Cycloalkyl and heterocyclic modulators of TNF activity

Abstract

The present disclosure relates to compounds, compositions, and methods for treating diseases or disorders that are associated with aberrant tumor necrosis factor receptor 1 (TNFR1) signaling.

Description

Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO CYCLOALKYL AND HETEROCYCLIC MODULATORS OF TNF ACTIVITY RELATED APPLICATIONS

[0001] This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No: 63 / 655,377, filed June 3, 2024, U.S. Provisional Application No: 63 / 688,624, filed August 29, 2024, and U.S. Provisional Application No: 63 / 785,891, filed April 9, 2025, each of which are incorporated herein by reference in their entireties. BACKGROUND

[0002] Tumor necrosis factor α (TNFα) is a cytokine and member of the TNF superfamily, which consists of various transmembrane proteins with a homologous TNF domain. TNF signaling occurs through two receptors, TNFR1 and TNFR2. TNFα is produced by macrophages / monocytes during acute inflammation and is responsible for a diverse range of signaling events within cells, leading to necrosis or apoptosis. TNFα promotes the inflammatory response, which, in turn, causes many of the clinical problems associated with autoimmune disorders.

[0003] Injected biological drugs, that bind to and inhibit TNFα, are used to treat inflammatory diseases, but suffer from compliance issues and suboptimal efficacy and safety windows. Small molecule drugs that bind TNFα and inhibit TNFR1 signaling selectively would be expected to improve compliance, efficacy, and safety. Although small molecule inhibitors have been developed for targeting TNFα previously (Vugler et al., Front. Pharmacol., 2022, 13:1037983; Javaid et al., Sci. Signal., 2022, 15:eabi8713; Sun et al., J. Med. Chem., 2020, 63(15):8146-8156; Dietrich et al., J. Med. Chem. 2021, 64(1):417-429; Xiao et al., J. Med. Chem., 2020, 63(23)15050-15071; O’Connell et al., Nat. Commun., 2019, 10:5795), many have issues with low TNFR1 signaling inhibition potency, low permeability, high efflux, low solubility, metabolic instability, phototoxicity, and / or cardiotoxicity, which may require undesirable formulation or dosing regimens. Accordingly, the development of new TNFα inhibitors with improved qualities is needed. SUMMARY

[0004] A first aspect of the present disclosure is directed to a compound having a structure represented by formula I: 1 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO R5R4N R1a pharmaceutically acceptable salt or stereoisomer thereof,X is CH, CF, CCl, CCN, or N; R1is hydrogen, C1-C6alkyl, C3-C8cycloalkyl, or (C3-C8) heterocycloalkyl, any of which groups can be optionally substituted by one or more substituents selected from fluoro, cyano, hydroxy, amino, (C3-C10) cycloalkyl or (C3-C10) heterocycloalkyl; R2 is (C3-C10) cycloalkyl or (C3-C10) heterocycloalkyl, either of which groups can be optionally substituted by one or more substituents selected from halo, hydroxy, (C1-C6) alkyl, (C1- C6) alkoxy, hydroxy(C1-C6) alkyl, amino, amino(C1-C6) alkyl, and amino-di(C1-C6) alkyl; R3 is hydrogen, halo, cyano, -CF3, -OCF3, -ORa, -SRa, -SORa, -SO2Ra, -NRbRc, -NRcCORd, -NRcCO2Rd, -NHCONRbRc, -NRcSO2Re, -CORd, -CO2Rd, -CONRbRc, -SO2NRbRc, - S(O)(N-Rb)Re, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C7) cycloalkyl, (C4-C7) cycloalkenyl, (C6-C14) aryl, (C6-C14) aryl(C1-C6)alkyl, (C3-C7) heterocycloalkyl, (C3-C7) heterocycloalkenyl, 5- to 14-membered heteroaryl, 5- to 14-membered heteroaryl(C1-C6)alkyl, (C3-C7) heterocycloalkyl(C1-C6)alkyl-(C6-C14) aryl, (C3-C7) heterocycloalkenyl-(C6-C14) aryl, (C3-C7) cycloalkyl-5- to 14-membered heteroaryl, (C3-C7) cycloalkyl-(C1-C6) alkyl-5- to 14- membered heteroaryl, (C4-C7) cycloalkenyl-5- to 14-membered heteroaryl, (C4-C9) bicycloalkyl- 5- to 14-membered heteroaryl, (C3-C7) heterocycloalkyl-5- to 14-membered heteroaryl, (C3-C7) heterocycloalkyl-(C1-C6) alkyl-5- to 14-membered heteroaryl, (C3-C7) heterocycloalkenyl-5- to 14-membered heteroaryl, (C4-C9) heterobicycloalkyl-5- to 14-membered heteroaryl, or (C4-C9) spiroheterocycloalkyl-5- to 14-membered heteroaryl, any of which groups can be optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (C1-C6) alkyl, (C3-C7) cycloalkyl, -CHF2, (C1-C6) alkoxy, hydroxy(C1-C6) alkyl, oxo, amino, amino(C1-C6) alkyl, amino- di(C1-C6) alkyl, -P(O)RfRg, -CO2Rh, -S(O)Rh, -S(O)2Rh, -CON(Rh)2, (C1-C6) alkyl-O-(C3-C7) heterocyclyl, (C3-C7) heterocyclyl, (C3-C7) heterocyclyl-(C3-C7) cycloalkyl, (C3-C7) heterocyclyl- (C3-C7) heterocyclyl, 5- to 14-membered heteroaryl, and (C6-C14) aryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more substituents 2 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO selected from cyano, hydroxy, (C1-C3) alkyl, amino, (C1-C3) alkylhydroxy, carboxyl, fluoro, (C1- C3) alkylhalo, and -P(O)RfRg; Rais (C1-C6) alkyl, (C3-C7) cycloalkyl, (C6-C14) aryl, (C6-C14) aryl-(C1-C6) alkyl, (C3-C7) heterocycloalkyl, 5- to 14-membered heteroaryl, 5- to 14-membered heteroaryl- (C1-C6) alkyl, any of which groups can be optionally substituted by one or more substituents selected from (C1-C6) alkoxy and oxo; Rbis hydrogen, (C1-C6) alkyl, (C6-C14) aryl-(C1-C6) alkyl, (C3-C7) heterocycloalkyl, or (C3-C7) heterocycloalkyl-(C1-C6) alkyl, any of which groups can be optionally substituted by one or more substituents selected from (C1-C6) alkoxy, (C1-C6) alkylthio, (C1-C6) alkylsulphinyl, (C1-C6) alkylsulphonyl, hydroxy, cyano, (C2-C6) alkoxycarbonyl, di(C1-C6)alkylamino, and (C2-C6) alkoxycarbonylamino; Rcis hydrogen, (C1-C6) alkyl, (C3-C7) cycloalkyl, or (C3-C7) heterocycloalkyl, any of which groups can be optionally substituted by one or more substituents selected from (C2-C6) alkylcarbonyl and (C2-C6) alkoxycarbonyl, or Rband Rc, taken together with the nitrogen atom to which they are attached, form azetidine- 1-yl, pyrrolidine-1-yl, oxazolidine-3-yl, isoxazolidin-2-yl, thiazolidine-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholine-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl, homopiperazin-1-yl, (imino)(oxo)thiazinam-4- yl, (oxo)thiazinam-4-yl, and (dioxo)thiazinam-4-yl, any of which can be optionally substituted by one or more substituents selected from (C1-C6) alkyl, (C1-C6) alkylsulphonyl, hydroxy, hydroxy(C1-C6) alkyl, amino(C1-C6) alkyl, cyano, oxo, (C2-C6) alkylcarbonyl, carboxy, (C2-C6) alkoxycarbonyl, amino, (C2-C6) alkylcarbonyl-amino, (C2- C6) alkylcarbonylamino(C1-C6) alkyl, (C2-C6) alkoxycarbonylamino, (C1-C6) alkyl- sulphonylamino, and aminocarbonyl; Rdis hydrogen, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C6-C14) aryl, (C3-C7) heterocycloalkyl, or 5- to 14-membered heteroaryl, any which can be optionally substituted by one or more substituents selected from halo, (C1-C6) alkyl, (C1-C6) alkoxy, oxo, (C2-C6) alkylcarbonyloxy, and di(C1-C6) alkylamino; Reis (C1-C6) alkyl, (C6-C14) aryl, or 5- to 14-membered heteroaryl, any of which can be optionally substituted by (C1-C6) alkyl; 3 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO Rfis hydroxy, optionally substituted (C1-C3) alkoxy, or optionally substituted (C1- C6) alkyl; Rgis hydroxy, optionally substituted (C1-C3) alkoxy, or optionally substituted (C1- C6) alkyl; or Rfand Rg, taken together with the phosphorus atom to which they are attached, form an optionally substituted phosphorus-containing 3- to 8-membered aliphatic alkyl ring; and Rhis hydrogen, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C1-C6) alkylamino, or optionally substituted di(C1-C6) alkylamino, wherein the one or more optional substituents of Rf, Rg, and Rhare independently selected from (C1-C3) alkyl, fluoro, hydroxy, cyano, and amino; R4 is hydrogen, halo, cyano, nitro, hydroxy, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -ORa, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl, or 5- to 14-membered heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl and heteroaryl can be optionally substituted by one or more substituents selected from hydroxy(C1-C6) alkyl and (C2-C6) alkoxycarbonyl; R5 and R6 are independently hydrogen, halo, cyano, hydroxy, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -ORa, (C1-C6) alkyl, (C3-C7) cycloalkyl, or (C3-C7) heterocycloalkyl, wherein said alkyl, cycloalkyl, and heterocycloalkyl can be optionally substituted by one or more substituents selected from hydroxy(C1-C6) alkyl and (C2-C6) alkoxycarbonyl; each R7is independently hydrogen, halo, cyano, hydroxy, amino, -CF3, (C1-C6) alkyl, (C1- C6) alkoxy, or (C3-C7) cycloalkyl; and n is 0, 1, or 2.

[0005] A second aspect of the present disclosure is directed to a pharmaceutical composition containing the compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0006] Another aspect of the present disclosure is directed to a method of treating a disease or disorder that is characterized or mediated by aberrant tumor necrosis factor receptor 1 (TNFR1) signaling, comprising administering to a subject in need thereof the compound of formula I, or a pharmaceutically acceptable salt thereof.

[0007] The present disclosure provides compounds of formula I, or pharmaceutically acceptable salts and stereoisomers thereof, for use in therapy. The present disclosure provides compounds of formula I, or pharmaceutically acceptable salts and stereoisomers thereof, for use in treating a 4 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO disease or disorder that is characterized or mediated by aberrant TNFR1 signaling. The present disclosure provides the use of a compound of formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, in the manufacture of a medicament for treating a disease or disorder that is characterized or mediated by aberrant TNFR1 signaling.

[0008] In some embodiments, the disease or disorder is an inflammatory or neuroinflammatory disease.

[0009] Further aspects of the present disclose are directed to methods of making the compounds. DETAILED DESCRIPTION

[0010] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the subject matter herein belongs. As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated in order to facilitate the understanding of the present disclosure.

[0011] As used in the description and the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. Therefore, for example, reference to “a composition” includes mixtures of two or more such compositions, reference to “an inhibitor” includes mixtures of two or more such inhibitors, and the like.

[0012] Unless stated otherwise, the term “about” means within 10% (e.g., within 5%, 2%, or 1%) of the particular value modified by the term “about.”

[0013] The transitional term “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. When used in the context of the number of heteroatoms in a heterocyclic structure, it means that the heterocyclic group that that minimum number of heteroatoms. By contrast, the transitional phrase “consisting of” excludes any element, step, or ingredient not specified in the claim. The transitional phrase “consisting essentially of” limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the disclosure.

[0014] With respect to compounds of the present disclosure, and to the extent the following terms are used herein to further describe them, the following definitions apply. 5 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0015] As used herein, the term “alkyl” refers to a saturated linear or branched-chain monovalent hydrocarbon radical. In some embodiments, and to the extent not disclosed otherwise for any one or more groups of the compounds of formula I, the alkyl radical is a C0-C6, C0-C5, C0-C3, C1-C6, C1-C5, C1-C4 or C1-C3 group (wherein C0 alkyl refers to a bond). In some embodiments, an alkyl group is a C1-C3 alkyl group.

[0016] As used herein, the term “cycloalkyl” or “carbocycle” (also "carbocyclyl") refer to a group that used alone or as part of a larger moiety, contains a saturated, partially unsaturated, or aromatic ring system having 3 to 12 carbon atoms, that is alone or part of a larger moiety (e.g., an alkcarbocyclic group). The term cycloalkyl includes mono-, bi-, tri-, fused, bridged, and spiro-ring systems, and combinations thereof. In some embodiment, cycloalkyl includes 3 to 10 carbon atoms (C3-C10). Representative examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, and naphthalene.

[0017] As used herein, the term "heterocyclyloalkyl" or "heterocyclyl" refers to a "carbocyclyl" that used alone or as part of a larger moiety, contains a saturated, partially unsaturated or aromatic ring system, wherein one or more (e.g., 1, 2, 3, 4, or 5) carbon atoms have been replaced with a heteroatom or heteroatom-containing group (e.g., O, N, N(O), S, S(O), or S(O)2). The term heterocyclyloalkyl includes mono-, bi-, tri-, fused, bridged, and spiro-ring systems, and combinations thereof. In some embodiments, a heterocyclyloalkyl group includes 3-12 ring atoms (C3-C12) and includes monocycles, bicycles, tricycles and spiro ring systems, wherein the ring atoms are carbon, and one to five ring atoms is a heteroatom such as nitrogen, sulfur or oxygen or heteroatom-containing group such as S(O), or S(O)2. In some embodiments, heterocyclyloalkyl includes 3- to 7-membered (C3-C7) monocycles having one or more heteroatoms selected from O, N, and S. Representative examples of heterocyclyloalkyl groups include pyrrolidinyl, dihydro-1H- pyrrolyl, dihydrofuranyl, tetrahydropyranyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, pyrrolinyl, and indolinyl.

[0018] As used herein, the term "aryl" used alone or as part of a larger moiety (e.g., "aralkyl", wherein the terminal carbon atom on the alkyl group is the point of attachment, e.g., a benzyl group). The term "aryl" may be used interchangeably with the term "aryl ring" and refers to a group that includes mono-, bi-, tri-, fused, and bridged-ring systems, and combinations thereof, wherein at least one ring in the system is aromatic. In one embodiment, aryl includes groups having 6 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO 6-14 carbon atoms. Representative examples of aryl groups include phenyl, benzyl, naphthyl, bicyclo[4.2.0]octa-1,3,5-trienyl, 2,3-dihydro-1H-indenyl, and 1,2,3,4-tetrahydronaphthalenyl.

[0019] As used herein, the term "heteroaryl" used alone or as part of a larger moiety (e.g., "heteroarylalkyl" (also “heteroaralkyl”), or "heteroarylalkoxy" (also “heteroaralkoxy”)) refers to a monocyclic, bicyclic or tricyclic ring system having 5 to 12 ring atoms, wherein at least one ring is aromatic and contains at least one heteroatom. In one embodiment, heteroaryl includes 5- to 6- membered monocyclic aromatic groups where one or more ring atoms is O, N, or S. Representative examples of heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, imidazopyridyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl, purinyl, deazapurinyl, benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl, 2,3-dihydrobenzofuryl, indolinyl, indolyl, 1,3-thiazol-2-yl, 1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-5-yl, 1,2,4- oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 1H-tetrazol-5-yl, and 1,2,3-triazol-5-yl.

[0020] As used herein, the term “halogen” (or “halo” or “halide”) refers to fluorine, chlorine, bromine, or iodine.

[0021] Unless stated otherwise, and to the extent not further defined for any particular group(s) in the compounds of formula I, any of the groups described herein may be substituted or unsubstituted. To the extent not disclosed otherwise for any particular group(s), the substituent(s) can be selected from the group consisting of halo, alkylhalo (e.g., CF3, CHF2, CH2F, CCl3, CHCl2, CH2Cl), cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, hydroxy(C1-C6) alkyl, amino, amino(C1- C6) alkyl, amino-di(C1-C6) alkyl, and (C3-C7) cycloalkyl.

[0022] In one aspect, compounds of the disclosure are represented by formula I: R5R N I), or a pharmaceutically acceptablewherein: X is CH, CF, CCl, CCN, or N; 7 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO R1 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or (C3-C8) heterocycloalkyl, any of which groups can be optionally substituted by one or more substituents selected from fluoro, cyano, hydroxy, amino, (C3-C10) cycloalkyl or (C3-C10) heterocycloalkyl; R2 is (C3-C10) cycloalkyl or (C3-C10) heterocycloalkyl, either of which groups can be optionally substituted by one or more substituents selected from halo, hydroxy, (C1-C6) alkyl, (C1- C6) alkoxy, hydroxy(C1-C6) alkyl, amino, amino(C1-C6) alkyl, and amino-di(C1-C6) alkyl; R3is hydrogen, halo, cyano, -CF3, -OCF3, -ORa, -SRa, -SORa, -SO2Ra, -NRbRc, -NRcCORd, -NRcCO2Rd, -NHCONRbRc, -NRcSO2Re, -CORd, -CO2Rd, -CONRbRc, -SO2NRbRc, - S(O)(N-Rb)Re, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C7) cycloalkyl, (C4-C7) cycloalkenyl, (C6-C14) aryl, (C6-C14) aryl(C1-C6)alkyl, (C3-C7) heterocycloalkyl, (C3-C7) heterocycloalkenyl, 5- to 14-membered heteroaryl, 5- to 14-membered heteroaryl(C1-C6)alkyl, (C3-C7) heterocycloalkyl(C1-C6)alkyl-(C6-C14) aryl, (C3-C7) heterocycloalkenyl-(C6-C14) aryl, (C3-C7) cycloalkyl-5- to 14-membered heteroaryl, (C3-C7) cycloalkyl-(C1-C6) alkyl-5- to 14- membered heteroaryl, (C4-C7) cycloalkenyl-5- to 14-membered heteroaryl, (C4-C9) bicycloalkyl- 5- to 14-membered heteroaryl, (C3-C7) heterocycloalkyl-5- to 14-membered heteroaryl, (C3-C7) heterocycloalkyl-(C1-C6) alkyl-5- to 14-membered heteroaryl, (C3-C7) heterocycloalkenyl-5- to 14-membered heteroaryl, (C4-C9) heterobicycloalkyl-5- to 14-membered heteroaryl, or (C4-C9) spiroheterocycloalkyl-5- to 14-membered heteroaryl, any of which groups can be optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (C1-C6) alkyl, (C3-C7) cycloalkyl, -CHF2, (C1-C6) alkoxy, hydroxy(C1-C6) alkyl, oxo, amino, amino(C1-C6) alkyl, amino- di(C1-C6) alkyl, -P(O)RfRg, -CO2Rh, -S(O)Rh, -S(O)2Rh, -CON(Rh)2, (C1-C6) alkyl-O-(C3-C7) heterocyclyl, (C3-C7) heterocyclyl, (C3-C7) heterocyclyl-(C3-C7) cycloalkyl, (C3-C7) heterocyclyl- (C3-C7) heterocyclyl, 5- to 14-membered heteroaryl, and (C6-C14) aryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more substituents selected from cyano, hydroxy, (C1-C3) alkyl, amino, (C1-C3) alkylhydroxy, carboxyl, fluoro, (C1- C3) alkylhalo, and -P(O)RfRg; Rais (C1-C6) alkyl, (C3-C7) cycloalkyl, (C6-C14) aryl, (C6-C14) aryl-(C1-C6) alkyl, (C3-C7) heterocycloalkyl, 5- to 14-membered heteroaryl, 5- to 14-membered heteroaryl-(C1-C6) alkyl, any of which groups can be optionally substituted by one or more substituents selected from (C1-C6) alkoxy and oxo; 8 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO Rbis hydrogen, (C1-C6) alkyl, (C6-C14) aryl-(C1-C6) alkyl, (C3-C7) heterocycloalkyl, or (C3-C7) heterocycloalkyl-(C1-C6) alkyl, any of which groups can be optionally substituted by one or more substituents selected from (C1-C6) alkoxy, (C1-C6) alkylthio, (C1-C6) alkylsulphinyl, (C1-C6) alkylsulphonyl, hydroxy, cyano, (C2-C6) alkoxycarbonyl, di(C1-C6)alkylamino, and (C2-C6) alkoxycarbonylamino; Rcis hydrogen, (C1-C6) alkyl, (C3-C7) cycloalkyl, or (C3-C7) heterocycloalkyl, any of which groups can be optionally substituted by one or more substituents selected from (C2-C6) alkylcarbonyl and (C2-C6) alkoxycarbonyl, or Rband Rc, taken together with the nitrogen atom to which they are attached, form azetidine-1-yl, pyrrolidine-1-yl, oxazolidine-3-yl, isoxazolidin-2-yl, thiazolidine- 3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholine-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl, homopiperazin-1-yl, (imino)(oxo)thiazinam-4-yl, (oxo)thiazinam-4-yl, and (dioxo)thiazinam-4-yl, any of which can be optionally substituted by one or more substituents selected from (C1-C6) alkyl, (C1-C6) alkylsulphonyl, hydroxy, hydroxy(C1-C6) alkyl, amino(C1- C6) alkyl, cyano, oxo, (C2-C6) alkylcarbonyl, carboxy, (C2-C6) alkoxycarbonyl, amino, (C2-C6) alkylcarbonyl-amino, (C2-C6) alkylcarbonylamino(C1-C6) alkyl, (C2-C6) alkoxycarbonylamino, (C1-C6) alkyl-sulphonylamino, and aminocarbonyl; Rdis hydrogen, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C6-C14) aryl, (C3-C7) heterocycloalkyl, or 5- to 14-membered heteroaryl, any which can be optionally substituted by one or more substituents selected from halo, (C1-C6) alkyl, (C1-C6) alkoxy, oxo, (C2-C6) alkylcarbonyloxy, and di(C1-C6) alkylamino; and Reis (C1-C6) alkyl, (C6-C14) aryl, or 5- to 14-membered heteroaryl, any of which can be optionally substituted by (C1-C6) alkyl; Rfis hydroxy, optionally substituted (C1-C3) alkoxy, or optionally substituted (C1- C6) alkyl; Rgis hydroxy, optionally substituted (C1-C3) alkoxy, or optionally substituted (C1- C6) alkyl; 9 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO or Rfand Rg, taken together with the phosphorus atom to which they are attached, form an optionally substituted phosphorus-containing 3- to 8-membered aliphatic alkyl ring; and Rhis hydrogen, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C1-C6) alkylamino, or optionally substituted di(C1- C6) alkylamino, wherein the one or more optional substituents of Rf, Rg, and Rhare independently selected from (C1-C3) alkyl, fluoro, hydroxy, cyano, and amino; R4 is hydrogen, halo, cyano, nitro, hydroxy, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -ORa, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl, or 5- to 14-membered heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl and heteroaryl can be optionally substituted by one or more substituents selected from hydroxy(C1-C6) alkyl and (C2-C6) alkoxycarbonyl; R5 and R6 are independently hydrogen, halo, cyano, hydroxy, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -ORa, (C1-C6) alkyl, (C3-C7) cycloalkyl, or (C3-C7) heterocycloalkyl, wherein said alkyl, cycloalkyl, and heterocycloalkyl can be optionally substituted by one or more substituents selected from hydroxy(C1-C6) alkyl and (C2-C6) alkoxycarbonyl; each R7is independently hydrogen, halo, cyano, hydroxy, amino, -CF3, (C1-C6) alkyl, (C1- C6) alkoxy, or (C3-C7) cycloalkyl; and n is 0, 1, or 2.

[0023] In some embodiments, the compound is of formula Ia: R5R4N a pharmaceutically acceptable salt or stereoisomer thereof.1is hydrogen or methyl. In some embodiments, R1is CD3. 10 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO OH F

[0025] In some embodiments R2 isF, , redheteroaryl(C1-C6)alkyl, (C3-C7) cycloalkyl-5- to 14-membered heteroaryl, (C3-C7) cycloalkyl-(C1- C6) alkyl-5- to 14-membered heteroaryl, (C4-C7) cycloalkenyl-5- to 14-membered heteroaryl, (C4- C9) bicycloalkyl-5- to 14-membered heteroaryl, (C3-C7) heterocycloalkyl-5- to 14-membered heteroaryl, (C3-C7) heterocycloalkyl-(C1-C6) alkyl-5- to 14-membered heteroaryl, (C3-C7) heterocycloalkenyl-5- to 14-membered heteroaryl, (C4-C9) heterobicycloalkyl-5- to 14-membered heteroaryl, or (C4-C9) spiroheterocycloalkyl-5- to 14-membered heteroaryl, any of which groups can be optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (C1- C6) alkyl, (C3-C7) cycloalkyl, -CHF2, hydroxy(C1-C6) alkyl, oxo, amino, and amino(C1-C6) alkyl, wherein said alkyl and cycloalkyl is optionally substituted by one or more substituents selected from cyano, hydroxy, (C1-C3) alkyl, (C1-C3) alkylhydroxy, carboxyl, fluoro, (C1-C3) alkylhalo, and amino.

[0027] In some embodiments, R4is hydrogen, halo, cyano, methoxy, -CF3, -CHF2, -CH2F, - OCF3, -OCHF2, (C1-C4) alkyl, (C3-C7) cycloalkyl, or (C3-C7) heterocycloalkyl, wherein said alkyl, cycloalkyl, and heterocycloalkyl can be optionally substituted by one or more substituents selected from hydroxy(C1-C6) alkyl and (C2-C6) alkoxycarbonyl.

[0028] In some embodiments, R5is hydrogen, halo, cyano, methoxy, -CF3, -CHF2, -CH2F, - OCF3, -OCHF2, (C1-C4) alkyl, (C3-C7) cycloalkyl, or (C3-C7) heterocycloalkyl, wherein said alkyl, cycloalkyl, and heterocycloalkyl can be optionally substituted by one or more substituents selected from hydroxy(C1-C6) alkyl and (C2-C6) alkoxycarbonyl.

[0029] In some embodiments, R6 is hydrogen, halo, cyano, methoxy, -CF3, -CHF2, -CH2F, - OCF3, -OCHF2, (C1-C4) alkyl, (C3-C7) cycloalkyl, or (C3-C7) heterocycloalkyl, wherein said alkyl, cycloalkyl, and heterocycloalkyl can be optionally substituted by one or more substituents selected 11 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO from hydroxy(C1-C6) alkyl and (C2-C6) alkoxycarbonyl.

[0030] The disclosed compounds also embrace combinations of the specific R1, R2, R3, R4, R5, and R6groups disclosed above.

[0031] In some embodiments, the compound is of formula Ib: N R8N N a pharmaceutically acceptable salt or stereoisomer thereof,Ring A is phenyl or 5- or 6-membered heteroaryl, wherein said phenyl and heteroaryl can be optionally substituted by one or more substituents selected from (C1-C4) alkyl and halo; R8is hydrogen or methyl; NH2CN OH NH2NH2NH2, H2, ,,, g p y y , p nyl and heteroaryl can be optionally substituted by one or more substituents selected from methyl and 12 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO fluoro.

[0033] In some embodiments, Ring A is pyrimidinyl, pyridinyl, imidazole, thiazole, isothiazole, oxazole, isoxazole, triazole, thiadiazol, oxadiazole, pyrazine, or pyridazine. In some embodiments, N N .NH2NH2, H2,R9groups disclosed above.

[0037] In some embodiments, the compound of formula Ib is of formula Ib1: N N a pharmaceutically acceptable salt or stereoisomer thereof,Ring A is phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms, wherein said phenyl and heteroaryl can be optionally substituted by one or more substituents selected from (C1-C4) alkyl and halo; 13 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO NH2NH2NH2NH2H2N HOH2N, and orR5R4N R of, ally, , ene, optionally substituted oxazolene, or optionally substituted thiazolene; Z1is N or CR11; Z2is N or CR12; Z3 is N or CR13; Z4 is N or CR14; R11, R12, R13, and R14are independently hydrogen, halo, -CN, -NH2, optionally substituted (C1-C3) alkyl, optionally substituted (C1-C3) alkoxy, or -NH(optionally substituted (C1-C3) alkyl); 14 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO L is a bond, -NH-, -(CH2)n-, -C(R’)(R”)-, -O(CH2)n-*, or -NH(CH2)n-*, wherein the * denotes the point of attachment to phosphorous; n is 1, 2, or 3; and R’ and R” are independently hydrogen, hydroxy, fluoro, or methyl.

[0039] In some embodiments, R1 is hydrogen or methyl. In some embodiments, R1 is CD3. OH F

[0040] In m mb dim nt R iF, F, -OCF3, -OCHF2, (C1-C4) alkyl, (C3-C7) cycloalkyl, or (C3-C7) heterocycloalkyl, wherein said alkyl, cycloalkyl, and heterocycloalkyl can be optionally substituted by one or more substituents selected from hydroxy(C1-C6) alkyl and (C2-C6) alkoxycarbonyl.

[0042] In some embodiments, R5is hydrogen, halo, cyano, methoxy, -CF3, -CHF2, -CH2F, - OCF3, -OCHF2, (C1-C4) alkyl, (C3-C7) cycloalkyl, or (C3-C7) heterocycloalkyl, wherein said alkyl, cycloalkyl, and heterocycloalkyl can be optionally substituted by one or more substituents selected from hydroxy(C1-C6) alkyl and (C2-C6) alkoxycarbonyl.

[0043] In some embodiments, R6is hydrogen, halo, cyano, methoxy, -CF3, -CHF2, -CH2F, - OCF3, -OCHF2, (C1-C4) alkyl, (C3-C7) cycloalkyl, or (C3-C7) heterocycloalkyl, wherein said alkyl, cycloalkyl, and heterocycloalkyl can be optionally substituted by one or more substituents selected from hydroxy(C1-C6) alkyl and (C2-C6) alkoxycarbonyl.

[0044] In some embodiments, L is a bond.

[0045] In some embodiments, Rfand Rgare both methyl.

[0046] The disclosed compounds also embrace combinations of the specific R1, R2, R4, R5, R6, L, Rf, and Rggroups disclosed above.

[0047] In some embodiments, the compounds of the present disclosure are represented by any of the following structures: 15 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO N N N NH N N N N HN O HN O 8), , ,Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO N N NH NH N N N O O 2),Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO N N F N N N N O H N N 2 O P N O HO O O NC HO O NC H2NAFSDODate of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO N N N N N N N O NO8),Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO N N NH N N OH2NNN N),4), 6), ),Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO N N N N N N N N HOOHOO 2), 4), ),Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO N N N N N N N HNO8), 0),Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO N N N N N N O N N O lly

[0048] Compounds of the present disclosure may be in the form of a free acid or free base, or a pharmaceutically acceptable salt. Pharmaceutically acceptable salts and common methodology for preparing them are well known in the art. See, for example, Stahl, P., et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use, (VCHA / Wiley-VCH, 2002); Gould, P. L., “Salt selection for basic drugs,” International Journal of Pharmaceutics, 33:201-217 (1986); Bastin, R. J., et al., “Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities,” Organic Process Research and Development, 4:427-435 (2000); and Berge, S. M., et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, 66:1-19 (1977).

