added 6-amino-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (0.0953 mmol, 1.0 eq.) and pyridine (23.1pL, 0.285 mmol, 3.0 eq.) in CH2CI2 (1 mL, 0.09 M). The reaction stirred for 10 minutes at 0 °C before addition of 2-bromobenzenesulfonyl chloride (48.6 mg, 0.190 mmol, 2.0 eq.) dropwise. The resulting solution was warmed to room temperature and stirred for 16 hours until completion. The reaction was quenched using H2O and extracted with EtOAc in triplicate. The organic layer was concentrated in vacuo and purified via column chromatography (0 to 25% EtOAc in Hex) to yield the desired product (7.7 mg, 19% over 2 steps). IR (neat) Umax = 3264, 2964, 2926, 1668, 1608, 1511, 1421, 1387, 1332, 1270, 1170, 1023, 927, 762, 741, 703 cm’1.1H NMR (500 MHz, CDCI3) 67.99 - 7.90 (m, 1H), 7.74 (dd, J = 6.51, 2.55 Hz, 1H), 7.44 - 7.35 (m, 2H), 7.10 (s, 1H), 6.86 (s, 1H), 6.79 (d, J = 8.50 Hz, 1H), 6.69 (d, J = 8.59 Hz, 1H), 4.52 (s, 2H), 3.78 (t, J = 7.71 Hz, 2H), 1.55 (h, 7 = 7.36 Hz, 2H), 0.95 (t, 7 = 7.39 Hz, 3H).13C NMR (125 MHz, CDC13) 5 163.8, 143.7, 137.6, 135.0, 134.2, 132.3, 130.2, 129.0, 128.0, 119.6, 118.6, 117.5, 110.8, 67.5, 42.6, 20.2, 11.2.

[0660] Me

[0661]

[0662] 2-bromo-N-(3-oxo-4-propyl-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)benzamide (3a):

[0663] To a flame dried flask was added 6-amino-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (0.0937 mmol, 1.0 eq.) and triethylamine (16.3 pL, 0.117 mmol, 1.3 eq.) in CH2CI2 (1 mL, 0.09 M). The reaction stirred for 10 minutes at 0 °C before addition of 2-bromobenzoyl chloride (15.4 pL, 0.117 mmol, 1.3 eq.) dropwise. The resulting solution was warmed to room temperature and stirred for 16 hours until completion. The reaction was quenched using sat. Naf ICCb and extracted with EtOAc in triplicate. The organic layer was concentrated in vacuo and purified via column chromatography (0 to 100% EtOAc in Hex) to yield the desired product (14.0 mg, 38% over 2 steps). IR (neat) Umax = 3282, 3054, 2967, 1662, 1616,4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0664] 1511, 1435, 1390, 1264, 1050, 732, 701 cm’1.1H NMR (500 MHz, CDCh) 87.73 (s, 1H), 7.67 (dd, 7= 17.34, 9.18 Hz, 3H), 7.42 (t, 7= 7.53 Hz, 1H), 7.34 (t, 7 = 7.78 Hz, 1H), 6.97 (s, 2H), 4.58 (s, 2H), 3.93 (t, 7 = 7.55 Hz, 2H), 1.75 (h, 7 = 7.53 Hz, 2H), 1.00 (t, 7 = 7.44 Hz, 3H).13C NMR (125 MHz, CDCh) 3 165.5, 164.3, 142.4, 137.5, 133.6, 132.7, 131.8, 129.9, 127.8, 119.2, 117.2, 115.0, 110.0, 107.9, 67.7, 42.8, 20.4, 11.2. HRMS (ESI) C18H17BrN2O3, Calculated: [M+H]+, 389.0501; Found: [M+H]+, 389.0501.

[0665] Me

[0666]

[0667] 2,4-dichloro-N-(3-oxo-4-propyl-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)benzamide (3b): To a flame dried flask was added 6-amino-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (0.0937 mmol, 1.0 eq.) and triethylamine (16.3 pL, 0.117 mmol, 1.3 eq.) in CH2Q2 (1 mL, 0.09 M). The reaction stirred for 10 minutes at 0 °C before addition of 2-bromobenzoyl chloride (16.4 pL, 0.117 mmol, 1.3 eq.) dropwise. The resulting solution was warmed to room temperature and stirred for 16 hours until completion. The reaction was quenched using sat. NaHCCh and extracted with EtOAc in triplicate. The organic layer was concentrated in vacuo and purified via column chromatography (0 to 20% EtOAc in Hex) to yield the desired product (12.7 mg, 36% over 2 steps). IR (neat) Umax = 3270, 3079, 2962, 1659, 1618, 1586, 1511, 1440, 1389, 1266, 1140, 1103, 1050, 823, 734 cm1.1H NMR (500 MHz, CDCh) 8 7.92 (s, 1H), 7.73 (d, 7 = 8.87 Hz, 2H), 7.48 (s, 1H), 7.37 (d, 7 = 8.47 Hz, 1H), 6.95 (q, 7 = 8.68 Hz, 2H), 4.58 (s, 2H), 3.91 (t, 7= 6.86 Hz, 2H), 1.75 (h, 7 = 9.70, 8.48 Hz, 2H), 1.00 (t, 3H).13C NMR (125 MHz, CDCh) 8 164.2, 163.4, 142.5, 137.5, 133.2, 132.5, 131.6, 131.4, 130.3, 129.0, 127.8, 117.2, 115.2, 108.0, 67.7, 42.8, 20.4, 11.2. HRMS (ESI) C18H16CI2N2O3, Calculated: [M+H]+, 379.6016; Found: [M+H]+, 379.6011.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0668] Me

[0669]

[0670] 3-nitro-N-(3-oxo-4-propyl-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)benzamide (3c): To a flame dried flask was added 6-amino-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (0.0937 mmol, 1.0 eq.) and triethylamine (16.3 pL, 0.117 mmol, 1.3 eq.) in CH2CI2 (1 mL, 0.09 M). The reaction stirred for 10 minutes at 0 °C before addition of 2-bromobenzoyl chloride (21.7 mg, 0.117 mmol, 1.3 eq.) dropwise. The resulting solution was warmed to room temperature and stirred for 16 hours until completion. The reaction was quenched using sat. Naf ICO / and extracted with EtOAc in triplicate. The organic layer was concentrated in vacuo and purified via column chromatography (0 to 35% EtOAc in Hex) to yield the desired product (12.7 mg, 36% over 2 steps). IR (neat) Umax = 3063, 2965, 1682, 1607, 1531, 1513, 1445, 1388, 1351, 1264, 1048, 732, 701 cm1.1H NMR (500 MHz, CDCh) 58.71 (s, 1H), 8.42 (d, J= 8.04 Hz, 1H), 8.28 (d, 7 = 7.77 Hz, 1H), 7.97 (s, 1H), 7.73 (t, 7 = 7.99 Hz, 1H), 7.68 (s, 1H), 7.06 -6.97 (m, 2H), 4.61 (s, 2H), 3.93 (t, 7 = 7.66 Hz, 2H), 1.76 (h, 7 = 7.43 Hz, 2H), 1.01 (t, 7 = 7.48 Hz, 3H).13C NMR (125 MHz, CDCh) 8 164.2, 163.3, 148.3, 142.6, 136.3, 133.4, 132.4, 130.2, 129.0, 126.5, 121.7, 117.3, 115.6, 108.3, 67.7, 42.8, 20.4, 11.2. HRMS (ESI) C18H17N3O5, Calculated: [M+H]+, 356.1246; Found: [M+H]+, 356.1241.

[0671] Me

[0672] H

[0673]

[0674] N-(3-oxo-4-propyl-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)-2-phenylacetamide (3d):

[0675] To a flame dried flask was added 6-amino-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (0.0937 mmol, 1.0 eq.) and triethylamine (16.3 pL, 0.117 mmol, 1.3 eq.) in CH2CI2 (1 mL, 0.09 M). The reaction stirred for 10 minutes at 0 °C before addition of phenylacetyl chloride (15.5 pL, 0.117 mmol, 1.3 eq.) dropwise. The resulting solution was warmed to room temperature and stirred for 16 hours until completion. The reaction was quenched using sat. NaHCCh and extracted with EtOAc in triplicate. The organic layer was concentrated in vacuo and purified via column chromatography (0 to 33% EtOAc in Hex) to yield the desired product (12.7 mg, 36% over 2 steps). IR (neat) Umax = 3297, 3062, 2962, 2931, 1682, 1615,4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0676] 1547, 1510, 1440, 1387, 1268, 1142, 1050, 857, 822, 730, 699 cm’1. ‘H NMR (500 MHz, CDCh) 57.63 (s, 1H), 7.40 (d, J = 6.36 Hz, 1H), 7.34 (d, 7 = 7.67 Hz, 3H), 6.85 (d, 7 = 8.52 Hz, 1H), 6.64 (dd, 7 = 7.89, 5.19 Hz, 1H), 4.54 (s, 2H), 3.87 (t, 7 = 7.59 Hz, 2H), 3.74 (s, 2H), 1.70 (h, 7 = 7.39 Hz, 2H), 0.96 (t, 7 = 7.21 Hz, 3H).13C NMR (125 MHz, CDCh) 3 169.2, 164.3, 142.0, 134.3, 133.0, 129.5, 129.3, 128.8, 127.7, 116.9, 114.8, 107.8, 67.7, 44.7, 42.7, 20.4, 11.2. HRMS (ESI) C19H20N2O3, Calculated: [M+H]+, 325.1552; Found: [M+H]+, 325.1554.

[0677] Me

[0678]

[0679] N-(3-oxo-4-propyl-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)benzamide (3e): To a flame dried flask was added 6-amino-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (0.0953 mmol, 1.0 eq.) and triethylamine (33.2 pL, 0.238 mmol, 2.5 eq.) in CH2Q2 (1 mL, 0.09 M). The reaction stirred for 10 minutes at 0 °C before addition of benzoyl chloride (27.7 pL, 0.238 mmol, 2.5 eq.) dropwise. The resulting solution was warmed to room temperature and stirred for 16 hours until completion. The reaction was quenched using sat. NaHCCh and extracted with EtOAc in triplicate. The organic layer was concentrated in vacuo and purified via column chromatography (0 to 35% EtOAc in Hex) to yield the desired product (9.0 mg, 30% over 2 steps). IR (neat) umax= 2962, 2906, 1686, 1608, 1507, 1449, 1389, 1337, 1051, 708 cm1.1H NMR (500 MHz, CDCh) 37.94 - 7.81 (m, 3H), 7.74 (s, 1H), 7.57 (t, 7 = 7.40 Hz, 1H), 7.50 (t, 7= 7.52 Hz, 2H), 7.02 - 6.90 (m, 2H), 4.59 (s, 2H), 3.93 (t, 7= 7.61 Hz, 2H), 1.75 (h, 7= 7.38 Hz, 2H), 1.00 (t, 7= 7.37 Hz, 3H).13C NMR (125 MHz, CDCh) 8 165.8, 164.3, 142.2, 134.7, 133.1, 132.0, 128.9, 127.0, 117.1, 115.2, 108.1, 67.7, 42.8, 20.4, 11.2.

[0680] Me

[0681]

[0682] 3-bromo-N-(3-oxo-4-propyl-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)benzamide (3f):

[0683] To a flame dried flask was added 6-amino-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (0.0953 mmol, 1.0 eq.) and triethylamine (33.2 pL, 0.238 mmol, 2.5 eq.) in CH2Q2 (1 mL,4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0684] 0.09 M). The reaction stirred for 10 minutes at 0 °C before addition of 3-bromobenzoyl chloride (31.5 |iL, 0.238 mmol, 2.5 eq.) dropwise. The resulting solution was warmed to room temperature and stirred for 16 hours until completion. The reaction was quenched using sat. NaHCCh and extracted with EtOAc in triplicate. The organic layer was concentrated in vacuo and purified via column chromatography (0 to 35% EtOAc in Hex) to yield the desired product (13.2 mg, 36% over 2 steps). IR (neat) Umax = 3305, 2962, 2929, 1667, 1617, 1511, 1441, 1391, 1258, 1087,1051, 918, 739 cm H NMR (500 MHz, CDCh) 58.01 (s, 1H), 7.84 - 7.78 (m, 2H), 7.72 - 7.66 (m, 2H), 7.38 (t, J = 7.89 Hz, 1H), 6.97 (s, 2H), 4.59 (s, 2H), 3.92 (t, 7= 7.63 Hz, 2H), 1.75 (h, J= 7.38 Hz, 2H), 1.00 (t, 7 = 7.40 Hz, 3H).13C NMR (125 MHz, CDCh) 5 164.3, 164.2, 142.4, 136.7, 135.0, 132.8, 130.4, 130.2, 128.9, 125.6, 123.0, 117.2, 115.4, 108.2, 67.7, 42.8, 20.4, 11.2. HRMS (ESI) Ci8Hi7BrN2O3, Calculated:

[0685] [M+H]+, 389.0501; Found: [M+H]+, 389.0494.

[0686]

[0687] 2,3-dimethyl-N-(3-oxo-4-propyI-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)benzamide (3g): To a flame dried flask was added 6-amino-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (0.0852 mmol, 1.0 eq.) and triethylamine (10.8 pL, 0.107 mmol, 1.3 eq.) in CH2CI2 (1 mL, 0.08 M). The reaction stirred for 10 minutes at 0 °C before addition of 2-bromobenzoyl chloride (18.0 mg, 0.107 mmol, 1.3 eq.) dropwise. The resulting solution was warmed to room temperature and stirred for 16 hours until completion. The reaction was quenched using sat. NaHCCh and extracted with EtOAc in triplicate. The organic layer was concentrated in vacuo and purified via column chromatography (0 to 25% EtOAc in Hex) to yield the desired product (4.3 mg, 15% over 2 steps). IR (neat) Umax = 3288, 1916, 1665, 1616, 1512, 1444, 1389, 1266, 1212, 1053 cm1.1H NMR (500 MHz, CDCh) 57.72 (d, J = 2.22 Hz, 1H), 7.41 (s, 1H), 7.31 (d, J = 6.95 Hz, 1H), 7.26 (d, J = 7.57 Hz, 1H), 7.18 (q, J = 7.56, 6.73 Hz, 1H), 6.99 - 6.90 (m, 2H), 4.58 (s, 2H), 3.93 (t, 2H), 2.38 (s, 3H), 2.33 (s, 3H), 1.76 (h, J = 7.43 Hz, 2H), 1.00 (t, J = 7.34 Hz, 3H).13C NMR (125 MHz, CDCh) 5 177.68, 138.27, 137.03, 134.36, 133.27, 131.66, 128.92, 125.69, 124.89, 124.16, 117.10, 114.67, 107.50, 67.71,4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0688] 42.79, 20.39, 20.27, 16.35, 11.20. HRMS (ESI) C20H22N2O3, Calculated: [M+H]+, 339.1709; Found: [M+H]+, 339.1707.

[0689]

[0690] 6-bromo-2H-benzo[b][l,4]oxazin-3(4H)-one (14): To a flame dried flask was added 2-amino-4-bromophenol (2.00 g, 10.6 mmol, 1.0 eq.) and potassium carbonate (2.94 g, 21.3 mmol, 2.0 eq.) in anhydrous MeCN (41 ml, 0.26 M). The resulting mixture was allowed to stir at room temperature for 10 min before the slowly addition of chloroacetyl chloride (1.01 mL, 10.6 mmol, 1.2 eq.). The mixture was then heated to reflux (75 °C) for 20 hours until completion. After cooling down to room temperature, the resulting mixture was quenched with water and extracted with EtOAc in triplicate. The organic phase was concentrated in vacuo and used without further purification as a brown powder.1H NMR (500 MHz, DMSO) 58.35 (s, 1H), 7.09 (dd, J = 8.59, 2.20 Hz, 1H), 6.96 (d, J = 2.19 Hz, 1H), 6.86 (d, J = 8.59 Hz, 1H), 4.62 (s, 2H).13C NMR (125 MHz, DMSO) 5 165.1, 143.1, 129.5, 125.8, 118.5, 118.4, 113.7, 67.1. HRMS (ESI) C8H6BrNO2, Calculated: [M+H]+, 227.9660; Found:

[0691] [M+H]+, 227.9657.

[0692] Me

[0693]

[0694] 6-bromo-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (16): To a flame dried flask was added 6-bromo-2H-benzo[b][l,4]oxazin-3(4H)-one (250 mg, 1.10 mmol, 1.0 eq.) in anhydrous DMF (2.2 mL, 0. 5 M). The mixture was cooled down to 0 °C and sodium hydride (87.7 mg, 2.19 mmol, 2.0 eq., 60% dispersion in mineral oil) was slowly added into the reaction vessel. Then 1 -bromopropane (105 |_iL, 1.32 mmol, 1.2 eq.) was added into the reaction mixture at 0 °C. The resulting solution was warmed to room temperature and stirred overnight until completion. The organic layer was concentrated in vacuo and purified via column chromatography (0 to 10% EtOAc in Hex) to yield the desired product (221.1 mg, 75%).1H NMR (500 MHz, CDCh) 67.10 - 7.06 (m, 2H), 6.85 (d, J = 8.14 Hz, 1H), 4.57 (s, 2H), 3.89 - 3.79 (m, 2H), 1.68 (h, 7= 7.44 Hz, 2H), 0.98 (t, 7 = 7.43 Hz, 3H).13C NMR (1254239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0695] MHz, CDCh) 5 163.8, 144.5, 129.9, 126.3, 118.5, 117.80, 114.9, 67.5, 42.7, 20.2, 11.1. HRMS (ESI) C11H12BrNO2, Calculated: [M+H]+, 270.0130; Found: [M+H]+, 270.0127.

[0696] Me

[0697]

[0698] 6-phenyl-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (4a): To a microwave vial was added 6-bromo-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (25.0 mg, 0.0925 mmol, 1.0 eq.), tetrakis(triphenylphosphine)palladium(0) (10.7 mg, 0.0093 mmol, 10 mol %), and phenylboronic acid (22.6 mg, 0.185 mmol, 2.0 eq.) in 1,4-dioxane (3.27 mL, 0.03M) and cesium carbonate (121 mg, 0.370 mmol, 4.0 eq.) in H2O (0.578 mL, 0.64 M relative to base). The reaction was heated using microwave irradiation for 45 min at 120 °C. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 15% EtOAc in Hex) to yield the desired product (21.6 mg, 87%). IR (neat) Umax = 2963, 2875, 1678, 1607, 1486, 1430, 1372, 1266, 1133, 1056, 970, 866, 761 cm1.1H NMR (500 MHz, CDCh) 57.53 (d, J = 7.05 Hz, 2H), 7.46 (t, J = 7.60 Hz, 2H), 7.36 (t, J = 7.23 Hz, 1H), 7.21 (dd, J = 8.33, 2.02 Hz, 1H), 7.16 (d, J= 2.04 Hz, 1H), 7.06 (d, J= 8.28 Hz, 1H), 4.64 (s, 2H), 3.97 (t, J = 7.64 Hz, 2H), 1.76 (h, J = 7.55 Hz, 2H), 1.01 (t, J = 7.45 Hz, 3H).13C NMR (125 MHz, CDCh) 8 164.2, 144.9, 140.6, 136.3, 128.9, 128.79, 127.3, 127.0, 122.5, 117.4, 113.8, 67.7, 42.6, 20.5, 11.3. HRMS (ESI) C17H18NO2, Calculated: [M+H]+, 268.1338; Found: [M+H]+, 268.1337.

[0699] Me Me

[0700]

[0701] 4-propyl-6-(m-tolyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (4b): To a microwave vial was added 6-bromo-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (25.0 mg, 0.0925 mmol, 1.0 eq.), tetrakis(triphenylphosphine)palladium(0) (10.7 mg, 0.0093 mmol, 10 mol %), and m-tolylboronic acid (25.2 mg, 0.185 mmol, 2.0 eq.) in 1,4-dioxane (3.27 mL, 0.03M) and cesium carbonate (121 mg, 0.370 mmol, 4.0 eq.) in H2O (0.578 mL, 0.64 M relative to base).4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0702] The reaction was heated using microwave irradiation for 45 min at 120 °C. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 10% EtOAc in Hex) to yield the desired product (18.1 mg, 70%). IR (neat) Umax = 2962, 1683, 1605, 1516, 1485, 1444, 1368, 1278, 1062, 1044, 864, 827, 784, 701 cm’1. ‘H NMR (500 MHz, CDCI3) 57.34 (q, J = 7.48 Hz, 3H), 7.19 (dd, J = 8.28, 1.98 Hz, 2H), 7.15 (d, J = 2.00 Hz, 1H), 7.05 (d, J= 8.21 Hz, 1H), 4.63 (s, 2H), 3.97 (t, 2H), 2.44 (s, 3H), 1.75 (h, J = 7.44 Hz, 2H), 1.00 (t, J= 7.42 Hz, 3H).13C NMR (125 MHz, CDCh) 5 164.3, 144.8, 140.6, 138.5, 136.5, 128.8, 128.1, 127.8, 127.0, 124.1, 122.6, 117.3, 113.8, 67.7, 42.6, 21.6, 20.5, 11.2. HRMS (ESI) C18H19NO2, Calculated: [M+H]+, 282.1494; Found: [M+H]+, 282.1492.