[0049] Compounds of the present disclosure may have at least one chiral center and thus may be 23 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO in the form of a stereoisomer, which as used herein, embraces all isomers of individual compounds that differ only in the orientation of their atoms in space. The term stereoisomer includes mirror image isomers (enantiomers which include the (R-) or (S-) configurations of the compounds), mixtures of mirror image isomers (physical mixtures of the enantiomers, and racemates or racemic mixtures) of compounds, geometric (cis / trans or E / Z, R / S) isomers of compounds and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers). Additionally, the skilled artisan will appreciate that additional chiral centers may be created in the compounds of the invention by the selection of certain variables. The present disclosure contemplates all individual enantiomers or diastereomers, as well as mixtures of the enantiomers and diastereomers of said compounds including racemates. The skilled artisan will also appreciate that the Cahn-Ingold-Prelog (R) or (S) designations for all chiral centers will vary depending on the substitution patterns of the compound. The single enantiomers or diastereomers may be prepared beginning with chiral reagents or by stereoselective or stereospecific synthetic techniques. Alternatively, the single enantiomers or diastereomers may be isolated from mixtures by standard chiral chromatographic or crystallization techniques at any convenient point in the synthesis of compounds of the disclosure.

[0050] In some embodiments, a compound of the present disclosure is an isotopic derivative in that it has at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. As used herein, the term “hydrogen”, i.e., H, refers to all isotopes of hydrogen, including protium (1H) and deuterium (2H). As used herein, the term “compound” embraces isotopic derivatives.

[0051] Compounds of the present disclosure may also be in the form of N-oxides, crystalline forms (also known as polymorphs), co-crystals, active metabolites of the compounds having the same type of activity, prodrugs, tautomers, and unsolvated as well as solvated (e.g., hydrated) forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, of the compounds. As used herein, the term “compound” embraces all these forms. Methods of Synthesis

[0052] In some aspects, the present disclosure is directed to a method for making a compound of formula I, or a pharmaceutically acceptable salt or stereoisomer thereof. Broadly, the compounds or pharmaceutically acceptable salts or stereoisomers thereof, may be prepared by any process known to be applicable to the preparation of chemically related compounds. The 24 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO compounds of the present disclosure will be better understood in connection with the synthetic schemes that described in various working examples that illustrate non-limiting methods by which the compounds of the disclosure may be prepared.

[0053] The compounds of formula I can be prepared by methods known by those skilled in the art. In one non-limiting example the disclosed compounds can be made by scheme I. Scheme 1. Representative synthetic procedure for compounds of formula I. N N N Cl PhNTf R Cl2Cl N RKCOR N1 KOtBuN N1 2 3N N1O Pharmace

[0054] Another aspect of the present disclosure is directed to a pharmaceutical composition that includes the compound of formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier,” as known in the art, refers to a pharmaceutically acceptable material, composition or vehicle, suitable for administering compounds of the present disclosure to mammals. Suitable carriers may include, for example, liquids (both aqueous and non-aqueous alike, and combinations thereof), solids, encapsulating materials, gases, and combinations thereof (e.g., semi-solids), and gases, that function to carry or transport the compound from one organ, or portion of the body, to another organ, or portion of the body. A carrier is “acceptable” in the sense of being physiologically inert to and compatible with the other ingredients of the formulation and not injurious to the subject 25 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO (also referred to herein as “patient”). Depending on the type of formulation, the composition may also include one or more pharmaceutically acceptable excipients.

[0055] Broadly, compounds of formula I, and their pharmaceutically acceptable salts may be formulated into a given type of composition in accordance with conventional pharmaceutical practice such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping and compression processes (see, e.g., Remington: The Science and Practice of Pharmacy (A. Gennaro, et. al., eds., 22nd ed., Loyd V., ed., Pharmaceutical Press, 2012), each of which is incorporated herein by reference in its entirety. The type of formulation depends on the mode of administration which may include enteral (e.g., oral, buccal, sublingual and rectal), parenteral (e.g., subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), and intrasternal injection, or infusion techniques, intra-ocular, intra-arterial, intramedullary, intrathecal, intraventricular, transdermal, interdermal, intravaginal, intraperitoneal, mucosal, nasal, intratracheal instillation, bronchial instillation, and inhalation) and topical (e.g., transdermal).

[0056] In general, the most appropriate route of administration will depend upon a variety of factors including, for example, the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). For example, parenteral (e.g., intravenous) administration may also be advantageous in that the compound may be administered relatively quickly such as in the case of a single-dose treatment and / or an acute condition.

[0057] Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, ophthalmic or rectal administration, or a form suitable for administration by inhalation or insufflation.

[0058] For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they 26 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives. The preparations may also contain buffer salts, flavoring agents, coloring agents or sweetening agents, as appropriate.

[0059] Preparations for oral administration may be suitably formulated to give controlled release of the active compound.

[0060] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0061] The compounds of formula (I) may be formulated for parenteral administration by injection, e.g. by bolus injection or infusion. Formulations for injection may be presented in unit dosage form, e.g. in glass ampoules or multi-dose containers, e.g. glass vials. The compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, preserving and / or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.

[0062] In addition to the formulations described above, the compounds of formula (I) may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation or by intramuscular injection.

[0063] For nasal administration or administration by inhalation, the compounds according to the present invention may be conveniently delivered in the form of an aerosol spray presentation for pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.

[0064] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispensing device may be accompanied by instructions for administration.

[0065] For topical administration the compounds of use in the present invention may be conveniently formulated in a suitable ointment containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Particular carriers include, for example, mineral oil, liquid petroleum, propylene glycol, polyoxyethylene, polyoxypropylene, 27 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO emulsifying wax and water. Alternatively, the compounds of use in the present invention may be formulated in a suitable lotion containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Particular carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2- octyldodecanol and water.

[0066] For ophthalmic administration the compounds of use in the present invention may be conveniently formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate. Alternatively, for ophthalmic administration compounds may be formulated in an ointment such as petrolatum.

[0067] For rectal administration the compounds of use in the present invention may be conveniently formulated as suppositories. These can be prepared by mixing the active component with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and so will melt in the rectum to release the active component. Such materials include, for example, cocoa butter, beeswax and polyethylene glycols. Dosage Amounts

[0068] As used herein, the term, "therapeutically effective amount" refers to an amount of a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof; or a composition including a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, effective in producing the desired therapeutic response in a particular subject in need thereof. Therefore, the term "therapeutically effective amount" includes the amount of a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, that when administered, induces a positive modification in the disease or disorder to be treated, or is sufficient to prevent development or progression of the disease or disorder, or alleviate to some extent, one or more of the symptoms of the disease or disorder being treated in a subject, or reduces the amount of tumor necrosis factor receptor 1 (TNFR1) signaling in diseased cells.

[0069] The compounds of the present disclosure are effective over a dosage range. It will be understood that the amount of the compound administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the selected compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms. See, for example, Goodman 28 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO and Gilman’s The Pharmacological Basis of Therapeutics, 10th Edition, A. Gilman, J. Hardman and L. Limbird, eds., McGraw-Hill Press, 155-173, 2001.

[0070] Compounds of formula I, and their pharmaceutically acceptable salts and stereoisomers may be effective over a wide dosage range. In some embodiments, the daily dosages may range from around 10 ng / kg to 1000 mg / kg, typically from 100 ng / kg to 100 mg / kg, e.g. around 0.01 mg / kg to 40 mg / kg. Methods of Use

[0071] In some aspects, the present disclosure provides a method of treating a disease or disorder that is associated with (e.g., characterized or mediated by) aberrant TNFR1 signaling, comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof.

[0072] In a related aspect, the present disclosure provides a compound of formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, for use in treating a disease or disorder that is associated with (e.g., characterized or mediated by) aberrant TNFR1 signaling.

[0073] In another related aspect, the present disclosure provides a compound of formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, for use in therapy, in particular for treating a disease or disorder that is associated with (e.g., characterized or mediated by) aberrant TNFR1 signaling.

[0074] In yet another related aspect, the present disclosure provides the use of a compound of formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, in the manufacture of a medicament for treating a disease or disorder that is associated with (e.g., characterized or mediated by) aberrant TNFR1 signaling.

[0075] The term “subject” (or “patient”) as used herein includes all members of the animal kingdom prone to or suffering from the indicated disease or disorder. In some embodiments, the subject is a mammal, preferably a human.

[0076] In some embodiments, the disease or disorder is an inflammatory or neuroinflammatory disease.

[0077] In some embodiments, the inflammatory disease is rheumatoid arthritis, psoriasis, hidradenitis suppurativa, polyarticular juvenile idiopathic arthritis, non-infectious uveitis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, or psoriatic arthritis. 29 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0078] In some embodiments, the neuroinflammatory disease is multiple sclerosis, Alzheimer’s disease, or amyotrophic lateral sclerosis.

[0079] Modes of administration and dosage amounts are as disclosed above.

[0080] These and other aspects of the present disclosure will be further appreciated upon consideration of the following Examples, which are intended to illustrate certain particular embodiments of the disclosure but are not intended to limit its scope, as defined by the claims. EXAMPLES

[0081] Example 1: Synthesis of (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-1- cyclopropyl-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (1) N N N N N N N NClNON BF KOtBu, THFClN OPhNTf3KCN 2, K2CO3ClOlO,5] imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0083] To a solution of (7R,14R)-11-chloro-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (500 mg, 1.28 mmol, 1 eq) in THF (6.4 mL) was added t-BuOK (1 M in THF, 6.4 mL, 5 eq), then the reaction mixture was stirred at 20°C for 2 hr under N2. The reaction mixture was concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=50 / 1 to 0 / 1) to give the title compound as a white solid (300 mg, 865 μmol, 67% yield, 98% purity).1H NMR (400 MHz, DMSO-d6) δ = 10.57 (b, 1H), 7.89-7.82 (m, 1H), 7.61 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.24-7.17 (m, 2H), 7.14-7.10 (m, 1H), 6.27 (d, J = 7.2 Hz, 1H), 5.17 (d, J = 7.2 Hz, 1H), 3.46-3.36 (m, 1H), 3.31 (s, 3H), 2.73 (d, J = 13.7 Hz, 1H). 30 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0084] (7R,14R)-11-chloro-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5] imidazo[1,2-a][1,4]diazocin-1-yl trifluoromethanesulfonate

[0085] To a solution of (7R,14R)-11-chloro-1-hydroxy-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (200 mg, 588 μmol, 1 eq) in THF (4 mL) was added K2CO3 (163 mg, 1.18 mmol, 2 eq) at 0°C, then 1,1,1-trifluoro-N-phenyl- N-(trifluoromethylsulfonyl)methanesulfonamide (231 mg, 647 μmol, 1.1 eq) was added to the mixture at 0°C and stirred at 20°C for 2 hr under N2. The reaction mixture was treated with H2O (10 mL) and extracted with EtOAc (8 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (300 mg).1H NMR (400 MHz, CDCl3) δ = 8.71-8.66 (m, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.60-7.49 (m, 2H), 7.34 (d, J = 1.9 Hz, 1H), 7.25- 7.21 (m, 1H), 6.03 (d, J = 7.3 Hz, 1H), 4.98 (d, J = 7.2 Hz, 1H), 3.57-3.49 (m, 4H), 2.94 (d, J = 13.7 Hz, 1H).

[0086] (7R,14R)-11-chloro-1-cyclopropyl-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5] imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0087] To a solution of (7R,14R)-11-chloro-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-1-yl trifluoromethanesulfonate (120 mg, 254 μmol, 1 eq) and potassium;cyclopropyl(trifluoro)boranuide (45 mg, 305 μmol, 1.2 eq) in toluene (1 mL) and H2O (0.1 mL) was added Cs2CO3(249 mg, 763 μmol, 3 eq) and Pd(dppf)Cl2(9 mg, 13 μmol, 0.05 eq), then the reaction mixture was stirred at 100°C for 4 hr under N2. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuo to give a residue (combined with another batch at 5 mg scale) which was purified by prep-HPLC (column: WePure Biotech XP tC18 150*40*7µm;mobile phase: [H2O(10 mM NH4HCO3)- ACN];gradient:25%-55% B over 8.0 min) to give the title compound as a white solid (20 mg, 95% purity).1H NMR (400 MHz, DMSO-d6) δ = 8.22-8.13 (m, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.35-7.25 (m, 2H), 7.23-7.19 (m, 1H), 6.63 (d, J = 7.5 Hz, 1H), 5.18 (d, J = 7.0 Hz, 1H), 3.55-3.43 (m, 1H), 3.28 (s, 3H), 2.78-2.66 (m, 2H), 1.30-1.18 (m, 2H), 1.04-0.97 (m, 1H), 0.76-0.68 (m, 1H).

[0088] tert-Butyl(1-(5-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2-yl)cyclobutyl) carbamate 31 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0089] To a solution of (7R,14R)-11-chloro-1-cyclopropyl-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (15 mg, 41 μmol, 1 eq) and [2-[1-(tert-butoxycarbonylamino)cyclobutyl]pyrimidin-5-yl]boronic acid (18 mg, 61 μmol, 1.5 eq) in THF (1 mL) was added K3PO4 (0.5 M, 165 μL, 2 eq), then [2-(2-aminophenyl)phenyl]- chloro-palladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (3 mg, 4 μmol, 0.1 eq) was added to the mixture and the mixture was stirred at 100°C for 4 hr under N2. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuo to give the title compound as a yellow solid (30 mg, crude). The crude product was used in next step directly.

[0090] (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-1-cyclopropyl-6-methyl-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (1)

[0091] A solution of tert-butyl (1-(5-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2- yl)cyclobutyl)carbamate (30 mg, 52 μmol, 1 eq) in HCl / EtOAc (4 M, 2 mL, 153.8 eq) was stirred at 20°C for 1 hr. The reaction mixture was concentrated in vacuo to give a residue (combined with another batch at 10 mg scale) which was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:25%-55% B over 8.0 min) to give the title compound as a white solid (5 mg, 98% purity).1H NMR (400 MHz, CDCl3) δ = 8.90 (s, 2H), 8.45 (t, J = 4.7 Hz, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.52 (s, 1H), 7.44 (br d, J = 8.4 Hz, 1H), 7.33 (d, J = 4.8 Hz, 2H), 6.64 (d, J = 7.5 Hz, 1H), 4.96 (d, J = 7.0 Hz, 1H), 3.53-3.44 (m, 4H), 2.90 (d, J = 13.2 Hz, 1H), 2.85-2.76 (m, 2H), 2.50-2.42 (m, 1H), 2.28-2.14 (m, 3H), 2.05-1.97 (m, 1H), 1.34-1.26 (m, 2H), 1.16-1.09 (m, 1H), 0.77-0.70 (m, 1H). MS: [M+H]+= 477.3.

[0092] Example 2: Synthesis of (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-1- cyclopropyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- one (2) 32 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO OOt- St-BuBu O EtO O CHOH N S(S) EtS(S)2 Br (S) t-BuNBr (E) OOHN (R)HCl / EtOAc Br SOhFH O

[0094] To a solution of 2-bromo-6-cyclopropyl-benzaldehyde (24 g, 106.63 mmol, 1 eq) and (S)-2-methylpropane-2-sulfinamide (14 g, 117.29 mmol, 1.1 eq) in THF (240 mL) was added Ti(OEt)4 (36 g, 159.94 mmol, 33.2 mL, 1.5 eq) at 10oC and the reaction mixture was stirred at 40°C for 12 hr under N2. The reaction mixture was poured into sat. brine (300 mL) and stirred for 30 min, after which it was filtered and the filtrate was concentrated in-vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 0 / 1) to give the title compound as a colorless oil (25 g, 76.16 mmol, 71% yield, 94% purity).1H NMR (400 MHz, METHANOL-d4) δ = 9.07 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.28 (t, J = 7.9 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 2.54-2.47 (m, 1H), 1.30 (s, 9H), 1.06-0.95 (m, 2H), 0.80-0.66 (m, 2H).

[0095] (R)-Ethyl3-(2-bromo-6-cyclopropylphenyl)-3-((S)-1,1-dimethylethylsulfinamido) propanoate 33 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0096] To a solution of Zn (30 g, 462.18 mmol, 6.1 eq) in THF (220 mL) was added CuCl (14 g, 137.08 mmol, 3.3 mL, 1.8 eq) at 20°C under N2 and the solution was stirred at 70°C for 1 hr. The solution was cooled to 20°C and ethyl 2-bromoacetate (51 g, 304.63 mmol, 33.7 mL, 4 eq) in THF (20 mL) was added dropwise. After addition, the solution was stirred at 50°C for 0.5 hr. The solution was then cooled to 0°C and (S,E)-N-[(2-bromo-6-cyclopropyl-phenyl)methylene]-2- methyl-propane-2-sulfinamide (25 g, 76.16 mmol, 1 eq) in THF (20 mL) was added dropwise. The reaction mixture was stirred at 20°C for 12 hr. The reaction mixture was diluted with TBME (500 mL) and a solution of citric acid (45 g) in H2O (200 mL) was added at 20 °C and extracted with TBME (300 mL x 2). The combined organic layers were washed with H2O (300 mL x 3), saturated aqueous NaHCO3solution (300 mL x 3), and saturated aqueous brine solution (300 mL x 3). The organic phase was concentrated in-vacuo to give a residue which was purified by column chromatography (SiO2,Petroleum ether / Ethyl acetate=1 / 0 to 0 / 1) to give the title compound as a colorless oil (27 g, 64.85 mmol, 86% yield, 92% purity).1H NMR (400 MHz, METHANOL-d4) δ = 7.52-7.36 (m, 1H), 7.25-6.79 (m, 2H), 6.11-5.84 (m, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.42 (m, 1H), 3.07 (dd, J = 5.9, 15.8 Hz, 1H), 2.65-2.13 (m, 1H), 1.21 (t, J = 7.2 Hz, 3H), 1.18-1.12 (m, 9H), 1.09-0.99 (m, 2H), 0.80-0.57 (m, 2H).

[0097] (R)-Ethyl 3-amino-3-(2-bromo-6-cyclopropylphenyl)propanoate

[0098] Ethyl (3R)-3-(2-bromo-6-cyclopropyl-phenyl)-3-[[(S)-tert- butylsulfinyl]amino]propanoate (27 g, 64.85 mmol, 1 eq) was dissolved in HCl / EtOAc (2 M, 245 mL) and the solution was stirred at 20°C for 1 hr. The solution was poured into H2O (300 mL) and extracted with ethyl acetate (300 mL x 2). The aqueous layer was adjusted to pH=7~8 with Na2CO3. The aqueous layer was extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated in-vacuo give the title compound as a colorless oil (18 g, 57.66 mmol, 88% yield, 99% purity).1H NMR (400 MHz, METHANOL-d4) δ = 7.46 (d, J = 8.7 Hz, 1H), 7.23-7.02 (m, 2H), 5.53-5.38 (m, 1H), 4.18-4.07 (m, 2H), 3.20 (m, 1H), 3.03-2.88 (m, 1H), 2.19 (br s, 1H), 1.21 (t, J = 7.2 Hz, 3H), 1.13-0.92 (m, 2H), 0.74 (br s, 2H).

[0099] (R)-Ethyl-3-(2-bromo-6-cyclopropylphenyl)-3-((5-chloro-2- nitrophenyl)amino)propanoate

[0100] To a solution of (R)-ethyl 3-amino-3-(2-bromo-6-cyclopropyl-phenyl)propanoate (18 g, 57.66 mmol, 1 eq) in DIEA (8.94 g, 69.19 mmol, 12 mL, 1.2 eq) was added 4-chloro-2-fluoro-1- 34 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO nitro-benzene (9.11 g, 51.89 mmol, 0.9 eq) and the reaction mixture was stirred at 90°C for 1 hr. The reaction mixture was poured into saturated aqueous citric acid (300 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated in-vacuo give the title compound as a yellow oil (23 g, 49.17 mmol, 85% yield, 99% purity).1H NMR (400 MHz, CDCl3) δ = 9.23-8.80 (m, 1H), 8.10 (d, J = 9.1 Hz, 1H), 7.45 (br s, 1H), 7.08 (br s, 2H), 6.99-6.76 (m, 1H), 6.59 (dd, J = 1.9, 9.1 Hz, 1H), 6.06 (br s, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.53-3.21 (m, 1H), 2.94 (dd, J = 4.3, 15.6 Hz, 1H), 2.20 (br s, 1H), 1.26 (t, J = 7.1 Hz, 3H), 1.15-1.01 (m, 1H), 0.92-0.81 (m, 1H), 0.77 (m, 2H).

[0101] (R)-3-(2-Bromo-6-cyclopropylphenyl)-3-((5-chloro-2-nitrophenyl)amino)propan-1-ol

[0102] To a solution of (R)-ethyl 3-(2-bromo-6-cyclopropylphenyl)-3-((5-chloro-2- nitrophenyl)amino)propanoate (23 g, 49.17 mmol, 1 eq) in THF (230 mL) was added DIBAL-H (2.5 M, 59 mL, 3 eq) at -70°C under N2and the reaction mixture was stirred at 20°C for 1 hr. The reaction mixture with another 3.5 g batch was quenched with H2O (21 mL) and 15% aq. NaOH (42 mL) at 0°C and stirred for 30 min. The resulting mixture was filtered and the filtrate was concentrated in-vacuo to give the title compound as a yellow solid (18 g, 42.28 mmol, 94% purity) as a yellow solid.1H NMR (400 MHz, METHANOL-d4) δ = 9.10-8.92 (m, 1H), 8.11 (d, J = 9.1 Hz, 1H), 7.57-7.34 (m, 1H), 7.12-7.06 (m, 1H), 7.02-6.85 (m, 1H), 6.61 (dd, J = 2.0, 9.1 Hz, 1H), 5.87-5.55 (m, 1H), 3.88-3.74 (m, 2H), 2.66-2.44 (m, 1H), 2.32-2.16 (m, 2H), 1.16-0.94 (m, 2H), 0.93-0.70 (m, 2H).

[0103] (R)-3-(2-Bromo-6-cyclopropylphenyl)-3-((5-chloro-2-nitrophenyl)amino)propanal

[0104] To a solution of (R)-3-(2-bromo-6-cyclopropylphenyl)-3-((5-chloro-2- nitrophenyl)amino)propan-1-ol (13 g, 35.25 mmol, 1 eq) in DCM (130 mL) was added TEA (9.75 g, 91.62 mmol, 3 eq) at 0°C. A solution of SO3.Py (15 g, 91.63 mmol, 3 eq) in DMSO (30 mL) was then added dropwise at 0°C. The resulting mixture was stirred at 15°C for 1 hr and then poured into ice water (200 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in-vacuo to give a residue which was purified by column chromatography (SiO2, petroleum ether: Ethyl acetate = 1:0 to 3:1) to give the title compound as a yellow solid (10 g, 22.4 mmol, 80% yield, 80% purity) as a yellow solid.1H NMR (400 MHz, CDCl3) δ = 9.88 (s, 1H), 9.01-8.96 (m, 1H), 8.10 (d, J = 35 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO 8.8 Hz, 1H), 7.47 (br s, 1H), 7.09-6.77 (m, 3H), 6.61 (dd, J = 2.0, 9.2 Hz, 1H), 6.18 (br s, 1H), 3.68-3.62 (m, 1H), 3.14-3.10 (m, 1H), 2.17 (br s, 1H), 1.29-0.87 (m, 4H).

[0105] (4R)-4-(2-Bromo-6-cyclopropyl-phenyl)-4-(5-chloro-2-nitro-anilino)-2- trimethylsilyloxy-butanenitrile

[0106] To a solution of (R)-3-(2-bromo-6-cyclopropylphenyl)-3-((5-chloro-2- nitrophenyl)amino)propanal (10 g, 24.54 mmol, 1 eq) in DCM (120 mL) was added diiodozinc (2 g, 1.89 mmol, 4.9 eq) and TEA (373 mg, 3.69 mmol, 0.15 eq) at 15°C. The reaction mixture was degassed and purged with N2 for 3 times. TMSCN (5 g, 49.08 mmol, 2 eq) was then added to the reaction mixture at 15°C and the reaction mixture was stirred for 2 hr at 15°C under N2. The reaction mixture was poured into ice water (200 mL) and extracted with DCM (80 mL x 4). The combined organic layers were washed with brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in-vacuo to give the title compound as a yellow oil (11 g, crude).

[0107] (1R)-1-(2-bromo-6-cyclopropyl-phenyl)-7-chloro-2,3-dihydro-1H-pyrrolo[1,2- a]benzimidazol-3-ol

[0108] To a solution of (4R)-4-(2-bromo-6-cyclopropyl-phenyl)-4-(5-chloro-2-nitro-anilino)- 2-trimethylsilyloxy-butanenitrile (11 g, 21.03 mmol, 1 eq) in EtOH (110 mL) was added SnCl2.2H2O (24 g, 105.18 mmol, 5 eq) and the reaction mixture was stirred at 75°C for 4 hr. The reaction mixture was poured into ice water (100 mL) and the suspension was filtered through a pad of Celite®. The Celite® pad was eluted with ethyl acetate (200 mL). The aqueous phase was extracted with ethyl acetate (100 mL x 3) and the combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in-vacuo to give a residue which was purified by column chromatography (SiO2, petroleum ether: ethyl acetate=1:0 to 0:1) to give the title compound as a yellow solid (4 g, 9.46 mmol, 45% yield, 95% purity).1H NMR (400 MHz, METHANOL-d4) δ = 7.67-7.57 (m, 1H), 7.43-7.38 (m, 1H), 7.29- 7.14 (m, 2H), 6.99-6.85 (m, 1H), 6.75-6.52 (m, 1H), 5.57-5.36 (m, 1H), 3.67-3.32 (m, 1H), 3.01 (m, 1H), 2.35-2.22 (m, 1H), 1.28 (s, 1H), 1.18-1.09 (m, 1H), 0.92-0.55 (m, 3H).

[0109] (1R)-3-Azido-1-(2-bromo-6-cyclopropyl-phenyl)-7-chloro-2,3-dihydro-1H- pyrrolo[1,2-a]benzimidazole

[0110] To a solution of (1R)-1-(2-bromo-6-cyclopropyl-phenyl)-7-chloro-2,3-dihydro-1H- pyrrolo[1,2-a]benzimidazol-3-ol (4 g, 9.91 mmol, 1 eq) in THF (40 mL) was added DPPA (5 g, 36 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO 19.82 mmol, 4.3 mL, 2 eq) and DBU (2 g, 12.88 mmol, 1.94 mL, 1.3 eq) at 0°C. After addition, the reaction mixture was warmed to 20°C for 1 hr and then heated to 50°C for 1 hr. The reaction mixture was poured into H2O (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in-vacuo to give the title compound as a brown solid (3.5 g, crude). MS: [M+H]+= 427.9.

[0111] (1R)-1-(2-Bromo-6-cyclopropyl-phenyl)-7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]benz imidazol-3-amine

[0112] To a solution of (1R)-3-azido-1-(2-bromo-6-cyclopropyl-phenyl)-7-chloro-2,3-dihydro- 1H-pyrrolo[1,2-a]benzimidazole (4 g, 8.16 mmol, 1 eq) in THF (50 mL) and H2O (10 mL) was added trimethylphosphane (1 M, 16.3 mL, 2 eq) at 0°C and the reaction mixture was stirred at 20°C for 12 hr. The reaction mixture was poured into H2O (50 mL), extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in-vacuo to give a residue which was purified by column chromatography (SiO2, petroleum ether: ethyl acetate=1:0 to 0:1) to give the title compound as a brown solid (2.0 g, 4.22 mmol, 52% yield, 85% purity).1H NMR (400 MHz, CDCl3) δ = 7.65 (d, J = 8.4 Hz, 1H), 7.44-7.37 (m, 1H), 7.37-7.31 (m, 1H), 7.21-7.15 (m, 2H), 6.92-6.66 (m, 1H), 6.50-6.45 (m, 1H), 4.79-4.68 (m, 1H), 3.55-3.40 (m, 1H), 2.87-2.75 (m, 1H), 2.17-2.11 (m, 1H), 1.21-1.05 (m, 2H), 0.91-0.77 (m, 2H).

[0113] (7R,14R)-11-Chloro-1-cyclopropyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0114] To a solution of (1R)-1-(2-bromo-6-cyclopropyl-phenyl)-7-chloro-2,3-dihydro-1H- pyrrolo[1,2-a]benz imidazol-3-amine (500 mg, 1.24 mmol, 1 eq) in DMSO (6 mL) was added K2CO3 (515 mg, 3.72 mmol, 3 eq), dichloropalladium;(5-diphenylphosphanyl-9,9-dimethyl- xanthen-4-yl)-diphenyl-phosphane (94 mg, 124 μmol, 0.1 eq), and PhOH (257 mg, 2.73 mmol, 240 μL, 2.2 eq) under N2. The suspension was degassed and purged with CO three times. Four batches of the reaction mixture were stirred under CO (15 psi) at 100°C for 12 hr. Each of the reaction mixtures were diluted with H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and the filtrate was concentrated in-vacuo to give a residue which was purified by column chromatography (SiO2, ethyl acetate: methanol =1:0 to 20:1) to give the title compound as a brown solid (800 mg, 37 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO 1.60 mmol, 32% yield, 70% purity).1H NMR (400 MHz, CDCl3) δ = 8.40 (d, J = 8.1 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.44-7.39 (m, 1H), 7.38-7.32 (m, 1H), 7.30 (s, 1H), 7.20 (d, J = 8.6 Hz, 1H), 6.82 (br d, J = 4.8 Hz, 1H), 6.65 (d, J = 7.6 Hz, 1H), 4.87 (t, J = 6.4 Hz, 1H), 3.51-3.40 (m, 1H), 2.85 (d, J = 13.4 Hz, 1H), 2.51-2.41 (m, 1H), 1.34-1.26 (m, 2H), 1.17-1.10 (m, 1H), 0.74- 0.66 (m, 1H).

[0115] tert-Butyl (1-(5-((7R,14R)-1-cyclopropyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2- yl)cyclobutyl)carbamate

[0116] A mixture of ((7R,14R)-11-chloro-1-cyclopropyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (0.1 g, 286 μmol, 1 eq), [2- [1-(tert-butoxy carbonylamino)cyclobutyl]pyrimidin-5-yl]boronic acid (126 mg, 429 μmol, 1.5 eq), K3PO4 (0.5 M, 1.1 mL, 2 eq), and [2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl- [3-(2,4,6-triisopropylphenyl)phenyl]phosphane (22 mg, 28 μmol, 0.1 eq) in THF (10 mL) was degassed and purged with N2 three times, and then the reaction mixture was stirred at 100°C for 4 hr under N2. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with saturated aqueous brine solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in-vacuo to give the title compound as a brown solid (150 mg, crude). MS: [M+H]+= 563.2.