[0703] Me

[0704]

[0705] 4-propyl-6-(o-tolyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (4c): To a microwave vial was added 6-bromo-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (25.0 mg, 0.0925 mmol, 1.0 eq.), tetrakis(triphenylphosphine)palladium(0) (10.7 mg, 0.0093 mmol, 10 mol %), and o-tolylboronic acid (25.2 mg, 0.185 mmol, 2.0 eq.) in 1,4-dioxane (3.27 mL, 0.03M) and cesium carbonate (121 mg, 0.370 mmol, 4.0 eq.) in H2O (0.578 mL, 0.64 M relative to base). The reaction was heated using microwave irradiation for 45 min at 120 °C. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 15% EtOAc in Hex) to yield the desired product (25.2 mg, 97%). IR (neat) Umax = 2963, 2785, 1682, 1608, 1484, 1434, 1385, 1266, 1133, 1056, 971, 825, 766 cm1.1H NMR (500 MHz, CDCh) 57.30 - 7.23 (m, 3H), 7.21 (d, 7 = 6.79 Hz, 1H), 7.02 (d, 7= 8.11 Hz, 1H), 6.96 - 6.90 (m, 2H), 4.64 (s, 2H), 3.88 (t, 2H), 2.28 (s, 3H), 1.70 (h, 7 = 7.38 Hz, 2H), 0.96 (t, 7 = 7.32 Hz, 3H).13C NMR (125 MHz, CDCh) 5 163.7, 143.7, 140.5, 136.0, 134.8, 129.9, 129.2, 127.5, 126.9, 125.3, 123.9, 116.1, 115.2, 67.1, 42.1, 19.9, 19.8, 10.6. HRMS (ESI) C18H19NO2, Calculated: [M+H]+, 282.1484; Found: [M+H]+, 282.1491.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0706] Me

[0707]

[0708] 6-(2,4-dichlorophenyl)-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (4d): To a microwave vial was added 6-bromo-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (25.0 mg, 0.0925 mmol, 1.0 eq.), tetrakis(triphenylphosphine)palladium(0) (10.7 mg, 0.0093 mmol, 10 mol %), and (3-5-dichlorophenyl)boronic acid (35.3 mg, 0.185 mmol, 2.0 eq.) in 1,4-dioxane (3.27 mL, 0.03M) and cesium carbonate (121 mg, 0.370 mmol, 4.0 eq.) in H2O (0.578 mL, 0.64 M relative to base). The reaction was heated using microwave irradiation for 45 min at 120 °C. The reaction was quenched with H2O and extracted with EtOAc in triplicate, in vacuo, and purified via column chromatography (0 to 15% EtOAc in Hex) to yield the desired product (21.6 mg, 87%). IR (neat) umax= 2964, 1683, 1608, 1469, 1444, 1388, 1275, 1103, 816, 801 cm1.XH NMR (500 MHz, CDCl3) δ 7.50 (s, 1H), 7.29 (dd, 7 = 23.80, 8.43 Hz, 2H), 7.06 -6.97 (m, 3H), 4.65 (s, 2H), 3.89 (t, 7 = 6.41 Hz, 2H), 1.71 (h, 7 = 9.55, 9.02 Hz, 2H), 0.98 (t, 7= 6.20 Hz, 3H).13C NMR (125 MHz, CDCh) 5 163.5, 144.5, 137.6, 133.3, 132.6, 132.2, 131.4, 129.3, 127.5, 126.7, 124.0, 116.3, 115.6, 67.0, 42.1, 19.8, 10.6. HRMS (ESI) C17H15CI2NO2, Calculated: [M+H]+, 336.0558; Found: [M+H]+, 336.0553.

[0709] Me

[0710]

[0711] 6-(2-hydroxyphenyl)-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (4e): To a microwave vial was added 6-bromo-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (25.0 mg, 0.0925 mmol, 1.0 eq.), tetrakis(triphenylphosphine)palladium(0) (10.7 mg, 0.0093 mmol, 10 mol %), and (2-hydroxyphenyl)boronic acid (25.5 mg, 0.185 mmol, 2.0 eq.) in 1,4-dioxane (3.27 mL, 0.03M) and cesium carbonate (121 mg, 0.370 mmol, 4.0 eq.) in H2O (0.578 mL, 0.64 M relative to base). The reaction was heated using microwave irradiation for 45 min at 120 °C. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 15% EtOAc in Hex) to yield the desired product (23.5 mg, 90%). IR (neat) Umax = 3318, 2964, 1656, 1603, 1436, 1393, 1270, 1057, 818, 754 cm’1. 'H NMR (500 MHz, CDCh) 54239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0712] 7.30 - 7.22 (m, 2H), 7.14 - 7.07 (m, 3H), 7.00 (dd, J= 16.42, 7.79 Hz, 2H), 5.42 (s, 1H), 4.64 (s, 2H), 3.91 (t, 7 = 7.51 Hz, 2H), 1.71 (h, 7 = 7.05 Hz, 2H), 0.97 (t, 7 = 7.44 Hz, 3H).

[0713] 13C NMR (125 MHz, CDC13) 5 164.3, 152.6, 145.0, 131.9, 130.3, 129.2, 129.0, 127.5, 124.4, 121.0, 117.6, 116.0, 115.4, 67.6, 42.7, 20.4, 11.2. HRMS (ESI) C17H18NO3, Calculated: [M+H]+, 284.1287; Found: [M+H]+, 284.1280.

[0714] Me

[0715]

[0716] 6-(2-methoxyphenyl)-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (4f): To a microwave vial was added 6-bromo-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (24.6 mg, 0.0911 mmol, 1.0 eq.), tetrakis(triphenylphosphine)palladium(0) (10.7 mg, 0.0093 mmol, 10 mol %), and (2-methoxyphenyl)boronic acid (28.1 mg, 0.185 mmol, 2.0 eq.) in 1,4-dioxane (3.27 mL, 0.03M) and cesium carbonate (121 mg, 0.370 mmol, 4.0 eq.) in H2O (0.578 mL, 0.64 M relative to base). The reaction was heated using microwave irradiation for 1 hour at 120 °C. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 10% EtOAc in Hex) to yield the desired product (20.0 mg, 74%). IR (neat) Umax = 2958, 2874, 2831, 1678, 1608, 1485, 1442, 1384, 1239, 1049, 1025, 750 cm1. 'H NMR (500 MHz, CDCI3) 57.37 - 7.29 (m, 2H), 7.21 (d, 7= 1.93 Hz, 1H), 7.13 (dd, 7 = 8.24, 1.95 Hz, 1H), 7.07 - 6.99 (m, 3H), 4.63 (s, 2H), 3.97 - 3.88 (m, 2H), 3.83 (s, 3H), 1.74 (h, 7= 14.96, 7.47 Hz, 2H), 0.99 (t, 7= 7.43 Hz, 3H).13C NMR (125 MHz, CDCI3) 6 164.3, 156.3, 144.4, 133.0, 130.6, 129.7, 128.8, 127.9, 124.7, 121.0, 116.7, 116.5, 111.3, 67.7, 55.5, 42.6, 20.3, 11.2. HRMS (ESI) C18H19NO3, Calculated: [M+H]+, 298.1443; Found: [M+H]+, 298.1440.

[0717] Me

[0718]

[0719] 6-(2,4-difhiorophenyl)-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (4g): To a microwave vial was added 6-bromo-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (25.0 mg, 0.0925 mmol, 1.0 eq.), tetrakis(triphenylphosphine)palladium(0) (10.7 mg, 0.0093 mmol, 10 mol %),4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0720] and (2,4-difluorophenyl)boronic acid (29.2 mg, 0.185 mmol, 2.0 eq.) in 1,4-dioxane (3.27 mL, 0.03M) and cesium carbonate (121 mg, 0.370 mmol, 4.0 eq.) in H2O (0.578 mL, 0.64 M relative to base). The reaction was heated using microwave irradiation for 1 hour at 120 °C. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 8% EtOAc in Hex) to yield the desired product (11.0 mg, 39%). IR (neat) Umax = 2964, 1683, 1609, 1493, 1419, 1379, 1272, 1139, 1101, 1052, 850, 811 cm1.1H NMR (500 MHz, CDCh) 87.36 (q, J= 8.27 Hz, 1H), 7.12 - 7.07 (m, 2H), 7.05 (d, 7= 8.18 Hz, 1H), 6.94 (dt, 7 = 19.82, 8.82 Hz, 2H), 4.63 (s, 2H), 3.93 (t, J= 7.64 Hz, 2H), 1.72 (h, J= 7.48 Hz, 2H), 0.98 (t, 7= 7.41 Hz, 3H).13C NMR (125 MHz, CDCh) 6 163.5, 162.6, 144.4, 130.6 (d, 7 = 4.42 Hz), 130.5 (d, 7 = 4.60 Hz), 129.0, 127.9, 123.5, 116.6, 115.0 (d, 7= 3.73 Hz), 111.2 (d, 7 = 3.41 Hz), 111.0 (d), 103.9 (t, 7 = 26.12 Hz), 67.0, 42.0, 19.7, 10.6. HRMS (ESI) C17H16F2NO2, Calculated: [M+H]+, 304.1149; Found: [M+H]+, 304.1143.

[0721] Me

[0722]

[0723] 4-propyl-6-(pyridin-4-yl)-2H-benzo[b][l,4]oxazin-3(4H)-one (4h): To a microwave vial was added 6-bromo-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (25.0 mg, 0.0925 mmol, 1.0 eq.), tetrakis(triphenylphosphine)palladium(0) (10.7 mg, 0.0093 mmol, 10 mol %), and pyridine-4-ylboronic acid (22.8 mg, 0.185 mmol, 2.0 eq.) in 1,4-dioxane (3.27 mL, 0.03M) and cesium carbonate (121 mg, 0.370 mmol, 4.0 eq.) in H2O (0.578 mL, 0.64 M relative to base). The reaction was heated using microwave irradiation for 1 hour at 120 °C. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 50% EtOAc in Hex) to yield the desired product (13.8 mg, 56%). IR (neat) Umax = 2963, 1681, 1596, 1487, 1445, 1384, 1275, 1057, 810 cm’1. 'HNMR (500 MHz, CDCh) 88.66 (d, 7 = 4.67 Hz, 2H), 7.50 - 7.38 (m, 2H), 7.32 - 7.23 (m, 1H), 7.19 (s, 1H), 7.09 (d, 7 = 8.34 Hz, 1H), 4.65 (s, 2H), 3.97 (t, 7= 7.57 Hz, 2H), 1.75 (h, 7 = 7.26 Hz, 2H), 1.01 (t, 7 = 7.45 Hz, 3H).13C NMR (125 MHz, CDCh) 8 163.9, 150.4, 147.6, 146.2, 133.1, 129.2, 122.5, 121.4,4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0724] 117.8, 113.5, 67.6, 42.6, 20.5, 11.3. HRMS (ESI) C16H16N2O2, Calculated: [M+H]+, 269.1290; Found: [M+H]+, 269.1290.

[0725] Me

[0726]

[0727] 4-propyl-6-(3-(trifluoromethoxy)phenyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (4i): To a microwave vial was added 6-bromo-4-propyl-2H-benzo[b][1,4]oxazin-3(4H)-one (25.0 mg, 0.0925 mmol, 1.0 eq.), tetrakis(triphenylphosphine)palladium(0) (10.7 mg, 0.0093 mmol, 10 mol %), and (3-(trifluoromethoxy)phenyl)boronic acid (38.1 mg, 0.185 mmol, 2.0 eq.) in 1,4-dioxane (3.27 mL, 0.03M) and cesium carbonate (121 mg, 0.370 mmol, 4.0 eq.) in H2O (0.578 mL, 0.64 M relative to base). The reaction was heated using microwave irradiation for 1 hour at 120 °C. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 10% EtOAc in Hex) to yield the desired product (22.6 mg, 70%). IR (neat) umax= 2965, 1683, 1607, 1484, 1251, 1216, 1160, 1057, 791, 734, 703 cm1.

[0728] NMR (500 MHz, CDCI3) 37.49 - 7.43 (m, 2H), 7.35 (s, 1H), 7.23 - 7.15 (m, 2H), 7.12 (d, J= 2.14 Hz, 1H), 7.06 (d, J = 8.25 Hz, 1H), 4.64 (s, 2H), 3.96 (t, J= 7.65 Hz, 2H), 1.75 (h, J = 7.50 Hz, 2H), 1.00 (t, J = 7.45 Hz, 3H).13C NMR (125 MHz, CDCI3) 6 163.5, 149.1, 144.8, 142.0, 134.1, 129.6, 128.3, 124.6, 121.9, 120.9, 118.9, 116.9, 113.1, 67.0, 42.0, 19.8, 10.6. HRMS (ESI) C18H16F3NO3, Calculated: [M+H]+, 352.1161; Found: [M+H]+, 352.1159.

[0729] Me

[0730]

[0731] 6-(2,3-dimethyl)-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (4j): To a microwave vial was added 6-bromo-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (50.0 mg, 0.185 mmol, 1.0 eq.), tetrakis(triphenylphosphine)palladium(0) (21.4 mg, 0.0185 mmol, 10 mol %), and (2,3-dimethylphenyl)boronic acid (55.5 mg, 0.370 mmol, 2.0 eq.) in 1,4-dioxane (6.54 mL, 0.03M) and cesium carbonate (241 mg, 0.740 mmol, 4.0 eq.) in H2O (1.16 mL, 0.64 M relative to base). The reaction was heated using microwave irradiation for 1 hour at 120 °C.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0732] The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 10% EtOAc in Hex) to yield the desired product (31.4 mg, 57%). IR (neat) Umax = 2965, 1683, 1607, 1484, 1428, 1385, 1251, 1216, 1160, 1059, 791, 734, 703 cm’1. 'H NMR (500 MHz, CDCI3) 57.21 - 7.14 (m, 2H), 7.08 (dd, J = 6.92, 1.48 Hz, 1H), 7.03 (d, J= 7.96 Hz, 1H), 6.96 - 6.89 (m, 2H), 4.65 (s, 2H), 3.89 (t, 2H), 2.36 (s, 3H), 2.18 (s, 3H), 1.71 (h, 7 = 7.47 Hz, 2H), 0.97 (t, 7= 7.42 Hz, 3H).13C NMR (125 MHz, CDCI3) 5 164.3, 144.2, 141.4, 137.4, 137.2, 134.1, 129.1, 128.0, 127.6, 125.4, 124.6, 116.6, 116.0, 67.7, 42.6, 20.7, 20.4, 17.0, 11.2. HRMS (ESI) C19H21NO2, Calculated: [M+H]+, 296.1651; Found: [M+H]+, 296.1645.

[0733] Me

[0734]

[0735] Me

[0736] 6-((2,3-dimethylphenyl)amino)-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (5a): To a flame dried flask was added 6-bromo-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (25.0 mg, 0.0925 mmol, 1.0 eq.), tris(dibenzylideneacetone)dipalladium(0) (4.2 mg, 0.0046 mmol, 5 mol %), BINAP (5.8 mg, 0.00925 mmol, 10 mol %), cesium carbonate (60.3 mg, 0.185 mmol, 2.0 eq.) and 2,3-dimethylaniline (13.5 pL, 0.111 mmol, 1.2 eq.) in toluene (1 mL, 0.1 M). The reaction was heated at 110 °C for 24 h. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 15% EtOAc in Hex) to yield the desired product (9.5 mg, 33%). IR (neat) Umax = 3354, 2960, 2904, 1667, 1606, 1511, 1471, 1389, 1331, 1262, 1206, 1051, 811, 771, 741, 709 cm. 'H NMR ’H NMR (500 MHz, MeOD) 57.02 - 6.93 (m, 2H), 6.85 (d, 7 = 7.47 Hz, 1H), 6.80 (d, 7 = 8.60 Hz, 1H), 6.58 (d, 7 = 2.46 Hz, 1H), 6.46 (dd, 7= 8.44, 2.06 Hz, 1H), 4.48 (s, 2H), 3.78 (t, 2H), 2.29 (s, 3H), 2.14 (s, 3H), 1.62 (h, 7= 14.96, 7.46 Hz, 2H), 0.90 (t, 7 = 7.43 Hz, 3H).13C NMR (125 MHz, MeOD) 8 165.5, 142.0, 141.6, 138.4, 137.4, 129.0, 128.6, 125.5, 124.2, 119.0, 116.8, 111.3, 103.4, 67.4, 42.2, 20.0, 19.2, 12.5, 9.9. HRMS (ESI) C19H22N2O2, Calculated: [M+H]+, 311.1760; Found: [M+H]+, 311.1765.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0737] Me

[0738]

[0739] Cl

[0740] 6-((3-chloro-2-methylphenyl)amino)-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (5b):

[0741] To a flame dried flask was added 6-bromo-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (25.0 mg, 0.0925 mmol, 1.0 eq.), tris(dibenzylideneacetone)dipalladium(0) (4.2 mg, 0.0046 mmol, 5 mol %), BINAP (5.8 mg, 0.00925 mmol, 10 mol %), cesium carbonate (60.3 mg, 0.185 mmol, 2.0 eq.) and 3-chloro-2-methylaniline (13.3 pL, 0.111 mmol, 1.2 eq.) in toluene (1 mL, 0.1 M). The reaction was heated at 110 °C for 24 h. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 10% EtOAc in Hex) to yield the desired product (25.9 mg, 85%). IR (neat) Umax = 3367, 2963, 1675, 1612, 1573, 1509, 1455, 1384, 1264, 1213, 1051, 1014, 733, 702 cm’1. 'H NMR (500 MHz, CDCI3) 5 7.02 (d, 7= 6.98 Hz, 2H), 6.96 (d, 7= 9.00 Hz, 1H), 6.91 (d, 7= 8.44 Hz, 1H), 6.63 (d, 7 = 13.51 Hz, 2H), 4.57 (s, 2H), 3.81 (t, 2H), 2.33 (s, 3H), 1.66 (h, 7 = 7.47 Hz, 2H), 0.94 (t, 7 = 7.41 Hz, 3H).13C NMR (125 MHz, CDCI3) 5 164.4, 143.7, 140.5, 138.4, 135.4, 129.4, 127.0, 125.1, 122.3, 117.7, 115.6, 114.9, 107.0, 67.8, 42.6, 20.4, 14.4, 11.1. HRMS (ESI) C18H19CIN2O2, Calculated: [M+H]+, 331.1213; Found: [M+H]+, 331.1208.

[0742] Me

[0743]

[0744] Br

[0745] 6-((3-bromophenyl)amino)-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (5c): To a flame dried flask was added 6-bromo-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (25.0 mg, 0.0925 mmol, 1.0 eq.), tris(dibenzylideneacetone)dipalladium(0) (4.2 mg, 0.0046 mmol, 5 mol %), BINAP (5.8 mg, 0.00925 mmol, 10 mol %), cesium carbonate (60.3 mg, 0.185 mmol, 2.0 eq.) and 3 -bromoaniline (12.1 pL, 0.111 mmol, 1.2 eq.) in toluene (1 mL, 0.1 M). The reaction was heated at 110 °C for 24 h. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0746] vacuo, and purified via column chromatography (0 to 10% EtOAc in Hex) to yield the desired product (8.5 mg, 25%). IR (neat) Umax = 3343, 2963, 2874, 1669, 1589, 1510, 1477, 1412, 1384, 1337, 1275, 1214, 1051, 988, 843, 769 cm-1. 'H NMR (500 MHz, MeOD) 67.18 - 7.04 (m, 2H), 6.91 (d, 7= 6.30 Hz, 3H), 6.78 (d, 7= 8.76 Hz, 1H), 4.55 (s, 2H), 3.88 (t, 7 = 7.65 Hz, 2H), 1.69 (h, 2H), 1.02 - 0.93 (m, 3H).13C NMR (125 MHz, MeOD) 8 164.8, 146.0, 139.9, 137.4, 129.8, 128.3, 122.0, 121.0, 117.2, 116.6, 114.1, 113.7, 106.3, 66.8, 41.7, 19.5, 9.5. HRMS (ESI) C17H17CIN2O2, Calculated: [M+H]+, 361.0552; Found: [M+H]+, 361.0547.

[0747]

[0748] 6-((2-bromophenyl)amino)-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (5d): To a flame dried flask was added 6-bromo-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (25.0 mg, 0.0925 mmol, 1.0 eq.), tris(dibenzylideneacetone)dipalladium(0) (4.2 mg, 0.0046 mmol, 5 mol %), BINAP (5.8 mg, 0.00925 mmol, 10 mol %), cesium carbonate (60.3 mg, 0.185 mmol, 2.0 eq.) and 2 -bromoaniline (12.7 pL, 0.111 mmol, 1.2 eq.) in toluene (1 mL, 0.1 M). The reaction was heated at 110 °C for 24 h. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 6% EtOAc in Hex) to yield the desired product (3.4 mg, 10%). IR (neat) vmax= 3393, 2926, 1685, 1590, 1511, 1454, 1385, 1276, 1050, 1022, 744 cm1.1H NMR (500 MHz, CDCh) 57.52 (dd, 7 = 7.99, 1.48 Hz, 1H), 7.14 (ddd, 7= 8.44, 7.24, 1.47 Hz, 1H), 7.02 (dd, 7= 8.19, 1.54 Hz, 1H), 6.98 - 6.93 (m, 1H), 6.83 - 6.77 (m, 2H), 6.72 (ddd, 7 = 8.00, 7.25, 1.55 Hz, 1H), 5.99 (s, 1H), 4.59 (s, 2H), 3.85 (t, 2H), 1.68 (h, 7= 15.06, 7.50 Hz, 2H), 0.97 (t, 7 = 7.43 Hz, 3H).13C NMR (126 MHz, CDCh) 8 164.3, 142.3, 141.6, 136.4, 133.0, 129.4, 128.2, 120.5, 117.7, 117.4, 114.7, 111.3, 109.4, 67.7, 42.6, 20.4, 11.2. HRMS (ESI) C17H17CIN2O2, Calculated: [M+H]+, 361.0552; Found: [M+H]+, 361.0546.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0749]

[0750] 6-(phenylamino)-4-propyl-2H-benzo[b][1,4]oxazin-3(4H)-one (5e): To a flame dried flask was added 6-bromo-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (50.0 mg, 0.185 mmol, 1.0 eq.), tris(dibenzylideneacetone)dipalladium(0) (8.5 mg, 0.009 mmol, 5 mol %), BINAP (11.5 mg, 0.019 mmol, 10 mol %), cesium carbonate (120.6 mg, 0.370 mmol, 2.0 eq.) and 2-bromoaniline (20.3 pL, 0.222 mmol, 1.2 eq.) in toluene (2 mL, 0.1 M). The reaction was heated at 110 °C for 24 h. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 12% EtOAc in Hex) to yield the desired product (30.3 mg, 58%). IR (neat) Umax = 3358, 3049, 2964, 1672, 1596, 1510, 1495, 1457, 1424, 1385, 1334, 1263, 1236, 1213, 1050, 1005, 812, 742 cm’1.XH NMR (500 MHz, CDCh) 57.26 (t, 2H), 6.98 (d, J = 7.90 Hz, 2H), 6.91 (d, J = 8.51 Hz, 2H), 6.76 (s, 1H), 6.72 (d, J = 8.60 Hz, 1H), 5.62 (s, 1H), 4.57 (s, 2H), 3.83 (t, 2H), 1.68 (h, J = 7.42 Hz, 2H), 0.96 (t, J = 7.43 Hz, 3H).