[0117] (7R,14R)-11-(2-(1-Aminocyclobutyl)pyrimidin-5-yl)-1-cyclopropyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0118] A mixture of tert-butyl (1-(5-((7R,14R)-1-cyclopropyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2- yl)cyclobutyl)carbamate (150 mg, 266 μmol, 1 eq) in 4M HCl / EtOAc (10 mL) was stirred at 25°C for 2 hr. The reaction mixture was filtered and concentrated in-vacuo to give a residue which was purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*5 μm;mobile phase: [H2O(0.2% FA)-ACN];gradient:1%-40% B over 8.0 min) to give the title compound as a white solid (30 mg, 64 μmol, 24% yield, 99% purity).1H NMR (400 MHz, DMSO-d6) δ = 9.09 (s, 2 H), 8.97 (d, J = 3.6 Hz, 1 H),8.22-8.18 (m, 1 H), 7.78-7.76 (m, 2 H), 7.60-7.58 (m, 1 H), 7.33-7.30 (m, 2 H), 6.76-6.73 (m, 1 H), 4.87 (t, J = 3.2 Hz, 1 H), 3.5-3.40 (m, 1H), 2.87-2.81 (m, 1 H), 2.74-2.71 (m, 1 H), 2.67-2.61 (m, 3 H), 2.20-2.12 (m, 2 H), 2.06-1.96 (m, 1H), 1.91-1.81 (m, 1 H), 1.33-1.21 (m, 2 H), 1.04-0.99 (m, 1 H), 0.77-0.72 (m, 1 H). MS: [M+H]+= 463.3. 38 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0119] Example 3: Synthesis of (1S,3s)-3-(5-((7R,14R)-1-cyclopropyl-5-oxo-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2-yl)- 3-hydroxy-1-methylcyclobutanecarbonitrile (3) BrHONN NB2pin2(5 eq),Pd2(dba)3N(s)NN (R) (R)•PHCHO N NH Odihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0121] A solution of (7R,14R)-11-chloro-1-cyclopropyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (30 mg, 86 μmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (109 mg, 429 μmol, 5 eq), Pd2(dba)3(24 mg, 26 μmol, 0.3 eq), tricyclohexylphosphonium;tetrafluoroborate (6 mg, 17 μmol, 0.2 eq), and potassium;acetate (25 mg, 257 μmol, 3 eq) in dioxane (1.2 mL) was degassed and purged with N2three times. The reaction mixture was stirred at 120°C for 12 hr under N2. The reaction was quenched with H2O (25 mL) and extracted with EtOAc (15 mL x 2). The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue which was purified by prep-HPLC (column: WePure Biotech XP tC18 150*40*7µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:38%-68% B over 8.0 min) to give the title compound as a white solid (15 mg, 37% yield, 94% purity).

[0122] (1S,3s)-3-(5-((7R,14R)-1-Cyclopropyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f] benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2-yl)-3-hydroxy-1- methylcyclobutanecarbonitrile

[0123] A solution of (7R,14R)-1-cyclopropyl-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (15 mg, 34 μmol, 1 eq), 3-(5-bromopyrimidin-2-yl)-3-hydroxy-1-methyl-cyclobutanecarbonitrile (18 mg, 68 μmol, 2 eq), K3PO4 (0.5 M, 136 μL, 2 eq), and [2-(2-aminophenyl)phenyl]-chloro- palladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (3 mg, 3 μmol, 0.1 eq) in THF (0.15 mL) was degassed and purged with N2 three times. The reaction mixture was 39 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO stirred at 100°C for 3 hr under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: WePure Biotech XP tC18150*40*7µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:25%-55% B over 8.0 min ) to give the title compound as a white solid (7 mg, 41% yield, 100% purity).1H NMR (400 MHz, CDCl3) δ = 8.91 (s, 2H), 8.42 (dd, J = 1.1, 7.8 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.49 (s, 1H), 7.43 (dd, J = 1.6, 8.4 Hz, 1H), 7.41-7.38 (m, 1H), 7.37-7.32 (m, 1H), 7.09 (br d, J = 6.0 Hz, 1H), 6.74 (d, J = 7.5 Hz, 1H), 5.08 (br s, 1H), 4.95 (t, J = 6.3 Hz, 1H), 3.51 (m, 1H), 3.05- 2.98 (m, 2H), 2.95-2.87 (m, 3H), 2.52-2.43 (m, 1H), 1.77 (s, 3H), 1.35-1.29 (m, 2H), 1.13 (m, 1H), 0.80-0.73 (m, 1H).

[0124] Example 4: Synthesis of (7R,14R)-1-cyclopropyl-11-(2-(1- (methylamino)cyclobutyl)pyrimidin-5-yl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (5) NB(OH)2N N N N NHO,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2- yl)cyclobutyl)(methyl) carbamate

[0126] To a solution of (7R,14R)-11-chloro-1-cyclopropyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (0.02 g, 57 μmol, 1 eq) and [2-[1-[tert-butoxycarbonyl (methyl) amino]cyclobutyl]pyrimidin-5-yl]boronic acid (18 mg, 57 μmol, 1 eq) in THF (0.2 mL) was added [2-(2-aminophenyl)phenyl]-chloro- palladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl) phenyl]phosphane (5 mg, 6 μmol, 0.1 eq) and K3PO4(0.5 M, 229 μL, 2 eq) and the reaction mixture was stirred at 100°C for 4 hr under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a black oil (0.03 g, crude).

[0127] (7R,14R)-1-Cyclopropyl-11-(2-(1-(methylamino)cyclobutyl)pyrimidin-5-yl)-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one 40 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0128] A solution of tert-butyl (1-(5-((7R,14R)-1-cyclopropyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2- yl)cyclobutyl)(methyl)carbamaten (0.03 g, 52 μmol, 1 eq) in 4M HCl / EtOAc (1 mL) was stirred at 25°C for 1 hr. The reaction mixture was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: WePure Biotech XP tC18150*40*7µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:15%-65% B over 8.0 min) to give the title compound as a white solid (12 mg, 48% yield, 99% purity).1H NMR (400 MHz, CDCl3) δ = 8.92 (s, 2H), 8.41 (dd, J = 1.3, 7.9 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 1.1 Hz, 1H), 7.46 (dd, J = 1.6, 8.4 Hz, 1H), 7.43 - 7.39 (m, 1H), 7.37-7.32 (m, 1H), 6.85 (br d, J = 5.8 Hz, 1H), 6.75 (d, J = 7.5 Hz, 1H), 4.92 (t, J = 6.3 Hz, 1H), 3.55-3.45 (m, 1H), 2.89 (d, J = 13.1 Hz, 1H), 2.64 (m, 2H), 2.52-2.43 (m, 1H), 2.36-2.27 (m, 2H), 2.23 (s, 3H), 2.18-2.09 (m, 1H), 1.99-1.90 (m, 1H), 1.41-1.24 (m, 2H), 1.17- 1.10 (m, 1H), 0.78-0.69 (m, 1H).

[0129] Example 5: Synthesis of (1R,3r)-3-(5-((7R,14R)-1-cyclopropyl-5-oxo-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2-yl)- 3-hydroxy-1-methylcyclobutanecarbonitrile (6) N B(OH)2 N HO N N H O

[0130] To a solution of (7R,14R)-11-chloro-1-cyclopropyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (0.02 g, 57 μmol, 1 eq) and [2-(3-cyano-1-hydroxy-3-methyl-cyclobutyl)pyrimidin-5-yl]boronic acid (20 mg, 86 μmol, 1.5 eq) in THF (0.2 mL) was added [2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3- (2,4,6-triisopropylphenyl)phenyl]phosphane (5 mg, 6 μmol, 0.1 eq) and K3PO4 (0.5 M, 230 μL, 2 eq). The reaction mixture was stirred at 100°C for 4 hr under N2. The reaction mixture was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: WePure Biotech XP tC18150*40*7µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:20%-55% B over 8.0 min). Then it was further purified by prep-HPLC (column: Phenomenex Luna C18 100*40mm*5µm;mobile phase: [H2O(0.2% FA)-ACN];gradient:25%-45% B over 8.0 min) to 41 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO give the title compound as a white solid (4 mg, 14% yield, 100% purity).1H NMR (400 MHz, CDCl3) δ = 8.95 (s, 2H), 8.41 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.50 (s, 1H), 7.46-7.40 (m, 2H), 7.38-7.32 (m, 1H), 6.88-6.83 (m, 1H), 6.76 (d, J = 7.4 Hz, 1H), 5.12 (s, 1H), 4.93 (br t, J = 6.3 Hz, 1H), 3.56-3.47 (m, 1H), 3.42 (br d, J = 13.3 Hz, 2H), 2.90 (d, J = 13.0 Hz, 1H), 2.56- 2.43 (m, 3H), 1.83 (s, 3H), 1.40-1.30 (m, 2H), 1.14 (m, 1H), 0.74 (m, 1H).

[0131] Example 6: Synthesis of (1S,3s)-3-(5-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo- 5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl) pyrimidin-2-yl)-3-hydroxy-1-methylcyclobutanecarbonitrile (7) NBrOH N N N O

[0132] ethyl-1,3,2- dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (20 mg, 43 μmol, 1 eq) and (1s,3s)-3-(5-bromopyrimidin-2-yl)-3-hydroxy-1- methylcyclobutanecarbonitrile (17 mg, 65 μmol, 1.5 eq) in dioxane (0.8 mL) was added Pd2(dba)3 (4 mg, 4 μmol, 0.1 eq), tricyclohexylphosphonium; tetrafluoroborate (3 mg, 8 μmol, 0.2 eq), and K3PO4(0.5 M, 176 μL, 2 eq). The reaction mixture was stirred at 100°C for 2 hr under N2. The reaction mixture was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: We Pure Biotech XP tC18 150*40*7µm;mobile phase: [H2O(10 mM NH4HCO3)- ACN];gradient:25%-65% B over 8.0 min) to give the title compound as a white solid (8 mg, 36% yield, 100% purity).1H NMR (400 MHz, DMSO-d6) δ = 9.08 (s, 2H), 8.19 (dd, J = 2.5, 6.9 Hz, 1H), 7.83-7.73 (m, 2H), 7.62-7.55 (m, 1H), 7.32-7.26 (m, 2H), 6.68 (d, J = 7.4 Hz, 1H), 5.83 (s, 1H), 5.16 (d, J = 6.9 Hz, 1H), 3.60-3.49 (m, 1H), 3.33 (s, 3H), 2.97-2.88 (m, 2H), 2.82-2.75 (m, 4H), 1.48 (s, 3H), 1.30-1.24 (m, 2H), 1.05-0.96 (m, 1H), 0.83-0.73 (m, 1H).

[0133] Example 7: Synthesis of (1R,3r)-3-(5-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo- 5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl) pyrimidin-2-yl)-3-hydroxy-1-methylcyclobutanecarbonitrile (8) 42 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO N Br O I(1 eq)OHNBrOHN Br(1.25 eq) N +Bpin2N N

[0134] rile and(1s,3s)-3-(5-bromopyrimidin-2-yl)-3-hydroxy-1-methylcyclobutanecarbonitrile

[0135] A solution of 5-bromo-2-iodo-pyrimidine (3 g, 10.53 mmol, 1 eq) and 1-methyl-3-oxo- cyclobutanecarbonitrile (1.03 g, 9.48 mmol, 0.9 eq) in DCM (30 mL) was degassed and purged with N2 three times. n-BuLi (2.5 M, 4.63 mL, 1.1 eq) was added dropwise at -78°C under N2 and the reaction mixture stirred for 1 hr and then at 20°C for 1 hr. The reaction was quenched with H2O (20 mL), filtered, and the filtrate was extracted with DCM (30 mL x 3). The combine organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1:0 to 3:7) to give the title compounds as a yellow solid (2 g, 70% yield, 99% purity).3-(5-Bromopyrimidin-2-yl)-3-hydroxy-1-methyl-cyclobutanecarbonitrile (2 g, 7.39 mmol) was separated by p-HPLC (column: CD05-Phenomenex Luna C18 150*40*10µm;mobile phase: [H2O(FA)-ACN];gradient:17%-47% B over 25 min) and lyophilized to give (1r,3r)-3-(5-bromopyrimidin-2-yl)-3-hydroxy-1-methylcyclobutanecarbonitrile as a yellow solid (950 mg, 47% yield);1H NMR (400 MHz, CDCl3) δ = 8.84 (s, 2H), 4.78 (s, 1H), 3.34 (d, J = 13.6 Hz, 2H), 2.53-2.45 (m, 2H), 1.80 (s, 3H); and (1s,3s)-3-(5-bromopyrimidin-2-yl)-3- hydroxy-1-methylcyclobutanecarbonitrile as a yellow solid (590 mg, 30% yield);1H NMR (400 MHz, CDCl3) δ = 8.81 (s, 2H), 4.73 (s, 1H), 3.03-2.94 (m, 2H), 2.89-2.80 (m, 2H), 1.72 (s, 3H)

[0136] (2-((1r,3r)-3-Cyano-1-hydroxy-3-methylcyclobutyl)pyrimidin-5-yl)boronic acid

[0137] To a solution of (1r,3r)-3-(5-bromopyrimidin-2-yl)-3-hydroxy-1- methylcyclobutanecarbonitrile (950 mg, 3.54 mmol, 1 eq) in dioxane (9.5 mL) was added 4,4,5,5- 43 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.08 g, 4.25 mmol, 1.2 eq) and KOAc (695 mg, 7.09 mmol, 2 eq) and the reaction mixture was degassed with N2for 15 min. Pd(dppf)Cl2(259 mg, 354 μmol, 0.1 eq) was then added and the reaction mixture was heated to 80°C and stirred for 11.5 hr under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: CD05-Phenomenex Luna C18150*40*10µm; mobile phase: [H2O(FA)-ACN];gradient:0%-20% B over 25 min) and lyophilized to give the title compound as a white solid (50 mg, 6% yield).

[0138] (1R,3r)-3-(5-((7R,14R)-1-Cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2-yl)-3-hydroxy-1- methylcyclobutanecarbonitrile

[0139] To a solution of (7R,14R)-11-chloro-1-cyclopropyl-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (20 mg, 55 μmol, 1 eq) and (2-((1r,3r)-3-cyano-1-hydroxy-3-methylcyclobutyl)pyrimidin-5-yl)boronic acid (19 mg, 82 μmol, 1.5 eq) in THF (1 mL) was added tripotassium; phosphate (0.5 M, 220 μL, 2 eq) and [2-(2- aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3-(2,4,6- triisopropylphenyl)phenyl]phosphane (4 mg, 5 μmol, 0.1 eq). The reaction mixture was stirred at 100°C for 4 hr under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: We Pure Biotech XP tC18 150*40*7µm; mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:25%-65% B over 8.0 min) to give the title compound as a white solid (10 mg, 35% yield, 100% purity).1H NMR (400 MHz, DMSO-d6) δ = 9.15 (s, 2H), 8.17 (dd, J = 2.4, 7.1 Hz, 1H), 7.84-7.76 (m, 2H), 7.63 (dd, J = 1.7, 8.4 Hz, 1H), 7.32-7.25 (m, 2H), 6.68 (d, J = 7.5 Hz, 1H), 6.08 (s, 1H), 5.21 (d, J = 7.0 Hz, 1H), 3.60-3.47 (m, 1H), 3.31 (s, 3H), 3.31-3.26 (m, 2H), 2.85-2.76 (m, 2H), 2.40 (d, J = 13.3 Hz, 2H), 1.68 (s, 3H), 1.29-1.22 (m, 2H), 1.08-0.94 (m, 1H), 0.76 (dt, J = 3.6, 5.4 Hz, 1H).

[0140] Example 8: Synthesis of (7R,14R)-11-(6-(1-aminocyclobutyl)-5-fluoropyridin-3-yl)-1- cyclopropyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- one (9) 44 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO N B(OH)2 N BocHN N N Cl (R) NHBN (R) N (R) NocHNF N NHHCl / EtOAcH2NN NH O 14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)-3-fluoropyridin-2-yl)cyclobutyl) carbamate

[0142] A solution of [6-[1-(tert-butoxycarbonylamino)cyclobutyl]-5-fluoro-3-pyridyl]boronic acid (40 mg, 129 μmol, 1.5 eq), (7R,14R)-11-chloro-1-cyclopropyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5] imidazo[1,2-a][1,4]diazocin-5(14H)-one (0.03 g, 86 μmol, 1 eq), K3PO4 (0.5 M, 343 μL, 2 eq), and [2-(2-aminophenyl)phenyl]-chloropalladium; dicyclohexyl-[3- (2,4,6-triisopropylphenyl)phenyl]phosphane (7 mg, 9 μmol, 0.1 eq) in THF (3 mL) was degassed and purged with N2 three times. The reaction mixture was stirred at 100°C for 4 hr under N2. The reaction was quenched with H2O (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with saturated aqueous brine solution (5 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give the title compound as a black solid (50 mg, crude).

[0143] (7R,14R)-11-(6-(1-Aminocyclobutyl)-5-fluoropyridin-3-yl)-1-cyclopropyl-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0144] A solution of tert-butyl (1-(5-((7R,14R)-1-cyclopropyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)-3-fluoropyridin-2- yl)cyclobutyl)carbamate (0.05 g, 86 μmol, 1 eq) in HCl / EtOAc (4M, 2 mL) was stirred at 25°C for 1 hr. The reaction mixture was concentrated in vacuo to give a residue which was purified by prep- HPLC (column: Phenomenex Luna C18 100*40mm*5µm;mobile phase: [H2O(0.2% FA)- ACN];gradient:10%-40% B over 8.0 min) to give the title compound as a white solid (16 mg, 39% yield, 99.9% purity).1H NMR (400 MHz, CDCl3) δ = 8.45 (s, 1H), 8.33 (dd, J = 1.4, 8.0 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.45 (dd, J = 1.9, 11.8 Hz, 1H), 7.42 (d, J = 1.3 Hz, 1H), 7.36-7.30 (m, 2H), 7.29-7.23 (m, 1H), 6.95 (br d, J = 5.6 Hz, 1H), 6.66 (d, J = 7.5 Hz, 1H), 4.85 (t, J = 6.3 Hz, 1H), 3.48-3.34 (m, 1H), 2.80 (d, J = 13.0 Hz, 1H), 2.77-2.65 (m, 2H), 2.43-2.34 (m, 1H), 2.24- 2.08 (m, 3H), 1.85-1.74 (m, 1H), 1.31-1.16 (m, 2H), 1.05 (m, 1H), 0.72-0.61 (m, 1H).19F NMR (376 MHz, CDCl3) δ = -123.70 (s, 1F). 45 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0145] Example 9: Synthesis (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-6-methyl- 1-((1S,2R)-2-methylcyclopropyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (10) and (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-6- methyl-1-((1R,2S)-2-methylcyclopropyl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (11) NN B(OH)2N N B(OH)2 N N NN O N N NHBoc Omethanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0147] To a solution of (7R,14R)-11-chloro-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-1-yl trifluoromethanesulfonate (0.2 g, 424 μmol, 1 eq) and ((1R,2S)-2-methylcyclopropyl)boronic acid (50 mg, 508 μmol, 1.2 eq) in dioxane (3 mL) was added K2CO3 (117 mg, 847 μmol, 2 eq) and XPHOS-PD-G2 (100 mg, 127 μmol, 0.3 eq) and the reaction mixture was stirred at 100°C for 4 hr under N2. The reaction mixture (combined with another batch at 200 mg scale) was then treated with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with H2O, dried over Na2SO4, and concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1 to 0 / 1) to give the title compound as a yellow oil (90 mg).

[0148] tert-Butyl (1-(5-((7R,14R)-6-methyl-1-((1R,2S)-2-methylcyclopropyl)-5-oxo-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2- yl)cyclobutyl)carbamate 46 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0149] To a solution of (7R,14R)-11-chloro-6-methyl-1-((1R,2S)-2-methylcyclopropyl)-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (90 mg, 238 μmol, 1 eq) and (2-(1-((tert-butoxycarbonyl)amino)cyclobutyl)pyrimidin-5-yl)boronic acid (69 mg, 238 μmol, 1 eq) in THF (4 mL) was added K2CO3 (0.5 M, 953 μL, 2 eq) and XPHOS-PD-G2 (18 mg, 23 μmol, 0.1 eq) and the reaction mixture was stirred at 100°C for 4 hr under N2. The reaction mixture was treated with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with H2O, dried over Na2SO4, and concentrated in vacuo to give a residue which was purified by prep-TLC (SiO2, PE:EtOAc=1:2) to give the title compound as a yellow oil (100 mg, 49% yield, 70% purity).

[0150] (7R,14R)-11-(2-(1-Aminocyclobutyl)pyrimidin-5-yl)-6-methyl-1-((1S,2R)-2- methylcyclopropyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4] diazocin- 5(14H)-one and (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-6-methyl-1-((1R,2S)-2- methylcyclopropyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4] diazocin- 5(14H)-one

[0151] A solution of tert-butyl (1-(5-((7R,14R)-6-methyl-1-((1R,2S)-2-methylcyclopropyl)-5- oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11- yl)pyrimidin-2-yl)cyclobutyl) carbamate (0.1 g, 169 μmol, 1 eq) in HCl / EtOAc (5 mL) was stirred at 20°C for 1 hr. The reaction mixture was concentrated in vacuo to give a residue which was purified by prep-HPLC (HCl condition; column: Phenomenex Luna C18100*40mm*5µm; mobile phase: [H2O(0.04% HCl)-ACN];gradient:10%-45% B over 8.0 min) to give compound 10 as a white solid (3 mg, 3% yield, 95% purity, HCl);1H NMR (400 MHz, DMSO-d6) δ = 9.23 (s, 2H), 8.92 (s, 3H), 8.20 (d, J = 7.9 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.75 (s, 1H), 7.66 (dd, J = 1.4, 8.5 Hz, 1H), 7.45 (d, J = 7.4 Hz, 1H), 7.38-7.27 (m, 1H), 6.54 (d, J = 7.4 Hz, 1H), 5.27 (d, J = 6.9 Hz, 1H), 3.66-3.60 (m, 1H), 3.32 (s, 3H), 2.86-2.53 (m, 6H), 2.28-2.11 (m, 2H), 1.61-1.49 (m, 1H), 1.26 (dt, J = 4.9, 8.2 Hz, 1H), 0.85-0.76 (m, 1H), 0.71 (d, J = 6.3 Hz, 3H); and compound 11 as a white solid (3 mg, 3% yield, 95% purity, HCl) as a white solid;1H NMR (400 MHz, DMSO-d6) δ = 9.23 (s, 2H), 9.00 (s, 3H), 8.18 (d, J = 7.1 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.81 (s, 1H), 7.76- 7.69 (m, 1H), 7.41-7.35 (m, 1H), 7.34-7.27 (m, 1H), 6.76 (d, J = 7.5 Hz, 1H), 5.31 (d, J = 7.0 Hz, 1H), 3.55 (td, J = 7.1, 13.9 Hz, 1H), 3.33 (s, 3H), 2.91-2.79 (m, 2H), 2.76-2.56 (m, 4H), 2.30-2.08 (m, 2H), 1.67-1.51 (m, 1H), 1.40 (dt, J = 4.4, 8.5 Hz, 1H), 0.88-0.73 (m, 4H). 47 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0152] Example 10: Synthesis of (7R,14R)-11-(6-(1-aminocyclobutyl)-5-fluoropyridin-3-yl)- 1-cyclopropyl-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (12) Br (1.2 eBocBrBpin2 q)Pd(dp B(OH)2 N2O(1 eq)N pf)Cl2(0.1 eq) N H2N TEA(5 eq) BocHN KOAc(1.5 eq) BocHN O [

[0154] To a solution of 1-(5-bromo-3-fluoro-2-pyridyl)cyclobutanamine (10 g, 35.52 mmol, 1 eq, HCl salt) in THF (100 mL) was added TEA (17.97 g, 177.59 mmol, 25 mL, 5 eq) and Boc2O (7.75 g, 35.52 mmol, 8 mL, 1 eq) and the reaction mixture was stirred at 25°C for 2 hr. The reaction mixture filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow oil (12 g, 35 mmol, 98% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 8.44 (s, 1H), 7.68- 7.50 (m, 1H), 5.32 (s, 1H), 2.85-2.75 (m, 2H), 2.38 (m, 2H), 2.17-2.05 (m, 1H), 1.91-1.79 (m, 1H), 1.81-1.25 (m, 9H).

[0155] [6-[1-(tert-Butoxycarbonylamino)cyclobutyl]-5-fluoro-3-pyridyl]boronic acid

[0156] To the solution of tert-butyl N-[1-(5-bromo-3-fluoro-2-pyridyl)cyclobutyl]carbamate (2 g, 5.79 mmol, 1 eq) in dioxane (40 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.77 g, 6.95 mmol, 1.2 eq) and KOAc (853 mg, 8.69 mmol, 1.5 eq) and the reaction mixture was degassed by purging N2 for 15 min at 25°C. Pd(dppf)Cl2 (424 mg, 579 μmol, 0.1 eq) was added to the reaction mixture that was then degassed for additional 15 min at 25°C and then heated at 80°C for 2 hr. The reaction mixture was filtered and concentrated in vacuo to give a residue which was purified by prep-HPLC (column: CD05- Phenomenex Luna C18150*40*10µm;mobile phase: [H2O(FA)-ACN];gradient:22%-52% B over 25 min) to give the title compound as a white solid (770 mg, 43% yield).1H NMR (400 MHz, 48 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO DMSO-d6) δ = 8.62 (s, 2H), 7.35 (d, J = 12 Hz, 1H), 7.67-7.45(m, 1H), 2.75-2.67(m, 2H), 2.41- 2.26(m, 2H), 2.03-1.83(m, 1H), 1.77-1.58(m, 1H) , 1.29(m, 9H).

[0157] tert-Butyl (1-(5-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)-3-fluoropyridin-2-yl) cyclobutyl)carbamate

[0158] A mixture of [6-[1-(tert-butoxycarbonylamino)cyclobutyl]-5-fluoro-3-pyridyl]boronic acid (64 mg, 206 μmol, 1.5 eq), (7R,14R)-11-chloro-1-cyclopropyl-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (50 mg, 137 μmol, 1 eq), K3PO4(0.5 M, 550 μL, 2 eq), and [2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3- (2,4,6-triisopropylphenyl)phenyl] phosphane (11 mg, 13 μmol, 0.1 eq) in THF (3 mL) was degassed and purged with N2 three times. The reaction mixture was stirred at 100°C for 4 hr under N2. The reaction was quenched with H2O (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with saturated aqueous brine solution (5 mL), filtered, and concentrated in vacuo to give the title compound as a black solid (50 mg, crude). MS: [M+H]+= 594.1.

[0159] (7R,14R)-11-(6-(1-Aminocyclobutyl)-5-fluoropyridin-3-yl)-1-cyclopropyl-6-methyl- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0160] A mixture of tert-butyl (1-(5-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)-3-fluoropyridin- 2-yl)cyclobutyl) carbamate (50 mg, 84 μmol, 1 eq) in HCl / EtOAc (4 M, 5 mL, 237 eq) was degassed, purged with N2 three times, and stirred at 25°C for 1 hr under N2. The reaction mixture was filtered and concentrated in vacuo to give a residue which was purified by prep-HPLC (column: Phenomenex Luna C18 100*40mm*5μm;mobile phase: [H2O(0.2% FA)- ACN];gradient:15%-45% B over 8.0 min) to give the title compound as a white solid (20 mg, 99% purity).1H NMR (400 MHz, DMSO-d6) δ = 8.63 (s, 1H), 8.16 (m, 1H), 7.95-7.92 (m, 1H), 7.92- 7.91 (m 1H), 7.76-7.74 (m, 2H), 7.57-7.55 (m, 1H), 7.30-7.27 (m, 2H), 6.67 (d, J = 7.6 Hz, 1H), 5.21 (d, J = 6.8 Hz, 1H), 3.54-3.51 (m, 1H), 3.31 (s, 3H), 2.81-2.76 (m, 2H), 2.69-2.66 (m, 2H), 2.11-2.07 (m, 3H), 1.67 (m, 1H), 1.27-1.23 (m, 2H), 0.99 (m, 1H), 0.78-0.77 (m, 1H). MS: [M+H]+= 494.2. 49 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0161] Example 11: Synthesis of (7R,14R)-1-cyclopropyl-6-methyl-11-(2-(1- (methylamino)cyclobutyl)pyrimidin-5-yl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4] diazocin-5(14H)-one (13) N Cl N N O

[0163] To a solution of tert-butyl N-[1-(5-bromopyrimidin-2-yl)cyclobutyl]carbamate (3 g, 9.14 mmol, 1 eq) in DMF (30 mL) was added NaH (731 mg, 18.28 mmol, 60% purity, 2 eq) portion wise and the reaction mixture was stirred at 25°C for 0.5 hr. MeI (1.95 g, 13.71 mmol, 854 μL, 1.5 eq) was added dropwise at 25°C under N2and the reaction mixture was stirred at 25°C for 1.5 hr under N2. The reaction was quenched with aq. NH4Cl (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with saturated aqueous brine solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=5 / 1 to 0 / 1) to give the title compound as a white solid (2 g, 63% yield, 98% purity).1H NMR (400 MHz, DMSO-d6) δ = 8.99 (s, 2H), 2.89 (s, 3H), 2.55-2.53 (m, 2H), 2.06-1.98 (m, 1H), 1.84-1.77 (m, 1H), 1.33 (s, 2H), 1.11 (s, 9H).

[0164] (2-(1-((tert-Butoxycarbonyl)(methyl)amino)cyclobutyl)pyrimidin-5-yl)boronic acid

[0165] A mixture of tert-butyl N-[1-(5-bromopyrimidin-2-yl)cyclobutyl]-N-methyl-carbamate (1 g, 2.92 mmol, 1 eq), Pd(dppf)Cl2 (214 mg, 292 μmol, 0.1 eq), KOAc (860 mg, 8.77 mmol, 3 eq) and 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (816 mg, 3.21 mmol, 1.1 eq) in dioxane (10 mL) was degassed and purged with N2three times. The reaction mixture was stirred at 80°C for 3 hr under N2. The reaction mixture was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: Welch Xtimate C18 50 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO 250*70mm*10µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:5%-40% B over 17.0 min) to give the title compound as a white solid (0.5 g, 56% yield, 100% purity).1H NMR (400 MHz, DMSO-d6) δ = 9.01 (d, J=13.2 Hz, 2H), 8.60 (d, J=12.4 Hz, 2H), 2.88 (s, 3H), 2.11 (m, 1H), 1.84-1.79 (m, 1H), 1.35-1.30 (m, 2H), 1.13 (s, 9H).

[0166] tert-Butyl (1-(5-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2-yl)cyclobutyl) (methyl)carbamate

[0167] A mixture of [2-[1-[tert-butoxycarbonyl(methyl)amino]cyclobutyl]pyrimidin-5- yl]boronic acid (63 mg, 206 μmol, 1.5 eq), (7R,14R)-11-chloro-1-cyclopropyl-6-methyl-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (50 mg, 137 μmol, 1 eq), K3PO4 (0.5 M, 550 μL, 2 eq), and [2-(2-aminophenyl)phenyl]-chloro- palladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl] phosphane (11 mg, 13 μmol, 0.1 eq) in THF (5 mL) was degassed and purged with N2three times. The reaction mixture was stirred at 100°C for 4 hr under N2. The reaction was quenched with H2O (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with saturated aqueous brine solution (5 mL), filtered, and the filtrate was concentrated in vacuo to give the title compound as a brown solid (50 mg, 41% yield, 67% purity).

[0168] (7R,14R)-1-Cyclopropyl-6-methyl-11-(2-(1-(methylamino)cyclobutyl)pyrimidin-5-yl)- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0169] A mixture of tert-butyl (1-(5-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2- yl)cyclobutyl) (methyl) carbamate (0.05 g, 85 μmol, 1 eq) in HCl / EtOAc (4 M, 2 mL) was stirred at 25°C for 1 hr. The reaction mixture was filtered and concentrated in vacuo to give a residue which was purified by prep-HPLC (column: Phenomenex Luna C18100*40mm*5µm;mobile phase: [H2O(0.2% FA)-ACN];gradient:15%-45% B over 8.0 min) to give the title compound as a white solid (20 mg, 99.8% purity).1H NMR (400 MHz, CDCl3) δ = 8.94 (s, 2H), 8.45 (m, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.53 (s, 1H), 7.53-7.46 (m, 1H), 7.45-7.44 (m, 1H), 7.34-7.32 (m, 2H), 6.66 (d, J = 7.6 Hz, 1H), 4.98 (d, J = 6.8 Hz, 1H), 3.53-3.47 (m, 4H), 2.91-2.88 (m, 1H), 2.66-2.64 (m, 2H), 2.48-2.45 (m, 3H), 2.43 (s, 3H), 2.29-2.16 (m, 1H), 2.16-2.00 (m, 1H), 1.33-1.30 (m, 2H), 1.29-1.14 (m, 1H), 0.74-0.73 (m, 1H). 51 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0170] Example 12: Synthesis of (7R,14R)-1-cyclopropyl-11-(2-(1- (dimethylamino)cyclobutyl)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a] [1,4]diazocin-5(14H)-one (14) NaH(2 eq) Br NBr, N MeI(1.5 eq)(Bpin)2, KOAcNDMF, 25 oPd(,NHC, 2 h dppf)Cl2dioxane 100 oC, 3 hNCl N N O

[0171] 1-(

[0172] To a solution of 1-(5-bromopyrimidin-2-yl)cyclobutanamine (2 g, 8.77 mmol, 1 eq) in DMF (20 mL) was added NaH (1.75 g, 43.84 mmol, 60% purity, 5 eq) portion wise and the reaction mixture was stirred at 25°C for 0.5 hr. MeI (1.87 g, 13.15 mmol, 819 μL, 1.5 eq) was added dropwise at 25°C under N2and the reaction mixture was stirred at 25°C for 1.5 hr under N2. The reaction was quenched with aq. NH4Cl (50 mL) and then extracted with EtOAc (100 mL x 3). The combined organic layers were washed with saturated aqueous brine solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=5 / 1 to 0 / 1) to give the title compound as a white solid (0.5 g, 21% yield, 96% purity).1H NMR (400 MHz, DMSO-d6) δ = 9.01 (s, 2H), 2.55-2.52 (m, 2H), 2.18-2.15 (m, 2H), 1.98 (s, 6H), 1.75-1.47 (m, 1H), 1.44-1.40 (m, 1H).

[0173] (2-(1-(Dimethylamino)cyclobutyl)pyrimidin-5-yl)boronic acid

[0174] A mixture of 1-(5-bromopyrimidin-2-yl)-N,N-dimethyl-cyclobutanamine (0.2 g, 781 μmol, 1 eq), Pd(dppf)Cl2(57 mg, 78 μmol, 0.1 eq), KOAc (230 mg, 2.34 mmol, 3 eq), and 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (218 mg, 859 μmol, 1.1 eq) in dioxane (2 mL) was degassed and purged with N2three times. The reaction mixture was stirred at 100°C for 3 hr under N2. The reaction mixture was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: Waters Xbridge BEH C18 52 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO 100*30mm*10µm;mobile phase:[H2O(10 mM NH4HCO3)-ACN];gradient:1%-10% B over 8.0 min) to give the title compound as a white solid (50 mg, 29% yield, 99% purity). MS: [M+H]+= 222.3.

[0175] (7R,14R)-1-Cyclopropyl-11-(2-(1-(dimethylamino)cyclobutyl)pyrimidin-5-yl)-6- methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0176] A mixture of [2-[1-(dimethylamino)cyclobutyl]pyrimidin-5-yl]boronic acid (46 mg, 206 μmol, 1.5 eq)，(7R,14R)-11-chloro-1-cyclopropyl-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (50 mg, 137 μmol, 1 eq), K3PO4(0.5 M, 549 μL, 2 eq), and [2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3- (2,4,6-triisopropylphenyl) phenyl]phosphane (111 mg, 14 μmol, 0.1 eq) in THF (5 mL) was degassed and purged with N2three times. The reaction mixture was stirred at 100°C for 4 hr under N2. The reaction mixture was filtered and concentrated in vacuo to give a residue which was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10µm; mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:35%-65% B over 8.0 min) to give the title compound as a white solid (15 mg, 99% purity).1H NMR (400 MHz, DMSO-d6) δ = 9.11 (s, 2H), 8.18-8.16 (m, 1H), 7.80-7.77 (m, 2H), 7.63-7.601H), 7.30-7.29 (m, 2H), 6.69 (d, J = 7.6 Hz, 1H), 5.21 d, J = 6.8 Hz, 1H), 3.55 -3.52 (m, 1H), 3.31 (s, 3H), 2.82-2.77 (m, 2H), 2.67-2.62 (m, 2H), 2.22-2.19 (m, 2H), 2.04 (s, 6H), 1.50 (m, 1H), 1.26-1.25 (m, 1H), 1.25-1.24 (m, 2H), 1.01-1.00 (m, 1H), 0.75-0.74 (m, 1H).

[0177] Example 13: Synthesis of (7R,14R)-1-cyclopropyl-11-(4-(2-hydroxypropan-2- yl)phenyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (15) B(OH)2 N N H O [0017, , ydro-7,14- methanobenzo[f]benzo[4,5] imidazo[1,2-a][1,4]diazocin-5(14H)-one (30 mg, 86 μmol, 1 eq) and [4-(1-hydroxy-1-methyl-ethyl)phenyl]boronic acid (23 mg, 128 μmol, 1.5 eq) in THF (3 mL) was 53 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO added K3PO4 (0.5 M, 343 μL, 2 eq) the solution was degassed and purged with N2 three times. Then [2-(2-aminophenyl)phenyl]-chloropalladium; dicyclohexyl-[3-(2,4,6-triisopropylphenyl) phenyl]phosphane (7 mg, 9 μmol, 0.1 eq) was added and the reaction mixture was stirred at 100°C for 2 hr. The reaction mixture was filtered and concentrated in vacuo to give a residue which was purified by prep-HPLC (neutral condition: column: WePure Biotech XPt C18150*40*7µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:25%-65% B over 8.0 min) to give the title compound as a white solid (5 mg, 97% purity).1H NMR (400 MHz, DMSO-d6) δ = 8.98-8.90 (m, 1H), 8.19 (dd, J = 1.9, 7.4 Hz, 1H), 7.69 -7.62 (m, 2H), 7.54 (s, 4H), 7.44 (br d, J = 8.1 Hz, 1H), 7.32-7.24 (m, 2H), 6.74 (d, J = 7.4 Hz, 1H), 5.03 (s, 1H), 4.84 (br s, 1H), 3.46 (td, J = 6.7, 13.2 Hz, 1H), 2.85-2.78 (m, 1H), 2.71 (d, J = 13.2 Hz, 1H), 1.45 (s, 6H), 1.34-1.20 (m, 2H), 1.04-0.96 (m, 1H), 0.82-0.75 (m, 1H).

[0179] Example 14: Synthesis of (7R,14R)-1-cyclopropyl-11-(2-(2-hydroxypropan-2- yl)pyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (16) NB(OH)2N N N H O

[0180] ihydro-7,14- methanobenzo[f]benzo[4,5] imidazo[1,2-a][1,4]diazocin-5(14H)-one (30 mg, 86 μmol, 1 eq) and [2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl] boronic acid (23 mg, 128 μmol, 1.5 eq) in THF (3 mL) was added K3PO4 (0.5 M, 343 μL, 2 eq) and the solution was degassed and purged with N2 three times. Then [2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3-(2,4,6- triisopropylphenyl) phenyl]phosphane (6 mg, 8 μmol, 0.1 eq) was added and the reaction mixture was stirred at 100°C for 2 hr under N2. The reaction mixture was filtered and concentrated in vacuo to get a residue which was purified by prep-HPLC (neutral condition: column: WePure Biotech XP tC18150*40*7µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:15%-45% B over 8.0 min) to give the title compound as a white solid (10 mg, 100% purity).1H NMR (400 MHz, DMSO-d6) δ = 9.06 (s, 2H), 8.95 (d, J = 6.4 Hz, 1H), 8.21-8.17 (m, 1H), 7.78-7.74 (m, 2H), 7.58 54 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO (dd, J = 1.6, 8.5 Hz, 1H), 7.33-7.28 (m, 2H), 6.75 (d, J = 7.4 Hz, 1H), 5.10 (s, 1H), 4.86 (m,1H), 3.53-3.43 (m, 1H), 2.87-2.79 (m, 1H), 2.71 (d, J = 13.2 Hz, 1H), 1.54 (s, 6H), 1.31-1.20 (m, 2H), 1.05-0.97 (m, 1H), 0.79-0.70 (m, 1H).

[0181] Example 15: Synthesis of (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-1- cyclobutyl-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (17)N B(OH)N2Br N (R) l N (R) N N ) [00182methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0183] A mixture of (7R,14R)-11-chloro-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5] imidazo[1,2-a][1,4]diazocin-1-yl trifluoromethanesulfonate (0.2 g, 423 μmol, 1 eq), bromocyclobutane (114 mg, 847 μmol, 80 μL, 2 eq), bis[3,5-difluoro-2-[5- (trifluoromethyl)-2-pyridyl]phenyl]iridium(1+) 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine hexafluorophosphate (5 mg, 4 μmol, 0.01 eq), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine dichloronickel (1 mg, 2 μmol, 0.005 eq), TTMSS (105 mg, 423 μmol, 130 μL, 1 eq), and disodium carbonate (90 mg, 847 μmol, 2 eq) in DME (4 mL) was degassed and purged with N2 three times. The reaction mixture was stirred at 20°C for 12 hr under N2 and under 34 W blue LED. The reaction was quenched with H2O (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (5 mL), dried with anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue which was purified by prep-HPLC(column: Phenomenex Luna C18100*40mm*5 μm;mobile phase: [H2O(0.04% HCl)-ACN];gradient:40%-60% B over 10.0 min) to give the title compound as a white solid (12 mg, 31 μmol, 7% yield, 98% purity).1H NMR (400 MHz, METHANOL-d4) δ = 8.31 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.67 (d, 55 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO J = 8.8 Hz, 1H), 7.49-7.40 (m, 2H), 7.38 (d, J = 8.8 Hz, 1H), 6.34 (d, J = 7.5 Hz, 1H), 5.32 (d, J = 6.6 Hz, 1H), 4.42 (t, J = 8.6 Hz, 1H), 3.56 (td, J = 7.3, 14.0 Hz, 1H), 3.40 (s, 3H), 2.89 (d, J = 13.8 Hz, 1H), 2.74-2.58 (m, 3H), 2.35-2.22 (m, 1H), 2.18-2.07 (m, 1H), 2.03 (dt, J = 2.8, 8.9 Hz, 1H).

[0184] tert-Butyl (1-(5-((7R,14R)-1-cyclobutyl-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2-yl) cyclobutyl)carbamate

[0185] To a solution of (7R,14R)-11-chloro-1-cyclobutyl-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (12 mg, 31 μmol, 1 eq), and [2-[1-(tert-butoxycarbonylamino)cyclobutyl]pyrimidin-5-yl]boronic acid (14 mg, 47 μmol, 1.5 eq) in THF (0.5 mL) was added K3PO4(0.5 M, 127 μL, 2 eq) and [2-(2-aminophenyl)phenyl]- chloro-palladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (2 mg, 3 μmol, 0.1 eq) and the reaction mixture was stirred at 100°C for 4 hr under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a black oil (18 mg, crude).

[0186] (7R,14R)-11-(2-(1-Aminocyclobutyl)pyrimidin-5-yl)-1-cyclobutyl-6-methyl-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0187] A mixture of tert-butyl (1-(5-((7R,14R)-1-cyclobutyl-6-methyl-5-oxo-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2- yl)cyclobutyl)carbamate (18 mg, 30 μmol, 1 eq) in 4M HCl / EtOAc (1 mL) was degassed, stirred at 20°C for 1 hr, and then concentrated in vacuo. The residue was purified by prep-HPLC(column: WePure Biotech XP tC18 150*40*7μm;mobile phase: [H2O(10 mM NH4HCO3)- ACN];gradient:20%-65% B over 8.0 min) to give the title compound as a white solid (6 mg, 95% purity).1H NMR (400 MHz, DMSO-d6) δ = 9.05 (s, 2H), 8.19-8.11 (m, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.65-7.60 (m, 2H), 7.58 (dd, J = 1.6, 8.4 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 6.16 (d, J = 7.5 Hz, 1H), 5.19 (d, J = 6.9 Hz, 1H), 4.52 (quin, J = 8.6 Hz, 1H), 3.48 (td, J = 7.1, 13.9 Hz, 1H), 3.28 (s, 3H), 2.72 (d, J = 13.6 Hz, 1H), 2.65-2.58 (m, 3H), 2.53 (br s, 2H), 2.23-2.15 (m, 1H), 2.14-2.02 (m, 3H), 2.02-1.88 (m, 2H), 1.86-1.75 (m, 1H).

[0188] Example 16: Synthesis of (7R,14R)-1-cyclopropyl-11-(4-(2-hydroxypropan-2- yl)phenyl)-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (18) 56 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO N B(OH)2 N ClN NHON N O [0018 ydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (30 mg, 82 μmol, 1 eq) and [4-(1-hydroxy-1-methyl-ethyl)phenyl]boronic acid (22 mg, 123 μmol, 1.5 eq) in THF (1 mL) was added K3PO4 (0.5 M, 330 μL, 2 eq), then [2-(2-aminophenyl)phenyl]-chloro- palladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (6 mg, 8 μmol, 0.1 eq) was added and the reaction mixture was stirred at 100°C for 4 hr under N2. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: We Pure Biotech XP tC18 150*40*7μm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:40%-70% B over 8.0 min) to give the title compound as a white solid (10 mg, 26% yield, 99% purity).1H NMR (400 MHz, DMSO-d6) δ = 8.18 (d, J = 7.9 Hz, 1H), 7.70-7.65 (m, 2H), 7.54 (s, 4H), 7.46 (d, J = 8.5 Hz, 1H), 7.32-7.27 (m, 1H), 7.26-7.23 (m, 1H), 6.66 (d, J = 7.4 Hz, 1H), 5.18 (d, J = 7.0 Hz, 1H), 5.03 (s, 1H), 3.55-3.46 (m, 1H), 3.30 (s, 3H), 2.83-2.74 (m, 2H), 1.45 (s, 6H), 1.33-1.20 (m, 2H), 1.03-0.96 (m, 1H), 0.84- 0.77 (m, 1H).

[0190] Example 17: Synthesis of (7R,14R)-11-(4-(1-aminocyclobutyl)phenyl)-1-cyclopropyl- 6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (20)Br H2N O

[0191] , , , , amethyl-1,3,2- dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (20 mg, 44 μmol, 1 eq) and 1-(4-bromophenyl)cyclobutanamine (15 mg, 66 mmol, 1.5 eq) in THF (1 mL) was added [2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3- 57 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO (2,4,6-triisopropylphenyl)phenyl]phosphane (4 mg, 4 μmol, 0.1 eq) and aq. K3PO4 (0.5 M, 176 uL, 2 eq) under N2 and the reaction mixture was stirred at 100°C for 2 hr under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: Phenomenex Luna C18100*30mm*5µm;mobile phase: [H2O(0.2% FA)- ACN];gradient:10%-40% B over 8.0 min) to give the title compound as a white solid (2.8 mg, 13% yield, 96% purity, FA salt).1H NMR (400 MHz, DMSO-d6) δ = 8.18 (dd, J = 1.3, 7.9 Hz, 1H), 7.71-7.65 (m, 2H), 7.60-7.50 (m, 4H), 7.47 (dd, J = 1.6, 8.5 Hz, 1H), 7.33-7.27 (m, 1H), 7.26- 7.21 (m, 1H), 6.67 (d, J = 7.4 Hz, 1H), 5.18 (d, J = 6.9 Hz, 1H), 3.50 (m, 1H), 3.30 (s, 3H), 2.84- 2.74 (m, 2H), 2.42 (ddd, J = 5.9, 8.8, 11.6 Hz, 2H), 2.18-2.09 (m, 2H), 2.05-1.93 (m, 1H), 1.73- 1.59 (m, 1H), 1.34-1.19 (m, 2H), 1.04-0.94 (m, 1H), 0.86-0.76 (m, 1H).

[0192] Example 18: Synthesis of (1S,3s)-3-(4-((7R,14R)-1-Cyclopropyl-6-methyl-5-oxo- 5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)-2- fluorophenyl)-3-hydroxy-1-methylcyclobutane-1-carbonitrile (21) Br HO N O

[0193] methyl-1,3,2- dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (20 mg, 44 μmol, 1 eq) and 3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-1-methyl- cyclobutanecarbonitrile (19 mg, 66 μmol, 1.5 eq) in THF (1 mL) was added aq. K3PO4 (0.5 M, 176 μL, 2 eq) and [2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3-(2,4,6- triisopropylphenyl)phenyl]phosphane (4 mg, 4 μmol, 0.1 eq) and the reaction mixture was stirred at 100°C for 4 hr under N2. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuo to get a residue which was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10µm;mobile phase: [H2O(10 mM NH4HCO3)- ACN];gradient:15%-60% B over 18.0 min) to give the title compound as a white solid (11 mg, 46% yield, 98% purity).1H NMR (400 MHz, DMSO-d6) δ = 8.20-8.14 (m, 1H), 7.73-7.66 (m, 2H), 7.53-7.47 (m, 1H), 7.46-7.38 (m, 3H), 7.33-7.26 (m, 1H), 7.25-7.21 (m, 1H), 6.66 (d, J = 7.4 Hz, 1H), 5.99 (s, 1H), 5.19 (d, J = 6.9 Hz, 1H), 3.55-3.50 (m, 1H), 3.30 (s, 3H), 2.83-2.70 (m, 6H), 58 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO 1.43 (s, 3H), 1.32-1.20 (m, 2H), 1.02-0.95 (m, 1H), 0.84-0.77 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ = -114.83 (1F).

[0194] Example 19: Synthesis of (1R,3r)-3-(4-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo- 5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)-2- fluorophenyl)-3-hydroxy-1-methylcyclobutane-1-carbonitrile (22) N BrOBNN O O N Br B N O leand (1s,3s)-3-(4-bromo-2-fluorophenyl)-3-hydroxy-1-methylcyclobutane-1-carbonitrile

[0196] To a solution of 4-bromo-2-fluoro-1-iodo-benzene (500 mg, 1.7 mmol, 1 eq) and 1- methyl-3-oxo-cyclobutanecarbonitrile (163 mg, 1.5 mmol, 0.9 eq) in DCM (10 mL) was added dropwise n-BuLi (2.5 M, 997 μL, 1.5 eq) at -70 °C under N2. The reaction mixture was stirred for 1 hr under N2and then at 25°C for 1 hr. The reaction was quenched with H2O (20 mL), filtered, and the filtrate was extracted with DCM (30 mL x 3). The combine organic layers were washed with sat. brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give a residue. The residue (combined with another batch at 100 mg scale) was purified by prep-HPLC(column: CD24-WePure Biotech XPT C18 150*25*7µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:30%-60% B over 10.0 min) to give (1s,3s)-3-(4- bromo-2-fluorophenyl)-3-hydroxy-1-methylcyclobutane-1-carbonitrile as a colorless oil (65 mg, 100% purity);1H NMR (400 MHz, DMSO-d6) δ = 7.53 (d, J = 10.4 Hz, 1H), 7.44-7.41 (m, 2H), 6.02 (s, 1H), 3.16-3.08 (d, J = 13.2 Hz, 2H), 2.45-2.41 (d, J = 12.8 Hz, 2H), 1.65 (s, 3H); and (1r,3r)-3-(4-bromo-2-fluorophenyl)-3-hydroxy-1-methylcyclobutane-1-carbonitrile as a colorless oil (120 mg, 99% purity);1H NMR (400 MHz, DMSO-d6) δ = 7.50 (dd, J = 1.9, 10.8 Hz, 1H), 7.40 (dd, J = 1.8, 8.3 Hz, 1H), 7.34-7.26 (m, 1H), 6.04 (s, 1H), 2.79-2.62 (m, 4H), 1.41 (s, 3H).

[0197] (1R,3r)-3-(4-((7R,14R)-1-Cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)-2-fluorophenyl)-3-hydroxy-1- methylcyclobutane-1-carbonitrile 59 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0198] To a solution of (7R,14R)-1-cyclopropyl-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (20 mg, 44 μmol, 1 eq) and 3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-1-methyl- cyclobutanecarbonitrile (19 mg, 66 μmol, 1.5 eq) in THF (1 mL) was added aq. K3PO4 (0.5 M, 176 μL, 2 eq) and [2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3-(2,4,6- triisopropylphenyl)phenyl]phosphane (4 mg, 4 μmol, 0.1 eq) and the reaction mixture was stirred at 100°C for 4 hr under N2. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10µm;mobile phase: [H2O(10 mM NH4HCO3)- ACN];gradient:15%-60% B over 18.0 min) to give the title compound as a white solid (8 mg, 34% yield, 99% purity).1H NMR (400 MHz, DMSO-d6) δ = 8.23-8.13 (m, 1H), 7.74-7.68 (m, 2H), 7.55-7.43 (m, 4H), 7.32-7.21 (m, 2H), 6.67 (br d, J = 7.5 Hz, 1H), 5.97 (s, 1H), 5.19 (d, J = 7.0 Hz, 1H), 3.55-3.49 (m, 1H), 3.31 (s, 3H), 3.16 (br d, J = 12.6 Hz, 2H), 2.86-2.75 (m, 2H), 2.45 (br s, 1H), 1.68 (s, 3H), 1.34-1.19 (m, 2H), 1.03-0.95 (m, 1H), 0.85-0.77 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ = -113.70 (1F).

[0199] Example 20: Synthesis of (7R,14R)-1-cyclopropyl-11-(4-(dimethylphosphoryl)-5- fluoro-2-methylphenyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (23) N H O

[0200] To a4-tetramethylborolan-1- yl)phenyl)dimethylphosphine oxide (27 mg, 86 μmol, 1.5 eq) and (7R,14R)-11-chloro-1- cyclopropyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- one (0.02 g, 57 μmol, 1 eq) in THF (0.2 mL) was added K3PO4(0.5 M, 229 μL, 2 eq) and [2-(2- aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3-(2,4,6- triisopropylphenyl)phenyl]phosphane (5 mg, 6 μmol, 0.1 eq) and the reaction mixture was stirred at 100°C for 2 hr under N2. The reaction mixture was concentrated in vacuo to give a reside which was purified by prep-HPLC (column: WePure Biotech XP tC18 150*40*7µm;mobile phase: 60 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO [H2O(10 mM NH4HCO3)-ACN];gradient:15%-50% B over 8.0 min) to give the title compound as a white solid (13 mg, 46% yield, 100% purity).1H NMR: (400 MHz, CDCl3) δ = 8.41 (dd, J = 1.5, 7.8 Hz, 1H), 7.85 (dd, J = 6.7, 12.4 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.41-7.37 (m, 1H), 7.37- 7.32 (m, 1H), 7.24 (s, 1H), 7.19 (dd, J = 1.5, 8.4 Hz, 1H), 7.01-6.96 (m, 1H), 6.95-6.89 (m, 1H), 6.71 (d, J = 7.5 Hz, 1H), 4.97 (t, J = 6.3 Hz, 1H), 3.50 (td, J = 6.5, 13.0 Hz, 1H), 2.88 (d, J = 13.1 Hz, 1H), 2.44-2.34 (m, 1H), 2.22 (s, 3H), 1.85 (s, 3H), 1.82 (d, J = 0.6 Hz, 3H), 1.30-1.18 (m, 2H), 1.13-1.03 (m, 1H), 0.73-0.64 (m, 1H).31P NMR (162 MHz, DMSO-d6) δ 30.39 (1P).19F NMR (376 MHz, DMSO-d6) δ -111.05 (1F).

[0201] Example 21: Synthesis of (7R,14R)-1-cyclopropyl-11-(4-(dimethylphosphoryl)-3- fluorophenyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- one (24) N NNHl H O

[0203] To a solution of 4-bromo-1-dimethylphosphoryl-2-fluoro-benzene (2 g, 5.58 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.98 g, 7.81 mmol, 1.4 eq) in dioxane (20 mL) was added Pd(dppf)Cl2(408 mg, 558 μmol, 0.1 eq) and potassium;acetate (1.37 g, 13.94 mmol, 2.5 eq) and the reaction mixture was stirred at 100°C for 2 hr under N2. The reaction mixture was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: Phenomenex Luna C18 (250*70mm,10µm);mobile phase: [H2O(FA)-ACN];gradient:0%-27% B over 20 min) to give the title compound as a white solid (900 mg, 75% yield, 100% purity).1H NMR (400 MHz, DMSO-d6) δ = 8.41 (s, 2H), 7.74 (d, J = 3.6 Hz, 1H), 7.59 (dd, J = 4.8, 10.8 Hz, 1H), 1.72 (s, 3H), 1.69 (s, 3H).

[0204] (7R,14R)-1-Cyclopropyl-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0205] A solution of (7R,14R)-11-chloro-1-cyclopropyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo [1,2-a][1,4]diazocin-5(14H)-one (20 mg, 57 μmol, 1 eq), (4- 61 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO dimethylphosphoryl-3-fluoro-phenyl) boronic acid (19 mg, 86 μmol, 1.5 eq), tripotassium;phosphate (0.5 M, 229 μL, 2 eq), and [2-(2-aminophenyl)phenyl]-chloro- palladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (5 mg, 6 μmol, 0.1 eq) in THF (0.8 mL) was degassed and purged with N2 three times. The reaction mixture was stirred at 100°C for 1 hr under N2. The reaction mixture was filtered and concentrated in vacuo to give a residue which was purified by prep-HPLC (column: XPT C18150*30 mm*7µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:20%-50% B over 8.0 min) to give the title compound as a white solid (16 mg, 59% yield, 100% purity).1H NMR (400 MHz, DMSO-d6) δ = 8.96 (d, J = 6.4 Hz, 1H), 8.19 (dd, J = 1.8, 7.6 Hz, 1H), 7.83 (td, J = 7.6, 11.8 Hz, 1H), 7.76-7.69 (m, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.62-7.52 (m, 2H), 7.35-7.23 (m, 2H), 6.74 (d, J = 7.5 Hz, 1H), 4.86 (t, J = 6.5 Hz, 1H), 3.48 (td, J = 6.8, 13.5 Hz, 1H), 2.91-2.80 (m, 1H), 2.72 (d, J = 13.3 Hz, 1H), 1.75 (s, 3H), 1.72 (s, 3H), 1.35-1.20 (m, 2H), 1.04-0.97 (m, 1H), 0.83-0.75 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ = -105.64 (1F).31P NMR (162 MHz, DMSO-d6) δ = 28.43 (1P).

[0206] Example 22: Synthesis of (7R,14R)-1-cyclopropyl-11-(4- ((dimethylphosphoryl)methyl)phenyl)-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (25) Br N O N (R)PinB (R)NN P N N O

[0207] To a solution of (7R,14R)-1-cyclopropyl-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (30 mg, 66 μmol, 1 eq) and 1-bromo-4-(dimethylphosphorylmethyl)benzene (24 mg, 98 μmol, 1.5 eq) in dioxane (1.2 mL) was added (1E,4E)-1,5-diphenylpenta-1,4-dien-3- one;palladium (6 mg, 7 μmol, 0.1 eq), tricyclohexyl phosphonium;tetrafluoroborate (5 mg, 13 μmol, 0.2 eq), and tripotassium;phosphate (0.5 M, 264 μL, 2 eq) and the reaction mixture was stirred at 100°C for 2 hr under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: XPT C18 150*30 mm*7µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:15%-45% B over 8.0 62 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO min) to give the title compound as a white solid (18 mg, 54% yield, 96% purity).1H NMR (400 MHz, DMSO-d6) δ = 8.18 (dd, J = 1.3, 7.8 Hz, 1H), 7.71-7.65 (m, 2H), 7.57 (d, J = 8.1 Hz, 2H), 7.48 (dd, J = 1.6, 8.4 Hz, 1H), 7.33 (dd, J = 1.9, 8.3 Hz, 2H), 7.28 (d, J = 7.8 Hz, 1H), 7.26-7.21 (m, 1H), 6.66 (d, J = 7.5 Hz, 1H), 5.18 (d, J = 7.0 Hz, 1H), 3.51 (td, J = 7.2, 13.9 Hz, 1H), 3.30 (s, 3H), 3.17 (d, J = 15.0 Hz, 2H), 2.85-2.73 (m, 2H), 1.38 (s, 3H), 1.34 (s, 3H), 1.32-1.21 (m, 2H), 1.04-0.95 (m, 1H), 0.86-0.75 (m, 1H).31P NMR (162 MHz, DMSO-d6) δ 38.42 (1P).