[0751] 13C NMR (126 MHz, CDCh) 5 164.5, 144.0, 140.4, 138.1, 129.4, 120.6, 117.6, 116.7, 114.7, 106.7, 67.8, 42.6, 20.4, 11.2. HRMS (ESI) C17H19N2O2, Calculated: [M+H]+, 283.1447; Found: [M+H]+, 283.1444.

[0752] N CK ^NH

[0753]

[0754] Cl

[0755] 2-chloro-N-((5-cyclobutyl-l,2,4-oxadiazol-3-yI)methyl)acetamide (9e): To a flame dry flask was added (5-cyclobutyl-l,2,4-oxadiazol-3-yl)methanamine (100 mg, 0.527 mmol) in anhydrous CH2Q2 (0.86 mL, 0.5 M), and the reaction flask was cooled to 0 °C.

[0756] Triethylamine (73.5 pL, 0.527 mmol) was added dropwise and the mixture was stirred for 10 min before addition of chloroacetyl chloride (35.0 pL, 0.439 mmol). The reaction was stirred for 16 hours before quenching with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 5% MeOH in CH2Q2) to yield the desired product (91.5 mg, 92%).1H NMR (500 MHz,4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0757] CDC13) 87.17 (s, 1H), 4.61 (d, J = 5.59 Hz, 2H), 4.11 (s, 2H), 3.74 (p, J = 9.07 Hz, 1H), 2.49 - 2.40 (m, 4H), 2.13 (dq, J= 11.30, 8.77 Hz, 1H), 2.04 (dq, J= 13.77, 6.69 Hz, 1H).13C NMR (125 MHz, CDC13) 5 182.9, 166.7, 166.1, 42.4, 35.8, 31.3, 27.1, 18.8.

[0758] O

[0759]

[0760] Ts

[0761] (5-cyclobutyl-1,2,4-oxadiazol-3-yl)methyl 4-methylbenzenesulfonate (S3): To a flame dry flask was added (5-cyclobutyl-l,2,4-oxadiazol-3-yl)methanol (100 mg, 0.649 mmol) in anhydrous CH2Q2 (0.65 mL, 1.0 M), and the reaction flask was cooled to 0 °C.

[0762] Triethylamine (181 pL, 1.30 mmol) was added dropwise and the mixture was stirred for 15 min before addition of 4- toluenesulfonyl chloride (186 mg, 0.973 mmol). The reaction was stirred for 2 hours before quenching with NaHCCh and extracted with CH2Cl2 in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 20% MeOH in CH2Cl2) to yield the desired product (33.9 mg, 17%).

[0763] 'H NMR (500 MHz, CDCI3) 87.83 (d, J = 8.34 Hz, 2H), 7.34 (d, J = 7.88 Hz, 2H), 5.13 (s, 2H), 3.70 (pd, J= 8.51, 1.12 Hz, 1H), 2.44 (s, 3H), 2.45 - 2.35 (m, 4H), 2.17 - 2.08 (m, 1H), 2.08 - 1.97 (m, 1H).13C NMR (125 MHz, CDCI3) 5 164.4, 145.2, 132.5, 129.9, 128.2, 61.4, 31.2, 27.1, 21.7, 18.8.

[0764] O

[0765]

[0766] Ms

[0767] (5-cyclobutyl-1,2,4-oxadiazol-3-yl)methyl methanesulfonate (S4): To a flame dry flask was added (5-cyclobutyl-l,2,4-oxadiazol-3-yl)methanol (100 mg, 0.689 mmol) in anhydrous THF (0.65 mL, 1.0 M), and the reaction flask was cooled to 0 °C. Triethylamine (240 pL, 1.72 mmol) was added dropwise and the mixture was stirred for 5 min before addition of methanesulfonyl chloridechloride (64.0 pL, 0.827 mmol). The reaction mixture was concentrated in vacuo and provided the desired crude product (147.8 mg). 'H NMR (500 MHz, CDCI3) 55.32 (s, 2H), 3.78 (p, J = 8.58 Hz, 1H), 3.16 (s, 3H), 2.50 - 2.40 (m, 4H), 2.21 - 2.11 (m, 1H), 2.11 - 2.00 (m, 1H).13C NMR (125 MHz, CDCI3) 5 183.5, 164.8, 61.1, 56.4, 38.5, 31.3, 27.2, 18.8.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0768] C

[0769]

[0770] l

[0771] 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (17) To a flame dried vial was added (5-cyclobutyl-l,2,4-oxadiazol-3-yl)methanol (100 mg, 0.65 mmol) in 0.04 M DCE followed by triphenylphosphine (511 mg, 1.95 mmol). Carbon tetrachloride (0.56 ml, 5.85 mmol) was added dropwise, and the mixture was stirred at room temperature for 5 h. After completion, the reaction was concentrated in vacuo to be purified by silica gel column chromatograph (0 to 10% MeOH in CH2Q2) to afford the final product as a colorless oil (98.13 mg, 88%).

[0772]

[0773] 4-((5-cyclobutyl-1,2,4-oxadiazol-3-yl)methyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (7g): To a flame dried flask cooled to 0 °C was added sodium hydride (19.19 mg, 0.80 mmol.) and 6 2H-benzo[b][l,4]oxazin-3(4H)-one (200 mg, 0.67 mmol) as a solution in 0.05M THF. The mixture was stirred for 20 minutes before the addition of 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (138 mg, 0.80 mmol) and tetra-n-butylammonium iodide (495 mg, 1.34 mmol). The reaction was heated to 65 °C for 30 minutes. The reaction was quenched with H2O and extracted with CH2CI2 (3 x). The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 30% EtOAc in Hex) to yield the desired product (364.9 mg, 92%). 'H NMR (500 MHz, CDCh) 56.98 (d, J = 2.3 Hz, 5H), 5.20 (s, 2H), 4.68 (s, 2H), 3.71 (p, J = 8.6 Hz, 1H), 2.48 - 2.34 (m, 4H), 2.15 - 2.05 (m, 1H), 2.04 - 1.96 (m, 1H).13C NMR (125 MHz, CDCI3) 5 182.9, 166.1, 164.5, 145.2, 128.4, 124.2, 122.9, 117.1, 115.1, 67.5, 37.2, 31.4, 27.1, 18.8.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0774]

[0775] 4-((5-cyclobutyl-1,2,4-oxadiazol-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl chloride (S5): To a flame dried flask cooled to 0 °C was added 4-((5-cyclobutyl-1,2,4-oxadiazol-3-yl)methyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (63 mg, 0.21 mmol) in 0.25M CH2CI2. Chlorosulfuric acid (0.04ml, 0.63 mmol) was added dropwise into the reaction flask dropwise. The resulting mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was poured into the iced water once it went to complete via thin layer chromatography (0 to 30% EtOAc in Hex) check and extracted with EtOAc (3x). The organic layer was combined and concentrated in vacuo to yield the desired product which was used as a crude for the next step.1H NMR (500 MHz, CDCI3) δ 4.57 (s, 2H), 3.76 (pd, J = 8.6, 1.1 Hz, 1H), 2.52 – 2.40 (m, 4H), 2.18 – 2.08 (m, 1H), 2.09 – 1.96 (m, 1H).13C NMR (125 MHz, CDCh) δ 183.2, 166.9, 77.3, 77.0, 76.8, 34.6, 31.4, 27.1, 18.7.

[0776]

[0777] 4-((5-cyclobutyl-1,2,4-oxadiazol-3-yl)methyl)-N-(2,3-dimethylphenyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonamide (Compound 19): To a flame dried reaction flask filled with argon containing 0.4 ml of CH2CI2, 2,3-dimethylaniline (0.01 ml, 0.11 mmol) and pyridine (0.02 ml, 0.20 mmol) were added. The reaction was stirred at room temperature for 15 min. Then,, 4-((5-cyclobutyl-1,2,4-oxadiazol-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl chloride (37 mg, 0.10 mmol) was added in 0.6 ml of CH2Cl2. The reaction was allowed to stir at room temperature for 1 hour. The reaction mixture was diluted with diluted with water and organic phase was separated. The aqueous phase was extracted with CH2Q2 (3 x) and the combined organic extracts were washed with brine, dried with Na₂SO₄ and concentrated in vacuo to be purified by silica gel column

[0778] - ill -4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0779] chromatograph (0 to 50% MeCN: in CH2Cl2) to afford the final product as a white powder (25.73 mg, 85% over two steps) IR (neat) υmax = 3266, 2949, 1698, 1604, 1574, 1504, 1434, 1378, 1330, 1277, 1159, 1099, 1036, 937, 862, 736 cm1. 'H NMR (500 MHz, DMSO-d6) δ 7.38 (m, 2H), 6.99 (m, 4H), 6.52 (s, 1H), 5.11 (s, 2H), 4.76 (s, 2H), 3.70 (p, J = 1.11 Hz, 1H), 2.41 (m, 4H), 2.22 (s, 3H), 2.10 (m, 1H), 2.02 (m, 1H), 1.95 (s, 3H).13C NMR (125 MHz, DMSO-d6) δ 183.1, 165.3, 163.5, 148.4, 138.0, 133.9, 131.6, 128.4, 126.0, 124.0, 123.1, 117.4, 114.4, 67.3, 37.3, 31.4, 27.1, 20.6, 18.8, 13.8. HRMS (ESI) C23H24N4O5S, Calculated:

[0780] [M+H]+, 469.1546; Found: [M+H]+, 469.1547.

[0781]

[0782] 6-bromo-4-((5-cyclobutyl-1,2,4-oxadiazol-3-yl)methyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (18): To a flame dried flask cooled to 0 °C was added sodium hydride (7.92 mg, 0.33 mmol, 1.3 eq.) and 6-bromo-4-propyl-2H-benzo[b][1,4]oxazin-3(4H)-one (63 mg, 0.28 mmol, 1.0 eq.) as a solution in THF (5 mL, 0.05M). The mixture was stirred for 20 minutes before the addition of 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (57 mg, 0.33 mmol, 1.2 eq.) and tetra-n-butylammonium iodide (203 mg, 0.55 mmol, 2.0 eq.). The reaction was heated to 65 °C for 30 minutes. The reaction was quenched with H2O and extracted with CH2CI2 in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 30% EtOAc in Hex) to yield the desired product (81.88 mg, 82%). 'H NMR (500 MHz, CDCh) δ 7.13 (d, J = 2.1 Hz, 1H), 7.09 (dd, J = 8.5, 2.1 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 5.16 (s, 2H), 4.67 (s, 2H), 3.73 (p, J = 8.6 Hz, 1H), 2.49 – 2.37 (m, 4H), 2.18 – 2.05 (m, 1H), 2.05 – 1.96 (m, 1H).13C NMR (125 MHz, CDCI3) δ183.2, 165.7, 164.2, 144.3, 129.8, 127.0, 118.5, 118.1, 115.1, 67.4, 37.4, 31.4, 27.2, 18.8.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0783] Me

[0784]

[0785] 6-(2,3-dimethylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (19a): To a microwave vial was added 6-bromo-4-propyl-2H-benzo[b][1,4]oxazin-3(4H)-one (50.0 mg, 0.219 mmol, 1.0 eq.), tetrakis(triphenylphosphine)palladium(0) (25.3 mg, 0.0219 mmol, 10 mol %), and (2,3-dimethylphenyl)boronic acid (65.8 mg, 0.439 mmol, 2.0 eq.) in 1,4-dioxane (7.75 mL, 0.03M) and cesium carbonate (286 mg, 0.877 mmol, 4.0 eq.) in H2O (1.37 mL, 0.64 M relative to base). The reaction was heated using microwave irradiation for 1 hour at 120 °C. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 15% EtOAc in Hex) to yield the desired product (33.0 mg, 59%). IR (neat) Umax = 3047, 1693, 1601, 1491, 1394, 1315, 1258, 1212, 1123, 1048, 897, 877, 786, 731, 707 cm’1. H NMR (500 MHz, CDCI3) δ 8.70 (s, 1H), 7.14 (dt, J = 14.85, 7.37 Hz, 2H), 7.02 (dd, J = 15.89, 7.47 Hz, 2H), 6.90 (dd, J = 8.22, 1.99 Hz, 1H), 6.75 (d, J = 2.00 Hz, 1H), 4.65 (s, 2H), 2.33 (s, 3H), 2.15 (s, 3H).13C NMR (125 MHz, CDCI3) δ 166.0, 142.4, 140.9, 137.5, 137.3, 134.0, 129.0, 127.5, 125.6, 125.2, 116.8, 116.8, 116.3, 67.3, 20.7, 16.9. HRMS (ESI) C16H15NO2, Calculated: [M+H]+, 254.1181; Found: [M+H]+, 254.1175.

[0786]

[0787] 6-(2-hydroxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (19b): To a microwave vial was added 6-bromo-4-propyl-2H-benzo[b][1,4]oxazin-3(4H)-one (100 mg, 0.439 mmol, 1.0 eq.), tetrakis(triphenylphosphine)palladium(0) (50.7 mg, 0.0439 mmol, 10 mol %), and (2-hydroxyphenyl)boronic acid (65.8 mg, 0.877 mmol, 2.0 eq.) in 1,4-dioxane (15.5 mL, 0.03M) and cesium carbonate (572 mg, 1.75 mmol, 4.0 eq.) in H2O (2.74 mL, 0.64 M relative to base). The reaction was heated using microwave irradiation for 1 hour at 120 °C. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 50% EtOAc in Hex) to yield the desired product (73.6 mg, 68%). IR (neat) Umax = 3330, 3025,4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0788] 2970, 1668, 1460, 1409, 1351, 1285, 1214, 1131, 1053, 1042, 945, 882, 816, 754 cm’1.XH NMR (500 MHz, MeOD) 5 8.70 (s, 1H), 7.14 (dt, J= 14.85, 7.37 Hz, 2H), 7.02 (dd, J = 15.89, 7.47 Hz, 2H), 6.90 (dd, J = 8.22, 1.99 Hz, 1H), 6.75 (d, J = 2.00 Hz, 1H), 4.65 (s, 2H), 2.33 (s, 3H), 2.15 (s, 3H).13C NMR (125 MHz, MeOD) δ 166.3, 153.9, 142.6, 133.5, 123.0, 128.0, 127.5, 126.1, 124.5, 119.5, 116.8, 115.5, 115.5, 66.8. HRMS (ESI) C14H11NO3, Calculated: [M+H]+, 242.0817; Found: [M+H]+, 242.0812.

[0789] O

[0790]

[0791] 6-(2-methylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (19c): To a microwave vial was added 6-bromo-4-propyl-2H-benzo[b][1,4]oxazin-3(4H)-one (50.0 mg, 0.219 mmol, 1.0 eq.), tetrakis(triphenylphosphine)palladium(0) (25.3 mg, 0.0219 mmol, 10 mol %), and (2-methylphenyl)boronic acid (59.6 mg, 0.439 mmol, 2.0 eq.) in 1,4-dioxane (7.75 mL, 0.03M) and cesium carbonate (286 mg, 0.877 mmol, 4.0 eq.) in H2O (1.37 mL, 0.64 M relative to base). The reaction was heated using microwave irradiation for 1 hour at 120 °C. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 5% MeCN in CH2Q2) to yield the desired product (27.5 mg, 52%). IR (neat) υmax = 3221, 2970, 2887, 1753, 1691, 1598, 1483, 1392, 1315, 1224, 1027, 1124, 1054, 1045, 945, 886, 766, 740 cm-1.1H NMR (500 MHz, CDCl3) δ 8.87 (s, 1H), 7.30 – 7.21 (m, 3H), 7.18 (d, J = 7.20 Hz, 1H), 7.01 (d, J = 8.21 Hz, 1H), 6.93 (dd, J = 8.21, 1.99 Hz, 1H), 6.79 (d, J = 1.99 Hz, 1H), 4.66 (s, 2H), 2.26 (s, 3H).13C NMR (125 MHz, CDCI3) δ 166.0, 142.5, 140.6, 136.8, 135.3, 130.4, 129.7, 127.5, 125.8, 125.7, 125.1, 116.7, 116.4, 67.3, 20.5. HRMS (ESI) C15H13NO2, Calculated: [M+H]+, 240.1025; Found: [M+H]+, 240.1021.

[0792]

[0793] 6-(3-(trifluoromethoxy)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (19d): To a microwave vial was added 6-bromo-4-propyl-2H-benzo[b][1,4]oxazin-3(4H)-one (50.0 mg,4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0794] 0.219 mmol, 1.0 eq.), tetrakis(triphenylphosphine)palladium(0) (25.3 mg, 0.0219 mmol, 10 mol %), and (2-(trifluoromethoxy)phenyl)boronic acid (90.3 mg, 0.439 mmol, 2.0 eq.) in 1,4-dioxane (7.75 mL, 0.03M) and cesium carbonate (286 mg, 0.877 mmol, 4.0 eq.) in H2O (1.37 mL, 0.64 M relative to base). The reaction was heated using microwave irradiation for 1 hour at 120 °C. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 5% MeCN in CH2Cl2) to yield the desired product (39.6 mg, 58%). IR (neat) υmax = 3180, 3095, 1682, 1604, 1500, 1409, 1254, 1215, 1159, 1059, 1039, 868, 779, 739, 705 cm-1.1H NMR (500 MHz, CDCl3) δ 8.91 (s, 1H), 7.49 – 7.41 (m, 2H), 7.36 (s, 1H), 7.19 (dd, J = 8.30, 2.12 Hz, 2H), 7.06 (d, J = 8.34 Hz, 1H), 7.02 (d, J = 2.12 Hz, 1H), 4.68 (s, 2H).13C NMR (125 MHz, CDCI3) δ 165.8, 149.7, 143.6, 142.1, 134.7, 130.2, 126.5, 125.2, 123.0, 119.6, 119.4, 117.3, 114.6, 67.3. HRMS (ESI) C15H10F3NO3, Calculated: [M+H]+, 310.0691; Found: [M+H]+, 310.0683.

[0795]

[0796] 6-(2,4-dichlorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (19e) To a microwave reaction vial, Pd(PPh3)4 (25mg, 10 mol%) was added. Then, the vial was flushed with Argon (3x). 6-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (50mg, 0.22 mmol) was added in 6 ml of 1,4-dioxane followed by Cs2CO3 (286 mg, 0.88 mmol) in 3 ml of H2O. Then, (2,4-dichlorophenyl)boronic acid (84 mg, 0.44 mmol) was added in 3 ml of 1,4-dioxane. The reaction was then heated using microwave irradiation at 120°C for 1.5 hour. The crude reaction was filtered to remove the palladium using a PTFE filter and diluted with water. Then, the aqueous phase extracted using EtOAc (3x), and the combied organic extracts were dried with Na2SO4 and concentrated in vacuo to be purified by silica gel column chromatograph (MeCN: CH2Cl2 / 40:60) to afford the product as a white powder (16.55 mg, 25%). 'H NMR (500 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.71 (d, J = 2.2 Hz, 1H), 7.49 (dd, J = 8.3, 2.2 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 6.97 (d, J = 2.1 Hz, 1H), 6.95 – 6.92 (m, 1H), 4.63 (s, 2H).13C NMR (125 MHz, DMSO-d6) δ 165.2, 143.4, 138.5, 133.3, 133.0, 132.8, 132.1, 129.7, 128.2, 127.5, 124.4, 117.0, 116.5, 67.2.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0797]

[0798] 6-(3-methylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (19f): To a microwave vial was added 6-bromo-4-propyl-2H-benzo[b][1,4]oxazin-3(4H)-one (50.0 mg, 0.219 mmol, 1.0 eq.), tetrakis(triphenylphosphine)palladium(0) (25.3 mg, 0.0219 mmol, 10 mol %), and (3-methylphenyl)boronic acid (59.6 mg, 0.439 mmol, 2.0 eq.) in 1,4-dioxane (7.75 mL, 0.03M) and cesium carbonate (286 mg, 0.877 mmol, 4.0 eq.) in H2O (1.37 mL, 0.64 M relative to base). The reaction was heated using microwave irradiation for 1 hour at 120 °C. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 5% MeCN in CH2Cl2) to yield the desired product (25.1 mg, 48%). IR (neat) υmax = 3205, 3043, 2191, 1664, 1608, 1495, 1411, 1212, 1127, 1039, 870, 814, 776, 731 cm-1.1H NMR (500 MHz, CDCI3) δ 8.87 (s, 1H), 7.35 – 7.30 (m, 3H), 7.20 (dd, J = 8.35, 2.10 Hz, 1H), 7.18 – 7.13 (m, 1H), 7.06 – 7.00 (m, 2H), 4.66 (s, 2H), 2.42 (s, 3H).13C NMR (125 MHz, CDCI3) δ 166.0, 143.0, 139.9, 138.4, 136.4, 128.7, 128.1, 127.6, 126.2, 123.9, 123.0, 117.0, 114.6, 67.3, 21.5. HRMS (ESI) C15H13NO2, Calculated: [M+H]+, 240.1025; Found: [M+H]+, 240.1021.

[0799]

[0800] 6-(2-methoxylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (19g): To a microwave vial was added 6-bromo-4-propyl-2H-benzo[b][1,4]oxazin-3(4H)-one (50.0 mg, 0.219 mmol, 1.0 eq.), tetrakis(triphenylphosphine)palladium(0) (25.3 mg, 0.0219 mmol, 10 mol %), and (2-methoxyphenyl)boronic acid (66.6 mg, 0.439 mmol, 2.0 eq.) in 1,4-dioxane (7.75 mL, 0.03M) and cesium carbonate (286 mg, 0.877 mmol, 4.0 eq.) in H2O (1.37 mL, 0.64 M relative to base). The reaction was heated using microwave irradiation for 1 hour at 120 °C. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0801] 70% EtOAc in Hex) to yield the desired product (29.8 mg, 53%). IR (neat) υmax = 3178. 3127. 2956. 2831. 1686, 1600, 1485, 1391, 1317, 1239, 1225, 1122, 1057, 1027, 937, 894, 872, 757 cm-1.1H NMR (500 MHz, CDCl3) δ 8.80 (s, 1H), 7.31 (ddd, J = 8.19, 7.39, 1.78 Hz, 1H), 7.26 (dd, J = 7.83, 2.08 Hz, 1H), 7.12 (dd, J = 8.28, 2.05 Hz, 1H), 7.04 – 6.99 (m, 3H), 6.97 (d, J = 8.27 Hz, 1H), 4.63 (s, 2H), 3.81 (s, 3H).13C NMR (125 MHz, CDCh) δ 166.0, 156.3, 142.7, 133.3, 130.6, 129.3, 128.8, 125.6, 125.4, 120.9, 117.1, 116.4, 111.2, 67.3, 55.6. HRMS (ESI) C15H13NO3, Calculated: [M+H]+, 256.0974; Found: [M+H]+, 256.0970.

[0802]

[0803] 6-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one (19h): To a microwave vial was added 6-bromo-4-propyl-2H-benzo[b][1,4]oxazin-3(4H)-one (100 mg, 0.439 mmol, 1.0 eq.), tetrakis(triphenylphosphine)palladium(0) (50.7 mg, 0.0439 mmol, 10 mol %), and phenylboronic acid (114 mg, 0.877 mmol, 2.0 eq.) in 1,4-dioxane (15.5 mL, 0.03M) and cesium carbonate (572 mg, 1.75 mmol, 4.0 eq.) in H2O (2.74 mL, 0.64 M relative to base). The reaction was heated using microwave irradiation for 1 hour at 120 °C. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 15% EtOAc in Hex) to yield the desired product (50.2 mg, 51%). IR (neat) υmax = 3176, 3042, 2969, 2889, 1688, 1599, 1523, 1484, 1399, 1309, 1228, 1190, 1128, 1050, 1038, 895, 868, 789, 765, 702 cm-1.1H NMR (500 MHz, DMSO) δ 10.77 (s, 1H), 7.52 (d, J = 6.90 Hz, 2H), 7.43 (t, J = 7.69 Hz, 2H), 7.35 – 7.30 (m, 1H), 7.19 (dd, J = 8.31, 2.20 Hz, 1H), 7.12 (d, J = 2.17 Hz, 1H), 7.01 (d, J = 8.28 Hz, 1H), 4.59 (s, 2H).13C NMR ‘(125 MHz, DMSO) 5 165.3, 143.4, 140.0, 135.1, 129.4, 128.1, 127.6, 126.7, 121.8, 117.0, 114.4, 67.3. HRMS (ESI) C14H11NO2, Calculated: [M+H]+, 226.0868; Found: [M+H]+, 226.0864.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0804]

[0805] 6-(2,4-difluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (19i): To a microwave vial was added 6-bromo-4-propyl-2H-benzo[b][1,4]oxazin-3(4H)-one (50.0 mg, 0.219 mmol, 1.0 eq.), tetrakis(triphenylphosphine)palladium(0) (25.3 mg, 0.0219 mmol, 10 mol %), and (2,4-difluorophenyl)boronic acid (69.56 mg, 0.44 mmol, 2.0 eq.) in 1,4-dioxane (7.75 mL, 0.03M) and cesium carbonate (286 mg, 0.877 mmol, 4.0 eq.) in H2O (1.37 mL, 0.64 M relative to base). The reaction was heated using microwave irradiation for 1 hour at 120 °C. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 70% EtOAc in Hex) to yield the desired product (34.77 mg, 61%).1H NMR (500 MHz, CDCI3) δ 9.27 (s, 1H), 7.35 (td, J = 8.7, 6.4 Hz, 1H), 7.10 (dt, J = 8.4, 1.7 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.98 (t, J = 1.7 Hz, 1H), 6.96 – 6.87 (m, 2H), 4.67 (s, 2H).13C NMR (125 MHz, CDCI3) δ166.1, 163.3, 160.5, 143.3, 131.2, 131.1, 131.1, 129.7, 126.1, 124.8, 116.9, 116.5, 116.5, 111.7, 111.6, 104.6, 104.4, 104.2, 67.2.

[0806]

[0807] 6-(2,3-dichlorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (19j) To a microwave reaction vial, Pd(PPh3)4 (25mg, 10 mol%) was added. Then, the vial was flushed with Argon (3x). 6-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (50mg, 0.22 mmol) was added in 6 ml of 1,4-dioxane followed by Cs2CO3 (286 mg, 0.88 mmol) in 3 ml of H2O. Then, (2,3-dichlorophenyl)boronic acid (84 mg, 0.44 mmol) was added in 3 ml of 1,4-dioxane. The reaction was then heated using microwave irradiation at 120°C for 1.5 hour. The crude reaction was filtered to remove the palladium using a PTFE filter and diluted with water. Then, the aqueous phase extracted using EtOAc (3x), and the combied organic extracts were dried with Na2SO4 and concentrated in vacuo to be purified by silica gel column chromatograph (0 to 40% MeCN in CH2Cl2) to afford the product as a white powder (48.05 mg, 75%).

[0808]

[0809] NMR (500 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.65 (dd, J= 8.00, 1.58 Hz, 1H),4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0810] 7.42 (t, 7 = 7.84 Hz, 1H), 7.34 (dd, 7= 7.66, 1.59 Hz, 1H), 7.04 (d, 7= 8.22 Hz, 1H), 6.97 (dd, 7= 8.25, 2.11 Hz, 1H), 6.93 (d, 7= 2.11 Hz, 1H), 4.64 (s, 2H).13C NMR (125 MHz, DMSO-d6) δ 164.8, 143.1, 141.6, 132.6, 132.3, 130.0, 129.7, 128.3, 127.0, 123.9, 116.4, 116.0, 66.8.

[0811]

[0812] 6-(2-fluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (19k) To a microwave reaction vial, Pd(PPh3)4 (25mg, 10 mol%) was added. Then, the vial was flushed with Argon (3x). 6-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (50mg, 0.22 mmol) was added in 6 ml of 1,4-dioxane followed by Cs2CO3 (286 mg, 0.88 mmol) in 3 ml of H2O. Then, (2-fluorophenyl)boronic acid (61 mg, 0.44 mmol) was added in 3 ml of 1,4-dioxane. The reaction was then heated using microwave irradiation at 120°C for 1.5 hour. The crude reaction was filtered to remove the palladium using a PTFE filter and diluted with water. Then, the aqueous phase extracted using EtOAc (3x), and the combined organic extracts were dried with Na2SO4 and concentrated in vacuo to be purified by silica gel column chromatograph (0 to 70% EtOAc in Hex) to afford the product (34.92 mg, 33%) 'H NMR (500 MHz, DMSO) δ 9.38 (s, 1H), 6.03 (t, J = 7.1 Hz, 1H), 5.97 (dt, J = 7.8, 3.6 Hz, 1H), 5.90 – 5.81 (m, 1H), 5.69 – 5.66 (m, 1H), 5.62 (d, J = 8.8 Hz, 1H), 3.20 (s, 2H).13C NMR (125 MHz, DMSO) δ 165.2, 160.4, 158.4, 143.5, 130.9, 130.9, 129.8, 129.8, 129.6, 128.0, 127.9, 127.8, 125.4, 125.4, 123.9, 116.8, 116.7, 116.6, 116.6, 116.5, 67.2.

[0813]

[0814] 6-(3-fluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (19l) To a microwave reaction vial, Pd(PPh3)4 (25mg, 10 mol%) was added. Then, the vial was flushed with Argon (3x). 6-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (50mg, 0.22 mmol) was added in 6 ml of 1,4-dioxane followed by Cs2CO3 (286 mg, 0.88 mmol) in 3 ml of H2O. Then, (3-fluorophenyl)boronic acid (61 mg, 0.44 mmol) was added in 3 ml of 1,4-dioxane. The4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0815] reaction was then heated using microwave irradiation at 120°C for 1.5 hour. The crude reaction was filtered to remove the palladium using a PTFE filter and diluted with water. Then, the aqueous phase extracted using EtOAc (3x), and the combined organic extracts were dried with Na2SO4 and concentrated in vacuo to be purified by silica gel column chromatograph (0 to 70% EtOAc in Hex) to afford the desired product (26.84 mg, 25%)1H NMR (500 MHz, DMSO) δ δ 10.79 (s, 1H), 7.48 (q, J = 60.7 Hz, 1H), 7.37 (t, J = 20.98 Hz, 2H), 7.24 (dd, J = 8.3, 2.2 Hz, 1H), 7.16 (m, 2H), 7.03 (d, J = 8.3 Hz, 1H), 4.61 (s, 2H).13C NMR (125 MHz, DMSO) δ 165.2, 164.1, 162.1, 143.8, 142.5, 142.5, 133.7, 131.4, 131.3, 128.2, 122.8, 122.8, 122.1, 117.1, 114.5, 114.4, 114.2, 113.5, 113.3, 67.2.

[0816]

[0817] 6-(2-(trifluoromethyl)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (19m) To a microwave reaction vial, Pd(PPh3)4 (25mg, 10 mol%) was added. Then, the vial was flushed with Argon (3x). 6-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (50mg, 0.22 mmol) was added in 6 ml of 1,4-dioxane followed by Cs2CO3 (286 mg, 0.88 mmol) in 3 ml of H2O. Then, (2-(trifluoromethyl)phenyl)boronic acid (83 mg, 0.44 mmol) was added in 3 ml of 1,4-dioxane. The reaction was then heated using microwave irradiation at 120°C for 1.5 hour. The crude reaction was filtered to remove the palladium using a PTFE filter and diluted with water. Then, the aqueous phase extracted using EtOAc (3x), and the combined organic extracts were dried with Na2SO4 and concentrated in vacuo to be purified by silica gel column chromatograph (0 to 10% MeCN in CH2CI2) to afford the product (59.56 mg, 46%) ’H NMR (500 MHz, DMSO) δ 10.80 (s, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.87 – 6.78 (m, 2H), 4.64 (s, 2H).13C NMR (125 MHz, DMSO) δ 165.3, 143.3, 140.5, 133.8, 132.8, 132.6, 128.5, 127.1, 126.5, 124.0, 116.6, 116.1, 67.2.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0818]

[0819] 6-(2,3-difluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (19n): To a microwave vial was added 6-bromo-4-propyl-2H-benzo[b][1,4]oxazin-3(4H)-one (50.0 mg, 0.219 mmol, 1.0 eq.), tetrakis(triphenylphosphine)palladium(0) (25.3 mg, 0.0219 mmol, 10 mol %), and (2,3-difluorophenyl)boronic acid (68.6 mg, 0.439 mmol, 2.0 eq.) in 1,4-dioxane (7.75 mL, 0.03M) and cesium carbonate (286 mg, 0.877 mmol, 4.0 eq.) in H2O (1.37 mL, 0.64 M relative to base). The reaction was heated using microwave irradiation for 1 hour at 120 °C. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 70% EtOAc in Hex) to yield the desired product (44.6 mg, 78%). IR (neat) Umax = 3041, 2359, 1917, 1694, 1583, 1469, 1402, 1278, 1220, 904, 870, 814, 778 cm’1. ¹H NMR (500 MHz, DMSO) δ 10.82 (s, 1H), 7.40 - 7.31 (m, 1H), 7.26 - 7.18 (m, 2H), 7.08 (dd, J = 5.81, 1.54 Hz, 2H), 7.02 (d, J = 8.88 Hz, 1H), 4.61 (s, 2H).13C NMR (126 MHz, CDCl₃) δ 165.2, 151.8 (d, J = 13.18 Hz), 149.7 (d, J= 13.33 Hz), 148.3 (d, J= 13.05 Hz), 146.4 (d, J= 13.16 Hz), 143.9, 130.3 (d, J = 9.60 Hz), 128.1 (d, 7= 50.63 Hz), 125.9, 125.5 (t), 124.0, 116.7 (d, 7 = 53.60 Hz), 116.7 (d, 7= 17.16 Hz), 67.2.

[0820] HRMS (ESI) C₁₄H₉F₂NO₂, Calculated: [M+H]+, 262.0680; Found: [M+H]+, 262.0675.

[0821]

[0822] 6-(2-chlorophenyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (19o): To a microwave vial was added 6-bromo-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (50.0 mg, 0.219 mmol, 1.0 eq.), tetrakis(triphenylphosphine)palladium(0) (25.3 mg, 0.0219 mmol, 10 mol %), and (2-chlorophenyl)boronic acid (68.6 mg, 0.439 mmol, 2.0 eq.) in 1,4-dioxane (7.75 mL, 0.03M) and cesium carbonate (286 mg, 0.877 mmol, 4.0 eq.) in H2O (1.37 mL, 0.64 M relative to base). The reaction was heated using microwave irradiation for 1 hour at 120 °C. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 70%4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0823] EtOAc in Hex) to yield the desired product (37.9 mg, 66%). IR (neat) Umax = 2962, 1691, 1604, 1496, 1470, 1400, 1227, 1204, 1131, 1073, 1046, 943, 874, 817, 757, 748, 701 cm'1.

[0824] ¹H NMR (500 MHz, CDCl₃) δ 9.01 (s, 1H), 7.45 (t, J = 6.13 Hz, 1H), 7.33 - 7.27 (m, 3H), 7.09 - 7.00 (m, 2H), 6.92 (d, J = 1.85 Hz, 1H), 4.67 (s, 2H).13C NMR (126 MHz, CDCl₃) δ 166.0, 143.1, 139.2, 134.12, 132.5, 131.2, 130.0, 128.7, 126.9, 125.6, 125.4, 117.1, 116.5, 67.2. HRMS (ESI) C₁₄H₁₀ClNO₂, Calculated: [M+H]⁺, 260.0478; Found: [M+H]⁺, 260.0475.

[0825]

[0826] 6-(3-chlorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (19p): To a microwave vial was added 6-bromo-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (50.0 mg, 0.219 mmol, 1.0 eq.), tetrakis(triphenylphosphine)palladium(0) (25.3 mg, 0.0219 mmol, 10 mol %), and (3-chlorophenyl)boronic acid (68.6 mg, 0.439 mmol, 2.0 eq.) in 1,4-dioxane (7.75 mL, 0.03M) and cesium carbonate (286 mg, 0.877 mmol, 4.0 eq.) in H2O (1.37 mL, 0.64 M relative to base). The reaction was heated using microwave irradiation for 1 hour at 120 °C. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 70% EtOAc in Hex) to yield the desired product (27.1 mg, 48%). IR (neat) Umax = 2956, 1662, 1596, 1495, 1408, 1232, 1203, 1131, 1100, 1064, 1035, 871, 776, 714 cm-1. 'H NMR (500 MHz, DMSO) 5 10.76 (s, 1H), 7.55 (s, 1H), 7.46 (dt, J= 15.43, 7.78 Hz, 2H), 7.37 (d, J = 7.51 Hz, 1H), 7.21 (dd, J = 8.29, 2.27 Hz, 1H), 7.13 (d, 7 = 2.25 Hz, 1H), 7.00 (d, 7= 8.35 Hz, 1H), 4.60 (s, 2H).13C NMR (125 MHz, DMSO) 5 165.1, 143.8, 142.2, 134.1, 133.4, 131.2, 129.2, 128.2, 127.4, 125.4, 122.0, 117.1, 114.5, 67.2. HRMS (ESI) C14H10ClNO2, Calculated: [M+H]+, 260.0478; Found: [M+H]+, 260.0474.

[0827]

[0828] 6-(3-chloro-2-methylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (19q): To a microwave vial was added 6-bromo-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (50.0 mg, 0.219 mmol,4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0829] 1.0 eq.), tetrakis(triphenylphosphine)palladium(0) (25.3 mg, 0.0219 mmol, 10 mol %), and (3-chloro-2-methylphenyl)boronic acid (68.6 mg, 0.439 mmol, 2.0 eq.) in 1,4-dioxane (7.75 mL, 0.03M) and cesium carbonate (286 mg, 0.877 mmol, 4.0 eq.) in H2O (1.37 mL, 0.64 M relative to base). The reaction was heated using microwave irradiation for 1 hour at 120 °C. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 70% EtOAc in Hex) to yield the desired product (44.7 mg, 75%). IR (neat) υmax= 2971, 1697, 1604, 1497, 1434, 1384, 1315, 1234, 1216, 1123, 1054, 1034, 1000, 974, 816, 774, 721, 704 cm1. ¹H NMR (400 MHz, CDCl₃) δ 9.55 (s, 1H), 7.36 (dd, J = 7.86, 1.45 Hz, 1H), 7.19 - 7.11 (m, 1H), 7.08 (dd, J = 7.64, 1.47 Hz, 1H), 7.01 (d, J = 8.21 Hz, 1H), 6.89 (dd, J = 8.25, 1.98 Hz, 1H), 6.78 (d, J = 1.96 Hz, 1H), 4.66 (s, 2H), 2.27 (s, 3H).13C NMR (100 MHz, CDCl₃) δ 166.5, 142.8, 142.7, 136.3, 135.3, 133.8, 128.4, 128.2, 126.4, 125.8, 125.1, 116.8, 116.5, 67.2, 17.9. HRMS (ESI) C15H12CINO2, Calculated: [M+H]+, 274.0635; Found:

[0830] [M+H]+, 274.0630.

[0831]

[0832] 6-(2-chloro-3-methylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (19r): To a microwave vial was added 6-bromo-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (50.0 mg, 0.219 mmol, 1.0 eq.), tetrakis(triphenylphosphine)palladium(0) (25.3 mg, 0.0219 mmol, 10 mol %), and (3-chloro-2-methylphenyl)boronic acid (68.6 mg, 0.439 mmol, 2.0 eq.) in 1,4-dioxane (7.75 mL, 0.03M) and cesium carbonate (286 mg, 0.877 mmol, 4.0 eq.) in H2O (1.37 mL, 0.64 M relative to base). The reaction was heated using microwave irradiation for 1 hour at 120 °C. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 70% EtOAc in Hex) to yield the desired product (24.7 mg, 38%). IR (neat) υmax= 2979, 1688, 1609, 1499, 1403, 1378, 1215, 1127, 1036, 966, 874, 802, 781, 729, 700 cm-1. ¹H NMR (400 MHz, CDCl₃) δ 8.96 (s, 1H), 7.25 - 7.22 (m, 1H), 7.19 (t, J = 7.45 Hz, 1H), 7.15 - 7.10 (m, 1H), 7.02 (d, J = 1.19 Hz, 2H), 6.90 (t, J = 1.19 Hz, 1H), 4.67 (s, 2H), 2.45 (s, 3H).13C NMR (100 MHz, CDCl3) δ 166.0, 143.0, 139.7, 137.0, 134.9, 132.8, 130.1, 128.8,4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0833] 126.2, 125.5, 125.4, 117.1, 116.4, 67.3, 21.0. HRMS (ESI) C15H12CINO2, Calculated:

[0834] [M+H]+, 274.0635; Found: [M+H]+, 274.0630.

[0835]

[0836] 6-(2-isopropylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (19s): To a microwave vial was added 6-bromo-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (50.0 mg, 0.219 mmol, 1.0 eq.), tetrakis(triphenylphosphine)palladium(0) (25.3 mg, 0.0219 mmol, 10 mol %), and (2-isopropylphenyl)boronic acid (68.6 mg, 0.439 mmol, 2.0 eq.) in 1,4-dioxane (7.75 mL, 0.03M) and cesium carbonate (286 mg, 0.877 mmol, 4.0 eq.) in H2O (1.37 mL, 0.64 M relative to base). The reaction was heated using microwave irradiation for 1 hour at 120 °C. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 70% EtOAc in Hex) to yield the desired product (37.9 mg, 65%). IR (neat) Umax = 2956, 1694, 1614, 1598, 1481, 1381, 1264, 1223, 1207, 1084, 1052, 939, 877, 758, 734 cm’1.1H NMR (500 MHz, CDCl₃) δ 9.33 (s, 1H), 7.36 (dt, J = 14.64, 7.39 Hz, 2H), 7.23 - 7.16 (m, 1H), 7.13 (d, J = 7.26 Hz, 1H), 7.00 (d, J = 8.19 Hz, 1H), 6.90 (dd, J = 8.17, 1.99 Hz, 1H), 6.79 (d, J = 1.98 Hz, 1H), 4.66 (s, 2H), 3.04 (p, J = 6.90 Hz, 1H), 1.17 (d, J = 6.85 Hz, 6H).

[0837] 13C NMR (126 MHz, CDCl₃) δ 166.4, 146.4, 142.5, 139.7, 136.9, 129.87, 127.9, 125.6, 125.6, 125.3, 125.1, 116.9, 116.2, 67.2, 29.4, 24.3. HRMS (ESI) C17H17NO2, Calculated: [M+H]+, 268.1338; Found: [M+H]+, 268.1338.

[0838]

[0839] 6-(3-isopropylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (19t): To a microwave vial was added 6-bromo-4-propyl-2H-benzo[b][l,4]oxazin-3(4H)-one (50.0 mg, 0.219 mmol, 1.0 eq.), tetrakis(triphenylphosphine)palladium(0) (25.3 mg, 0.0219 mmol, 10 mol %), and (3-isopropylphenyl)boronic acid (68.6 mg, 0.439 mmol, 2.0 eq.) in 1,4-dioxane (7.75 mL, 0.03M) and cesium carbonate (286 mg, 0.877 mmol, 4.0 eq.) in H2O (1.37 mL, 0.64 M4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0840] relative to base). The reaction was heated using microwave irradiation for 1 hour at 120 °C. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 70% EtOAc in Hex) to yield the desired product (27.2 mg, 46%). IR (neat) vmax= 2960, 1686, 1602, 1493, 1405, 1212, 1130, 1056, 1038, 957, 904, 844, 787, 703 cm’1. ¹H NMR (500 MHz, CDCl₃) δ 8.86 (s, 1H), 7.39 - 7.30 (m, 3H), 7.24 - 7.19 (m, 2H), 7.04 (dd, J = 5.22, 3.12 Hz, 2H), 4.66 (s, 2H), 2.97 (hept, J = 6.97 Hz, 1H), 1.30 (d, J = 6.93 Hz, 6H).13C NMR (126 MHz, CDCl₃) δ 166.0, 149.5, 143.0, 140.0, 136.7, 128.8, 126.2, 125.4, 125.1, 124.4, 123.1, 117.0, 114.7, 67.3, 34.2, 24.0. HRMS (ESI) C17H17NO2, Calculated: [M+H]+, 268.1338; Found: [M+H]+, 268.1335.