[0208] Example 23: Synthesis of (7R,14R)-1-cyclopropyl-11-(4-(dimethylphosphoryl)-3- fluorophenyl)-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (26)O

[0209] To a,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (30 mg, 66 μmol, 1 eq) and 4-bromo-1-dimethylphosphoryl-2-fluoro-benzene (25 mg, 99 μmol, 1.5 eq) in dioxane (1.2 mL) was added (1E,4E)-1,5-diphenylpenta-1,4-dien-3- one;palladium (6 mg, 7 μmol, 0.1 eq), tricyclohexylphosphonium;tetrafluoroborate (5 mg, 13 μmol, 0.2 eq), and tripotassium;phosphate (0.5 M, 264 μL, 2 eq) and the reaction mixture was stirred at 100°C for 2 hr under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: XPT C18 150*30mm*7µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:15%-45% B over 8.0 min) to give the title compound as a white solid (14 mg, 44% yield, 99% purity).1H NMR (400 MHz, DMSO-d6) δ = 8.17 (dd, J = 1.2, 7.8 Hz, 1H), 7.83 (td, J = 7.6, 11.8 Hz, 1H), 7.77-7.71 (m, 2H), 7.65 (d, J = 7.9 Hz, 1H), 7.62-7.54 (m, 2H), 7.34-7.21 (m, 2H), 6.67 (d, J = 7.4 Hz, 1H), 5.20 (d, J = 7.0 Hz, 1H), 3.58-3.47 (m, 1H), 3.31 (s, 3H), 2.87-2.76 (m, 2H), 1.75 (s, 3H), 1.72 (s, 3H), 1.32-1.21 (m, 2H), 1.04-0.96 (m, 1H), 0.85-0.76 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ = - 105.66 (1F).31P NMR (162 MHz, DMSO-d6) δ = 28.31 (1P). 63 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0210] Example 24: Synthesis of (7R,14R)-1-cyclopropyl-11-(4- (dimethylphosphoryl)phenyl)-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (27) BPin O

[0211] To ,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (20 mg, 57 μmol, 1 eq) and1- dimethylphosphoryl-4-methyl-benzene (14 mg, 86 μmol, 1.5 eq) in THF (2 mL) was added K3PO4 (0.5 M, 229 μL, 2 eq) and XPHOS-PD-G2 (5 mg, 6 μmol, 0.1 eq) under N2. The reaction mixture was stirred at 100°C for 4 hr under N2. The reaction was quenched with H2O (5 mL) and extracted with EtOAc (5 mL x 2). The combined organic layers were washed with sat. NaHCO3(5 mL), brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give the residue which was purified by prep-HPLC (neutral condition; column: WePure Biotech XP tC18 150*40*7µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:20%-50% B over 8.0 min) to give the title compound as a white solid (11 mg, 40% yield, 96% purity).1H NMR (400 MHz, DMSO-d6) δ = 8.97 (d, J = 6.4 Hz, 1H), 8.19 (dd, J = 1.7, 7.6 Hz, 1H), 7.8dd, J = 8.3, 11.0 Hz, 2H), 7.79-7.66 (m, 4H), 7.52 (dd, J = 1.5, 8.5 Hz, 1H), 7.35-7.21 (m, 2H), 6.75 (d, J = 7.5 Hz, 1H), 4.85 (t, J = 6.5 Hz, 1H), 3.47 (td, J = 6.8, 13.5 Hz, 1H), 2.88-2.79 (m, 1H), 2.72 (d, J = 13.3 Hz, 1H), 1.69 (s, 3H), 1.66 (s, 3H), 1.35-1.20 (m, 2H), 1.06-0.94 (m, 1H), 0.85-0.72 (m, 1H).31P NMR (162 MHz, DMSO-d6) δ = 32.23 (1P).

[0212] Example 25: Synthesis of (7R,14R)-1-cyclopropyl-11-(4- (dimethylphosphoryl)phenyl)-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (28) 64 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO BPin N N PN NO

[0213] To -6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (20 mg, 55 μmol, 1 eq) and 1-dimethylphosphoryl-4-methyl-benzene (14 mg, 82 μmol, 1.5 eq) in THF (2 mL) was added K3PO4 (0.5 M, 220 μL, 2 eq) and XPHOS-PD-G2 (4 mg, 6 μmol, 0.1 eq) under N2. The reaction mixture was stirred at 100°C for 4 hr under N2. The reaction was quenched with H2O (5 mL) and extracted with EtOAc (5 mL x 2). The combined organic layers were washed with sat. NaHCO3 (5 mL), brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue which was purified by prep-HPLC (neutral condition; column: WePure Biotech XP tC18 150*40*7µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:20%-50% B over 8.0 min ) to give the title compound as a white solid (12 mg, 46% yield, 98% purity).1H NMR (400 MHz, DMSO-d6) δ = 8.18 (d, J = 6.8 Hz, 1H), 7.89-7.81 (m, 2H), 7.79-7.70 (m, 4H), 7.53 (dd, J = 1.2, 8.6 Hz, 1H), 7.35-7.20 (m, 2H), 6.68 (d, J = 7.5 Hz, 1H), 5.20 (d, J = 7.0 Hz, 1H), 3.56-3.46 (m, 1H), 3.31 (s, 3H), 2.86-2.75 (m, 2H), 1.69 (s, 3H), 1.65 (s, 3H), 1.35-1.18 (m, 2H), 1.06-0.94 (m, 1H), 0.86-0.74 (m, 1H).31P NMR (162 MHz, DMSO-d6) δ = 32.23 (1P).

[0214] Example 26: Synthesis of (7R,14R)-1-cyclopropyl-11-(4-(dimethylphosphoryl)-5- fluoro-2-methylphenyl)-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (29)O

[0215] To a, y y y , , ,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (20 mg, 44 μmol, 1 eq) and 1-bromo-4-dimethylphosphoryl-5-fluoro-2-methyl- 65 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO benzene (17 mg, 66 μmol, 1.5 eq) in THF (0.5 mL) was added K3PO4 (0.5 M, 176 μL, 2 eq) and [2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3-(2,4,6- triisopropylphenyl)phenyl]phosphane (3 mg, 4 μmol, 0.1 eq) and the reaction mixture was stirred at 100°C for 2 hr under N2. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: WePure Biotech XP tC18150*40*7µm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 20%-50% B over 8.0 min) to give the title compound as a white solid (10 mg, 44% yield, 99% purity).1H NMR (400 MHz, DMSO-d6) δ = 8.22-8.15 (m, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.68-7.62 (m, 1H), 7.43 (s, 1H), 7.33-7.25 (m, 2H), 7.22-7.13 (m, 2H), 6.65 (d, J = 7.4 Hz, 1H), 5.20 (d, J = 7.0 Hz, 1H), 3.55-3.47 (m, 1H), 3.31 (s, 3H), 2.77 (d, J = 13.6 Hz, 1H), 2.70-2.63 (m, 1H), 2.20 (s, 3H), 1.74 (s, 3H), 1.71 (s, 3H), 1.25-1.07 (m, 2H), 1.01-0.91 (m, 1H), 0.73-0.63 (m, 1H).31P NMR (162 MHz, DMSO-d6) δ 28.19 (1P).19F NMR (376 MHz, DMSO-d6) δ -110.81 (1F).

[0216] Example 27: Synthesis of (7R,14R)-11-(2-(5-aminospiro[2.3]hexan-5-yl)pyrimidin-5- yl)-1-cyclopropyl-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (30) N Br Br O

[0218] To a solution of 5-bromo-2-iodo-pyrimidine (3 g, 10 mmol, 1 eq) in DCM (20 mL) was added n-BuLi (2.5 M, 5 mL, 1 eq) under N2at -78°C and after for 5 min a solution of spiro[2.3]hexan-5-one (1 g, 10 mmol, 1 eq) in DCM (5 mL ) was added dropwise at -78°C and was stirred at -78°C for 1 hr. The reaction was quenched with sat. NH4Cl (30 mL), diluted with H2O (30 mL), and extracted with DCM (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was 66 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=5 / 1 to 0 / 1) to give the title compound as a yellow solid (0.8 g, 90% purity, 30% yield).1H NMR (400 MHz, CDCl3) δ = 8.82 (s, 2H), 2.79 (d, J = 10.4 Hz, 2H), 2.58 (d, J = 10.4 Hz, 2H), 0.68-0.52 (m, 4H).

[0219] [5-(5-Bromopyrimidin-2-yl)spiro[2.3]hexan-5-yl] methanesulfonate

[0220] To a solution of 5-(5-bromopyrimidin-2-yl)spiro[2.3]hexan-5-ol (250 mg, 900 μmol, 1 eq) in DCM (2 mL) was added TEA (500 mg, 4 mmol, 600 μL, 4 eq) and MsCl (0.5 g, 5 mmol, 345 μL, 5 eq) at 0°C under N2. The reaction mixture was stirred at 25°C for 1 hr under N2. The reaction was quenched with NaHCO3 (10 mL), diluted with H2O (10 mL), and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow oil (261 mg, crude).

[0221] 2-(5-Azidospiro[2.3]hexan-5-yl)-5-bromopyrimidine

[0222] To a solution of [5-(5-bromopyrimidin-2-yl)spiro[2.3]hexan-5-yl] methanesulfonate (260 mg, 780 μmol, 1 eq) in DMSO (1 mL) was added NaN3(0.27 g, 4.15 mmol, 5.30 eq) in H2O (0.3 mL) and reaction the mixture was stirred at 80°C for 8 hr under N2. The reaction mixture was diluted with sat. Na2CO3 (20 mL) and extracted with EtOAc (15 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 0 / 1) to give the title compound as a yellow oil (0.28 g, crude).

[0223] (7R,14R)-11-(2-(5-Azidospiro[2.3]hexan-5-yl)pyrimidin-5-yl)-1-cyclopropyl-6-methyl- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0224] To a solution of (7R,14R)-1-cyclopropyl-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one and 2-(5-azidospiro[2.3]hexan-5-yl)-5-bromo-pyrimidine (25 mg, 90 μmol, 1 eq) in THF (0.5 mL) was added K3PO4 (0.5 M, 350 μL, 2 eq) and [2-(2-aminophenyl)phenyl]- chloro-palladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (7 mg, 10 μmol, 0.1 eq) and the reaction mixture was stirred at 100°C for 4 hr under N2. The reaction mixture was diluted with sat. Na2CO3 (10 mL) and extracted with EtOAc (5 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow oil (0.05 g, crude). 67 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0225] (7R,14R)-11-(2-(5-Aminospiro[2.3]hexan-5-yl)pyrimidin-5-yl)-1-cyclopropyl-6- methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0226] A solution of (7R,14R)-11-(2-(5-azidospiro[2.3]hexan-5-yl)pyrimidin-5-yl)-1- cyclopropyl-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (0.05 g, 75 μmol, 1 eq) and Me3P (1 M, 110 μL, 1 eq) in THF (0.5 mL) and H2O (0.05 mL) was degassed and purged with N2for 3 times, and reaction mixture was stirred at 25°C for 2 hr . The reaction mixture was diluted with sat. Na2CO3(10 mL) and extracted with EtOAc (5 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which (combined with another batch at 10 mg scale) was purified by prep-HPLC (H2O(0.2% FA)-ACN]; gradient:3%-35% B over 9.0 min ) to give the title compound as a white solid (10 mg, 99% purity, 30% yield).1H NMR (400 MHz, CDCl3) δ = 8.92 (s, 2H), 8.50-8.37 (m, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 1.3 Hz, 1H), 7.44 (dd, J = 1.7, 8.4 Hz, 1H), 7.36-7.31 (m, 2H), 6.64 (d, J = 7.5 Hz, 1H), 4.97 (d, J = 6.9 Hz, 1H), 3.55-3.42 (m, 4H), 3.04 (d, J = 12.9 Hz, 2H), 2.46 (ddd, J = 2.8, 5.5, 8.2 Hz, 1H), 2.31 (d, J = 12.9 Hz, 2H), 1.35-1.25 (m, 3H), 1.13 (br dd, J = 4.2, 9.3 Hz, 1H), 0.73 (br dd, J = 4.1, 5.3 Hz, 1H), 0.70-0.62 (m, 2H), 0.55-0.48 (m, 2H).

[0227] Example 28: Synthesis of N-(5-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2-yl)- N-methylglycine (31) N N N O [00228py g, , q , ethyl 2- (methylamino) acetate;hydrochloride (8 g, 52 mmol, 2 eq), and TEA (8 g, 78 mmol, 11 mL, 68 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO 3 eq) in DMF (50 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 100°C for 3 hr under N2. The reaction was quenched with H2O (150 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layers were dried with anhydrous Na2SO4, filtered and the filtrated was concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=0 / 1 to 10 / 1) to give the title compound as a yellow solid (4.8 g, 67% yield, 99% purity).1H NMR (400 MHz, CDCl3) δ = 8.31 (br s, 2H), 4.31 (s, 2H), 4.19 (q, J = 7.2 Hz, J=14.4 Hz, 2H), 3.22 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H).

[0229] Ethyl N-(5-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methano benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-11-yl)pyrimidin-2-yl)-N-methylglycinate

[0230] A solution of (7R,14R)-1-cyclopropyl-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]69iazocine- 5(14H)-one (50 mg, 110 μmol, 1 eq), ethyl 2-[(5-bromopyrimidin-2-yl)-methyl-amino]acetate (30 mg, 110 μmol, 1 eq), K3PO4(0.5 M, 439 μL, 2 eq), and XPHOS-PD-G2 (9 mg, 11 μmol, 0.1 eq) in THF (2.5 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 100°C for 4 hr under N2. The reaction was quenched with H2O (40 mL) and extracted with ethyl acetate (35 mL x 3). The combined organic layers were dried with anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow solid (100 mg, crude).

[0231] N-(5-((7R,14R)-1-Cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-11-yl)pyrimidin-2-yl)-N-methylglycine

[0232] A solution of ethyl N-(5-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-11-yl)pyrimidin-2-yl)-N- methylglycinate (80 mg, 153 μmol, 1 eq) and LiOH.H2O (13 mg, 306 μmol, 2 eq) in EtOH (2 mL) and H2O (0.5 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 20°C for 2 hr under N2. The reaction mixture (combined with another batch at 20 mg scale) and HCl (1 M), was added to pH=5 and then concentrated in vacuo to give a residue which was purified by prep-HPLC (column: WePure Biotech XP tC18 150*40*7µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:10%-40% B over 8.0 min) to give the title compound as a white solid (9 mg, 97% purity).1H NMR (400 MHz, DMSO-d6) δ = 8.65 (br s, 2H), 8.17 (dd, J = 2.3, 7.2 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 1.0 Hz, 1H), 7.44 (dd, J = 1.6, 8.4 Hz, 1H), 7.33-7.24 (m, 2H), 6.64 (d, J = 7.4 Hz, 1H), 5.17 (d, J = 6.9 Hz, 1H), 4.32 (s, 69 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO 2H), 3.50 (td, J = 7.1, 13.9 Hz, 1H), 3.30 (s, 3H), 3.19 (s, 3H), 2.83-2.73 (m, 2H), 1.31-1.19 (m, 2H), 1.04-0.95 (m, 1H), 0.83-0.67 (m, 1H).

[0233] Example 29: Synthesis of N-(5-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyridin-2-yl)-N- methylglycine (32) N BPinNN O O

[0235] To a solution of 5-bromo-N-methylpyridin-2-amine (5 g, 26 mmol, 1 eq) in DMF (100 mL) was added NaH (1.6 g, 40 mmol, 60% purity, 1.5 eq) at 0°C under N2 and the reaction mixture was stirred at 0°C for 0.5 hr. Ethyl 2-bromoacetate (9 g, 53 mmol, 6 mL, 2 eq) was added at 0°C and the reaction mixture was stirred under N2 at 20°C for 1 hr and then at 70°C for 10.5 hr. The reaction was quenched with H2O (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100:1-1:1) to give the title compound as a white oil (2 g, 24% yield, 89% purity).

[0236] Ethyl N-(5-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methano benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyridin-2-yl)-N-methylglycinate

[0237] To a solution of ethyl N-(5-bromopyridin-2-yl)-N-methylglycinate (20 mg, 73 μmol, 1 eq) and (7R,14R)-1-cyclopropyl-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (33 mg, 73 μmol, 1 eq) in THF (2 mL) was added K3PO4 (0.5 M, 293 μL, 2 eq) and XPHOS-PD-G2 (5 mg, 7 μmol, 0.1 eq) under N2and the reaction mixture was stirred at 100°C for 4 hr. The reaction was 70 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO quenched with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow oil (40 mg, crude).

[0238] N-(5-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyridin-2-yl)-N-methylglycine

[0239] To a solution of ethyl N-(5-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyridin-2-yl)-N- methylglycinate (40 mg, 77 μmol, 1 eq) in EtOH (2 mL) and H2O (1 mL) was added LiOH.H2O (6 mg, 153 μmol, 2 eq) and the reaction mixture was stirred at 20°C for 1 hr. The reaction mixture was adjusted with HCl (1 M) to a pH of 5. The reaction mixture was concentrated in vacuo to give a residue which was purified by prep-HPLC (neutral condition; column: Waters Xbridge BEH C18 100*30mm*10µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:5%-50% B over 8.0 min) to give the title compound as a white solid (3 mg, 7% yield, 98% purity).1H NMR (400 MHz, DMSO-d6) δ = 8.34 (d, J = 2.4 Hz, 1H), 8.17 (dd, J = 1.2, 7.6 Hz, 1H), 7.79 (dd, J = 2.0, 8.8 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.58 (s, 1H), 7.41 (dd, J = 1.6, 8.4 Hz, 1H), 7.34-7.22 (m, 2H), 6.74 (d, J = 9.2 Hz, 1H), 6.64 (d, J = 7.6 Hz, 1H), 5.17 (d, J = 6.8 Hz, 1H), 4.28 (s, 2H), 3.54-3.45 (m, 1H), 3.30 (s, 3H), 3.08 (s, 3H), 2.83-2.74 (m, 2H), 1.33-1.19 (m, 2H), 1.03-0.95 (m, 1H), 0.83- 0.74 (m, 1H).

[0240] Example 30: Synthesis of ((7R,14R)-11-((S)-4-amino-4-methylchroman-7-yl)-1- cyclopropyl-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one and (7R,14R)-11-((R)-4-amino-4-methylchroman-7-yl)-1-cyclopropyl-6-methyl-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (33 and 34) 71 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO Br Br Br Br CHO3MgBr (3 eq)NaN3, TFA PMe3, THF, H2O o HODCM, 0~20 oN3oH2N O-60~20C, 3 hOC, 3 hO70C, 3 hO [

[0242] To a solution of 7-bromochroman-4-one (4 g, 18 mmol, 1 eq) in DCM (80 mL) was added MeMgBr (3 M, 18 mL, 3 eq) dropwise at -60°C under N2, and the reaction mixture was stirred at 20°C for 3 hr under N2. The reaction was quenched with saturated NH4Cl (100 mL) slowly and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (80 mL), dried with anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: Welch Xtimate C18 250*70mm*10µm;mobile phase:[H2O(10 mM NH4HCO3)-ACN];gradient:25%-60% B over 20.0 min) to give the title compound as a white solid (2 g, 46% yield, 99% purity).1H NMR (400 MHz, CDCl3) δ = 7.34 (d, J = 8.3 Hz, 1H), 7.05 (dd, J = 1.9, 8.3 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H), 4.35- 4.18 (m, 2H), 2.09-2.03 (m, 2H), 1.61 (s, 3H).

[0243] 4-Azido-7-bromo-4-methyl-chromane

[0244] To a solution of 7-bromo-4-methyl-chroman-4-ol (1 g, 4 mmol, 1 eq) in DCM (15 mL) was added NaN3(0.6 g, 9 mmol, 2.2 eq) at 20°C and then TFA (1.4 g, 12 mmol, 920 μL, 3 eq) in DCM (5 mL) was added dropwise at 0°C and the reaction mixture was stirred at 0°C for 3 hr under N2. The reaction mixture was basified to pH=8 with saturated NaHCO3. The aqueous layer was extracted with EtOAc (40 mL x 3). The combined organic layers were concentrated in vacuo to give the title compound as a yellow oil (1 g, crude).1H NMR (400 MHz, CDCl3) δ = 7.23 (d, J = 8.3 Hz, 1H), 7.12-7.07 (m, 1H), 7.06 (d, J = 2.0 Hz, 1H), 4.32-4.21 (m, 2H), 2.08-2.02 (m, 2H), 1.67 (s, 3H).

[0245] 7-Bromo-4-methyl-chroman-4-amine 72 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0246] To a solution of 4-azido-7-bromo-4-methyl-chromane (1 g, 4 mmol, 1 eq) in H2O (2 mL) and THF (15 mL) was added Me3P (1 M, 4 mL, 1 eq) in THF (5 mL), and the reaction mixture was stirred at 70°C for 3 hr under N2. The reaction was quenched with H2O (80 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=3 / 1 to 0 / 1) to give the title compound as a yellow oil (700 mg, 70% yield, 90% purity).1H NMR (400 MHz, CDCl3) δ = 7.30 (d, J = 8.4 Hz, 1H), 7.03 (dd, J = 2.0, 8.4 Hz, 1H), 6.97 (d J = 2.0 Hz, 1H), 4.30-4.19 (m, 2H), 2.06-1.90 (m, 2H), 1.64 (b, 2H), 1.48 (s, 3H).

[0247] (7R,14R)-11-(4-Amino-4-methylchroman-7-yl)-1-cyclopropyl-6-methyl-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-5(14H)-one

[0248] A solution of 7-bromo-4-methyl-chroman-4-amine (50 mg, 207 μmol, 1 eq), (7R,14R)- 1-cyclopropyl-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5] midazo[1,2-a][1,4]diazocine-5(14H)-one (94 mg, 207 μmol, 1 eq), K3PO4 (0.5 M, 826 μL, 2 eq), and XPHOS-PD-G2 (16 mg, 21 μmol, 0.1 eq) in THF (2.5 mL) was degassed and purged with N2for 3 times, and the reaction mixture was stirred at 100°C for 4 hr under N2. The reaction was quenched with H2O (15 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layers were dried with anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10µm;mobile phase: [H2O(10 mM NH4HCO3)- ACN];gradient:25%-65% B over 8.0 min) to give the title compound as a white solid (40 mg, 39% yield, 100% purity) which was separated by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10µm);mobile phase: [CO2-EtOH(0.1%NH3H2O)];B%:45%, isocratic elution mode) to give (7R,14R)-11-((S)-4-amino-4-methylchroman-7-yl)-1-cyclopropyl-6-methyl-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (6 mg, 30% yield, 100% purity);1H NMR (400 MHz, DMSO-d6) δ = 8.17 (d, J = 7.9 Hz, 1H), 7.67-7.57 (m, 3H), 7.42 (br d, J = 8.5 Hz, 1H), 7.33-7.21 (m, 2H), 7.10 (br d, J = 8.1 Hz, 1H), 6.91 (s, 1H), 6.65 (br d, J = 7.3 Hz, 1H), 5.18 (d, J = 6.9 Hz, 1H), 4.32-4.12 (m, 2H), 3.49 (td, J = 7.0, 13.8 Hz, 1H), 3.30 (s, 3H), 2.83-2.74 (m, 2H), 2.07 (br s, 2H), 1.88 (br t, J = 5.3 Hz, 2H), 1.39 (s, 3H), 1.32-1.22 (m, 2H), 1.02-0.93 (m, 1H), 0.85-0.78 (m, 1H); and (7R,14R)-11-((R)-4-amino-4-methylchroman- 7-yl)-1-cyclopropyl-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- 73 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO a][1,4]diazocin-5(14H)-one (6 mg, 30% yield, 100% purity);1H NMR (400 MHz, DMSO-d6) δ = 8.17 (d, J = 7.8 Hz, 1H), 7.67-7.57 (m, 3H), 7.42 (d, J = 8.5 Hz, 1H), 7.32-7.22 (m, 2H), 7.10 (dd, J = 1.1, 8.0 Hz, 1H), 6.91 (s, 1H), 6.65 (d, J = 7.4 Hz, 1H), 5.18 (d, J = 6.9 Hz, 1H), 4.30-4.13 (m, 2H), 3.49 (m, 1H), 3.30 (s, 3H), 2.82-2.74 (m, 2H), 2.07 (br s, 2H), 1.88 (br t, J = 5.3 Hz, 2H), 1.39 (s, 3H), 1.31-1.22 (m, 2H), 1.02-0.94 (m, 1H), 0.86-0.78 (m, 1H).

[0249] Example 31: Synthesis of (1S,3s)-3-amino-3-(5-((7R,14R)-1-cyclopropyl-6-methyl-5- oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)-3- fluoropyridin-2-yl)-1-methylcyclobutane-1-carbonitrile and (1R,3r)-3-amino-3-(5-((7R,14R)-1- cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)-3-fluoropyridin-2-yl)-1-methylcyclobutane-1-carbonitrile (35 and 36) N BrNN NPinBO O N O O

[0251] To a solution of 1-methyl-3-oxo-cyclobutanecarbonitrile (1 g, 9 mmol, 1 eq) and 2- methylpropane-2-sulfinamide (1.2 g, 10 mmol, 1.1 eq) in THF (20 mL) was added Ti(i-PrO)4(4 g, 14 mmol, 4 mL, 1.5 eq) and the reaction mixture was stirred at 75°C for 12 hr. The reaction was quenched with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 3 / 1) to give the title compound as a yellow oil (0.8 g, 41% yield).1H NMR (400 MHz, DMSO-d6) δ = 3.92-3.77 (m, 1H), 3.77-3.64 (m, 1H), 3.57-3.39 (m, 1H), 3.30-3.19 (m, 1H), 1.58 (s, 3H), 1.16 (s, 9H). 74 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0252] N-(1-(5-bromo-3-fluoropyridin-2-yl)-3-cyano-3-methylcyclobutyl)-2-methylpropane-2- sulfinamide

[0253] A solution of 2,5-dibromo-3-fluoro-pyridine (800 mg, 3 mmol, 1 eq) and 4A MS (80 mg) in DCM (16 mL) was cooled to -78°C under N2 and n-BuLi (2.5 M, 1.2 mL, 0.95 eq) was added dropwise over 10 min and then a solution of N-(3-cyano-3-methyl-cyclobutylidene)-2- methyl-propane-2-sulfinamide (606 mg, 2.9 mmol) in DCM (4 mL) was added dropwise and the reaction mixture was stirred at -78°C for 50 min and then at 25°C for 11 hr. The reaction mixture was quenched with sat. NH4Cl (30 mL), diluted with H2O (30 mL), and extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo to give residue which was purified by prep-HPLC (column: Phenomenex Luna C18 100*40mm*5µm;mobile phase: [H2O(0.2% FA)-ACN];gradient:25%- 55% B over 8.0 min) to give the title compound as a yellow solid (90 mg, 7% yield).

[0254] N-(3-cyano-1-(5-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)-3-fluoropyridin-2-yl)-3- methylcyclobutyl)-2-methylpropane-2-sulfinamide

[0255] To a solution of (7R,14R)-1-cyclopropyl-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (47 mg, 103 μmol, 1 eq) and N-[1-(5-bromo-3-fluoro-2-pyridyl)-3-cyano-3-methyl- cyclobutyl]-2-methyl-propane-2-sulfinamide (40 mg, 103 μmol, 1 eq) in THF (2 mL) was added K3PO4(0.5 M, 412 μL, 2 eq) and XPHOS-PD-G2(8 mg, 10 μmol, 0.1 eq) under N2and the reaction mixture was stirred at 100°C for 2 hr. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow solid (60 mg, crude).

[0256] 3-Amino-3-(5-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)-3-fluoropyridin-2-yl)-1- methylcyclobutane-1-carbonitrile A solution of N-(3-cyano-1-(5-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)-3-fluoropyridin-2-yl)-3- methylcyclobutyl)-2-methylpropane-2-sulfinamide (55 mg, 86 μmol, 1 eq) in HCl / EtOAc (2 mL) was degassed and purged with N2for 3 times, and the reaction mixture was stirred at 20°C for 0.5 hr. The reaction mixture was concentrated in vacuo to give a residue which was purified by prep- HPLC (FA condition; column: Phenomenex Luna C18 100*40mm*5µm;mobile phase: 75 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO [H2O(0.2% FA)-ACN];gradient:10%-50% B over 8.0 min) to give the title compound as a white solid (12 mg, 26% yield) which was separated by SFC (column: ChiralPak IH, 250*30mm, 10µm;mobile phase: [CO2-IPA(0.1%NH3H2O)];B%:40%, isocratic elution mode) to give (1S,3s)- 3-amino-3-(5-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4] diazocin-11-yl)-3-fluoropyridin-2-yl)-1- methylcyclobutane-1-carbonitrile (2 mg, 23% yield, 97% purity);1H NMR (400 MHz, DMSO-d6) δ = 8.67 (s, 1H), 8.17 (m, 1H), 7.99 (m, 1H), 7.78-7.72 (m, 2H), 7.62-7.54 (m, 1H), 7.33-7.23 (m, 2H), 6.67 (d, J = 7.6 Hz, 1H), 5.20 (d, J = 7.2 Hz, 1H), 3.58-3.46 (m, 1H), 3.31 (s, 3H), 3.29 (m, 2H), 3.26 (m, 1H), 2.85-2.76 (m, 2H), 2.34-2.31 (m, 2H), 1.68 (s, 3H), 1.34-1.19 (m, 3H), 1.05- 0.95 (m, 1H), 0.81-0.72 (m, 1H); and (1R,3r)-3-amino-3-(5-((7R,14R)-1-cyclopropyl-6-methyl-5- oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)-3- fluoropyridin-2-yl)-1-methylcyclobutane-1-carbonitrile (2 mg, 22% yield, 95% purity)1H NMR (400 MHz, DMSO-d6) δ = 8.63 (s, 1H), 8.17 (m, 1H), 7.97 (m, 1H), 7.78-7.71 (m, 2H), 7.59-7.53 (m, 1H), 7.33-7.24 (m, 2H), 6.66 (d, J = 7.2 Hz, 1H), 5.20 (d, J = 6.8 Hz, 1H), 3.52 (m, 1H), 3.30 (s, 3H), 2.82 (m, 1H), 2.81-2.76 (m, 2H), 2.65~2.65 (m, 2H), 1.34 (s, 3H), 1.31-1.17 (m, 4H), 1.03- 0.97 (m, 1H), 0.80-0.73 (m, 1H) (absolute chirality not defined).