[0841]

[0842] 6-(2-((tert-butyldimethylsilyl)oxy)phenyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (S6) To a flame dried flask, 6-(2-hydroxyphenyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (30 mg, 0.12 mmol) was added in 0.04 CH₂Cl₂. Then, imidazole (16.33 mg, 0.24 mmol) was added. The reaction was stirred at 0 °C for 20 min. Then, TBSC1 (27.12 mg, 0.18 mmol) was added. The resulting solution was warmed to room temperature and stirred for 17 hours until completion. Once completed, the reaction was quenched with H2O and extracted with CH2CI2 in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 30% EtOAc in Hex) to yield the desired product as a orange powder (37.76 mg, 85%). ¹H NMR (500 MHz, CDCl₃) δ 9.22 (s, 1H), 7.26 (dd, J = 7.6, 1.8 Hz, 1H), 7.21 (td, J = 7.7, 1.8 Hz, 1H), 7.11 (dd, J = 8.3, 2.0 Hz, 1H), 7.02 (dd, J = 6.8, 1.6 Hz, 2H), 76.99 (m, 1H), 6.90 (dd, J = 8.1, 1.2 Hz, 1H), 4.64 (s, 2H), 0.84 (s, 9H), -0.01 (s, 5H).13C NMR (125 MHz, CDCl₃) δ 166.3, 152.5, 142.5, 134.0, 132.1, 130.6, 128.4, 125.6, 125.4, 121.7, 120.4, 117.5, 116.2, 67.3, 25.6, 18.1, -4.5.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0843]

[0844] 4-((5-cyclobutyl-1,2,4-oxadiazol-3-yl)methyl)-6-(2,3-dimethylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (4k): To a flame dried flask cooled to 0 °C was added sodium hydride (3.9 mg, 0.0965 mmol, 1.3 eq.) and 6-(2,3-dimethylphenyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (18.8 mg, 0.0742 mmol, 1.0 eq.) as a solution in THF (1.48 mL, 0.05M). The mixture was stirred for 10 minutes before the addition of 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (15.7 mg, 0.0891 mmol, 1.2 eq.) and tetra-n-butylammonium iodide (54.8 mg, 0.148 mmol, 2.0 eq.). The reaction was heated to 65 °C for 30 minutes. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 30% EtOAc in Hex) to yield the desired product (11.6 mg, 40%). IR (neat) Umax = 3031, 2947, 1697, 1575, 1513, 1435, 1374, 1273, 1045, 914, 786, 733 cm'1.

[0845]

[0846] ¹H NMR (500 MHz, CDCl₃) δ 7.13 (dd, J = 14.63, 7.24 Hz, 2H), 7.03 (dd, J = 12.10, 8.00 Hz, 2H), 6.94 (d, J = 8.12 Hz, 1H), 6.91 (s, 1H), 5.21 (s, 2H), 4.76 (s, 2H), 3.72 (p, J = 8.63 Hz, 1H), 2.50 - 2.37 (m, 4H), 2.32 (s, 3H), 2.16 - 1.97 (m, 5H).13C NMR (125 MHz, CDCl₃) δ 182.9, 166.0, 164.7, 144.0, 141.1, 137.4, 134.1, 129.1, 127.9, 127.6, 125.3, 125.2, 116.7, 116.3, 67.7, 37.4, 31.4, 27.2, 20.7, 18.8, 16.8.

[0847] HRMS (ESI) C23H23N3O3, Calculated: [M+H]+, 390.1818; Found: [M+H]+, 390.1813.

[0848]

[0849] 6-(2-((tert-butyldimethylsilyl)oxy)phenyl)-4-((5-cyclobutyl-1,2,4-oxadiazol-3-yl)methyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (S7) To a flame dried flask cooled to 0 °C was added Cs₂CO₃ (17 mg, 0.052 mmol) and 6-(2-((tert-butyldimethylsilyl)oxy)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (15 mg, 0.04 mmol) as a solution in THF (1 mL). The mixture was stirred for 20 minutes before the addition of 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (7 mg, 0.04 mmol) and tetra-n-butylammonium iodide (30 mg, 0.0524239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0850] mmol). The reaction was heated to 65 °C for 2 hour. The reaction was quenched with H2O and extracted with CH₂Cl₂ in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 30% EtOAc in Hex) to yield the desired product (17.11 mg, 82%). ¹H NMR (500 MHz, CDCl₃) δ 7.20 (td, J = 7.3, 1.6 Hz, 2H), 7.16 (dd, J = 8.3, 1.9 Hz, 1H), 7.08 (d, J = 1.9 Hz, 1H), 7.02 (m, 1H), 7.01 (m, 1H), 6.89 (dd, J = 8.6, 1.3 Hz, 1H), 5.23 (s, 2H), 4.72 (s, 2H), 3.70 (qd, J = 8.5, 1.1 Hz, 1H), 2.49 - 2.35 (m, 4H), 2.15 - 2.04 (m, 1H), 2.04 - 1.96 (m, 1H), 0.79 (s, 11H), -0.07 (s, 7H).13C NMR (125 MHz, CDCl₃) δ 182.8, 165.9, 164.6, 152.6, 144.1, 134.2, 132.5, 130.7, 128.5, 127.9, 126.0, 121.6, 120.4, 116.4, 116.3, 67.7, 37.2, 31.4, 27.1, 25.6, 18.8, -4.5.

[0851]

[0852] 4-((5-cyclobutyl-1,2,4-oxadiazol-3-yl)methyl)-6-(2-methoxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (4l): To a microwave vial containing a mixture of DMF:H₂O (10:1), 6-(2-((tert-buty ldimethylsilyl)oxy)phenyl)-4-((5 -cyclobutyl- 1,2,4-oxadiazol-3-yl)methyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (17 mg, 0.03 mmol) was added followed by Cs₂CO₃ (10 mg, 0.03 mmol). The reaction was stirred at room temperature for 2 hr. Once the reaction was done, it was extracted EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 40% EtOAc in Hex) to yield the desired product (9.72 mg, 74%). IR (neat) Umax = 3333, 2950, 1672, 1605, 1574, 1433, 1376, 1271, 1055, 909, 822, 755, 736, cm’1. ¹H NMR (500 MHz, CDCl₃) δ 7.27 - 7.22 (m, 1H), 7.23 - 7.17 (m, 2H), 7.12 (s, 2H), 6.97 (ddd, J = 14.36, 7.76, 1.17 Hz, 2H), 5.48 (s, 1H), 5.26 (s, 2H), 4.74 (s, 2H), 3.73 (p, J = 8.93, 8.51 Hz, 1H), 2.52 - 2.37 (m, 4H), 2.21 - 2.07 (m, 1H), 2.03 - 1.97 (m, 1H).13C NMR (126 MHz, CDCl₃) δ 183.1, 165.7, 164.4, 152.6, 144.7, 131.9, 130.1, 129.2, 128.5, 127.1, 125.0, 120.9, 117.8, 116.2, 116.0, 67.6, 36.8, 31.4, 27.1, 18.8. HRMS (ESI) C21H19N3O4, Calculated: [M+H]+, 378.1454; Found: [M+H]+, 378.1447.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0853]

[0854] 4-((5-cyclobutyl-1,2,4-oxadiazol-3-yl)methyl)-6-(2-methylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (4m): To a flamed dried reaction vial, 6-(o-tolyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (15 mg, 0.05 mmol) was added at 0°C in 0.4 ml THF, then, sodium hydride (NaH) (1.7 mg, 0.072 mmol). Then reaction was stirred at 0°C for 20min, subsequently tetrabutylammonium iodide (TBAI, 44mg, 0.12 mmol) was added followed by 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (15 mg, 0.09 mmol). The reaction mixture was heated at 65°C for 30min. The reaction was quench using water and the organic phase was separated. The aqueous phase was extracted with CH2CI2 (3 x) and the combined organic extracts were washed with brine, dried with Na2SO4 and concentrated in vacuo to be purified by silica gel column chromatograph (0 to 40% EtOAc in Hex) to afford the product (20.73 mg, 88%). IR (neat) umax= 2995, 2947, 1692, 1574, 1454, 1407, 1370, 1274, 1135, 1045, 916, 852, 785, 730 cm1.

[0855]

[0856] ¹H NMR (500 MHz, CDCl₃) δ 7.24 (m, 3H), 7.17 (d, J = 5.87 Hz, 1H), 7.05 (d, J = 8.05 Hz 1H), 6.96 (m, 2H), 5.22 (s, 2H), 4.76 (s, 2H), 3.72 (pd, J = 8.57, .13 Hz, 1H), 2.42 (m, 4H), 2.19 (s, 2H), 2.11 (m, 1H), 2.02 (m, 1H).13C NMR (125 MHz, CDCl₃) δ 182.8, 165.9, 164.5, 144.0, 140.7, 136.6, 135.3, 130.3, 129.6, 127.8, 127.3, 125.8, 124.9, 116.6, 116.0, 77.2, 76.9, 76.7, 67.5, 37.2, 31.3, 27.0, 20.2, 18.6. HRMS (ESI) C22H21N3O3, Calculated: [M+H]+, 376.1661; Found: [M+H]+, 376.1657.

[0857]

[0858] 4-((5-cyclobutyl-1,2,4-oxadiazol-3-yl)methyl)-6-(3-(trifluoromethoxy)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (4n): To a flamed dried reaction vial, 6-(3-(trifluoromethoxy)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (15 mg, 0.06 mmol) was added at 0°C in 0.4 ml THF, then, sodium hydride (NaH) (1.7 mg, 0.072 mmol). Then reaction was stirred at 0 °C for 20 min, subsequently tetrabutylammonium iodide (TBAI,4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0859] 44mg, 0.12 mmol) was added followed by 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (15.5 mg, 0.09 mmol). The reaction mixture was heated at 65°C for 30min. The reaction was quench using water and the organic phase was separated. The aqueous phase was extracted with CH2CI2 (3x) and the combined organic extracts were washed with brine, dried with Na2SO4 and concentrated in vacuo to be purified by silica gel column chromatograph (0 to 40% EtOAc in Hex) to afford the product (20.45 mg, 87%). IR (neat) Umax = 3013, 2950, 1695, 1609, 1575, 1519, 1485, 1425, 1371, 1249, 1216, 1160, 1055, 954, 792, 706 cm1. ¹H NMR (500 MHz, CDCl₃) δ 7.44 (m, 2H), 7.29 (dd, J = 17.45, 15.49 Hz, 2H), 7.22 (dd, J = 8.22, 2.00 Hz, 2H), 7.18 (m, 1H), 7.08 (d, J = 8.28 Hz 1H), 5.29 (s, 3H), 4.75 (s, 3H), 3.75 (p, J = 8.61 Hz, 1H), 2.44 (m, 5H), 2.12 (m, 1H), 2.03 (m, 1H).13C NMR (125 MHz, CDCl₃) δ 183.3, 166.0, 164.3, 149.7, 145.1, 142.3, 134.7, 130.2, 128.8, 125.6, 123.0, 119.5, 119.4, 117.6, 114.1, 37.1, 31.4, 27.2, 18.8.

[0860]

[0861] 4-((5-cyclobutyl-1,2,4-oxadiazol-3-yl)methyl)-6-(2,4-dichlorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (4o): To a flamed dried reaction vial, 6-(2,4-dichlorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (14 mg, 0.05 mmol) was added at 0°C in 0.4 ml THF, then, sodium hydride (NaH) (1.7 mg, 0.072 mmol). Then reaction was stirred at 0°C for 20min, subsequently tetrabutylammonium iodide (TBAI, 44mg, 0.12 mmol) was added followed by 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (15 mg, 0.09 mmol). The reaction mixture was heated at 65°C for 30min. The reaction was quench using water and the organic phase was separated. The aqueous phase was extracted with CH2CI2 (3 x) and the combined organic extracts were washed with brine, dried with Na2SO4 and concentrated in vacuo to be purified by silica gel column chromatograph (0 to 40% EtOAc in Hex) to afford the product (17.24 mg, 84%). IR (neat) Umax = 2951, 1694, 1574, 1471, 1444, 1369, 1245, 1103, 1046, 908, 818, 803, 733, 702 cm1. ¹H NMR (500 MHz, CDCl₃) δ 7.45 (d, J = 2.11 Hz, 1H), 7.40 (m, 1H), 7.28 (dd, J = 8.26, 2.12 Hz, 1H), 7.21 (d, J = 8.29 Hz, 1H), 7.05 (m, 2H), 5.23 (s, 2H), 4.77 (d, J = 11.68 Hz, 2H), 3.75 (m, 1H), 2.44 (m, 4H), 2.12 (m, 1H), 2.03 (m, 1H).13C NMR (125 MHz, CDCl₃) δ 183.0, 165.9, 164.4, 144.9, 137.9, 133.9, 133.2,4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0862] 132.9, 131.9, 129.8, 129.0, 128.1, 128.0, 127.3, 125.3, 116.9, 116.4, 113.8, 77.3, 77.1, 77.0, 76.8, 67.6, 63.7, 37.2, 31.4, 27.2, 27.1, 18.8, 18.8. HRMS (ESI) C₂₁H₁₇Cl₂N₃O₃, Calculated: [M+H]+, 430.0725; Found: [M+H]+, 430.0723.

[0863]

[0864] 4-((5-cyclobutyl-1,2,4-oxadiazol-3-yl)methyl)-6-(3-methylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (4p): To a flamed dried reaction vial, 6-(m-tolyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (15 mg, 0.06 mmol) was added at 0°C in 0.4 ml THF, then, sodium hydride (NaH) (1.7 mg, 0.072 mmol). Then reaction was stirred at 0°C for 20min, subsequently tetrabutylammonium iodide (TBAI, 44mg, 0.12 mmol) was added followed by 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (15.5 mg, 0.09 mmol). The reaction mixture was heated at 65°C for 30min. The reaction was quench using water and the organic phase was separated. The aqueous phase was extracted with CH2CI2 (3 x) and the combined organic extracts were washed with brine, dried with Na2SO4 and concentrated in vacuo to be purified by silica gel column chromatograph (0 to 40% EtOAc in Hex) to afford the product (20.45 mg, 87%). IR (neat) Umax = 2997, 2948, 1692, 1606, 1573, 1518, 1485, 1442, 1416, 1368, 1279, 1235, 1135, 1061, 1033, 864, 830, 765, 736, 701 cm ’. ¹H NMR (500 MHz, CDCl₃) δ 7.30 (m, 3H), 7.26 (d, J = 2.13 Hz, 1H), 7.22 (dd, J = 8.27, 2.00 Hz, 1H), 7.15 (m, 1H), 7.06 (d, J = 8.25 Hz, 1H), 5.29 (s, 2H), 4.74 (s, 2H), 3.74 (pd, J = 8.58, 1.16 Hz, 1H), 2.45 (m, 4H), 2.41 (s, 3H), 2.12 (m, 1H), 2.03 (m, 1H).13C NMR (125 MHz, CDCl₃) δ 183.0, 166.1, 164.6, 144.6, 140.2, 138.5, 136.5, 128.8, 128.6, 128.1, 127.7, 124.0, 123.0, 117.3, 114.0, 67.6, 37.1, 31.4, 27.2, 21.5, 18.8.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0865]

[0866] 4-((5-cydobutyl-l,2,4-oxadiazol-3-yl)methyl)-6-(2-methoxyphenyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (4q): To a flamed dried reaction vial, 6-(2-methoxyphenyl)-2H-benzo[ / ?][l,4]oxazin-3(477)-one (15 mg, 0.06 mmol) was added at 0°C in 0.4 ml THF, then, sodium hydride (NaH) (1.7 mg, 0.072 mmol). Then reaction was stirred at 0°C for 20min, subsequently tetrabutylammonium iodide (TBAI, 44mg, 0.12 mmol) was added followed by 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (15.5 mg, 0.09 mmol). The reaction mixture was heated at 65°C for 30min. The reaction was quench using water and the organic phase was separated. The aqueous phase was extracted with CH2CI2 (3 x) and the combined organic extracts were washed with brine, dried with Na2SO4 and concentrated in vacuo to be purified by silica gel column chromatograph (0 to 40% EtOAc in Hex) to afford the product (12.08 mg, 53%). IR (neat) umax= 3043, 2949, 1687, 1610, 1574, 1518, 1487, 1421, 1388, 1272, 1048, 1026, 907, 822, 794, 733 cm1.1H NMR (500 MHz, CDCl3) δ 7.31 (ddd, J= 8.22, 7.39, 1.78 Hz, 1H), 7.25 (m, 2H), 7.17 (dd, J=. T1, 1.92 Hz, 1H), 7.02 (m, 2H), 6.96 (dd, J= 8.24, 1.12 Hz, 1H), 5.24 (s, 2H), 3.78 (s, 2H), 3.72 (m, 1H), 2.43 (m, 4H), 2.12 (m, 1H), 2.02 (m, 1H).13C NMR (125 MHz, CDCl3) δ 166.1, 164.7, 156.3, 144.2, 133.3, 130.6, 128.8, 127.9, 125.4, 121.0, 116.7, 116.4, 111.2, 77.3, 77.0, 76.8, 67.6, 63.7, 55.4, 37.2, 31.4, 27.2, 18.8. HRMS (ESI) C22H21N3O4, Calculated: [M+H]+, 392.1610; Found: [M+H]+, 392.1606.

[0867]

[0868] 4-((5-cyclobutyl-l,2,4-oxadiazol-3-yl)methyl)-6-(phenyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (4r): To a flamed dried reaction vial, 6-phenyl-2H-benzo[b][l,4]oxazin-3(4H)-one (10.8 mg, 0.05 mmol) was added at 0°C 0.05 M THF, then, sodium hydride (NaH) (2.49 mg, 0.06 mmol). Then reaction was stirred at 0°C for 20min, subsequently tetrabutylammonium iodide4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0869] (TBAI, 35 mg, 0.09 mmol) was added followed by 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (9.9 mg, 0.06 mmol). The reaction mixture was heated at 65 °C for 30min. The reaction was quench using water and the organic phase was separated. The aqueous phase was extracted with CH2CI2 (3 x) and the combined organic extracts were washed with brine, dried with Na₂SO₄ and concentrated in vacuo to be purified by silica gel column chromatograph 0 to 40% EtOAc in Hex) to afford the product (11.1 mg, 64%). IR (neat) Umax = 2993, 2948, 1697, 1574, 1487, 1432, 1374, 1279, 1059, 907, 763, 699 cm’1. 'H NMR (500 MHz, CDCl3) δ 7.50 (d, J = 7.50 Hz, 2H), 7.42 (t, J = 7.68 Hz, 2H), 7.34 (t, J = 7.33 Hz, 1H), 7.28 (d, J= 2.00 Hz, 1H), 7.24 (dd, J= 8.28, 1.99 Hz, 1H), 7.07 (d, J= 8.30 Hz, 1H), 5.29 (s, 2H), 4.74 (s, 2H), 3.74 (p, 7 = 8.51 Hz, 1H), 2.56 - 2.37 (m, 4H), 2.12 (dq, 7 = 11.53, 8.82 Hz, 1H), 2.04 (tdd, J= 11.96, 6.69, 4.13 Hz, 1H).13C NMR (125 MHz, CDCI3) δ 183.00, 166.04, 164.49, 144.61, 140.17, 136.31, 128.83, 128.60, 127.31, 126.86, 122.94, 117.34, 113.97, 67.62, 37.10, 31.41, 27.14, 18.76. HRMS (ESI) C21H19N3O3, Calculated: [M+H]+, 362.1505; Found: [M+H]+, 362.1497.

[0870]

[0871] 4-((5-cydobutyl-l,2,4-oxadiazol-3-yl)methyl)-6-(2,4-difluorophenyl)-2H-benzo[b][l,4] oxazin-3(4H)-one (4s): To a flamed dried reaction vial, 6-(2,4-difluorophenyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (27.13 mg, 0.10 mmol) was added at 0°C 0.05 M THF, then, sodium hydride (NaH) (5.39 mg, 0.13 mmol). Then reaction was stirred at 0°C for 20min, subsequently tetrabutylammonium iodide (TBAI, 76.68 mg, 0.21 mmol) was added followed by 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (21.50 mg, 0.12 mmol). The reaction mixture was heated at 65°C for 30min. The reaction was quench using water and the organic phase was separated. The aqueous phase was extracted with CH2CI2 (3 x) and the combined organic extracts were washed with brine, dried with Na / SCh and concentrated in vacuo to be purified by silica gel column chromatograph 0 to 40% EtOAc in Hex) to afford the product (16.26 mg, 39%). IR (neat) vmax= 3004, 2949, 1697, 1612, 1574, 1495, 1418, 1374, 1274, 1140, 1102, 1053, 966, 847, 812 cm1. 'HNMR (500 MHz, CDCl3) δ 7.32 (td, J= 8.72, 6.39 Hz, 1H), 7.18 - 7.11 (m, 2H), 7.07 (d, 7= 8.31 Hz, 1H), 6.97 - 6.84 (m, 2H), 5.26 (s, 2H),4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0872] 4.75 (s, 2H), 3.73 (pd, 7= 8.58, 1.10 Hz, 1H), 2.49 - 2.37 (m, 4H), 2.18 - 2.06 (m, 1H), 2.08 - 1.98 (m, 1H).13C NMR (125 MHz, CDCl3) δ 183.01, 165.93, 164.39, 144.79, 131.16 (d, 7 = 4.53 Hz), 131.10 (d), 129.74, 128.38, 124.78, 117.18, 115.74 (d, 7 = 2.94 Hz), 111.73 (d, 7 = 3.29 Hz), 111.56 (d, 7= 3.40 Hz), 104.45 (t, 7 = 25.81 Hz), 67.57, 37.12, 31.40, 27.12, 18.76. HRMS (ESI) C21H17F2N3O3, Calculated: [M+H]+, 398.1316; Found: [M+H]+, 398.1311.

[0873] N-0

[0874]

[0875] 4-((5-cyclobutyl-l,2,4-oxadiazol-3-yl)methyl)-6-(2,3-dichIorophenyl)-2H-benzo[b][l,4] oxazin-3(4H)-one (4t): To a flamed dried reaction vial, 6-(2,3-dichlorophenyl )-2H-benzo[b][1,4]oxazin-3(4H)-one (15 mg, 0.05 mmol) was added at 0°C in 0.05 M THF, then, sodium hydride (NaH) (1.7 mg, 0.072 mmol). Then reaction was stirred at 0°C for 20min, subsequently tetrabutylammonium iodide (TBAI, 44mg, 0.12 mmol) was added followed by 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (15 mg, 0.09 mmol). The reaction mixture was heated at 65°C for 30min. The reaction was quench using water and the organic phase was separated. The aqueous phase was extracted with CH2Q2 (3 x) and the combined organic extracts were washed with brine, dried with Na₂SO₄ and concentrated in vacuo to be purified by silica gel column chromatograph (0 to 40% EtOAc in Hex) to afford the product (18.95 mg, 86%). IR (neat) Umax = 2992, 2947, 1692, 1574, 1516, 1454, 1407, 1370, 1274, 1135, 1045, 916, 785, 730 cm1. H NMR (500 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.65 (dd, J = 8.00, 1.58 Hz, 1H), 7.42 (t, 7= 7.84 Hz, 1H), 7.34 (dd, 7 = 7.66, 1.59 Hz, 1H), 7.04 (d, 7 = 8.22 Hz, 1H), 6.97 (dd, 7= 8.25, 2.11 Hz, 1H), 6.93 (d, 7 = 2.11 Hz, 1H), 4.64 (s, 2H).13C NMR (125 MHz, DMSO-d6) δ 164.8, 143.1, 141.6, 132.6, 132.3, 130.0, 129.7, 128.3, 127.0, 123.9, 116.4, 116.0, 66.8. HRMS (ESI) C21H17CI2N3O3, Calculated: [M+H]+, 430.0725; Found: [M+H]+, 430.0720.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0876]

[0877] 4-((5-cydobutyl-l,2,4-oxadiazol-3-yl)methyl)-6-(2-fluorophenyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (4u): To a flamed dried reaction vial, 6-(2-fluorophenyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (33.67 mg, 0.14 mmol) was added at 0°C in 0.05 M THF, then, sodium hydride (NaH) (7.2 mg, 0.18 mmol). Then reaction was stirred at 0°C for 20min, subsequently tetrabutylammonium iodide (TBAI, 102.26 mg, 0.28 mmol) was added followed by 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (28.67 mg, 0.17 mmol). The reaction mixture was heated at 65°C for 30min. The reaction was quench using water and the organic phase was separated. The aqueous phase was extracted with CH2CI2 (3 x) and the combined organic extracts were washed with brine, dried with Na2SO4 and concentrated in vacuo to be purified by silica gel column chromatograph (0 to 40% EtOAc in Hex) to afford the product (32.95 mg, 63%). IR (neat) umax= 2991, 2949, 1693, 1611, 1574, 1485, 1431, 1374, 1261, 1108, 1053, 909, 813, 758 cm1. > HNMR (500 MHz, CDCI3) 57.36 (td, J = 1.11, 1.82 Hz, 1H), 7.33 - 7.27 (m, 1H), 7.24 - 7.16 (m, 3H), 7.12 (dd, 7= 10.35, 8.92 Hz, 1H), 7.07 (d, J= 8.26 Hz, 1H), 5.26 (s, 2H), 4.75 (s, 2H), 3.73 (p, J= 8.58 Hz, 1H), 2.53 -2.35 (m, 4H), 2.10 (dt, J= 11.41, 8.94 Hz, 1H), 2.06 - 1.97 (m, 1H).13C NMR (125 MHz, CDCI3) δ 183.0, 166.0, 164.5, 160.6, 158.6, 144.8, 130.6, 130.4 (d, J= 3.24 Hz), 129.0 (d, J = 8.20 Hz), 128.3, 128.0 (d, J = 13.12 Hz), 124.9 (d, J = 2.85 Hz), 124.4 (d, J= 3.71 Hz), 117.1, 116.3, 116.1, 115.9 (d, 7 = 3.41 Hz), 67.6, 37.2, 31.4, 27.1, 18.8. HRMS (ESI) C21H18FN3O3, Calculated: [M+H]+, 380.1410; Found: [M+H]+, 380.1407.

[0878]

[0879] 4-((5-cydobutyl-l,2,4-oxadiazol-3-yl)methyl)-6-(3-fluorophenyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (4v): To a flamed dried reaction vial, 6-(3-fluorophenyl)- 2H-benzo[b][l,4]oxazin-3(4H)-one (21.35 mg, 0.089 mmol) was added at 0°C in 0.05 M4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0880] THF, then, sodium hydride (NaH) (4.56 mg, 0.11 mmol). Then reaction was stirred at 0°C for 20min, subsequently tetrabutylammonium iodide (TBAI, 69.52 mg, 0.18 mmol) was added followed by 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (18.17 mg, 0.11 mmol). The reaction mixture was heated at 65°C for 30min. The reaction was quench using water and the organic phase was separated. The aqueous phase was extracted with CH2CI2 (3 x) and the combined organic extracts were washed with brine, dried with Na2SO4 and concentrated in vacuo to be purified by silica gel column chromatograph (0 to 40% EtOAc in Hex) to afford the product (28.47 mg, 86%). IR (neat) Umax = 2994, 2949, 1694, 1612, 1582, 1485, 1518, 1378, 1291, 1180, 1065, 872, 785 cm’1.1H NMR (500 MHz, CDCl3) δ 7.37 (td, 7= 7.98, 5.98 Hz, 1H), 7.31 - 7.25 (m, 2H), 7.20 (ddd, 7= 12.64, 8.25, 1.92 Hz, 2H), 7.07 (d, 7= 8.30 Hz, 1H), 7.02 (td, 7= 8.24, 1.86 Hz, 1H), 5.28 (s, 2H), 4.74 (s, 2H), 3.75 (p, 7= 8.37 Hz, 1H), 2.53 - 2.36 (m, 3H), 2.17 - 2.05 (m, 1H), 2.05 - 1.98 (m, 1H).13C NMR (125 MHz, CDCl3) δ 183.1, 165.97, 164.4, 164.1, 162.2, 145.0, 142.4 (d, 7= 7.66 Hz), 135.0, 130.3 (d, 7 = 8.41 Hz), 128.7, 122.9, 122.4, 117.5, 114.0, 114.3 - 113.5 (m), 67.6, 37.0, 31.4, 27.2, 18.8.

[0881] HRMS (ESI) C21H18FN3O3, Calculated: [M+H]+, 380.1410; Found: [M+H]+, 380.1404.

[0882]

[0883] 4-((5-cydobutyl-l,2,4-oxadiazol-3-yl)methyl)-6-(2-(trifluoromethyl)phenyl)-2H-benzo[b] [l,4]oxazin-3(4H)-one (4w): To a flamed dried reaction vial, 6-(2-(trifluoromethyl)phenyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (40.32 mg, 0.14 mmol) was added at 0°C in 0.05 M THF, then, sodium hydride (NaH) (7.15 mg, 0.18 mmol). Then reaction was stirred at 0°C for 20min, subsequently tetrabutylammonium iodide (TBAI, 101.57 mg, 0.27 mmol) was added followed by 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (28.48 mg, 0.16 mmol). The reaction mixture was heated at 65°C for 30min. The reaction was quench using water and the organic phase was separated. The aqueous phase was extracted with CH2CI2 (3 x) and the combined organic extracts were washed with brine, dried with Na2SO4 and concentrated in vacuo to be purified by silica gel column chromatograph (0 to 25% EtOAc in Hex) to afford the product (31.41 mg, 53%). IR (neat) Umax = 2951, 1694, 1575, 1488, 1436, 1374, 1313, 1270, 1168, 1125, 1109, 1034, 908, 848, 825, 770 cm’1.1H NMR (500 MHz, CDCl3) δ 7.714239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0884] (d, J= 7.80 Hz, 1H), 7.54 (t, J = 7.42 Hz, 1H), 7.45 (t, J = 7.63 Hz, 1H), 7.27 (d, 7= 7.63 Hz, 1H), 7.03 (d, 7= 8.17 Hz, 1H), 6.98 - 6.90 (m, 2H), 5.21 (s, 2H), 4.78 (s, 2H), 3.80 - 3.65 (m, 1H), 2.46 - 2.35 (m, 4H), 2.15 - 2.04 (m, 1H), 2.04 - 1.94 (m, 1H).13C NMR (125 MHz, CDCl3) δ 182.9, 165.9, 164.6, 144.7, 140.2, 134.4, 132.0, 131.4, 128.8, 128.5 (d, 7 = 29.73 Hz), 127.6 (d, 7= 12.59 Hz), 126.1 (q, 7 = 4.85 Hz), 124.9, 122.9, 116.5, 115.9, 67.55, 63.7, 37.2, 31.4, 27.1, 18.7. HRMS (ESI) C22Hi8F3N3O3, Calculated: [M+H]+, 430.1379; Found:

[0885] [M+H]+, 430.1381.

[0886] ji '

[0887] JI Nx / O

[0888] F

[0889]

[0890] 4-((5-cydobutyl-l,2,4-oxadiazol-3-yl)methyl)-6-(2,3-difluorophenyl)-2H-benzo[b][l,4] oxazin-3(4H)-one (4x): To a flamed dried reaction vial, 6-(2,3-difluorophenyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (69.7 mg, 0.27 mmol) was added at 0°C 0.05 M THF, then, sodium hydride (NaH) (13.87 mg, 0.34 mmol). Then reaction was stirred at 0°C for 20min, subsequently tetrabutylammonium iodide (TBAI, 197 mg, 0.53 mmol) was added followed by 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (55.26 mg, 0.32 mmol). The reaction mixture was heated at 65°C for 30min. The reaction was quench using water and the organic phase was separated. The aqueous phase was extracted with CH2Q2 (3 x) and the combined organic extracts were washed with brine, dried with Na2SO4 and concentrated in vacuo to be purified by silica gel column chromatograph (0 to 40% EtOAc in Hex) to afford the product (72.3 mg, 68%). IR (neat) υmax= 2990, 2943, 1696, 1574, 1521, 1474, 1436, 1373, 1263, 1 139, 1103, 1039, 939, 880, 784, 731 cm-1.1H NMR (500 MHz, CDCl3) δ 7.21 (s, 1H), 7.17 (d, J = 8.40 Hz, 1H), 7.15 - 7.09 (m, 3H), 7.07 (d, J = 8.30 Hz, 1H), 5.26 (s, 2H), 4.74 (s, 2H), 3.73 (p, J = 8.50 Hz, 1H), 2.54 - 2.30 (m, 4H), 2.15 - 2.06 (m, 1H), 2.06 - 1.93 (m, 1H).

[0891] 13C NMR (125 MHz, CDCl3) δ 183.0, 165.9, 164.3, 152.1 (d, J= 13.45 Hz), 150.1 (d, J = 13.37 Hz), 148.8 (d, 7 = 13.37 Hz), 146.8 (d, 7= 13.52 Hz), 145.1, 130.2 (d, J= 9.87 Hz), 129.4, 128.4, 124.9 (d, J= 13.95 Hz), 124.3 - 123.8 (m), 117.2, 116.1 (d, J= 17.43 Hz), 115.8 (d, J = 3.32 Hz), 67.5, 63.7, 37.1, 31.4, 27.1, 18.8. HRMS (ESI) C21H17F2N3O3, Calculated: [M+H]+, 398.1316; Found: [M+H]+, 398.1315.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0892]

[0893] 4-((5-cydobutyl-l,2,4-oxadiazol-3-yl)methyl)-6-(2-chIorophenyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (4y): To a flame dried flask cooled to 0 °C was added sodium hydride (4.0 mg, 0.100 mmol) and 6-(2-chlorophenyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (20.0 mg, 0.077 mmol) as a solution in THF (1.48 mL, 0.05M). The mixture was stirred for 10 min before the addition of 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (16.0 mg, 0.093 mmol) and tetra-n-butylammonium iodide (56.9 mg, 0.154 mmol). The reaction was heated to 65 °C for 30 minutes. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 30% EtOAc in Hex) to yield the desired product (23.2 mg, 76%). IR (neat) umax= 2949, 1689, 1573, 1516, 1470, 0124, 1374, 1258, 1135, 1045, 908, 847, 823, 756, 738, 701 cm’1. 'H NMR (500 MHz, MeOD) 57.44 (d, 7 = 7.11 Hz, 1H), 7.35 - 7.25 (m, 3H), 7.14 (s, 1H), 7.07 (s, 2H), 5.29 (s, 2H), 4.74 (s, 2H), 3.89 - 3.71 (m, 1H), 2.47 - 2.34 (m, 4H), 2.20 - 2.09 (m, 1H), 2.07 - 1.94 (m, 1H).13C NMR (125 MHz, MeOD) δ 183.2, 166.3, 165.1, 144.9, 139.4, 134.0, 132.0, 131.0, 129.6, 128.6, 127.7, 126.8, 125.0, 116.6, 116.3, 67.2, 63.1, 36.4, 31.1, 26.6, 18.2. HRMS (ESI) C21H18CIN3O3, Calculated: [M+H]+, 396.1115; Found: [M+H]+, 396.1113.

[0894]

[0895] 4-((5-cydobutyl-l,2,4-oxadiazol-3-yl)methyl)-6-(3-chlorophenyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (4z): To a flame dried flask cooled to 0 °C was added sodium hydride (4.0 mg, 0.100 mmol) and 6-(3-chlorophenyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (20.0 mg, 0.077 mmol) as a solution in THF (1.48 mL, 0.05M). The mixture was stirred for 10 min before the addition of 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (16.0 mg, 0.093 mmol) and tetra-n-butylammonium iodide (56.9 mg, 0.154 mmol). The4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0896] reaction was heated to 65 °C for 30 minutes. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 30% EtOAc in Hex) to yield the desired product (7.9 mg, 26%). IR (neat) umax= 2990, 2948, 2867, 1697, 1574, 1518, 1474, 1411, 1369, 1276, 1104, 1057, 914, 851, 785 cm-1.1H NMR (500 MHz, CDCl3) δ 7.47 (t, J = 1.54 Hz, 1H), 7.39 - 7.32 (m, 2H), 7.32 - 7.27 (m, 2H), 7.20 (dd, 7= 8.30, 1.99 Hz, 1H), 7.07 (d, 7= 8.30 Hz, 1H), 5.28 (s, 2H), 4.76 (d, 7 = 22.97 Hz, 2H), 3.81 - 3.67 (m, 1H), 2.56 - 2.37 (m, 4H), 2.20 - 2.08 (m, 1H), 2.08 - 1.99 (m, 1H).13C NMR (125 MHz, CDCl3) δ 183.1, 166.0, 164.3, 145.0, 142.0, 134.8, 134.7, 130.1, 128.7, 127.3, 127.0, 125.0, 123.0, 117.5, 114.0, 63.7, 37.1, 31.4, 27.2, 18.8. HRMS (ESI) C21H18CIN3O3, Calculated: [M+H]+, 396.1115; Found: [M+H]+, 396.1110.

[0897]

[0898] 4-((5-cydobutyl-l,2,4-oxadiazol-3-yl)methyl)-6-(3-chIoro-2-methylphenyl)-2H-benzo[b] [l,4]oxazin-3(4H)-one (4aa): To a flame dried flask cooled to 0 °C was added sodium hydride (6.9 mg, 0.172 mmol) and 6-(3-chloro-2-methylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (27.4 mg, 0.159 mmol) as a solution in THF (2.65 mL, 0.05M). The mixture was stirred for 10 min before the addition of 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (27.4 mg, 0.159 mmol) and tetra-n-butylammonium iodide (97.7 mg, 0.265 mmol). The reaction was heated to 65 °C for 30 minutes. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 30% EtOAc in Hex) to yield the desired product (18.5 mg, 30%). IR (neat) Umax = 2925, 1691, 1573, 1511, 1454, 1446, 1424, 1371, 1273, 1233, 1061, 1034, 911, 787, 734, 701

[0899]

[0900] cm’1. NMR (500 MHz, CDCl3) δ 7.35 (d, 7 = 7.77 Hz, 1H), 7.14 (t, 7 = 7.77 Hz, 1H), 7.10 - 7.03 (m, 2H), 6.94 - 6.89 (m, 2H), 5.22 (s, 2H), 4.76 (s, 2H), 3.73 (p, 7= 8.64 Hz, 1H), 2.48 - 2.36 (m, 4H), 2.19 (s, 3H), 2.15 - 2.07 (m, 1H), 2.07 - 1.97 (m, 1H).13C NMR (125 MHz, CDCl3) δ 183.0, 165.9, 164.6, 144.3, 142.8, 136.2, 135.4, 133.8, 128.4, 128.2, 128.0, 126.5, 125.0, 116.9, 116.1, 67.6, 37.2, 31.4,4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0901] 27.1, 18.8, 17.8. HRMS (ESI) C22H20CIN3O3, Calculated: [M+H]+, 410.1271; Found:

[0902] [M+H]+, 410.1270.

[0903]

[0904] 4-((5-cydobutyl-l,2,4-oxadiazol-3-yl)methyl)-6-(2-chIoro-3-methylphenyl)-2H-benzo[b] [l,4]oxazin-3(4H)-one (4bb): To a flame dried flask cooled to 0 °C was added sodium hydride (6.9 mg, 0.172 mmol) and 6-(2-chloro-3-methylphenyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (27.4 mg, 0.159 mmol) as a solution in THF (2.65 mL, 0.05M). The mixture was stirred for 10 min before the addition of 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (27.4 mg, 0.159 mmol) and tetra-n-butylammonium iodide (97.7 mg, 0.265 mmol). The reaction was heated to 65 °C for 30 minutes. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 30% EtOAc in Hex) to yield the desired product (22.1 mg, 41%). IR (neat) Umax = 2949, 1694, 1574, 1516, 1466, 1438, 1371, 1276, 1042, 866, 786, 732, 701 cm1. 'H NMR (500 MHz, CDCl3) δ 7.22 (d, J = 7.29 Hz, 1H), 7.18 (t, J= 7.50 Hz, 1H), 7.10 (dd, J = 7.47, 1.39 Hz, 1H), 7.07 - 7.02 (m, 3H), 5.23 (s, 2H), 4.77 (d, 7= 11.65 Hz, 3H), 3.82 - 3.67 (m, 1H), 2.50 - 2.43 (m, 3H), 2.42 (s, 3H), 2.41 - 2.39 (m, 1H), 2.17 - 2.07 (m, 1H), 2.06 - 1.98 (m, 1H).13C NMR (126 MHz, CDCI3) δ 182.9, 166.7, 165.9, 164.6, 144.5, 139.8, 137.1, 134.8, 132.7, 130.1, 128.8, 127.8, 126.2, 125.4, 116.6 (d, J= 14.00 Hz), 67.6, 63.7, 37.3, 31.4, 27.1, 21.0, 18.8. HRMS (ESI) C22H20CIN3O3, Calculated: [M+H]+, 410.1271; Found: [M+H]+, 410.1268.

[0905]

[0906] 4-((5-cydobutyl-l,2,4-oxadiazol-3-yl)methyl)-6-(2-isopropylphenyI)-2H-benzo[b][l,4] oxazin-3(4H)-one (4cc): To a flame dried flask cooled to 0 °C was added sodium hydride4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0907] (3.9 mg, 0.973 mmol) and 6-(2-isopropylphenyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (20.0 mg, 0.075 mmol) as a solution in THF (1.5 mL, 0.05M). The mixture was stirred for 10 min before the addition of 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (15.5 mg, 0.090 mmol) and tetra-n-butylammonium iodide (55.3 mg, 0.150 mmol). The reaction was heated to 65 °C for 30 minutes. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 30% EtOAc in Hex) to yield the desired product (15.4 mg, 51%). IR (neat) υmax= 2958, 1694, 1574, 1484, 1433, 1373, 1265, 1053, 903, 825, 733, 702 cm1.1H NMR (500 MHz, CDCl3) δ 7.34 (qd, J = 7.88, 1.44 Hz, 2H), 7.19 (td, 7 = 7.17, 6.71, 1.97 Hz, 1H), 7.13 - 7.09 (m, 1H), 7.05 (d, 7 = 8.14 Hz, 1H), 6.93 (dd, 7= 8.14, 1.83 Hz, 1H), 6.90 - 6.86 (m, 1H), 5.21 (s, 2H), 4.78 (d, 7 = 11.28 Hz, 2H), 3.75 - 3.66 (m, 1H), 3.01 - 2.89 (m, 1H), 2.42 (dt, 7= 17.49, 9.12 Hz, 4H), 2.17 - 2.06 (m, 1H), 2.06 - 1.97 (m, 1H), 1.09 (d, 7= 6.87 Hz, 6H).13C NMR (125 MHz, CDCl3) δ 182.9, 165.9, 164.7, 146.4, 144.1, 139.9, 136.8, 129.9, 127.9, 125.6, 125.3, 125.1, 116.6, 116.1, 67.6, 63.7, 37.4, 31.4, 29.3, 27.2, 27.1, 24.1, 18.8, 18.7. HRMS (ESI) C24H25N3O3, Calculated: [M+H]+, 404.1974;

[0908] Found: [M+H]+, 404.1967.