[0257] Example 32: Synthesis of 6-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)-3-methyl-2,3- dihydrobenzofuran-3-carboxylic acid (37) Br BrBu3N(2.2 eq),Br AcOH(1.1 eq) Br q) [002y - - - - p y y y 76 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0259] To a solution of methyl 2-(bromomethyl)prop-2-enoate (2 g, 12 mmol, 1.8 eq) in ACN (160 mL) was added Cs2CO3 (3 g, 9 mmol, 1.4 eq) and 5-bromo-2-iodophenol (2 g, 7 mmol, 1 eq) and the reaction mixture was stirred at 80°C for 5 hr under N2. EtOAc (10 mL) was added to the reaction mixture which was filtered and the filtrate was concentrated in vacuo to give a residue which was triturated with PE (10 mL) at 15°C for 30 min. Then the solution was filtered and the precipitate was dried to give the title compound as a white solid (1.98 g, 67% yield, 90% purity).1H NMR (400 MHz, CDCl3) δ = 7.63 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 2.0 Hz, 1H), 6.91 (dd, J = 2.0, 8.4 Hz, 1H), 6.49 (d, J = 0.8 Hz, 1H), 6.25 (d, J = 1.2 Hz, 1H), 4.79 (t, J = 2.0 Hz, 2H), 3.84 (s, 3H).

[0260] Methyl 6-bromo-3-methyl-2,3-dihydrobenzofuran-3-carboxylate

[0261] To a solution of N,N-dibutylbutan-1-amine (670 mg, 3.6 mmol, 861 μL, 2.9 eq) in ACN (14 mL) was added HCOOH (66 mg, 1.5 mmol, 1.1 eq) at 25°C under N2. After addition, the reaction mixture was stirred for 10 min and then a solution of methyl 2-((5-bromo-2- iodophenoxy)methyl)acrylate (0.5 g, 1.3 mmol, 1 eq) in ACN (5 mL) and Pd(OAc)2 (28 mg, 126 μmol, 0.1 eq) in ACN (1 mL) was added dropwise at 25°C and the reaction mixture was stirred at 60°C for 12 hr. The reaction mixture was concentrated in vacuo, diluted with H2O (20 mL), and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (20 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound as a white solid (0.4 g, crude).1H NMR (400 MHz, CDCl3) δ = 7.18 (d, J = 8.0 Hz, 1H), 7.04 (dd, J = 1.6, 8.0 Hz, 1H), 6.98 (d, J = 1.6 Hz, 1H), 5.11-5.05 (m, 1H), 4.31-4.24 (m, 1H), 3.75 (s, 3H), 1.61 (m, 3H).

[0262] 6-Bromo-3-methyl-2,3-dihydrobenzofuran-3-carboxylic acid

[0263] A solution of methyl 6-bromo-3-methyl-2,3-dihydrobenzofuran-3-carboxylate (0.1 g, 369 μmol, 1 eq) and NaOH (37 mg, 922 μmol, 2.5 eq) in MeOH (2 mL) and H2O (0.8 mL) was stirred at 25°C for 1 hr. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The aqueous layer was adjusted pH=4 (1M HCl) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (20 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound as a white solid (60 mg, 46% yield, 74% purity). 77 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0264] 6-((7R,14R)-1-Cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo [f]benzo[4,5]imidazo[1,2-a][1,4]78iazocine-11-yl)-3-methyl-2,3-dihydrobenzofuran-3- carboxylic acid

[0265] To a solution of (7R,14R)-1-cyclopropyl-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]78iazocine- 5(14H)-one (0.02 g, 44 μmol, 1 eq) and 6-bromo-3-methyl-2,3-dihydrobenzofuran-3-carboxylic acid (11 mg, 44 μmol, 1 eq) in THF (1 mL) was added XPHOS-Pd-G2 (3 mg, 4.4 μmol, 0.1 eq) and K3PO4 (0.5 M, 176 μL, 2 eq) and the reaction mixture was stirred at 100°C for 4 hr under N2. The reaction mixture was filtered through Celite® and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:10%-50% B over 8.0 min) to give the title compound as a white solid (4 mg, 17% yield, 97% purity).1H NMR (400 MHz, CDCl3) δ = 8.46-8.42 (m, 1H), 7.82-7.67 (m, 1H), 7.55-7.48 (m, 1H), 7.47-7.37 (m, 2H), 7.33-7.29 (m, 2H), 7.12-7.04 (m, 1H), 7.02-6.96 (m, 1H), 6.67-6.57 (m, 1H), 5.24-5.12 (m, 1H), 5.10-4.98 (m, 1H), 4.35 (d, J = 9.0 Hz, 1H), 3.56-3.41 (m, 4H), 2.87 (d, J = 13.2 Hz, 1H), 2.52- 2.41 (m, 1H), 1.72 (s, 3H), 1.34-1.25 (m, 2H), 1.15-1.06 (m, 1H), 0.76-0.66 (m, 1H).

[0266] Example 33: Synthesis of (1S,3s)-3-amino-3-(4-((7R,14R)-1-cyclopropyl-6-methyl-5- oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)-2- fluorophenyl)-1-methylcyclobutane-1-carbonitrile (38) Br Br Br Brp y y y y y 78 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0268] To a solution of 4-bromo-2-fluoro-1-iodo-benzene (2.5 g, 8 mmol, 0.9 eq) in DCM (20 mL) was added a solution of n-BuLi (2.5 M, 4 mL, 1.1 eq) at -78°C under N2 over 10 min. The resulting brown slurry was stirred at -78°C for 50 min. Then a solution of 1-methyl-3-oxo- cyclobutanecarbonitrile (1 g, 9 mmol, 1 eq) in DCM (5 mL) was added and the reaction mixture was stirred at -78°C for 1 hr under N2. The reaction was quenched with sat. NH4Cl (50 mL), diluted with H2O (50 mL), and extracted with ethyl acetate (80 mL x 2). The combined organic layers were dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 3 / 1) to give the title compound as a yellow solid (1.1 g, 36% yield, 85% purity).1H NMR (400 MHz, DMSO-d6) δ = 7.31-7.24 (m, 2H), 7.21-7.17 (m, 1H), 2.98-2.94 (m, 2H), 2.74-2.71 (m, 2H), 1.51 (s, 3H).

[0269] 1-(4-Bromo-2-fluorophenyl)-3-cyano-3-methylcyclobutyl methanesulfonate

[0270] To a solution of 3-(4-bromo-2-fluorophenyl)-3-hydroxy-1-methylcyclobutane-1- carbonitrile (750 mg, 2.6 mmol, 1 eq) and Et3N (534 mg, 5.2 mmol, 734 μL, 2 eq) in DCM (7.5 mL) was added MsCl (605 mg, 5.3 mmol, 408 μL, 2 eq) at 0 °C under N2. The reaction mixture was stirred at 25°C for 1 hr under N2. The reaction mixture was diluted with DCM (10 mL). The organic layer was washed with H2O (20 mL), sat. NaHCO3(20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow oil (1 g, crude).1H NMR (400 MHz, DMSO-d6) δ = 7.67-7.65 (m, 1H), 7.58-7.53 (m, 1H), 7.34 (t, J = 8.0 Hz, 1H), 3.58 (d, J = 13.6 Hz, 2H), 3.04 (d, J = 14.4 Hz, 2H), 1.75 (s, 3H), 1.59 (s, 3H).

[0271] 3-Azido-3-(4-bromo-2-fluorophenyl)-1-methylcyclobutane-1-carbonitrile

[0272] To a solution of 1-(4-bromo-2-fluorophenyl)-3-cyano-3-methylcyclobutyl methanesulfonate (1 g, 2.8 mmol, 1 eq) in DMSO (20 mL) was added NaN3(897 mg, 14 mmol, 5 eq) in DMSO (6 mL) and H2O (1.5 mL) and the reaction mixture was stirred at 80°C for 2 hr under N2. The reaction was quenched with addition sat. NaHCO3 (30 mL), extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow oil (500 mg, crude).1H NMR (400 MHz, DMSO-d6) δ = 7.65-7.62 (m, 1H), 7.49-7.47 (m, 1H), 7.34 (d, J = 8.0 Hz, 1H), 2.93-2.90 (m, 2H), 2.85-2.82 (m, 2H), 1.46 (s, 3H).

[0273] (1s,3s)-3-Amino-3-(4-bromo-2-fluorophenyl)-1-methylcyclobutane-1-carbonitrile 79 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0274] To a solution of 3-azido-3-(4-bromo-2-fluorophenyl)-1-methylcyclobutane-1- carbonitrile (500 mg, 1.6 mmol, 1 eq) in THF (10 mL) and H2O (1 mL) was added Me3P (1 M, 2.4 mL, 1.5 eq) and the reaction mixture was stirred at 25°C for 2 hr under N2. The reaction was quenched with sat. NaHCO3 (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: Phenomenex Luna C18 100*40mm*5µm;mobile phase: [H2O(0.2% FA)-ACN];gradient:1%-35% B over 8.0 min) to give the title compound as a yellow solid (80 mg, 17% yield, 99% purity).1H NMR (400 MHz, DMSO- d6) δ = 7.47 (dd, J = 1.6, 10.8 Hz, 1H), 7.38 (dd, J = 2.0, 8.0 Hz, 1H), 7.24 (t, J = 8.4 Hz,1H), 2.63- 2.59 (m, 2H), 2.55-2.50 (m, 2H), 2.34-2.30 (b, 2H), 1.38 (s, 3H).

[0275] (1S,3s)-3-amino-3-(4-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-11-yl)-2-fluorophenyl)-1- methylcyclobutane-1-carbonitrile

[0276] To a solution of (1s,3s)-3-amino-3-(4-bromo-2-fluorophenyl)-1-methylcyclobutane-1- carbonitrile (30 mg, 106 μmol, 1 eq) and (7R,14R)-1-cyclopropyl-6-methyl-11-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocine-5(14H)-one (48 mg, 106 μmol, 1 eq) in THF (1 mL) was added K3PO4(0.5 M, 423 μL, 2 eq) and XPHOS-PD-G2 (8 mg, 10 μmol, 0.1 eq) and the reaction mixture was stirred at 100°C for 4 hr under N2. The reaction mixture was filtered and concentrated in vacuo to give a residue which was purified by prep-HPLC (column: Waters Xbridge BEH C18150*30 mm*10 µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:35%-55% B over 8.0 min) to give the title compound as a white solid (14 mg, 24% yield, 96% purity).1H NMR (400 MHz, DMSO-d6) δ = 8.16 (d, J = 8.0 Hz, 1H), 7.71-7.67 (m, 2H), 7.49 (dd, J = 1.2, 8.4 Hz, 1H), 7.43-7.39 (m, 2H), 7.36-7.28 (m, 2H), 7.25-7.20 (m, 1H), 6.65 (d, J = 7.2 Hz, 1H), 5.18 (d, J = 6.8 Hz, 1H), 3.54-3.47 (m, 1H), 3.30 (s, 3H), 2.84-2.76 (m, 2H), 2.67-2.58 (m, 5H), 2.41-2.37 (m, 1H), 1.41 (s, 3H), 1.32- 1.20 (m, 2H), 1.02-0.98 (m, 1H), 0.83-0.78 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ = -116.10 (s, 1F). MS: [M+H]+=532.2.

[0277] Example 34: Synthesis of (7R,14R)-11-(2-(1-amino-3,3-difluorocyclobutyl)pyrimidin- 5-yl)-1-cyclopropyl-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (40) 80 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO Br O N HONBr Br MsCl, TEANN3NBr I NMsONaN N3NNO

[0279] To a solution of 5-bromo-2-iodo-pyrimidine (3.8 g, 13 mmol, 1.4 eq) in DCM (75 mL) was added n-BuLi (2.5 M, 5 mL, 1.3 eq) drop wise at -70°C under N2and was stirred for 0.5 hr. A solution of 3,3-difluorocyclobutanone (1 g, 9 mmol, 1 eq) in DCM (10 mL) was added dropwise at -70°C and the reaction mixture was stirred at -70°C for 1 hr and then at 25°C under for 1.5 hr under N2. The reaction was quenched slowly with sat. NH4Cl (70 mL), then poured into H2O (200 mL) and extracted with DCM (200 m L x 3). The organic layers were concentrated in vacuo to give a residue which was purified by prep-HPLC (FA condition; column: Phenomenex Luna C18 (250*70mm,15µm);mobile phase: [H2O(0.02%FA)-ACN];gradient:30%-60% B over 20.0 min) to give the title compound as a black solid (450 mg, 14% yield, 80% purity).1H NMR (400 MHz, CDCl3) δ = 8.84 (s, 2H), 4.73 (b, 1H), 3.45-3.26 (m, 2H), 3.09-2.89 (m, 2H).

[0280] [1-(5-Bromopyrimidin-2-yl)-3,3-difluoro-cyclobutyl] methanesulfonate

[0281] To a solution of 1-(5-bromopyrimidin-2-yl)-3,3-difluoro-cyclobutanol (450 mg, 1.7 mmol, 1 eq) and TEA (343 mg, 3.4 mmol, 472 μL, 2 eq) in DCM (5 mL) was added MsCl (0.7 g, 6 mmol, 473 μL, 3.6 eq) at 0°C under N2and the reaction mixture was stirred at 25°C for 1 hr. The reaction was slowly quenched with sat. NaHCO3(20 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give the title compound as a black oil (700 mg, crude).

[0282] 2-(1-Azido-3,3-difluoro-cyclobutyl)-5-bromo-pyrimidine

[0283] To a solution of [1-(5-bromopyrimidin-2-yl)-3,3-difluoro-cyclobutyl] methanesulfonate (700 mg, 2 mmol, 1 eq) in DMSO (15 mL) was added NaN3 (0.76 g, 12 mmol, 5.8 eq) in DMSO (8 mL) and H2O (2 mL) under N2and the reaction mixture was stirred at 80°C for 2 hr and then at 100°C for 4 hr. The reaction mixture was poured into 2M aq. NaOH to pH>9 and extracted with 81 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO EtOAc (100 mL x 3). The organic layers were combined and concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 0 / 1) to give the title compound as a yellow oil (180 mg, 27% yield, 90% purity).1H NMR (400 MHz, DMSO-d6) δ = 9.14 (s, 1H), 3.50-3.40 (m, 2H), 3.15-3.06 (m, 2H).

[0284] (7R,14R)-11-(2-(1-azido-3,3-difluorocyclobutyl)pyrimidin-5-yl)-1-cyclopropyl-6- methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0285] A solution of 2-(1-azido-3,3-difluoro-cyclobutyl)-5-bromo-pyrimidine (51 mg, 176 μmol, 1 eq), (7R,14R)-1-cyclopropyl-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (80 mg, 176 μmol, 1 eq), K3PO4(0.5 M, 703 μL, 2 eq), and XPHOS-PD-G2 (13 mg, 17 μmol, 0.1 eq) in THF (1.5 mL) was degassed and purged with N2 for 3 times, and the reaction mixture was stirred at 100°C for 2 hr under N2. The reaction mixture was partitioned between H2O (10 mL) and EtOAc (10 mL x 2). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 0 / 1) to give the title compound as a yellow oil (70 mg, 51% yield, 70% purity).1H NMR (400 MHz, DMSO-d6) δ = 9.22 (s, 2H), 8.13-8.20 (m, 1H), 7.83-7.78 (m, 2H), 7.67-7.61 (m, 1H), 7.30 (d, J = 5.2 Hz, 2H), 6.68 (d, J=7.2Hz, 1H), 5.21 (d, J = 6.8 Hz, 1H), 3.58-3.49 (m, 2H), 3.31 (s, 3H), 3.30-3.25 (m, 2H), 3.22-3.05 (m, 1H), 2.86-2.74 (m, 2H), 1.28-1.22 (m, 2H), 1.06-0.99 (m, 1H), 0.78-0.66 (m, 1H).

[0286] (7R,14R)-11-(2-(1-Amino-3,3-difluorocyclobutyl)pyrimidin-5-yl)-1-cyclopropyl-6- methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0287] A solution of (7R,14R)-11-(2-(1-azido-3,3-difluorocyclobutyl)pyrimidin-5-yl)-1- cyclopropyl-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (60 mg, 111 μmol, 1 eq) and Me3P (1 M, 167 μL, 1.5 eq) in THF (2 mL) and H2O (0.2 mL) was degassed and purged with N2for 3 times, and the reaction mixture was stirred at 25°C for 1 hr under N2. The reaction mixture was concentrated in vacuo to give a residue which was purified by prep-HPLC (FA condition; column: Phenomenex Luna C18100*40mm*5µm; mobile phase: [H2O(0.2% FA)-ACN];gradient:10%-40% B over 8.0 min) to give the title compound as a white solid (15 mg, 24% yield, 100% purity).1H NMR (400 MHz, DMSO-d6) δ = 9.11 (d, J = 4.4 Hz, 2H), 8.20-8.13 (m, 1H), 7.82-7.74 (m, 2H), 7.65-7.65 (m, 1H), 7.34-7.24 (m, 2H), 6.68 (d, J 82 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO = 7.2 Hz, 1H), 5.21 (d, J = 7.2 Hz, 1H), 3.59-3.47 (m, 1H), 3.31 (s, 3H), 3.29-3.24 (m, 1H), 2.86- 2.68 (m, 5H), 1.30-1.20 (m, 2H), 1.05-0.95 (m, 1H), 0.78-0.71 (m, 1H).

[0288] Example 35: Synthesis of (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-1-(1- fluorocyclopropyl)-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (41) N N N Cl Py. / HF( N N BF3K 1.2 eq), ClNN NBS(1.15 eq)ClN N OH)24,5] imidazo[1,2-a][1,4]diazocine-5(14H)-one

[0290] To a solution of (7R,14R)-11-chloro-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo [4,5]imidazo[1,2-a][1,4]diazocine-1-yl trifluoromethanesulfonate (600 mg, 1.3 mmol, 1 eq) and potassium hydride; trifluoro (vinyl)boron (170 mg, 1.3 mmol, 1 eq) in dioxane (12 mL) and H2O (2.4 mL) was added K2CO3(351 mg, 2.5 mmol, 2 eq), Sphos (52 mg, 127 μmol, 0.1 eq) and Pd(Oac)2(29 mg, 127 μmol, 0.1 eq) and the reaction mixture was stirred at 90°C for 12 hr under N2. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: WePure Biotech XP tC18150*40*7µm;mobile phase:[H2O(10 mM NH4HCO3)-ACN];gradient:20%-50% B over 8.0 min) to give the title compound as a white solid (250 mg, 51% yield, 91% purity).

[0291] (7R,14R)-1-(2-bromo-1-fluoroethyl)-11-chloro-6-methyl-6,7-dihydro-7,14- methanobenzo [f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-5(14H)-one 83 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0292] To a solution of (7R,14R)-11-chloro-6-methyl-1-vinyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5] imidazo[1,2-a][1,4]diazocine-5(14H)-one (150 mg, 429 μmol, 1 eq) in DCM (3 mL) was added NBS (88 mg, 493 μmol, 1.2 eq) and pyridine;hydrofluoride (51 mg, 515 μmol, 46 μL, 1.2 eq), then the reaction mixture was refluxed for 12 hr under N2. The reaction mixture was concentrated in vacuo to give the title compound as a yellow oil (300 mg, crude).

[0293] (7R,14R)-11-chloro-1-(1-fluorovinyl)-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-5(14H)-one

[0294] To a solution of (7R,14R)-1-(2-bromo-1-fluoroethyl)-11-chloro-6-methyl-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-5(14H)-one (300 mg, 669 μmol, 1 eq) in DCM (3 mL) was added DBU (326 mg, 2 mmol, 322 μL, 3 eq), then the reaction mixture was stirred at 45 °C for 2 hr under N2. H2O (10 mL) was added and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep- TLC (PE: EtOAc= 0:1) to give the title compound as a yellow solid (140 mg, 53% yield, 93% purity).1H NMR (400 MHz, CDCl3) δ = 8.65 (d, J = 8.0 Hz, 1H), 7.63-7.59 (m, 2H), 7.51 (s, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.20 (dd, J = 2.0, 8.4 Hz, 1H), 5.95 (d, J = 7.6 Hz, 1H), 5.38 (dd, J = 3.2, 15.6 Hz, 1H), 5.10-4.98 (m, 1H), 4.92 (d, J = 7.2 Hz, 1H), 3.48 (s, 3H), 3.45-3.40 (m, 1H), 2.87 (d, J = 13.6 Hz, 1H).

[0295] (7R,14R)-11-chloro-1-(1-fluorocyclopropyl)-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-5(14H)-one

[0296] To a solution of (7R,14R)-11-chloro-1-(1-fluorovinyl)-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-5(14H)-one (140 mg, 381 μmol, 1 eq) in DMF (3.8 mL) was added 8-(iodomethyl)-8,8’-spirobi[7,9-dioxa-8-silanuidabicyclo[4.3.0]nona- 1(6),2,4-triene];triethyl ammonium (278 mg, 571 μmol, 1.5 eq) and 2,4,5,6-tetra(diazocine-9- yl)benzene-1,3-dicarbonitrile (15 mg, 19 μmol, 0.05 eq) and the reaction mixture was stirred at 25°C for 12 hr under 30 W blue LED. H2O (10 mL) was added and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep- TLC (SiO2, PE: EtOAc = 0:1) to give the title compound as a yellow solid (30 mg, 21% yield). MS: [M+H]+= 381.9. 84 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0297] tert-Butyl(1-(5-((7R,14R)-1-(1-fluorocyclopropyl)-6-methyl-5-oxo-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-11-yl)pyrimidin-2- yl)cyclobutyl)carbamate

[0298] A mixture of (7R,14R)-11-chloro-1-(1-fluorocyclopropyl)-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-5(14H)-one (20 mg, 42 μmol, 1 eq), [2- [1-(tert-butoxycarbonylamino)cyclobutyl]pyrimidin-5-yl]boronic acid (12 mg, 42 μmol, 1 eq), K3PO4(0.5 M, 168 μL, 2 eq), and XPHOS-PD-G2(3 mg, 4.2 μmol, 0.1 eq) in THF (1 mL) was degassed and purged with N2 for 3 times, then the mixture was stirred at 100°C for 2 hr under N2. To the reaction mixture (combined with another batch at 10 mg scale) was added H2O (30 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were dried with anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-TLC (SiO2, Ethyl acetate : THF = 1.5:1) to give the title compound as a yellow solid (11 mg, 84% purity). MS: [M+H]+= 595.4.

[0299] (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-1-(1-fluorocyclopropyl)-6-methyl- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-5(14H)-one

[0300] A solution of tert-butyl (1-(5-((7R,14R)-1-(1-fluorocyclopropyl)-6-methyl-5-oxo- 5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-11- yl)pyrimidin-2-yl)cyclobutyl)carbamate (11 mg, 18 μmol, 1 eq) in HCl / EtOAc (4 M, 1 mL) was stirred at 25°C for 1 hr. The reaction mixture was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: Phenomenex Luna C18 100*40mm*5µm;mobile phase: [H2O(0.2% FA)-ACN];gradient:5%-30% B over 8.0 min ) to give the title compound as a white solid (1.2 mg, 13% yield, 100% purity).1H NMR (400 MHz, DMSO-d6) δ = 8.94 (s, 2H), 8.36 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 8.8 Hz, 3H), 7.60 (d, J = 8.4 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 6.63 (d, J = 7.2 Hz, 1H), 5.23 (d, J = 6.8 Hz, 1H), 3.59-3.54 (m, 1H), 3.30 (s, 3H), 2.83 (d, J = 13.6 Hz, 1H), 2.60-2.55 (m, 2H), 2.15-2.04 (m, 2H), 2.03-1.91 (m, 1H), 1.89-1.79 (m, 2H), 1.71-1.59 (m, 1H), 1.50-1.43 (m, 1H), 1.30-1.20 (m, 1H).

[0301] Example 36: Synthesis of 3-(5-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)-3-fluoropyridin- 2-yl)-3-hydroxy-1-methylcyclobutane-1-carbonitrile (42) 85 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO N (R) N N BpinN O O

[0302] y-1-methyl-cyclobutanecarbonitrile (10 mg, 35 μmol, 1 eq), (7R,14R)-1-cyclopropyl-6-methyl-11-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (16 mg, 35 μmol, 1 eq), K3PO4(0.5 M, 140 μL, 2 eq), and XPHOS- PD-G2 (3 mg, 4 μmol, 0.1 eq) in THF (1 mL) was degassed and purged with N2for 3 times, and the reaction mixture was stirred at 100°C for 3 hr under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (FA condition; column: Phenomenex Luna C18 100*40mm*5µm;mobile phase: [H2O(0.2% FA)- ACN];gradient:30%-70% B over 8.0 min) and further purified by prep-HPLC (neutral condition;column: Waters Xbridge BEH C18 100*30mm*10µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:45%-85% B over 8.0 min) to give the title compound as a white solid (2 mg, 10% yield, 100% purity).1H NMR (400 MHz, DMSO-d6) δ = 8.70 (s, 1H), 8.15-8.12 (m, 1H), 8.04-7.98 (m, 1H), 7.79-7.74 (m, 2H), 7.62-7.57 (m, 1H), 7.32-7.24 (m, 2H), 6.67 (d, J = 7.6 Hz, 1H), 6.12 (b, 1H), 5.21 (d, J = 6.8 Hz, 1H), 3.56-3.50 (m, 1H), 3.37 (s, 3H), 2.87-2.75 (m, 3H), 2.44 (m, 2H), 1.64 (s, 3H), 1.33-1.20 (m, 2H), 1.04-0.96 (m, 1H), 0.81-0.74 (m, 1H).

[0303] Example 37: Synthesis of (7R,14R)-1-cyclopropyl-11-(2-(3-hydroxy-1-methylazetidin- 3-yl)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (43) 86 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO NBrN Br Br (6 eq) O HO N NaBH(OAc)3I N 1A N HCl / EtOAc OH HCHO(37%, 3 eq) N [00

[0305] A solution of 5-bromo-2-iodo-pyrimidine (4 g, 14 mmol, 1 eq) in a mixture of toluene (40 mL) and M-XYLENE (13 mL) was cooled to -70°C under N2and a solution of n-BuLi (2.5 M, 6.7 mL, 1.2 eq) was added dropwise over 10 min. The reaction mixture was stirred at -70°C for 50 min, then a solution of tert-butyl 3-oxoazetidine-1-carboxylate (2.64g, 15 mmol, 1.1 eq) in toluene (4 mL) was added dropwise and the reaction mixture was allowed to warm to 25°C and stirred for 1 hr. The reaction was quenched with sat. NH4Cl (50 mL), diluted with H2O (50 mL), and extracted with ethyl acetate (80 mL x 2). The combined organic layers were dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 3 / 1) to give the title compound as a yellow solid (2 g, 43% yield, 97% purity).1H NMR (400 MHz, DMSO-d6) δ = 9.05 (s, 2H), 6.46 (s, 1H), 4.28 (m, 2H), 3.94 (d, J = 8.4 Hz, 2H), 1.39 (s, 9H).

[0306] 3-(5-Bromopyrimidin-2-yl)diazocine-3-ol

[0307] A solution of tert-butyl 3-(5-bromopyrimidin-2-yl)-3-hydroxy-azetidine-1-carboxylate (500 mg, 1.5 mmol, 1 eq) in HCl / EtOAc (4 M, 5 mL) was stirred at 25°C for 0.5 h. The reaction mixture was concentrated in vacuo to give the title compound as a yellow oil (350 mg, crude).

[0308] 3-(5-Bromopyrimidin-2-yl)-1-methylazetidin-3-ol

[0309] To a solution of 3-(5-bromopyrimidin-2-yl)diazocine-3-ol (300 mg, 1.3 mmol, 1 eq) in DCM (6 mL) was added formaldehyde (317 mg, 4 mmol, 291 μL, 37% purity, 3 eq) and NaBH(Oac)3(1.6 g, 8 mmol, 6 eq) and the reaction mixture was stirred at 25°C for 45 min. The reaction was quenched with H2O (0.5 mL) and concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 0 / 1) give the title 87 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO compound as a yellow solid (150 mg, 47% yield).1H NMR (400 MHz, DMSO-d6) δ = 9.04 (s, 2H), 4.00 (br d, J = 7.2 Hz, 2H), 3.45 (d, J = 7.2 Hz, 2H), 1.90 (s, 3H).

[0310] (7R,14R)-1-cyclopropyl-11-(2-(3-hydroxy-1-methylazetidin-3-yl)pyrimidin-5-yl)-6- methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0311] To a solution of (7R,14R)-1-cyclopropyl-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine- 5(14H)-one (40 mg, 88 μmol, 1 eq) and 3-(5-bromopyrimidin-2-yl)-1-methyl-azetidin-3-ol (21 mg, 88μmol, 1 eq) in THF (0.8 mL) was added K3PO4 (0.5 M, 351 μL, 2 eq) and XPHOS-PD-G2 (7 mg, 9 μmol, 0.1 eq) under N2and the reaction mixture was stirred at 100°C for 1 hr. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: 3_Phenomenex Luna C1875*30 mm*3µm;mobile phase: [H2O(0.2% FA)-ACN];gradient:10%-40% B over 8.0 min) to give the title compound as a white solid (3 mg, 7% yield, 99% purity).1H NMR (400 MHz, DMSO-d6) δ = 9.10 (s, 2H), 8.17 (dd, J = 2.4, 7.6 Hz, 1H), 7.81-7.78 (m, 2H), 7.61 (dd, J = 1.6, 8.4 Hz, 1H), 7.36-7.20 (m, 2H), 6.68 (d, J = 7.6 Hz, 1H), 6.08-5.94 (br s, 1H), 5.21 (d, J = 6.8 Hz, 1H), 3.91 (d, J = 7.6 Hz, 2H), 3.57-3.51 (m, 1H), 3.31 (s, 3H), 3.27-3.23 (m, 2H), 2.87-2.74 (m, 2H), 2.32 (s, 3H), 1.36-1.17 (m, 2H), 1.04-0.94 (m, 1H), 0.82-0.73 (m, 1H).

[0312] Example 38: Synthesis of (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-1-(1- fluorocyclobutyl)-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (44) N NN B(OH)2N N N N N N O, , , methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one 88 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0314] To a solution of (7R,14R)-11-chloro-1-(1-hydroxycyclobutyl)-6-methyl-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (20 mg, 50 μmol, 1 eq) in DCM (2 mL) was added DAST (82 mg, 508 μmol, 67 μL, 10 eq) under N2at 0°C. The reaction mixture was stirred at 0°C for 20 min, then at 20 °C for 40 min. The reaction was quenched with sat. NaHCO3 (10 mL) at 0°C, diluted with H2O (10 mL), and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep- TLC (SiO2, PE:EA=0:1) to give the tile compound as a yellow oil (10 mg, 93% purity).

[0315] tert-Butyl (1-(5-((7R,14R)-1-(1-fluorocyclobutyl)-6-methyl-5-oxo-5,6,7,14-tetrahydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2-yl) cyclobutyl)carbamate

[0316] To a solution of (7R,14R)-11-chloro-1-(1-fluorocyclobutyl)-6-methyl-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (5 mg, 12 μmol, 1 eq) and (2-(1-((tert-butoxycarbonyl)amino)cyclobutyl)pyrimidin-5-yl)boronic acid (5 mg, 16 μmol, 1.3 eq) in THF (2 mL) were added K3PO4 (0.5 M, 50 μL, 2 eq) and XPHOS-PD-G2 (994 μg, 1.2 μmol, 0.1 eq) under N2and the reaction mixture was stirred at 100°C for 2 hr. The reaction was quenched with sat. NH4Cl (10 mL) at 0°C, diluted with H2O (10 mL), and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-TLC (SiO2, PE:EA = 0:1) to give the title compound as a white solid (4 mg, 86% purity).