[0909]

[0910] 4-((5-cydobutyl-l,2,4-oxadiazol-3-yl)methyl)-6-(3-isopropylphenyl)-2H-benzo[b][l,4] oxazin-3(4H)-one (4dd): To a flame dried flask cooled to 0 °C was added sodium hydride (3.9 mg, 0.973 mmol) and 6-(3-isopropylphenyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (20.0 mg, 0.075 mmol) as a solution in THF (1.5 mL, 0.05M). The mixture was stirred for 10 min before the addition of 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (15.5 mg, 0.090 mmol) and tetra-n-butylammonium iodide (55.3 mg, 0.150 mmol). The reaction was heated to 65 °C for 30 minutes. The reaction was quenched with H2O and extracted with EtOAc in triplicate. The organic washes were combined, concentrated in vacuo, and purified via column chromatography (0 to 30% EtOAc in Hex) to yield the desired product (21.1 mg, 70%). IR (neat) vmax= 2948, 1689, 1610, 1573, 1517, 1470, 1424, 1374, 1258, 1135, 1045, 908, 847, 823, 757, 736, 701 cm1. 'H NMR (500 MHz, MeOD) 67.36 (d, 7 = 1.98 Hz, 2H),4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0911] 7.30 (d, J = 7.03 Hz, 2H), 7.25 (dd, J= 8.31, 1.98 Hz, 1H), 7.18 (dt, 7= 6.62, 1.68 Hz, 1H), 7.07 - 7.03 (m, 1H), 5.35 (s, 2H), 4.72 (d, J= 15.83 Hz, 2H), 3.83 - 3.73 (m, 1H), 2.93 (p, J = 6.92 Hz, 1H), 2.41 (dq, J = 18.97, 10.41, 8.85 Hz, 4H), 2.18 - 2.07 (m, 1H), 2.07 - 1.93 (m, 1H), 1.27 (d, J = 6.93 Hz, 6H).13C NMR (125 MHz, MeOD) 5 166.4, 165.1, 149.3, 144.7, 140.1, 136.3, 128.5, 128.3, 125.0, 124.5, 123.9, 122.5, 116.8, 114.0, 67.2, 63.1, 36.2, 34.1, 31.1, 26.6, 23.1, 18.18. HRMS (ESI) C24H25N3O3, Calculated: [M+H]+, 404.1974; Found: [M+H]+, 404.1972.

[0912]

[0913] Me

[0914] 6-((2,3-dimethylphenyl)amino)-2H-benzo[b][l,4]oxazin-3(4H)-one (20a) To a flame dried reaction flask, 6-bromo-2n-benzo[ / 2][l,4]oxazin-3(4H)-one (150 mgs, 0.66 mmol), Pd(OAc)2 (15 mg, 10 mol%), Xantphos (76 mg, 20 mol%), and NaOtBu (381 mg, 3.96 mmol) were added. The reaction flask was then flushed with argon (3x), 2,3-dimethylaniline (0.1 ml, 0.79 mmol) and degas anhydrous 1,4-dioxane (0.1M) were added. The reaction was heated for 22 hr. The crude reaction was filtered using celite, and concentrated in vacuo to be purified by silica gel column chromatograph (0 to 40% EtOAc in Hex) to afford the product 0.139 g, 79%). ‘H NMR (500 MHz, DMSO-d6) 5 10.51 (s, 1H), 7.25 (s, 1H), 6.97 (t, 7 = 7.66 Hz, 1H), 6.91 (d, 7 = 7.89 Hz, 1H), 6.81 (d, 7 = 7.30 Hz, 1H), 6.76 (d, 7= 8.58 Hz, 1H), 6.41 (d, 7 = 1.11 Hz, 2.58, 1H), 6.36 (dd, 7 = 8.59, 2.60 Hz, 1H), 4.44 (s, 2H), 2.24 (s, 3H), 2.06 (s, 3H).13C NMR (125 MHz, DMSO-d6) 5 165.6, 142.2, 141.4, 137.7, 136.5, 128.8, 128.2, 126.1, 124.1, 118.8, 116.9, 111.2, 104.3, 67.4, 20.8, 14.3.

[0915]

[0916] 6-((2-chlorophenyl)amino)-2H-benzo[b][1,4]oxazin-3(4H)-one (20b) To a flame dried reaction flask, 6-bromo-2n-benzo[ / 2][l,4]oxazin-3(4H)-one (100 mgs, 0.44 mmol), Pd(OAc)2 (10 mg, 10 mol%), Xantphos (51 mg, 20 mol%), and NaOtBu (254 mg, 2.64 mmol) were4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0917] added. The reaction flask was then flushed with argon (3x), 2-chloroaniline (0.05 ml, 0.48 mmol) and degas anhydrous 1,4-dioxane (0.1M) were added. The reaction was heated for 24 hr. The crude reaction was filtered using celite, and concentrated in vacuo to be purified by silica gel column chromatograph (0 to 10% MeCN in CH2CI2) to afford the product (88.22 mg, 73%). 'H NMR (500 MHz, DMSO-de) 5 10.63 (s, 1H), 7.52 (s, 1H), 7.38 (dd, J = 7.93, 1.48 Hz, 1H), 7.16 (ddd, J= 8.59,' 7.17, 1.51 Hz, 1H), 7.09 (dd, 7= 8.21, 1.56 Hz, 1H), 6.87 (d, 7 = 8.50 Hz, 1H), 6.83 (m, 1H), 6.69 (d, 7 = 2.55 Hz, 1H), 6.65 (dd, 7 = 8.58, 2.55 Hz, 1H), 4.51 (s, 2H).13C NMR (125 MHz, DMSO-d6) 5 165.6, 141.7, 138.6, 137.8, 130.4, 128.2, 122.3, 121.1, 117.7, 117.0, 115.1, 108.0, 67.3.

[0918]

[0919] Cl

[0920] 6-((2,3-dichlorophenyl)amino)-2H-benzo[b][1,4]oxazin-3(4H)-one (20c) To aflame dried reaction flask, 6-bromo-27 / -benzo[ >][l,4]oxazin-3(477)-one (100 mgs, 0.44 mmol), Pd(OAc)2 (10 mg, 10 mol%), Xantphos (51 mg, 20 mol%), and NaOtBu (254 mg, 2.64 mmol) were added. The reaction flask was then flushed with argon (3x), 2,3-dichloroaniline (0.03 ml, 0.26 mmol) and degas anhydrous 1,4-dioxane (0.1M) were added. The reaction was heated for 24 hr. The crude reaction was filtered using celite, and concentrated in vacuo to be purified by silica gel column chromatograph (0 to 30% EtOAc in Hex) to afford the product (51.65 mg, 76%). 'H NMR (500 MHz, DMSO-ds) 5 10.67 (s, 1H), 7.75 (s, 1H), 7.14 (t, J = 8.1 Hz, 1H), 7.02 (dd, J = 8.0, 1.4 Hz, 1H), 6.96 (dd, J = 8.3, 1.4 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 6.72 (d, J = 2.5 Hz, 1H), 6.70 (dd, J = 8.5, 2.6 Hz, 1H), 4.53 (s, 2H).13C NMR (125 MHz, DMSO-ds) 8 165.5, 144.2, 139.4, 136.9, 132.8, 128.6, 128.3, 120.6, 119.3, 117.1, 116.6, 114.7, 109.6, 67.3.

[0921]

[0922] 6-((2-fluorophenyl)amino)-2H-benzo[b][l,4]oxazin-3(4H)-one (20d) To a flame dried reaction flask, 6-bromo-277-benzo[ / ?][l,4]oxazin-3(4 / / )-one (100 mgs, 0.44 mmol), Pd(OAc)4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0923] (10 mg, 10 mol%), Xantphos (51 mg, 20 mol%), and NaOtBu (254 mg, 2.64 mmol) were added. The reaction flask was then flushed with argon (3x), 2-fluoroaniline (0.05 ml, 0.48 mmol) and degas anhydrous 1,4-dioxane (0.1M) were added. The reaction was heated for 24 hr. The crude reaction was filtered using celite, and concentrated in vacuo to be purified by silica gel column chromatograph (0 to 40% EtOAc in Hex) to afford the product (89.12 mg, 79%). 'H NMR (500 MHz, DMSO-d6) 5 10.59 (s, 1H), 7.78 (s, 1H), 7.17 (m, 2H), 7.04 (t, J = 8.73 Hz, 1H), 6.84 (m, 2H), 6.65 (d, J = 2.53 Hz, 1H), 6.58 (dd, J = 8.59, 2.58 Hz, 1H), 4.49 (s, 2H).13C NMR (125 MHz, DMSO-dfi) 5 165.7, 154.4, 152.5, 138.4, 137.9, 132.5, 132.4, 128.2, 125.1, 125.1, 120.9, 120.9, 118.7, 116.9, 116.2, 116.1, 113.2, 106.2, 67.3.

[0924]

[0925] 6-((2-isopropylphenyl)amino)-2H-benzo[b][l,4]oxazin-3(4H)-one (20e) To a flame dried reaction flask, 6-bromo-277-benzo[£>][l,4]oxazin-3(47 )-one (100 mgs, 0.44 mmol), Pd(OAc)2 (10 mg, 10 mol%), Xantphos (51 mg, 20 mol%), and NaOtBu (254 mg, 2.64 mmol) were added. The reaction flask was then flushed with argon (3x), 2-isopropylaniline (0.07 ml, 0.48 mmol) and degas anhydrous 1,4-dioxane (0.1M) were added. The reaction was heated for 1 hr. The crude reaction was filtered using celite and concentrated in vacuo to be purified by silica gel column chromatograph (0 to 40% EtOAc in Hex) to afford the product (102.21 mg, 83%). 'H NMR (500 MHz, DMSO-de) 5 10.49 (s, 1H), 7.27 (d, J= 1.56 Hz, 1H), 7.22 (s, 1H), 7.09 (t, J= 1.59 Hz, 1H), 7.05 (d, J= 1.58 Hz, 1H), 6.99 (t, J= 1.60 Hz, 1H), 6.76 (d, J = 8.58 Hz, 1H), 6.43 (d, J = 2.55 Hz, 1H), 6.37 (dd, J= 8.61, 2.59 Hz, 1H), 4.44 (s, 1H), 3.22 (h, J = 7.66 Hz, 6.861H), 1.14 (d, J = 6.85 Hz, 6H).13C NMR (125 MHz, DMSO-ds) 5 165.6, 142.1, 141.5, 140.8, 136.4, 128.2, 126.7, 126.4, 123.3, 122.5, 116.9, 110.9, 103.9, 67.4, 27.1, 23.6.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0926]

[0927] Me

[0928] 6-((2-chloro-3-methylphenyl)amino)-2H-benzo[b][1,4]oxazin-3(4H)-one (20f) To a flame dried reaction flask, 6-bromo-2 / / -benzo|b|| 1,4|oxazin-3(4 / / )-one (100 mgs, 0.44 mmol), Pd(OAc)2 (10 mg, 10 mol%), Xantphos (51 mg, 20 mol%), and NaOtBu (254 mg, 2.64 mmol) were added. The reaction flask was then flushed with argon (3x), 2-chloro-3-methylaniline (0.03 ml, 0.26 mmol) and degas anhydrous 1,4-dioxane (0.1M) were added. The reaction was heated for 1.4 hr. The crude reaction was filtered using celite and concentrated in vacuo to be purified by silica gel column chromatography (0 to 30% EtOAc in Hex) to afford the product (54.74 mg, 84%). ’H NMR (500 MHz, DMSO-de) 5 10.62 (s, 1H), 7.44 (s, 1H), 7.05 (t, J = 7.8 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 6.81 (d, J = 7.4 Hz, 1H), 6.68 (d, J = 2.5 Hz, 1H), 6.64 (dd, J = 8.5, 2.6 Hz, 1H), 4.50 (s, 2H), 2.32 (s, 3H).13C NMR (125 MHz, DMSO-de) 5 165.7, 141.8, 138.5, 138.1, 137.1, 128.2, 127.3, 122.7, 122.4, 117.0, 115.3, 115.1, 108.1, 67.3, 20.7.

[0929]

[0930] 6-((2,4-dichlorophenyl)amino)-2H-benzo[b][l,4]oxazin-3(4H)-one (20g) To aflame dried reaction flask, 6-bromo-2H-benzo[ ][l,4]oxazin-3(4H)-one (100 mgs, 0.44 mmol), Pd(OAc)2 (10 mg, 10 mol%), Xantphos (51 mg, 20 mol%), and NaOtBu (254 mg, 2.64 mmol) were added. The reaction flask was then flushed with argon (3x), 2,4-dichloroaniline (78 mg, 0.48 mmol) and degas anhydrous 1,4-dioxane (0.1M) were added. The reaction was heated for 24 hr. The crude reaction was filtered using celite, and concentrated in vacuo to be purified by silica gel column chromatograph (0 to 10% MeCN in CH2CI2) to afford the pure product (74.25 mg, 55%). 'H NMR (500 MHz, DMSO-d6) 8 10.65 (s, 1H), 7.66 (s, 1H), 7.50 (d, J = 2.46 Hz, 1H), 7.21 (dd, J = 8.81, 2.51 Hz, 1H), 7.04 (d, J = 8.83 Hz, 1H), 6.88 (d, J = 8.50 Hz, 1H), 6.67 (m, 2H), 4.52 (s, 2H).13C NMR (125 MHz, DMSO-d6) 8 165.6, 141.2, 139.0, 137.2, 129.5, 128.3, 128.2, 123.2, 122.5, 118.1, 117.1, 115.7, 108.8, 67.3.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0931]

[0932] Cl

[0933] 6-((3-chloro-2-methylphenyl)amino)-2H-benzo[b][l,4]oxazin-3(4H)-one (20h) To a flame dried reaction flask, 6-bromo-2 / 7-benzo[£>][l,4]oxazin-3(4H)-one (100 mgs, 0.44 mmol), Pd(OAc)2 (10 mg, 10 mol%), Xantphos (51 mg, 20 mol%), and NaOtBu (254 mg, 2.64 mmol) were added. The reaction flask was then flushed with argon (3x), 3-chloro-2-methylaniline (0.06 ml, 0.48 mmol) and degas anhydrous 1,4-dioxane (0.1M) were added. The reaction was heated for 5.4 hr. The crude reaction was filtered using celite and concentrated in vacuo to be purified by silica gel column chromatograph (0 to 40% EtOAc in Hex) to afford the product (98.0 mg, 77%). 'H NMR (500 MHz, DMSO-de) 5 10.57 (s, 1H), 7.07 (m, 1H), 6.98 (d, J = 7.98 Hz, 2H), 6.83 (d, J= 8.53 Hz, 1H), 6.53 (d, J= 2.53 Hz, 1H), 6.49 (dd, 7= 8.55, 2.57 Hz, 1H), 4.48 (s, 2H), 2.23 (s, 3H).13C NMR (125 MHz, DMSO-de) 5 165.7, 144.8, 139.6, 137.7, 134.7, 128.3, 127.6, 126.3, 121.8, 117.4, 117.0, 113.2, 106.2, 67.3, 15.2.

[0934]

[0935] iPr

[0936] 6-((3-isopropylphenyl)amino)-2H-benzo[b][1,4]oxazin-3(4H)-one (20i) To a flame dried reaction flask, 6-bromo-2 -benzo[£>][l,4]oxazin-3(4H)-one (100 mgs, 0.44 mmol), Pd(OAc)2 (10 mg, 10 mol%), Xantphos (51 mg, 20 mol%), and NaOtBu (254 mg, 2.64 mmol) were added. The reaction flask was then flushed with argon (3x), 3 -isopropylaniline (0.07 ml, 0.48 mmol) and degas anhydrous 1,4-dioxane (0.1M) were added. The reaction was heated for 1 hr. The crude reaction was filtered using celite, and concentrated in vacuo to be purified by silica gel column chromatograph (0 to 40% EtOAc in Hex) to afford the product (73.96 mg, 60%). 'H NMR (500 MHz, DMSO-d6) 5 10.62 (s, 1H), 7.94 (s, 1H), 7.10 (t, 7= 7.77 Hz, 1H), 6.83 (m, 2H), 6.79 (m, 1H), 6.70 (d, J= 2.55 Hz, 1H), 6.65 (m, 1H), 6.60 (dd, 7= 8.60, 2.56 Hz, 1H), 4.48 (s, 2H), 2.78 (hept, 7= 6.96 Hz, 1H), 1.18 (d, 7= 6.89 Hz, 6H).13C NMR (125 MHz, DMSO-de) 5 165.8, 149.8, 144.5, 138.9, 137.3, 129.4, 128.2, 117.7, 117.0, 114.6, 113.8, 112.7, 105.6, 67.35, 34.0, 24.3.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0937] H

[0938]

[0939] Me

[0940] 4-((5-cyclobutyl-l,2,4-oxadiazol-3-yl)methyl)-6-((2,3-dimethylphenyl)amino)-2H-benzofb] [l,4]oxazin-3(4H)-one (5f): To a flamed dried reaction vial, 6-(2-((tert-butyldimethylsilyl)oxy)phenyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (25 mg, 0.093 mmol) in 1 ml THF, then, CS2CO3 (61 mg, 0.186 mmol). Then reaction was stirred at room temperature for 20min, subsequently tetrabutylammonium iodide (TBAI) (69mg, 0.186 mmol) was added followed by 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (18 mg, 0.102 mmol) in 1 ml THF. The reaction mixture was heated at 65°C for 3 hours. The reaction was quench using water and the organic phase was separated. The aqueous phase was extracted with CH2Q2 (3 x) and the combined organic extracts were washed with brine, dried with Na₂SO₄ and concentrated in vacuo to be purified by silica gel column chromatograph (0 to 40% EtOAc in Hex) to afford the product (35.74 mg, 95%). IR (neat) Umax = 3370, 2948, 1685, 1615, 1575, 1512, 1472, 1376, 1263, 1049, 734 cm’1.

[0941]

[0942] NMR (500 MHz, DMSO-d6) 5 7.28 (s, 1H), 6.88 (m, 2H), 6.81 (d, J = 7.96 Hz, 1H), 6.78 (d, J= 7.41 Hz, 1H), 6.52 (d, 7= 2.38 Hz, 1H), 6.48 (dd, 7= 8.61, 2.42 Hz, 1H), 5.12 (s, 2H), 4.64 (s, 2H), 3.83 (p, 7= 8.52 Hz, 1H), 2.37 (m, 2H), 2.29 (m, 2H), 2.21 (s, 3H), 2.06 (m, 1H), 2.01 (s, 3H), 1.93 (m, 1H).13C NMR (125 MHz, DMSO-d6) 5 182.9, 166.6, 165.2, 141.9, 141.4, 138.0, 137.7, 129.2, 128.3, 126.0, 124.0, 117.9, 117.4, 111.9, 104.3, 67.7, 37.1, 30.9, 27.0, 20.7, 18.7, 14.1. HRMS (ESI) C23H24N4O3, Calculated: [M+H]+, 405.1927; Found: [M+H]+, 405.1924.

[0943]

[0944] 6-((2-chlorophenyl)amino)-4-((5-cyclobutyl-l,2,4-oxadiazol-3-yl)methyl)-2H-benzo[b] [l,4]oxazin-3(4H)-one (5g): To a flamed dried reaction vial 6-((2-chlorophenyl)amino)-2H-benzo[b][l,4]oxazin-3(4H)-one (20 mg, 0.07 mmol) in 1 ml THF, then, CS2CO3 (36 mg, 0.114239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0945] mmol). Then reaction was stirred at room temperature for 20min, subsequently tetrabutylammonium iodide (TBAI) (52 mg, 0.14mmol) was added followed by 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (13 mg, 0.077 mmol) in 1 ml THF. The reaction mixture was heated at 65°C for 1 hour. The reaction was quench using water and the organic phase was separated. The aqueous phase was extracted with CH2CI2 (3 x) and the combined organic extracts were washed with brine, dried with Na2SO4 and concentrated in vacuo to be purified by silica gel column chromatograph (0 to 40% EtOAc in Hex) to afford the product (27.45 mg, 92%). IR (neat) umax= 3362, 2990, 2946, 1690, 1590, 1574, 1511, 1467, 1455, 1420, 1370, 1262, 1127, 1049, 1035, 947, 837, 733, 699 cm’1.1H NMR (500 MHz, DMSO-d6) 67.51 (s, 1H), 7.35 (dd, 7 = 7.94, 1.48 Hz, 1H), 7.06 (ddd, 7= 8.58, 7.22, 1.52 Hz, 1H), 6.99 (dd, 7= 8.21, 1.56 Hz, 1H), 6.95 (d, 7= 8.56 Hz, 1H), 6.89 (d, 7= 2.36 Hz, 1H), 6.80 (ddd, 7= 8.69, 7.28, 1.56 Hz, 1H), 6.76 (dd, 7= 8.59, 2.36 Hz, 1H), 5.18 (s, 2H), 4.68 (s, 2H), 3.82 (pd, 7= 8.55, 1.11 Hz, 1H), 2.35 (m, 2H), 2.28 (m, 2H), 2.05 (m, 1H), 1.90 (m, 1H).13C NMR (125 MHz, DMSO-d6) 6 182.9, 166.6, 165.0, 141.4, 140.0, 137.9, 130.3, 129.2, 128.0, 122.0, 121.1, 117.5, 117.0, 115.6, 108.1, 67.6, 37.0, 30.9, 27.0, 18.7. HRMS (ESI) C21H19CIN4O3, Calculated: [M+H]+, 411.1224; Found: [M+H]+, 411.1219.

[0946]

[0947] 4-((5-cyclobutyl-l,2,4-oxadiazol-3-yl)methyl)-6-((2,4-dichlorophenyl)amino)-2H-benzofb] [l,4]oxazin-3(4H)-one (5h): To a flamed dried reaction vial 6-((2,4-dichlorophenyl)amino)-2H-benzo[b][l,4]oxazin-3(4H)-one (20 mg, 0.06 mmol) in 1 ml THF, then, CS2CO3 (29 mg, 0.09 mmol). Then reaction was stirred at room temperature for 20min, subsequently tetrabutylammonium iodide (TBAI) (44 mg, 0.12 mmol) was added followed by 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (11 mg, 0.066 mmol) in 0.05 M ml THF. The reaction mixture was heated at 65 °C for 1.5 hour. The reaction was quench using water and the organic phase was separated. The aqueous phase was extracted with CH2Q2 (3 x) and the combined organic extracts were washed with brine, dried with Na₂SO₄ and concentrated4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0948] in vacuo to be purified by silica gel column chromatograph (0 to 40% EtOAc in Hex) to afford the product (28.31 mg, 98%). IR (neat) Umax = 3359, 2948, 1691, 1613, 1589, 1573, 1511, 1466, 1435, 1368, 1263, 1212, 1130, 1100, 1048, 947, 866, 808, 733, 702 cm1. 'H NMR (500 MHz, DMSO-d6) 57.67 (s, 1H), 7.49 (d, 7= 2.46 Hz, 1H), 7.11 (dd, 7= 8.83, 2.47 Hz, 1H), 6.98 (t, 7= 8.72 Hz, 2H), 6.91 (d, 7= 2.41 Hz, 1H), 6.78 (dd, 7= 8.59, 2.39 Hz, 1H), 5.20 (s, 2H), 4.70 (s, 2H), 3.84 (pd, 7= 8.55, 1.14 Hz, 1H), 2.37 (m, 2H), 2.29 (m, 2H), 2.07 (m, 1H), 1.92 (m, 1H).13C NMR (125 MHz, DMSO-d6) 5 182.9, 166.6, 164.9, 140.9, 140.4, 137.4, 129.5, 129.2, 128.0, 123.2, 122.3, 117.7, 117.6, 116.3, 108.8, 67.6, 37.0, 30.9, 27.0, 18.7. HRMS (ESI) C21H18Cl2N4O3, Calculated: [M+H]+, 445.0834; Found:

[0949] [M+H]+, 445.0829.

[0950] 4-((5-cyclobutyl-1,2,4-oxadiazol-3-yl)methyl)-6-((2-fluorophenyl)amino)-2H-benzo[b][1,4] oxazin-3(4H)-one (5i): To a flamed dried reaction vial 6-((2,3-dichlorophenyl)amino)-2H-benzo[b][l,4]oxazin-3(4H)-one (20 mg, 0.08 mmol) in 1 ml THF, then, CS2CO3 (39 mg, 0.12 mmol). Then reaction was stirred at room temperature for 20min, subsequently tetrabutylammonium iodide (TBAI) (59 mg, 0.16 mmol) was added followed by 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (15 mg, 0.088 mmol) in 1 ml THF. The reaction mixture was heated at 65°C for 1 hour. The reaction was quench using water and the organic phase was separated. The aqueous phase was extracted with CH2CI2 (3 x) and the combined organic extracts were washed with brine, dried with Na₂SO₄ and concentrated in vacuo to be purified by silica gel column chromatograph (0 to 40% EtOAc in Hex) to afford the product (21.34 mg, 70%). IR (neat) umax= 3357, 2992, 2948, 1686, 1611, 1574, 1511, 1429, 1373, 1215, 1099, 1050, 948, 842, 745 cm1. 'H NMR (500 MHz, DMSO-d6) 57.81 (s, 1H), 7.14 (m, 1H), 7.08 (t, J = 8.42 Hz, 1H), 6.95 (m, 2H), 6.84 (m, 1H), 6.81 (d, J = 2.46 Hz, 1H), 6.69 (dd, J= 8.75, 2.08 Hz, 1H), 5.19 (s, 2H), 4.68 (s, 2H), 3.84 (p, 7= 8.57 Hz, 1H), 2.36 (m, 2H), 2.29 (m, 2H), 2.06 (m, 1H), 1.92 (m, 1H).13C NMR (125 MHz, DMSO-d6) 5 182.9, 166.6, 165.0, 154.1, 152.2, 139.3, 138.5, 132.3, 129.1, 124.9, 120.8 (d, 7 = 7.294239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0951] Hz), 117.7 (d, J = 59.34 Hz), 116.1 (d, J= 18.72 Hz), 113.9, 106.3, 67.60, 37.0, 30.9, 27.0, 18.7. HRMS (ESI) C21H19FN4O3, Calculated: [M+H]+, 395.1519; Found: [M+H]+, 395.1518.

[0952]

[0953] iPr

[0954] 4-((5-cyclobutyl-l,2,4-oxadiazol-3-yl)methyl)-6-((3-isopropylphenyl)amino)-2H-benzo[b] [l,4]oxazin-3(4H)-one (5j): To a flamed dried reaction vial 6-((3-isopropylphenyl)amino)-2H-benzo[b][l,4]oxazin-3(4H)-one (20 mg, 0.07 mmol) in 1 ml THF, then, Cs₂CO₃ (36 mg, 0.11 mmol). Then reaction was stirred at room temperature for 20min, subsequently tetrabutylammonium iodide (TBAI) (52 mg, 0.14mmol) was added followed by 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (13 mg, 0.077 mmol) in 0.05 M THF. The reaction mixture was heated at 65°C for 5 hour. The reaction was quench using water and the organic phase was separated. The aqueous phase was extracted with CH2CI2 (3 x) and the combined organic extracts were washed with brine, dried with Na2SO4 and concentrated in vacuo to be purified by silica gel column chromatograph (0 to 40% EtOAc in Hex) to afford the product (27.67 mg, 93%). IR (neat) umax= 3366, 2956, 2870, 1682, 1600, 1574, 1509, 1415, 1370, 1330, 1261, 1216, 1048, 997, 961, 782, 734, 700 cm. 'H NMR (500 MHz, DMSO-d6) 58.00 (s, 1H), 7.04 (t, J= 7.78 Hz, 1H), 6.94 (d, J= 8.62 Hz, 1H), 6.83 (m, 2H), 6.72 (d, J= 8.06 Hz, 1H), 6.69 (dd, 7= 8.61, 2.41 Hz, 1H), 6.64 (d, J = 7.58 Hz, 1H), 5.20 (s, 2H), 4.67 (s, 2H), 3.83 (p, J= 8.53 Hz, 1H), 2.74 (hept, J= 6.98 Hz, 1H), 2.36 (m, 2H), 2.28 (m, 2H), 2.06 (m, 1H), 1.91 (m, 1H), 1.14 (d, J= 6.88 Hz, 6H).13C NMR (125 MHz, DMSO-de) 5 182.9, 166.7, 165.1, 149.9, 144.2, 139.1, 138.8, 129.4, 129.2, 117.7, 117.6, 114.4, 113.5, 105.5, 67.7, 37.1, 33.9, 30.9, 27.0, 24.3, 18.7. HRMS (ESI) C24H26N4O3, Calculated: [M+H]+, 419.2083; Found: [M+H]+, 419.2086.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0955]

[0956] Me

[0957] 6-((2-chloro-3-methylphenyl)amino)-4-((5-cyclobutyl-1,2,4-oxadiazol-3-yl)methyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (5k): To a flamed dried reaction vial 6-((2-chloro-3-methylphenyl)amino)-2H-benzo[b][l,4]oxazin-3(4H)-one (20 mg, 0.07 mmol) in 1 ml THF, then, Cs₂CO₃ (36 mg, 0.11 mmol). Then reaction was stirred at room temperature for 20min, subsequently tetrabutylammonium iodide (TBAI) (52 mg, 0.14mmol) was added followed by 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (13 mg, 0.077 mmol) in 1 ml THF. The reaction mixture was heated at 65°C for 1 hour. The reaction was quench using water and the organic phase was separated. The aqueous phase was extracted with CH2Q2 (3 x) and the combined organic extracts were washed with brine, dried with Na₂SO₄ and concentrated in vacuo to be purified by silica gel column chromatograph (0 to 40% EtOAc in Hex) to afford the product (25.6 mg, 87%). IR (neat) umax= 3400, 2942, 1685, 1600, 1575, 1521, 1363, 1266, 1216, 1046, 851, 733, 702 cm1. 'H NMR (500 MHz, DMSO-d6) 5 7.47 (s, 1H), 6.97 (dd, 7= 8.41, 7.14 Hz, 2H), 6.88 (d, 7= 2.39 Hz, 1H), 6.85 (d, 7= 8.07 Hz, 1H), 6.80 (d, 7 = 8.16 Hz, 1H), 6.76 (dd, J= 8.59, 2.39 Hz, 1H), 5.19 (s, 2H), 4.69 (s, 2H), 3.83 (pd, 7= 8.53, 1.11Hz, 1H), 2.37 (m, 2H), 2.31 (s, 3H), 2.28 (m, 2H), 2.06 (m, 1H), 1.91 (m, 1H).13C NMR (125 MHz, DMSO-d6) 6 182.9, 166.6, 165.0, 141.4, 139.9, 138.2, 137.1, 129.1, 127.1, 122.4, 117.4, 115.4, 114.7, 108.0, 67.6, 37.0, 30.9, 27.0, 20.8, 18.7. HRMS (ESI) C22H21CIN4O3, Calculated: [M+H]+, 425.1380; Found: [M+H]+, 425.1380.

[0958]

[0959] 4-((5-cyclobutyl-l,2,4-oxadiazol-3-yl)methyl)-6-((2,3-dichlorophenyl)amino)-2H-benzofb] [l,4]oxazin-3(4H)-one (51): To a flamed dried reaction vial 6-((2,3-dichlorophenyl)amino)-2H-benzo[b][l,4]oxazin-3(4H)-one (20 mg, 0.07 mmol) in 1 ml THF,4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0960] then, Cs₂CO₃ (36 mg, 0.11 mmol). Then reaction was stirred at room temperature for 20min, subsequently tetrabutylammonium iodide (TBAI) (52 mg, 0.14mmol) was added followed by 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (13 mg, 0.077 mmol) in 1 ml THF. The reaction mixture was heated at 65°C for 1 hour. The reaction was quench using water and the organic phase was separated. The aqueous phase was extracted with CH2CI2 (3 x) and the combined organic extracts were washed with brine, dried with Na2SO4 and concentrated in vacuo to be purified by silica gel column chromatograph (0 to 40% EtOAc in Hex) to afford the product (18.37 mg, 64%). IR (neat) vmax= 3359, 2949, 1690, 1581, 1511, 1451, 1404, 1366, 1264, 1216, 1181, 1043, 956, 851, 766, 734, 701 cm’1. 'H NMR (500 MHz, DMSO-d6) 57.76 (s, 1H), 7.06 (m, 1H), 7.01 (m, 2H), 6.96 (d, J = 2.36 Hz, 1H), 6.88 (dd, 7= 8.09, 1.63 Hz, 1H), 6.82 (dd, 7= 8.56, 2.37 Hz, 1H), 5.21 (s, 2H), 4.72 (s, 2H), 3.83 (m, 1H), 2.37 (m, 2H), 2.28 (m, 2H), 2.05 (m, 1H), 1.92 (m, 1H).13C NMR (125 MHz, DMSO-d6) 5 182.9, 166.6, 164.9, 143.9, 140.8, 137.1, 132.7, 129.2, 128.5, 120.7, 120.7, 119.2, 117.6, 117.1, 117.0, 114.4, 109.6, 109.5, 67.6, 37.0, 30.9, 27.0, 18.7. HRMS (ESI) C21H18CI2N4O3, Calculated: [M+H]+, 445.0834; Found: [M+H]+, 445.0837.

[0961]

[0962] Cl

[0963] 6-((3-chloro-2-methylphenyl)ainino)-4-((5-cyclobutyl-l,2,4-oxadiazol-3-yl)inethyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (5m): To a flamed dried reaction vial, 6-((3-chloro-2-methylphenyl)amino)-2H-benzo[b][l,4]oxazin-3(4H)-one (15 mg, 0.052 mmol) in 1 ml THF, then, Cs₂CO₃ (25 mg, 0.078 mmol). Then reaction was stirred at room temperature for 20min, subsequently tetrabutylammonium iodide (TBAI) (28mg, 0.104 mmol) was added followed by 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (9.8 mg, 0.057 mmol) in 1 ml THF. The reaction mixture was heated at 65°C for 3 hours. The reaction was quench using water and the organic phase was separated. The aqueous phase was extracted with CH2CI2 (3 x) and the combined organic extracts were washed with brine, dried with Na₂SO₄ and concentrated in vacuo to be purified by silica gel column chromatograph (0 to 40% EtOAc in Hex) to afford the product (20.58 mg, 93%). IR (neat) vmax= 3368, 2949, 1686, 1615, 1573, 1511, 1456,4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025

[0964] 1370, 1284, 1217, 1049, 1012, 947, 770, 734, 702 cm. 'H NMR (500 MHz, DMSO-d6) 8 7.80 (s, 1H), 7.26 (dt, 7 = 10.29, 8.24 Hz, 3H), 7.19 (dd, 7 = 7.48, 1.92 Hz, 1H), 6.99 (d, 7 = 2.38 Hz, 1H), 6.92 (dd, 7 = 8.58, 2.40 Hz, 1H), 5.47 (s, 2H), 4.98 (s, 2H), 4.14 (p, 7= 8.52 Hz, 1H), 2.67 (m, 2H), 2.58 (m, 2H), 2.50 (s, 3H), 2.38 (m, 1H), 2.24 (m, 1H).13C NMR (125 MHz, DMSO-de) 8 182.9, 166.6, 165.1, 144.5, 139.7, 139.1, 134.7, 129.2, 127.5, 125.8, 121.7, 117.6, 116.6, 113.9, 106.3, 67.6, 37.0, 30.9, 27.0, 18.7, 15.1. HRMS (ESI) C21H19FN4O3, Calculated: [M+H]+, 395.1519; Found: [M+H]+, 395.1516.

[0965] IN

[0966] c

[0967]

[0968] 4-((5-cyclobutyl-1,2,4-oxadiazol-3-yl)methyl)-6-((2-isopropylphenyl)amino)-2H-benzo[b][1,4]oxazin-3(4H)-one (5n): To a flamed dried reaction vial 6-((2-isopropylphenyl)amino)-2H-benzo[b][l,4]oxazin-3(4H)-one (20 mg, 0.07 mmol) in 1 ml THF, then, Cs₂CO₃ (36 mg, 0.11 mmol). Then reaction was stirred at room temperature for 20min, subsequently tetrabutylammonium iodide (TBAI) (52 mg, 0.14mmol) was added followed by 3-(chloromethyl)-5-cyclobutyl-1,2,4-oxadiazole (13 mg, 0.077 mmol) in 1 ml THF. The reaction mixture was heated at 65°C for 1 hour. The reaction was quench using water and the organic phase was separated. The aqueous phase was extracted with CH2CI2 (3 x) and the combined organic extracts were washed with brine, dried with Na2SO4...

Claims

4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025We claim:

1. A compound according to Formula 1 or IIor a pharmaceutically acceptable salt thereof, wherein:L is a bond, -N(R9)-, -C(O)N(R9)-, -N(R9)C(O)-, -S(O)2N(R9)- or -N(R9)S(O)2-; R9is H or Ci -ealkyl;Ri is substituted or unsubstituted phenyl, substituted or unsubstituted phenyl-Ci-ealkyl, substituted or unsubstituted 5- or 6-membered cycloalkyl, substituted or unsubstituted 5- or 6-membered cycloalkylalkyl, substituted or unsubstituted 5- or 6-membered heterocyclyl, substituted or unsubstituted 5- or 6-membered heterocyclylalkyl, or substituted or unsubstituted 5- to 6-membered heteroaryl, or R9and Ri together with the atom to which they are attached forms a substituted or unsubstituted 5- or 6-membered heterocyclyl;R2is selected from H, alkyl, alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted 5- or 6-membered heteroaryl, substituted or unsubstituted 5- or 6-membered heteroaryl-Ci-ealkyl, substituted or unsubstituted Cs-ecycloalkyl-Ci-ealkyl, substituted or unsubstituted 5- or 6-membered heterocyclyl, and substituted or unsubstituted 5- or 6-membered heterocyclyl-C i-ealkyl;R3 and Re are independently selected from H, halo, alkyl, haloalkyl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted arylalkyl; andR4 and R5 independently are selected from H, hydroxy, Ci-ealkoxy, halo, Ci-ealkyl, Ci-ehaloalkyl or cyano;4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025iNN.,. Oand wherein the compound is not2. The compound of claim 1, wherein L is a bond.

3. The compound of claim 1, wherein L is -NHS(O)2-.

4. The compound of claim 1, wherein L is -NH-.

5. The compound of any one of claims 1-4, wherein Ri is substituted or unsubstituted phenyl.

6. The compound of claim 5, wherein Ri is phenyl substituted with 1, 2, 3, 4 or 5 substituents.

7. The compound of claim 5, wherein Ri is phenyl substituted with 1 or 2 substituents.

8. The compound of any one of claims 1-7, wherein Ri is substituted with one or more substituents selected from Ci-ealkyl, halo, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkyloxy, nitro (NO2), cyano, OH, 5- or 6-membered heterocyclyl, or R7C(O)- groups, where R7 is Ci-ealkyl or Ci-6haloalkyl.

9. The compound of any one of claims 1-8, wherein Ri is substituted with one or more substituents selected from Ci-ealkyl, halo, Ci-6alkoxy, 5- or 6-membered heterocyclyl, haloalkyl, NO2, OH, or Ci-ehaloalkoxy.

10. The compound of any one of claims 1-9, wherein Ri is substituted with one or more substituents selected from methyl, ethyl, isopropyl, Cl, Br, F, methoxy, ethoxy, isopropoxy, morpholinyl, piperidinyl, piperazinyl, CF3, or CF3O-.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025ACH 11. The compound of any one of claims 1-10, wherein Ri is312. The compound of any one of claims 1-11, wherein R2 is H, Ci-ealkyl, C2-ealkenyl, Cv / cycloalkyl, substituted or unsubstituted C6-10aryl, substituted or unsubstituted Ce ioaryl-Ci-ealkyl-, substituted or unsubstituted 5- or 6-membered heteroaryl, substituted or unsubstituted 5- or 6-membered heteroaryl-Ci-ealkyl-, substituted or unsubstituted C3-6cycloalkyl-Ci-ealkyl-, substituted or unsubstituted 5- or 6-membered heterocyclyl, or substituted or unsubstituted 5- or 6-membered heterocyclyl-Ci -ealkyl.

13. The compound of any one of claims 1-12, wherein R2 is substituted or unsubstituted 5- or 6-membered heteroaryl.

14. The compound of any one of claims 1-13, wherein R2 is substituted by one or more substituents independently selected from halo, haloalkyl, alkoxy, haloalkyloxy, nitro, cyano, or 4- to 6-membered cycloalkyl.

15. The compound of any one of claims 1-14, wherein R2 is optionally substituted imidazolyl or optionally substituted oxadiazolyl.

16. The compound of any one of claims 1-15, wherein R2 is 5 -membered^~R8heteroaryl having a formula " Y- Z whereinX and Z are independently CRa, or N, and Y is O, S, or NRa;each Raindependently is H or Rs; andeach Rs independently is Ci-ealkyl, C4-6cycloalkyl, phenyl, or 5- or 6-membered heteroaryl.

17. The compound of claim 16, wherein Rs is cyclobutyl, cyclopentyl, methyl, ethyl, n-propyl, isopropyl, isobutyl, or sec-butyl.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 202518. The compound of any one of claims 16-17, wherein R2 has a formula19. The compound of claim 18, wherein R2 is'20. The compound of any one of claims 1-19, wherein Re is H.

21. The compound of any one of claims 1-20, wherein R3 is H, methyl, or CF3.

22. The compound of any one of claims 1-21, wherein R4 and R5 independently are selected from H, hydroxy, C / , alkoxy, halo, Ci ealkyl, Ci ehaloalkyl or cyano;23. The compound of any one of claims 1-22, wherein R4 is H.

24. The compound of any one of claims 1-23, wherein R5 is H, halo, Ci-ealkyl.

25. The compound of claim 24, wherein R5 is H, Cl, F, methyl, ethyl, or isopropyl.

26. The compound of claim 25, wherein R5 is H.

27. The compound of claim 16 or claim 17, wherein the compound has a Formula IA or Formula IIA4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 2025IIA.

28. The compound of claim 27, wherein Rs is cyclobutyl.

29. The compound of claim 1, wherein the compound has a Formula IB or Formula IIBIBIIB.

30. The compound of any one of claims 1-11, wherein the compound has a formula selected from:4239-114920-02 10 / 09 / 25 FILED ELECTRONICALLY ON OCTOBER 9, 2025or a pharmaceutically acceptable salt thereof, wherein:each Rio independently is Ci-ealkyl, halo, Ci-ealkoxy, 5- or 6-membered heterocyclyl, haloalkyl, NO2, OH, or Ci -ehaloalkoxy;n is 0, 1, 2, 3, 4, or 5;X and Z are independently CRa, or N, and Y is O, S, or NRa;each Raindependently is H or Rs; andeach Rs independently is Ci ealkyl, C4 ecycloalkyl, phenyl, or 5- or 6-membered heteroaryl.

31. The compound of claim 30, wherein each Rio independently is methyl, ethyl, isopropyl, Br, Cl, F, methoxy, ethoxy, isopropoxy, morpholinyl, piperidinyl, piperazinyl, CF3, OH, CF3O-.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 202532. The compound of claim 31, wherein each Rio independently is methyl, CF3, or Cl.

33. The compound of any one of claims 30-32, wherein n is 1, 2 or 3.

34. The compound of claim 33, wherein n is 1.

35. The compound of claim 33, wherein n is 2.

36. The compound of claim 35, wherein each Rio is methyl.

37. The compound of claim 35 or claim 26, wherein Rio is located at the 2- and 3-positions on the phenyl.

38. The compound of claim 1, wherein the compound is39. The compound of claim 1, wherein the compound is40. The compound of claim 1, wherein the compound is selected from the compounds shown in Tables 1-11 of the present disclosure.

41. A pharmaceutial composition comprisng a compound according to any one of claims 1 -40 and a pharmaceutially accetpable excipient.4239-114920-02 10 / 09 / 25 E-186-2025-0-PC-01 FILED ELECTRONICALLY ON OCTOBER 9, 202542. A method, comprising adminsitering an effective amount of a compound according to any one of claims 1-40, or a pharmaceutial composition thereof, to a subject in need thereof.

43. The method of claim 42, wherein the subject has Machupo virus, Influenza A virus, HIV-1, Ebola virus, SARS-CoV-2, or Lassa virus.

44. A method of treating a disease or disorder where inhibition of autophagy could provide a benefit comprising administering to a subject an effective amount of a compound according to any one of claims 1-40.

45. A method of inhibiting autophagy, comprising contacting a cell with an effective amount of a compound according to any one of claims 1-40.

46. The method of claim 45, wherein the cell is infected with Machupo virus, Influenza A virus, HIV-1, Ebola virus, SARS-CoV-2, or Lassa virus.

47. A use of a compound in the preparation of a medicament for the treatment of Machupo virus, Influenza A virus, HIV-1, Ebola virus, SARS-CoV-2, or Lassa virus.

48. A use of a compound in the preparation of a medicament to inhibit autophagy.

49. A compound according to any one of claims 1-40 for use in a method of administration to a subject in need thereof.

50. The compound of claim 49, wherein the subject has Machupo virus, Influenza A virus, HIV-1, Ebola virus, SARS-CoV-2, or Lassa virus.

51. A compound according to any one of claims 1 -40 for use in a method of inhibiting autophagy.

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