[0317] (7R,14R)-11-(2-(1-Aminocyclobutyl)pyrimidin-5-yl)-1-(1-fluorocyclobutyl)-6-methyl- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0318] A solution of tert-butyl (1-(5-((7R,14R)-1-(1-fluorocyclobutyl)-6-methyl-5-oxo- 5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11- yl)pyrimidin-2-yl)cyclobutyl)carbamate (4 mg, 6 μmol, 1 eq) in HCl / EtOAc (4 M, 0.5 mL) was stirred at 20°C for 1 hr. The reaction mixture was concentrated in vacuo to give a residue which was purified by prep-HPLC (FA condition; column: Phenomenex Luna C18 100*40mm*5µm;mobile phase: [H2O(0.2% FA)-ACN];gradient:3%-30% B over 8.0 min ) to give the title compound as a white solid (0.8 mg, 23% yield, 97% purity).1H NMR (400 MHz, DMSO- d6) δ = 8.95 (s, 2H), 8.29 (d, J = 7.6 Hz, 1H), 7.87-7.73 (m, 3H), 7.58 (d, J = 8.4 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 6.11 (d, J = 6.8 Hz, 1H), 5.19 (d, J = 6.4 Hz, 1H), 3.55-3.50 (m, 1H), 3.26 (s, 3H), 89 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO 3.15-3.06 (m, 2H), 2.84-2.70 (m, 2H), 2.67-2.58 (m, 3H), 2.18-2.11 (m, 3H), 2.05-1.94 (m, 1H), 1.90-1.77 (m, 1H), 1.76-1.64 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ = -116.33 (s, 1F).

[0319] Example 39: Synthesis of (1R,3r)-3-amino-3-(5-((7R,14R)-1-cyclopropyl-6-methyl-5- oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11- yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carbonitrile (45) Br Br Br N )

[0321] To a solution of (1s,3s)-3-(5-bromopyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1- carbonitrile (0.2 g, 746 μmol, 1 eq) and TEA (340 mg, 3 mmol, 467 μL, 4.5 eq) in DCM (2 mL) was added MsCl (307 mg, 2.7 mmol, 208 μL, 3.6 eq) at 0°C under N2 and the reaction mixture was stirred at 25°C for 0.5 hr. The reaction was quenched with addition H2O (50 mL) and extracted with DCM (20 mL x 2). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow oil (0.22 g, 85% yield, 78% purity).

[0322] (1r, 3r)-3-Azido-3-(5-bromopyrimidin-2-yl)-1-methylcyclobutane-1-carbonitrile

[0323] To a solution of (1s,3s)-1-(5-bromopyrimidin-2-yl)-3-cyano-3-methylcyclobutyl methanesulfonate (0.22 g, 635 μmol, 1 eq) in DMSO (0.88 mL) was added NaN3 (149 mg, 2.3 mmol, 3.6 eq) in H2O (0.22 mL) and the reaction mixture was stirred at 80°C for 8 hr under N2. The reaction mixture was diluted with sat. Na2CO3(20 mL) and extracted with EtOAc (15 mL x 2). The combined organic layers were washed with brine (25 mL x 2), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by column 90 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 0 / 1) to give the title compound as a yellow oil (0.15 g, 80% yield, 91% purity).1H NMR (400 MHz, CDCl3) δ = 8.87 (s, 2H), 3.49 – 3.40 (m, 2H), 2.59-2.51 (m, 2H), 1.76 (s, 3H).

[0324] (1r,3r)-3-Amino-3-(5-bromopyrimidin-2-yl)-1-methylcyclobutane-1-carbonitrile

[0325] To a solution of (1r,3r)-3-azido-3-(5-bromopyrimidin-2-yl)-1-methylcyclobutane-1- carbonitrile (80 mg, 273 μmol, 1 eq) in THF (0.32 mL) and H2O (0.08 mL) was added Me3P (1 M, 327 μL, 1.2 eq) at 0°C and the reaction mixture was stirred at 20°C for 12 hr. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (25mL x 2). The combined organic layers were dried over Na2SO4,filtered and the filtrate was concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=40 / 1 to 0 / 1) to give the title compound as a white solid (50 mg, 68% yield).1H NMR (400 MHz, CDCl3) δ = 8.80 (s, 2H), 3.35 (d, J = 13.0 Hz, 2H), 2.32 (d, J = 12.9 Hz, 2H), 1.78 (s, 3H).

[0326] (1R,3r)-3-Amino-3-(5-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2-yl)-1- methylcyclobutane-1-carbonitrile

[0327] To a solution of (1r,3r)-3-amino-3-(5-bromopyrimidin-2-yl)-1-methylcyclobutane-1- carbonitrile (26 mg, 97 μmol, 2.2 eq) in THF (0.45 mL) was added K3PO4(0.5 M, 175 μL, 2 eq), (7R,14R)-1-cyclopropyl-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5] imidazo[1,2-a][1,4]diazocin-5(14H)-one (20 mg, 44 μmol, 1 eq), and [2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3-(2,4,6- triisopropylphenyl)phenyl] phosphane (3 mg, 4 μmol, 0.1 eq) and the reaction mixture was stirred at 100°C for 4 hr under N2. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (25mL x 2). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: WePure Biotech XP tC18150*40*7µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:25%-55% B over 8.0 min) to give the title compound as a white solid (3 mg, 13% yield).1H NMR (400 MHz, DMSO-d6) δ = 9.12 (s, 2H), 8.17 (d, J = 2.7, 6.7 Hz, 1H), 7.81–7.76 (m, 2H), 7.61 (d, J = 1.3, 8.7 Hz, 1H), 7.32–7.26 (m, 2H), 6.68 (d, J = 7.4 Hz, 1H), 5.21 (d, J = 7.0 Hz, 1H), 3.58 –3.48 (m, 1H), 3.31 (s, 3H), 3.23 (d, J = 13.1 Hz, 2H), 2.85–2.76 (m, 2H), 2.29 (d, J = 13.0 Hz, 2H), 1.72 (s, 3H), 1.31 –1.19 (m, 3H), 1.05-0.96 (m, 1H), 0.87 –0.79 (m, 1H), 0.78-0.72 (m, 1H). 91 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0328] Example 40: Synthesis of (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-1-(1- fluorocyclobutyl)-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (46)Br Br Br NMsCl (36 eq)NNaN3(36 eq)NPMe15 )1Ve

[0330] To a solution of (1r,3r)-3-(5-bromopyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1- carbonitrile (0.2 g, 746 μmol, 1 eq) in DCM (1 mL) was added TEA (340 mg, 3 mmol, 467 μL, 4.5 eq) and MsCl (308 mg, 2.7 mmol, 208 μL, 3.6 eq) at 0°C under N2and the reaction mixture was stirred at 25°C for 0.5 hr under N2. The reaction was quenched with addition H2O (50 mL) and extracted with DCM (20 mL x 2). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give the title compound as a white solid (0.22 g, 85% yield, 80% purity).

[0331] (1s,3s)-3-Azido-3-(5-bromopyrimidin-2-yl)-1-methylcyclobutane-1-carbonitrile

[0332] To a solution of (1r, 3r)-1-(5-bromopyrimidin-2-yl)-3-cyano-3-methylcyclobutyl methanesulfonate (0.22 g, 635 μmol, 1 eq) in DMSO (0.88 mL) was added NaN3(148mg, 2 mmol, 3.6 eq) in H2O (0.22 mL) and the reaction mixture was stirred at 80°C for 8 hr under N2. The reaction mixture was diluted with sat. Na2CO3 (20 mL) and extracted with EtOAc (15 mL x 2). The combined organic layers were washed with brine (25 mL x 2), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-TLC (SiO2, PE:EtOAC = 5:1) to give the title compound as a colorless oil (0.15 g, 80% yield, 91% purity).

[0333] (1s,3s)-3-Amino-3-(5-bromopyrimidin-2-yl)-1-methylcyclobutane-1-carbonitrile

[0334] To a solution of (1s,3s)-3-azido-3-(5-bromopyrimidin-2-yl)-1-methylcyclobutane-1- carbonitrile (80 mg, 273 μmol, 1 eq) in THF (0.32 mL) and H2O (0.08 mL) was added Me3P (1 M, 92 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO 409 μL, 1.5 eq) at 0°C and the reaction mixture was stirred at 20°C for 12 hr under N2. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (25 mL x 2). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=40 / 1 to 0 / 1 to give the title compound as a white solid (50 mg, 68% yield, 76% purity).1H NMR (400 MHz, CDCl3) δ = 8.77 (s, 2H), 2.87 (d, J = 13.6 Hz, 2H), 2.75 (d, J = 13.6 Hz, 2H), 1.58 (s, 3H).

[0335] (1S,3s)-3-amino-3-(5-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2-yl)-1- methylcyclobutane-1-carbonitrile

[0336] To a solution of (1s,3s)-3-amino-3-(5-bromopyrimidin-2-yl)-1-methylcyclobutane-1- carbonitrile (26 mg, 96 μmol, 2.2 eq) in THF (0.45 mL) was added K3PO4 (0.5 M, 176 μL, 2 eq), (7R,14R)-1-cyclopropyl-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5] imidazo[1,2-a][1,4]diazocin-5(14H)-one (20 mg, 44 μmol, 1 eq) and [2-2-aminophenyl)phenyl] chloro-palladium;dicyclohexyl-3-(2,4,6-triisopropylphenyl) henyl]phosphane (7 mg, 9 μmol, 0.2 eq) and the reaction mixture was stirred at 100°C for 12 hr under N2. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (25 mL x 2). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: WePure Biotech XP tC18150*40*7µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:25%-55% B over 8.0 min) to give the title compound as a white solid (2 mg, 9% yield).1H NMR (400 MHz, DMSO-d6) δ = 9.09 (s, 2H), 8.17 (d, J = 2.8, 6.6 Hz, 1H), 7.81 –7.75 (m, 2H), 7.59 (d, J = 9.8 Hz, 1H), 7.33 –7.26 (m, 2H), 6.67 (d, J = 7.4 Hz, 1H), 5.21 (d, J = 7.0 Hz, 1H), 3.59 –3.47 (m, 1H), 3.31 (s, 3H), 2.86 –2.75 (m, 4H), 2.61 (d, J = 12.6 Hz, 2H), 1.46 (s, 3H), 1.31 –1.19 (m, 3H), 1.04- 0.96 (m, 1H), 0.84 (d, J = 5.4 Hz, 1H), 0.78 –0.71 (m, 1H).

[0337] Example 41: Synthesis of (7R,14R)-1-cyclopropyl-6-methyl-11-(2-(3- oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)pyrimidin-5-yl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (47) 93 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO N N N NH N Cl O N .HCl BPin OHNN ONOyl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one

[0339] To a solution of 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (184 mg, 760 μmol, 1 eq) in dioxane (3 mL) was added TEA (116 mg, 1 mmol, 160 μL, 1.5 eq) and hexahydroimidazo[1,5-a]pyrazin-3(2H)-one (0.15 g, 844 μmol, 1.1 eq, HCl salt) under N2. The reaction mixture was stirred at 100°C for 45 min under N2. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (25 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 0 / 1) to give the title compound as a yellow solid (0.12 g, 45% yield).

[0340] (7R,14R)-1-cyclopropyl-6-methyl-11-(2-(3-oxohexahydroimidazo[1,5-a]pyrazin- 7(1H)-yl)pyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4] diazocin-5(14H)-one To a solution of 7-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2- yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one (19 mg, 55 μmol, 2 eq) and (7R,14R)-11-chloro- 1-cyclopropyl-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (10 mg, 27 μmol, 1 eq) in THF (1.4 mL) was added K3PO4(0.5 M, 110 μL, 2 eq) and [2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3-(2,4,6- triisopropylphenyl)phenyl]phosphane (4 mg, 5 μmol, 0.2 eq) under N2. The reaction mixture was stirred at 100°C for 12 hr. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (25 mL x 2). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: WePure Biotech XP tC18150*40*7µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:20%-50% B over 8.0 min) to give the title compound as a white solid (4 mg, 26% yield, 99% purity) .1H NMR (400 MHz, DMSO-d6) δ = 8.67 (s, 2H), 8.17 (d, J = 1.7, 7.7 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.62 (s, 1H), 7.45 (d, J = 1.6, 8.4 Hz, 1H), 7.33-7.23 (m, 2H), 6.64 (d, J = 7.5 Hz, 1H), 6.54 (s, 1H), 5.18 (d, J = 7.0 Hz, 1H), 4.74 (d, J = 3.1, 12.8 Hz, 1H), 4.66 (d, J = 9.6 Hz, 1H), 3.72 – 94 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO 3.58 (m, 2H), 3.50 (m, 1H), 3.44-3.38 (m, 1H), 3.30 (s, 3H), 3.00 (m, 1H), 2.89-2.72 (m, 5H), 1.31-1.17 (m, 2H), 1.08-0.93 (m, 1H), 0.88-0.67 (m, 1H).

[0341] Example 42: Synthesis of (7R,14R)-11-(2-(3-aminooxetan-3-yl)pyrimidin-5-yl)-1- cyclopropyl-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocine-5(14H)-one (48) N (R) N BpinNO [003

[0343] To a solution of oxetan-3-one (1 g, 14 mmol, 1 eq) and 2-methylpropane-2-sulfinamide (1.7 g, 14 mmol, 1 eq) in EtOH (20 mL) was added Ti(i-PrO)4(4 g, 14 mmol, 4 mL, 1 eq) and the reaction mixture was stirred at 80°C for 12 hr under N2. The reaction was quenched with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 0 / 1) to give the title compound as a yellow oil (450 mg, 28% yield, 90% purity).1H NMR (400 MHz, DMSO-d6) δ = 5.61-5.45 (m, 4H), 1.18 (s, 9H).

[0344] N-[3-(5-bromopyrimidin-2-yl)oxetan-3-yl]-2-methyl-propane-2-sulfinamide

[0345] To a solution of 5-bromo-2-iodo-pyrimidine (796 mg, 2.8 mmol, 1.4 eq) in DCM (16 mL) was added dropwise n-BuLi (2.5 M, 1 mL, 1.3 eq) at -75°C under N2and the reaction was stirred at -75°C for 0.5 hr. A solution of 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (350 mg, 2 mmol, 1 eq) in DCM (4 mL) was added dropwise at -75°C and the reaction mixture was stirred at -75°C for 1 hr and then at 25°C for 1.5 hr under N2. The reaction was slowly quenched with sat. NH4Cl (30 mL). H2O (30 mL) was added and extracted with DCM (20 mL x 95 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO 3). The organic layers were combined and concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 0 / 1) to give the title compound as a yellow oil (200 mg, 20% yield, 92% purity).1H NMR (400 MHz, DMSO-d6) δ = 9.08 (s, 2H), 6.39 (b, 1H), 5.07 (d, J = 6.4 Hz, 1H), 4.99 (d, J = 6.4 Hz, 1H), 4.89 (d, J = 6.4 Hz, 1H), 4.84 (d, J = 6.4 Hz, 1H), 1.10 (s, 9H).

[0346] N-(3-(5-((7R,14R)-1-Cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2-yl)oxetan-3-yl)-2- methyl propane-2-sulfinamide

[0347] A mixture of N-[3-(5-bromopyrimidin-2-yl)oxetan-3-yl]-2-methyl-propane-2- sulfinamide (37 mg, 110 μmol, 1 eq), (7R,14R)-1-cyclopropyl-6-methyl-11-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (50 mg, 110 μmol, 1 eq), K3PO4 (0.5 M, 439 μL, 2 eq), and XPHOS- PD-G2 (8 mg, 11 μmol, 0.1 eq) in THF (8 mL) was degassed and purged with N2for 3 times, and the reaction mixture was stirred at 100°C for 4 hr. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow oil (50 mg, crude).

[0348] (7R,14R)-11-(2-(3-aminooxetan-3-yl)pyrimidin-5-yl)-1-cyclopropyl-6-methyl-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0349] A mixture of N-(3-(5-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro- 7,14-methanobenzo [f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2-yl)oxetan-3-yl)- 2-methylpropane-2-sulfinamide (50 mg, 86 μmol, 1 eq) in DCM (1 mL) and TFA (0.5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25°C for 12 hr. The reaction mixture was concentrated in vacuo to give a residue which was purified by prep-HPLC (FA condition; column: Phenomenex Luna C18100*40mm*5 µm;mobile phase: [H2O(0.2% FA)- ACN];gradient:10%-35% B over 8.0 min) to give the title compound as a white solid (4 mg, 8% yield, 99% purity).1H NMR (400 MHz, DMSO-d6) δ = 9.14 (s, 2H), 8.20-8.14 (m, 1H), 7.83-7.76 (m, 2H), 7.66-7.59 (m, 1H), 7.34-7.26 (m, 2H), 6.68 (d, J = 7.2 Hz, 1H), 5.21 (d, J = 6.8 Hz, 1H), 4.99 (d, J = 6.0 Hz, 2H), 4.64 (d, J = 6.0 Hz, 2H), 3.57-3.49 (m, 1H), 3.31 (s, 3H), 2.85-2.76 (m, 2H), 2.55-25.2 (m, 2H), 1.31-1.19 (m, 2H), 1.05-0.97 (m, 1H), 0.80-0.72 (m, 1H) 96 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0350] Example 43: Synthesis of (7R,14R)-1-cyclopropyl-11-(4- (dimethylphosphoryl)piperidin-1-yl)-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (49) N N OClNO O

[0352] A suspension of Pd2(dba)3(869 mg, 949 μmol, 0.03 eq) and Xantphos (1.1 g, 2 mmol, 0.06 eq) in dioxane (50 mL) was stirred at 25°C for 10 min under N2.4-Bromopyridine (5 g, 32 mmol, 1 eq), K3PO4(7.4 g, 35 mmol, 1.1 eq), and methylphosphonoylmethane (2.7 g, 35 mmol, 1.1 eq) were added and the reaction mixture was stirred at 100°C for 12 hr under N2. The reaction mixture (combined with another batch at 0.5 g scale) was poured into H2O (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried with anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography (Ethylacetate / MeOH=50 / 1, 5 / 1) to give the title compound as a yellow solid (3.5 g, 80% purity).1H NMR (400 MHz, DMSO-d6) δ = 8.81-8.69 (m, 2H), 7.78-7.69 (m, 2H), 1.70 (d, J = 13.6 Hz, 6H).

[0353] Dimethyl(piperidin-4-yl)phosphine oxide

[0354] To a solution of dimethyl(pyridin-4-yl)phosphine oxide (0.5 g, 3 mmol, 1 eq) in MeOH (15 mL) was added Pd / C (100mg, 10% purity) under Ar and the reaction mixture was degassed under vacuum and purged with H2several times. The reaction mixture was stirred under H2(3 MPa) at 120°C for 24 hr. The reaction mixture was filtered through a pad of Celite® and the filter cake was washed with MeOH (200 mL). The filtrate was concentrated in vacuo to give the title compound as a black solid (0.5 g, crude).

[0355] (7R,14R)-1-Cyclopropyl-11-(4-(dimethylphosphoryl)piperidin-1-yl)-6-methyl-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-5(14H)-one

[0356] To a solution of (7R,14R)-11-chloro-1-cyclopropyl-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo [4,5]imidazo[1,2-a][1,4]diazocine-5(14H)-one (0.02 g, 55 μmol, 1 eq) in dioxane (0.5 mL) was added tBuONa (32 mg, 330 μmol, 6 eq), [2-(2-aminophenyl)phenyl]-chloro- 97 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO palladium;dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (4 mg, 5 μmol, 0.1 eq), and dimethyl(piperidin-4-yl)phosphine oxide (26 mg, 165 μmol, 3 eq) and the rection mixture was stirred at 110°C for 12 hr under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: Phenomenex Luna C18100*40mm*5 µm;mobile phase: [H2O(0.2% FA)-ACN];gradient:12%-42% B over 8.0 min) to give the title compound as a white solid (6 mg, 22% yield, 95% purity).1H NMR (400 MHz, CDCl3) δ = 8.43 (dd, J = 1.6, 7.8 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.35-7.28 (m, 2H), 6.95 (d, J = 8.8 Hz, 1H), 6.87 (s, 1H), 6.47 (d, J = 7.6 Hz, 1H), 4.88 (d, J = 7.2 Hz, 1H), 3.72-3.65 (m, 2H), 3.46 (s, 3H), 3.44-3.37 (m, 1H), 2.83 (d, J = 13.2 Hz, 1H), 2.75-2.63 (m, 2H), 2.46 (s, 1H), 2.04 (s, 2H), 1.84-1.74 (m, 3H), 1.49 (d, J = 12.4 Hz, 6H), 1.32-1.26 (m, 2H), 1.13-1.05 (m, 1H), 0.81-0.73 (m, 1H).

[0357] Example 44: Synthesis of (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-6- methyl-1-((1S,2S)-2-methylcyclopropyl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14 H)-one (50) N N N O n Omethanobenzo[f] benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0359] A mixture of (7R,14R)-11-chloro-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5] imidazo[1,2-a][1,4]diazocin-1-yl trifluoromethanesulfonate (0.15 g, 318 μmol, 1 eq), 4,4,5,5-tetramethyl-2-[(E)-prop-1-enyl]-1,3,2-dioxaborolane (48 mg, 286 μmol, 98 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO 0.9 eq), TMSOK (82 mg, 636 μmol, 2 eq), and dichloromethane;dicyclohexyl-[2-(2,6- dimethoxyphenyl)phenyl]phosphane;methanesulfonate;[2-[2- (methylamino)phenyl]phenyl]palladium(1+) (56 mg, 64 μmol, 0.2 eq) in THF (1 mL) was degassed and purged with N2 for 3 times. The reaction mixture was stirred at 100°C for 4 hr under N2. The reaction mixture (combined with other 5 batches at 150 mg scale) was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which purified by prep-HPLC (column: Waters XbridgeBEH C18100*30mm*10µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:40%-70% B over 8.0 min) to give the title compound as a white solid (95 mg, 261 μmol). MS: [M+H]+= 363.9.

[0360] (7R,14R)-11-chloro-6-methyl-1-((1S,2S)-2-methylcyclopropyl)-6,7-dihydro-7,14- methanobenzo[f] benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0361] A mixture of (7R,14R)-11-chloro-6-methyl-1-((E)-prop-1-en-1-yl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (43 mg, 118 μmol, 1 eq), diiodomethane (95 mg, 354 μmol, 3 eq), 8-(iodomethyl)-8,8'-spirobi [7,9-dioxa-8- silanuidabicyclo[4.3.0]nona-1(6),2,4-triene]; triethylammonium (288 mg, 591 μmol, 5 eq), and 2,4,5,6-tetra(carbazol-9-yl)benzene-1,3-dicarbonitrile (9 mg, 12 μmol, 0.1 eq) in DMSO (0.8 mL) was degassed and purged with N2 for 3 times. The reaction mixture was stirred at 25°C for 12 hr with 30 W blue LED under N2. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: WePure Biotech XP tC18 150*40*7µm;mobilephase: [H2O(10 mM NH4HCO3)- ACN];gradient:40%-70% B over 8.0 min) to give the title compound as a white solid (11 mg, 29 μmol). MS: [M+H]+= 377.9.

[0362] (7R,14R)-11-chloro-6-methyl-1-((1R,2R)-2-methylcyclopropyl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0363] (7R,14R)-11-chloro-6-methyl-1-((1S,2S)-2-methylcyclopropyl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (30 mg, 79 μmol, 1 eq) was separated by SFC (column: DAICELCHIRALCELOD(250mm*30mm,10µm);mobile phase:[CO2-IPA(0.1% NH3H2O)]; gradient 20%-40% B over 11.0 min) to give the title compound as a white solid (10 mg, 98% purity). 99 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0364] tert-Butyl(1-(5-((7R,14R)-6-methyl-1-((1S,2S)-2-methylcyclopropyl)-5-oxo-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2- yl)cyclobutyl)carbamate

[0365] To a solution of (7R,14R)-11-chloro-6-methyl-1-((1S,2S)-2-methylcyclopropyl)-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (7 mg, 18 μmol, 1 eq) and (2-(1-((tert-butoxycarbonyl)amino)cyclobutyl)pyrimidin-5-yl)boronic acid (8 mg, 28 μmol, 1.5 eq) in THF (1 mL) was added K3PO4(0.5 M, 74 μL, 2 eq) and XPHOS-PD-G2(2 mg, 2 μmol, 0.1 eq) under N2. The reaction mixture was stirred at 100°C for 4 hr under N2. The reaction mixture (combined with another batch at 5 mg scale) was filtered through a pad of Celite® and the filtrate was concentrated in vacuo to give the title compound as a crude black oil (18 mg, crude) as a black oil. MS: [M+H]+= 591.4.

[0366] (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-6-methyl-1-((1S,2S)-2- methylcyclo propyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14 H)-one

[0367] A solution of tert-butyl (1-(5-((7R,14R)-6-methyl-1-((1S,2S)-2-methylcyclopropyl)-5- oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11- yl)pyrimidin-2-yl)cyclobutyl) carbamate (18 mg, 30 μmol, 1 eq) in HCl / EtOAc (4 M, 1 mL) was stirred at 20°C for 1 hr. The reaction mixture was concentrated in vacuo to give a residue which was purified by prep-HPLC(column: Phenomenex Luna C18 100*30mm*5µm;mobile phase: [H2O(0.2% FA)-ACN];gradient:5%-40% B over 8.0 min) to give the title compound as a white solid (5.6 mg, 100% purity).1H NMR (400 MHz, MeOD-d4) δ = 9.00 (s, 2H), 8.25 (dd, J = 2.4, 7.2 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 1.2 Hz, 1H), 7.57 (dd, J = 1.6, 8.4 Hz, 1H), 7.32- 7.28 (m, 2H), 6.75 (d, J = 7.6 Hz, 1H), 5.19 (d, J = 7.2 Hz, 1H), 3.61-3.55 (m, 1H), 3.43 (s, 3H), 2.87 (d, J = 13.6 Hz, 1H), 2.80-2.73 (m, 2H), 2.43-2.38 (m, 1H), 2.32-2.25 (m, 2H), 2.14-2.04 (m, 2H), 1.55-1.47 (m, 1H), 1.45-1.43 (m, 3H), 1.12-1.07 (m, 1H), 0.96-0.93 (m, 1H). MS: [M+H]+= 491.3.

[0368] Example 45: Synthesis of (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-6- methyl-1-((1R,2R)-2-methylcyclopropyl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (51) 100 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO NN B(OH)2N N N N N N N O N O 4M HCl / EtOAc N NHB O Cl oc N N ,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2- yl)cyclobutyl)carbamate

[0370] To a solution of (7R,14R)-11-chloro-6-methyl-1-((1R,2R)-2-methylcyclopropyl)-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (7 mg, 19 μmol, 1 eq) and (2-(1-((tert-butoxycarbonyl)amino)cyclobutyl)pyrimidin-5-yl)boronic acid (7 mg, 24 μmol, 1.3 eq) in THF (1 mL) was added K3PO4 (0.5 M, 74 μL, 2 eq) and XPHOS-PD-G2 (1.5 mg, 2 μmol, 0.1 eq) under N2. The reaction mixture was stirred at 100°C for 4 hr under N2. The reaction mixture (combined with another batch at 3 mg scale) was treated with H2O (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with H2O, dried over Na2SO4and filtered. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (15 mg, crude). MS: [M+H]+= 591.5.

[0371] (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-6-methyl-1-((1R,2R)-2- methylcyclopropyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4] diazocin- 5(14H)-one

[0372] A solution of tert-butyl (1-(5-((7R,14R)-6-methyl-1-((1R,2R)-2-methylcyclopropyl)-5- oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11- yl)pyrimidin-2-yl)cyclobutyl) carbamate (15 mg, 25 μmol, 1 eq) in HCl / EtOAc (4 M, 1 mL) was stirred at 20°C for 1 hr. The reaction mixture was concentrated in vacuo to give a residue which was purified by prep-HPLC (HCl condition; column: Phenomenex Luna C18 100*40mm*5 µm;mobile phase: [H2O(0.04% HCl)-ACN];gradient:10%-45% B over 8.0 min) to give the title compound as a white solid (5.1 mg, 10 μmol, 99.8% purity.1H NMR (400 MHz, MeOD-d4) δ = 9.17 (s, 2H), 8.30 (dd, J = 1.2, 8.0 Hz, 1H), 7.99-7.96 (m, 2H), 7.90-7.87 (m, 1H), 7.37-7.33 (m, 1H), 7.30-7.27 (m, 1H), 6.95 (d, J = 7.2 Hz, 1H), 5.58 (d, J = 7.2 Hz, 1H), 3.81-3.73 (m, 1H), 3.46 (s, 3H), 3.07 (d, J = 13.6 Hz, 1H), 2.94-2.86 (m, 2H), 2.66-2.62 (m, 2H), 2.51-2.45 (m, 1H), 2.44- 2.25 (m, 2H), 1.43 (d, J = 5.6 Hz, 3H), 1.30-1.20 (m, 2H), 1.18-1.16 (m, 1H). MS: [M+H]+= 491.2. 101 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0373] Example 46: Synthesis of (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-1-(1- hydroxycyclobutyl)-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo [1,2- a][1,4]diazocin-5(14H)-one (52) N N N OCl NNB2Pin2 Cl NNCuBr2, TBAB Cl NN O O O DCM O -dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0375] To a solution of (7R,14R)-11-chloro-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-1-yl trifluoromethanesulfonate (1 g, 2 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (1.6 g, 6 mmol, 3 eq) in dioxane (10 mL) was added Pd(dppf)Cl2(77 mg, 106 μmol, 0.05 eq), KOAc (624 mg, 6 mmol, 3 eq) under N2. The reaction mixture was stirred at 100°C for 3 hr under N2. H2O (40 mL) was added and the reaction mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (neutral condition; column: WePure Biotech XP tC18250*70*10µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:40%-75% B over 20.0 min) to give the title compound as a white solid (450 mg, 96% purity).

[0376] (7R,14R)-1-bromo-11-chloro-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5] imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0377] To a solution of (7R,14R)-11-chloro-6-methyl-1-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (225 mg, 500 μmol, 1 eq) and dibromocopper (223 mg, 1 mmol, 2 eq) in DMF (4 mL), IPA (4 mL) and H2O (4 mL) was added TBAB (80 mg, 250 μmol, 0.5 eq) under N2. The reaction mixture was stirred at 100°C for 2 hr under N2. Sat. NH4Cl (10 mL) was then added at 0°C, followed by H2O (10 mL), and the solution was extracted with EtOAc (10 mL x 3). The combined 102 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and the filtrate concentrated in vacuo to give a residue which was purified by prep-HPLC (neutral condition;column: WePure Biotech XP tC18 150*40*7µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:37%-67% B over 8.0 min) to give the title compound as a white solid (95 mg, 93% purity).1H NMR (400 MHz, DMSO-d6) δ = 8.41 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 7.2 Hz, 1H), 7.67-7.65 (m, 2H), 7.39 (t, J = 8.0 Hz, 1H), 7.25-7.22 (dd, J = 1.6, 8.4 Hz, 1H), 6.39 (d, J = 7.6 Hz, 1H), 5.24 (d, J = 7.2 Hz, 1H), 3.54-3.47 (m, 1H), 3.32 (s, 3H), 2.86 (d, J = 13.6 Hz, 1H).

[0378] (7R,14R)-11-chloro-1-(1-hydroxycyclobutyl)-6-methyl-6,7-dihydro-7,14- methanobenzo[f] benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0379] To a solution of (7R,14R)-1-bromo-11-chloro-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (95 mg, 236 μmol, 1 eq) and cyclobutanone (25 mg, 354 μmol, 1.5 eq) in DCM (5 mL) was added n-BuLi (2.5 M, 570 μL, 6 eq) under N2 at -78°C. The reaction mixture was stirred at -78°C for 1 h, then it was allowed to warm to 20°C and stirred for 3 hr under N2. The reaction was quenched with sat. NH4Cl (10 mL) at 0 °C, diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: WePure Biotech XP tC18150*40*7µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:30%-60% B over 8.0 min ) to give the title compound as a white solid (50 mg, 51% yield, 94% purity).1H NMR (400 MHz, DMSO-d6) δ = 8.15 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.65-7.58 (m, 2H), 7.37 (t, J = 16.0 Hz, 1H), 7.16 (dd, J = 2.0, 8.4 Hz, 1H), 6.61 (s, 1H), 6.27 (d, J = 7.2 Hz, 1H), 5.11 (d, J = 6.4 Hz, 1H), 3.48-3.43 (m, 1H), 3.21 (s, 3H), 3.02-2.99 (m, 1H), 2.72 (d, J = 13.6 Hz, 1H), 2.67-2.63 (m, 1H), 2.44-2.33 (m, 2H), 2.09-1.99 (m, 1H), 1.63-1.53 (m, 1H).

[0380] tert-Butyl (1-(5-((7R,14R)-1-(1-hydroxycyclobutyl)-6-methyl-5-oxo-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2- yl)cyclobutyl)carbamate

[0381] To a solution of (7R,14R)-11-chloro-1-(1-hydroxycyclobutyl)-6-methyl-6,7-dihydro- 7,14-methanobenzo [f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (20 mg, 50 μmol, 1 eq) and [2-[1-(tert-butoxycarbonylamino)cyclobutyl]pyrimidin-5-yl]boronic acid (19 mg, 66 μmol, 1.3 eq) in THF (2 mL) was added K3PO4 (0.5 M, 203 μL, 2 eq) and XPHOS-Pd-G2 (4 mg, 5 μmol, 103 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO 0.1 eq) under N2. The reaction mixture was stirred at 100°C for 2 hr under N2. H2O (10 mL) was added and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow oil (30 mg, crude).

[0382] (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-1-(1-hydroxycyclobutyl)-6- methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0383] A solution of tert-butyl (1-(5-((7R,14R)-1-(1-hydroxycyclobutyl)-6-methyl-5-oxo- 5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11- yl)pyrimidin-2-yl)cyclobutyl)carbamate (30 mg, 49 μmol, 1 eq) in HCl / EtOAc (4 M, 1 mL) was stirred at 20°C for 1 hr. The reaction mixture was concentrated in vacuo to give a residue which was purified by prep-HPLC (HCl condition; column: Phenomenex Luna C18 100*40mm*5 µm;mobile phase: [H2O(0.04% HCl)-ACN];gradient:5%-40% B over 8.0 min) to give the title compound as a white solid (9.2 mg, 34% yield, 100% purity).1H NMR (400 MHz, DMSO-d6) δ = 9.19 (s, 2H), 8.88 (b, 3H), 8.39 (m, 1H), 8.16 (dd, J = 1.2, 8.0 Hz, 1H), 7.79-7.75 (m, 1H), 7.70- 7.64 (m, 2H), 7.38 (t, J = 8.0 Hz, 1H), 6.35 (d, J = 7.6 Hz, 1H), 5.19 (d, J = 6.8 Hz, 1H), 3.25 (s, 3H), 3.06–3.00 (m, 1H), 2.77 (d, J = 13.6 Hz, 1H), 2.73-2.66 (m, 3H), 2.61-2.54 (m, 3H), 2.46- 2.39 (m, 2H), 2.22-2.07 (m, 3H), 1.69-1.59 (m, 1H).

[0384] Example 47: Synthesis of (7R,14R)-11-(4-(1-aminocyclobutyl)-3-fluorophenyl)-1- cyclopropyl-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (53) Br Br Br BrO Br Br NC NC H2O2, K2CO3H2N 3N HCl / dioxane=1:1 TEA, DPPA HO2C 12 hN O

[0386] To a solution of 2-(4-bromo-2-fluoro-phenyl)acetonitrile (4 g, 19 mmol, 1 eq) and 1,3- dibromopropane (4 g, 21 mmol, 2 mL, 1.1 eq) in THF (5 mL) was added drop wise to a suspension of NaH (2 g, 41 mmol, 60% purity, 2.2 eq) in anhydrous DMA (20 mL) at 0°C and the reaction 104 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO mixture was stirred at 25°C for 1 hr. Then the reaction mixture was cooled to 0°C and quenched with sat. NH4Cl (50 mL) and extracted with ethyl acetate (50 ml x 3). The combined organic layers were dried with brine and Na2SO4, filtered and the filtrate was concentrated in vacuo give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 20 / 1) to give the title compound as a colorless oil (3 g, 65% yield).1H NMR (400 MHz, DMSO- d6) δ = 7.66 (dd, J = 1.6, 10.4 Hz, 1H), 7.50 (dd, J = 1.6, 8.4 Hz, 1H), 7.40 (t, J = 8.4 Hz, 1H), 2.80-2.70 (m, 2H), 2.70-2.60 (m, 2H), 2.39-2.23 (m, 1H), 2.02-1.92 (m, 1H).

[0387] 1-(4-Bromo-2-fluoro-phenyl) cyclobutanecarboxamide

[0388] H2O2(1 g, 12 mmol, 1 mL, 30% purity, 2 eq) was added to a suspension of 1-(4-bromo- 2-fluorophenyl) cyclobutanecarbonitrile (2 g, 6 mmol, 1 eq) and K2CO3(163 mg, 1 mmol, 0.2 eq) in DMSO (30 mL) under N2 and the reaction mixture was stirred at 20°C for 12 hr. The reaction mixture was poured into sat. Na2SO3 (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mLx2), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1 to 6 / 1) to give the title compound as a colorless oil (1.3 g, 80% yield).1H NMR (400 MHz, DMSO-d6) δ = 7.44 (dd, J = 1.8, 10.4 Hz, 1H), 7.41-7.38 (m, 1H), 7.36-7.30 (m, 1H), 6.97 (s, 1H), 6.88 (s, 1H), 2.71-2.63 (m, 2H), 2.37-2.29 (m, 2H), 1.98- 1.89 (m, 1H), 1.82-1.72 (m, 1H).

[0389] 1-(4-Bromo-2-fluoro-phenyl)cyclobutanecarboxylic acid

[0390] To a solution of 1-(4-bromo-2-fluoro-phenyl)cyclobutanecarboxamide (1.3 g, 5 mmol, 1 eq) in dioxane (13 mL) was added aq. HCl (3M, 13 mL) and the reaction mixture was stirred at 100°C for 12 hr. The reaction mixture was poured into H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mLx2), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give the title compound as a white solid (1.2 g, 93% yield).1H NMR (400 MHz, DMSO-d6) δ = 12.52 (b, 1H), 7.46 (dd, J = 1.6, 10.4 Hz, 1H), 7.43-7.37 (m, 1H), 7.34-7.25 (m, 1H), 2.73-2.57 (m, 2H), 2.48-2.35 (m, 2H), 2.19-2.00 (m, 1H), 1.98-1.65 (m, 1H).

[0391] tert-Butyl N-[1-(4-bromo-2-fluoro-phenyl)cyclobutyl]carbamate

[0392] A mixture of 1-(4-bromo-2-fluoro-phenyl)cyclobutanecarboxylic acid (0.1 g, 366 μmol, 1 eq), TEA (93 mg, 915 μmol, 127 μL, 2.5 eq), and DPPA (252 mg, 915 μmol, 198 μL, 2.5 eq) in t-BuOH (1 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was 105 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO stirred at 80°C for 12 hr. The reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with sat. NaHCO3 (50 mL x 2), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 6:1) to give the title compound as a white solid (20 mg, 14% yield, 87% purity).1H NMR (400 MHz, CDCl3) δ = 7.36-7.28 (m, 1H), 7.26-7.23 (m, 1H), 7.21-7.17 (m, 1H), 5.30-5.08 (m, 1H), 2.61-2.51 (m, 2H), 2.51-2.38 (m, 2H), 2.24-2.12 (m, 1H), 1.91-1.80 (m, 1H), 1.35 (s, 9H).

[0393] tert-Butyl(1-(4-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)-2-fluorophenyl) cyclobutyl)carbamate

[0394] A mixture of tert-butyl N-[1-(4-bromo-2-fluoro-phenyl)cyclobutyl]carbamate (20 mg, 51 μmol, 1 eq), (7R,14R)-1-cyclopropyl-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (23 mg, 51 μmol, 1 eq), K3PO4 (0.5 M, 202 μL, 2 eq), and XPHOS-PD-G2 (4 mg, 5 μmol, 0.1 eq) in THF (1 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 100°C for 6 hr. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 0:1) to give the title compound as a white solid (20 mg, 53% yield, 80% purity).

[0395] (7R,14R)-11-(4-(1-aminocyclobutyl)-3-fluorophenyl)-1-cyclopropyl-6-methyl-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0396] To a solution of tert-butyl (1-(4-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)-2- fluorophenyl)cyclobutyl)carbamate (15 mg, 25 μmol, 1 eq) in DCM (2 mL) was added TFA (0.3 mL) and the reaction mixture was stirred at 20°C for 1 hr. The reaction mixture (combined with another batch at 5 mg scale) was concentrated in vacuo to give a residue which was purified by prep-HPLC (NH4HCO3condition column: WePure Biotech XP tC18150*40*7µm;mobile phase: [H2O(10 mMNH4HCO3)-ACN];gradient:35%-70% B over 8.0 min) to give the title compound as a white solid (8 mg, 100% purity).1H NMR (400 MHz, DMSO-d6) δ = 8.17 (dd, J = 1.2, 8.0 Hz, 1H), 7.74-7.64 (m, 2H), 7.49 (dd, J = 1.6, 8.4 Hz, 1H), 7.45-7.33 (m, 3H), 7.32-7.26 (m, 1H), 7.26- 7.21 (m, 1H), 6.66 (d, J = 7.6 Hz, 1H), 5.19 (d, J = 6.8 Hz, 1H), 3.55-3.49 (m, 1H), 3.30 (s, 3H), 106 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO 2.85-2.75 (m, 2H), 2.47-2.42 (m, 1H), 2.17-2.08 (m, 4H), 1.77-1.64 (m, 1H), 1.34-1.16 (m, 2H), 1.06-0.91 (m, 1H), 0.85-0.75 (m, 1H).

[0397] Example 48: Synthesis of (7R,14R)-1-cyclopropyl-11-(4-hydroxy-4-methylchroman-7- yl)-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- one (54) N PinBNN O )

[0399] A solution of 7-bromochroman-4-one (5 g, 22 mmol, 1 eq), 2-methylpropane-2- sulfinamide (3 g, 24 mmol, 1.1 eq), and Ti(OEt)4(7.5 g, 33 mmol, 7 mL, 1.5 eq) in THF (50 mL) was degassed and purged with N2 for 3 times, and the reaction mixture was stirred at 45°C for 12 hr under N2. The reaction mixture was quenched with sat. NaHCO3 to pH=7-8, diluted with H2O (50 mL), and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~5% Ethyl acetate / Petroleum ethergradient @60 mL / min) to give the title compound as a yellow oil (2.47 g, 34% yield). MS: [M+H]+= 330.0.

[0400] N-(7-Bromo-4-methylchroman-4-yl)-2-methylpropane-2-sulfinamide

[0401] To a solution of (Z)-N-(7-bromochroman-4-ylidene)-2-methylpropane-2-sulfinamide (2.47 g, 7.5 mmol, 1 eq) in toluene (30 mL) was added MeMgBr (3 M, 7.5 mL, 3 eq) dropwise at -78°C under N2 and the reaction mixture was warmed to 20°C and stirred for 2 hr under N2. The reaction mixture was quenched with sat. NH4Cl (50 mL), diluted with H2O (50 mL), and extracted 107 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO with ethyl acetate (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~5% Ethyl acetate / Petroleum ethergradient @ 80 mL / min) to give the title compound as an orange solid (1.29 g, 50% yield). MS: [M+H]+= 346.1.

[0402] N-(7-((7R,14R)-1-Cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)-4-methylchroman-4-yl)-2- methylpropane-2-sulfinamide

[0403] A solution of N-(7-bromo-4-methylchroman-4-yl)-2-methylpropane-2-sulfinamide (32 mg, 94 μmol, 1 eq), (7R,14R)-1-cyclopropyl-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (43 mg, 94 μmol, 1 eq), XPHOS-PD-G2 (7 mg, 9 μmol, 0.1 eq), and K3PO4 (0.5 M, 377 μL, 2 eq) in THF (2 mL) was degassed and purged with N2for 3 times, and the reaction mixture was stirred at 100°C for 4 hr. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAC (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-TLC (Petroleum ether: Ethyl acetate=1:2) to give the title compound as a yellow solid (50 mg, crude).

[0404] (7R,14R)-1-cyclopropyl-11-(4-hydroxy-4-methylchroman-7-yl)-6-methyl-6,7-dihydro- 7,14 -methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0405] A solution of N-(7-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenz[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)-4-methylchroman-4-yl)-2- methylpropane-2-sulfinamide (50 mg, 84.07 μmol, 1 eq) in HCl / EtOAc (4 M, 1 mL) was stirred at 20°C for 1 hr. The reaction mixture was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:25%-80% B over 8.0 min) to give the title compound as a yellow solid (6.1 mg, 13% yield, 94% purity).1H NMR (400 MHz, DMSO-d6) δ = 12.17 (b, 1H), 8.17 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.77-7.68 (m, 1H), 7.61-7.53 (m, 1H), 7.31-7.27 (m, 1H), 7.24-7.16 (m, 3H), 6.68 (d, J = 7.2 Hz, 1H), 5.20 (d, J=6.8 Hz, 1H), 3.56-3.41 (m, 1H), 3.31 (s, 3H), 3.08 (t, J = 7.2 Hz, 2H), 2.82-2.75 (m, 1H), 1.70-1.64 (m, 2H), 1.29-1.23 (m, 3H), 1.02-0.94 (m, 4H), 0.85-0.80 (m, 1H). 108 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0406] Example 49: Synthesis of (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-1- cyclopropyl-2-fluoro-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (55) OOO OO OO t-Bu eq)y y p py 109 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0408] A mixture of methyl 6-amino-2-bromo-3-fluoro-benzoate (23 g, 77 mmol, 1 eq), cyclopropylboronic acid (10 g, 115 mmol, 1.5 eq), Pd(dppf)Cl2 (5.6 g, 8 mmol, 0.1 eq), and Cs2CO3(75 g, 231 mmol, 3 eq) in dioxane (190 mL) and H2O (38 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 100°C for 2 hr. The reaction mixture (combined with other 2 batches at 23 g scale and 11 g scale) was poured into H2O (200 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 50 / 1) to give the title compound as a colorless oil (44 g, 78% yield).1H NMR (400 MHz, DMSO-d6) δ = 6.94 (t, J = 9.2 Hz, 1H), 6.60 (dd, J = 4.4 Hz, J=9.2Hz, 1H), 5.24 (b, 2H), 3.82 (s, 3H), 1.82-1.73 (m, 1H), 0.86- 0.79 (m, 2H), 0.44-0.38 (m, 2H).

[0409] Methyl 6-bromo-2-cyclopropyl-3-fluorobenzoate

[0410] A mixture of methyl 6-amino-2-cyclopropyl-3-fluoro-benzoate (13 g, 62 mmol, 1 eq), CuBr (5.3 g, 37 mmol, 0.6 eq), CuBr2 (8.3 g, 37 mmol, 0.6 eq), and tert-butyl nitrite (9.6 g, 93 mmol, 11 mL, 1.5 eq) in MeCN (520 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 65°C for 2 hr. The reaction mixture (combined with other 2 batches at 13 g scale and 5 g scale) was poured into ice water (1 L) and extracted with EtOAc (800 mL x 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 1 / 0) to give the title compound as a yellow oil (40 g, 70% yield).1H NMR (400 MHz, DMSO-d6) δ = 7.59 (dd, J = 4.8, 8.8 Hz, 1H), 7.24 (dd, J = 9.2, 10.4 Hz, 1H), 3.90 (s, 3H), 1.79-1.74 (m, 1H), 0.95-0.87 (m, 2H), 0.71-0.64 (m, 2H).

[0411] (6-Bromo-2-cyclopropyl-3-fluorophenyl)methanol

[0412] Solution 1: methyl 6-bromo-2-cyclopropyl-3-fluoro-benzoate (40 g, 146 mmol, 1 eq) in DCM (400 mL). Solution 2: DIBAL-H (1 M, 586 mL, 5 eq). The solution 1 was pumped by Pump 1 (1.355 mL / min) to flow reactor 1 (PFA,Coils reactor,3.175(1 / 8’’) mm, 64.2 mL, 45°C). Solution 2 was pumped by Pump 2 (1.851 mL / min) to flow reactor 1 and the residence time of flow reactor 1 was 20 min. The reaction mixture was collected with a bottle (contained 200 mL sat. NaHCO3). The reaction mixture was filtered by Celite® and the filtrate was extracted with EtOAc (800 mL x 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give the title compound as a colorless oil (37 g, 81% yield).1H NMR 110 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO (400 MHz, DMSO-d6) δ = 7.49 (dd, J = 4.8, 8.8 Hz, 1H), 7.04 (dd, J = 8.8, 10.4 Hz, 1H), 5.04 (t, J = 5.2 Hz, 1H), 4.80 (d, J = 5.2 Hz, 2H), 1.94-1.88 (m, 1H), 1.01-0.97 (m, 2H), 0.79-0.75 (m, 2H).

[0413] 6-Bromo-2-cyclopropyl-3-fluorobenzaldehyde

[0414] To a solution of (6-bromo-2-cyclopropyl-3-fluoro-phenyl) methanol (17 g, 54 mmol, 1 eq) in DCE (340 mL) was added MnO2(47 g, 541mmol, 10 eq) and the reaction mixture was stirred at 80°C for 12 hr. The reaction mixture (combined with another batch at 17 g scale and 3.3 g scale) was filtered and the filtrate was concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 10 / 1) to give the title compound as yellow oil (24 g, 64% yield).1H NMR (400 MHz, DMSO-d6) δ = 10.37 (s, 1H), 7.65 (dd, J = 4.8, 8.8 Hz, 1H), 7.34 (dd, J = 8.8, 10.0 Hz, 1H), 2.03-1.97 (m, 1H), 0.99-0.94 (m, 2H), 0.63-0.59 (m, 2H).

[0415] (S,E)-N-(6-bromo-2-cyclopropyl-3-fluorobenzylidene)-2-methylpropane-2-sulfinamide

[0416] To a mixture of 6-bromo-2-cyclopropyl-3-fluoro-benzaldehyde (12 g, 44 mmol, 1 eq) and (S)-2-methylpropane-2-sulfinamide (5.9 g, 49 mmol, 1.1 eq) in THF (120 mL) was added Ti(OEt)4(15 g, 66 mmol, 14 mL, 1.5 eq) and the reaction mixture was stirred at 45°C for 12 hr. The reaction mixture (combined with another batch at 12 g scale) was added to sat. NH4Cl (500 mL), filtered and the filter cake was washed with THF (500 mL x 3). The combined organic layers were washed with sat. NaHCO3(800 mL), dried with anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 10 / 1) to give the title compound as a yellow oil (20 g, 62% yield).1H NMR (400 MHz, DMSO-d6) δ = 8.82 (s, 1H), 7.65 (dd, J = 4.8, 8.8 Hz, 1H), 7.25 (t, J = 9.2 Hz, 1H), 1.97-1.93 (m, 1H), 1.22 (s, 9H), 0.99-0.95 (m, 1H), 0.94-0.86 (m, 1H), 0.70-0.66 (m, 1H), 0.55-0.51 (m, 1H).

[0417] Ethyl (R)-3-(6-bromo-2-cyclopropyl-3-fluorophenyl)-3-(((S)-tert-butylsulfinyl)amino) propanoate

[0418] To a 500 mL three-necked round bottom flask was added THF (50 mL) followed by Zn (9.4 g, 144 mmol, 10 eq) and CuCl (2.1 g, 21 mmol, 1.5 eq) at 20°C under N2 and the reaction mixture was stirred at 70°C for 1 hr. The reaction mixture was cooled to 20°C and ethyl 2- bromoacetate (12 g, 72 mmol, 8 mL, 5 eq) in THF (10 mL) was added drop wise over 15 min. The reaction mixture was stirred at 50°C for 30 min. The reaction mixture was cooled to 0°C and 111 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO (NE,S)-N-[(6-bromo-2-cyclopropyl-3-fluoro-phenyl)methylene]-2-methyl-propane-2- sulfinamide (5 g, 14 mmol, 1 eq) in THF (10 mL) was added drop wise over 15 min. The reaction mixture was warmed to 20°C and stirred for 3 hr under N2. The reaction mixture (combined with other 2 batches both at 5 g scale) was diluted with TBME (150 mL) and a solution of citric acid (9 g) in H2O (50 mL) was then added, extracted with TBME (150 mL x 2), the combined organic layers were washed with H2O (150 mL x 3), saturated aqueous NaHCO3solution (160 mL x 3) and brine (100 mL x 3), then concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 5 / 1) to give the title compound (14 g, 67% yield, 90% purity).1H NMR (400 MHz, CDCl3) δ = 7.38 (dd, J = 4.8, 8.8 Hz, 1H), 6.81 (t, J = 9.2 Hz, 1H), 6.08 (d, J = 6.8 Hz, 1H), 4.74 (d, J = 8.8 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.73- 3.39 (m, 1H), 3.12-3.07 (m, 1H), 1.93-1.81 (m, 1H), 1.28-1.05 (m, 14H), 0.89-0.51 (m, 2H).

[0419] Ethyl (R)-3-amino-3-(6-bromo-2-cyclopropyl-3-fluorophenyl)propanoate

[0420] A solution of ethyl (3R)-3-(6-bromo-2-cyclopropyl-3-fluoro-phenyl)-3-[[(S)-tert- butylsulfinyl]amino]propanoate (14 g, 32 mmol, 1 eq) in HCl / EtOAc (4 M, 140 mL, 17 eq) was stirred at 25°C for 1 hr. The reaction mixture was poured into H2O (200 mL) and extracted with ethyl acetate (200 mL x 2). The aqueous layer was adjusted to pH=7~8 with sat. Na2CO3. The mixture was extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried with anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow oil (12 g, crude).1H NMR (400 MHz, MeOD-d4) δ = 7.46 (dd, J = 5.2, 8.8 Hz, 1H), 6.89 (dd, J = 8.8, 9.6 Hz, 1H), 5.51 (dd, J = 6.0, 8.4 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.18-3.14 (m, 1H), 3.00-2.94 (m, 1H), 1.84 (m, 1H), 1.19 (t, J = 7.2 Hz, 3H), 1.14-1.07 (m, 2H), 0.80-0.65 (m, 2H).

[0421] Ethyl (R)-3-(6-bromo-2-cyclopropyl-3-fluorophenyl)-3-((5-chloro-2- nitrophenyl)amino) propanoate

[0422] To a solution of ethyl (3R)-3-amino-3-(6-bromo-2-cyclopropyl-3-fluoro- phenyl)propanoate (12 g, 36 mmol, 1 eq) in DIEA (5.6 g, 44 mmol, 7.6 mL, 1.2 eq) was added 4- chloro-2-fluoro-1-nitro-benzene (5.7 g, 33 mmol, 0.9 eq) and the reaction mixture was stirred at 90°C for 1 hr under N2. The reaction was quenched with H2O (100 mL) at 25°C and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (150 mL x 2), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 10 / 1) to give the 112 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO title compound as a yellow oil (10 g, 51% yield, 90% purity).1H NMR (400 MHz, CDCl3) δ = 9.08 (b, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.45 (dd, J = 5.2, 8.8 Hz, 1H), 7.03-6.78 (m, 2H), 6.62 (dd, J = 2.0, 9.2 Hz, 1H), 6.19 (m, 1H), 4.19 (q, J = 7.2 Hz, 2H), 3.52-3.33 (m, 1H), 2.95 (dd, J = 4.0, 16.0 Hz, 1H), 1.89 (s, 1H), 1.30-1.19 (m, 5H), 0.93-0.66 (m, 2H).

[0423] (R)-3-(6-bromo-2-cyclopropyl-3-fluorophenyl)-3-((5-chloro-2-nitrophenyl)amino) propan-1-ol

[0424] Solution 1: ethyl (3R)-3-(6-bromo-2-cyclopropyl-3-fluoro-phenyl)-3-(5-chloro-2-nitro- anilino) propanoate (10 g, 20 mmol, 1 eq) in THF (100 mL). Solution 2: DIBAL-H (1 M, 72 mL, 3.5 eq). Solution 1 was pumped by Pump 1 (3.896 mL / min) to flow reactor 1 (10 min). Solution 2 was pumped by Pump 2 (2.524 mL / min) to flow reactor 1 (PFA,Coils reactor, 3.175(1 / 8’’) mm, 64.115 mL, 25°C). The residence time of flow reactor 1 was 10 min and the reaction mixture was collected with a bottle (contained 10 mL 15% aq. NaOH). The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow oil (10 g, crude).1H NMR (400 MHz, CDCl3) δ = 9.32-8.81 (m, 1H), 8.11 (d, J = 4.4Hz, 1H), 7.43 (m, 1H), 7.26-7.13 (m, 1H), 7.00 (m, 1H), 6.88-6.82 (m, 1H), 6.62-6.53 (m, 1H), 6.13-5.46 (m, 1H), 4.13-3.68 (m, 2H), 2.83-2.43 (m, 1H), 2.34-2.14 (m, 1H), 1.98-1.73 (m, 1H), 1.28-1.09 (m, 2H), 0.99-0.76 (m, 2H).

[0425] (R)-3-(6-bromo-2-cyclopropyl-3-fluorophenyl)-3-((5-chloro-2-nitrophenyl)amino) propanal

[0426] To a solution of (3R)-3-(6-bromo-2-cyclopropyl-3-fluoro-phenyl)-3-(5-chloro-2-nitro- anilino)propan-1-ol (10 g, 22 mmol, 1 eq) in DCM (100 mL) was added TEA (7 g, 66 mmol, 10 mL, 3 eq) at 0°C. Then SO3.Py (11 g, 66 mmol, 3 eq) in DMSO (14 mL) was added drop wise at 0°C and the reaction mixture was stirred at 25°C for 1 hr. The reaction was quenched with H2O (100 mL) at 25°C and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (150 mL x 2), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 5 / 1) to give the title compound as a yellow oil l (7 g, 60% yield, 85% purity).1H NMR (400 MHz, CDCl3) δ = 9.87 (s, 1H), 9.18-8.81 (m, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.46 (dd, J = 5.2, 8.8 Hz, 1H), 7.06-6.77 (m, 2H), 6.64 (dd, J = 2.0, 9.2 Hz, 1H), 6.43-6.14 (m, 1H), 3.72-3.65 (m, 1H), 3.15 (dd, J = 3.2, 18.4 Hz, 1H), 1.99-1.85 (m, 1H), 1.29-1.11 (m, 2H), 0.75 (m, 2H). 113 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0427] (4R)-4-(6-bromo-2-cyclopropyl-3-fluorophenyl)-4-((5-chloro-2-nitrophenyl)amino)-2- ((trimethylsilyl)oxy)butanenitrile

[0428] To a solution of (3R)-3-(6-bromo-2-cyclopropyl-3-fluoro-phenyl)-3-(5-chloro-2-nitro- anilino)propanal (4 g, 9 mmol, 1 eq) in DCM (40 mL) was added diiodozinc (578 mg, 1.8 mmol, 0.2 eq) and TEA (137 mg, 1.4 mmol, 189 μL, 0.15 eq) at 25°C and the reaction mixture was degassed and purged with N2for 3 times. TMSCN (2.3 g, 27 mmol, 2.8 mL, 2.5 eq) was added and reaction mixture was stirred for 2 hr at 25°C under N2. The reaction mixture was poured into ice water (200 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (150 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow oil (4.5 g, crude).1H NMR (400 MHz, CDCl3) δ = 9.14 (s, 1H), 8.17-8.10 (m, 1H), 7.45 (m, 1H), 7.12-6.81 (m, 2H), 6.69-6.61 (m, 1H), 6.21-5.74 (m, 1H), 4.80-4.50 (m, 1H), 2.59-2.31 (m, 1H), 1.98-1.76 (m, 1H), 1.25-1.06 (m, 2H), 1.01-0.76 (m, 2H), 0.29-0.10 (m, 9H).

[0429] (1R)-1-(6-bromo-2-cyclopropyl-3-fluorophenyl)-7-chloro-2,3-dihydro-1H-benzo[d] pyrrolo[1,2-a]imidazol-3-ol

[0430] To a solution of (4R)-4-(6-bromo-2-cyclopropyl-3-fluoro-phenyl)-4-(5-chloro-2-nitro- anilino)-2-trimethylsilyloxy-butanenitrile (4.5 g, 8 mmol, 1 eq) in EtOH (54 mL) was added SnCl2.2H2O (9.4 g, 42 mmol, 5 eq) and the reaction mixture was stirred at 75°C for 4 hr. The reaction mixture was poured into ice water (50 mL), the suspension was filtered through a pad of Celite®, and washed with ethyl acetate (200 mL). The aqueous layer was extracted with ethyl acetate (100 mL x 2) and the combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, petroleum ether: ethyl acetate=1:0 to 0:1) to give the title compound as a yellow solid (2 g, 51% yield, 90% purity).1H NMR (400 MHz, MeOH-d4) δ = 7.66-7.56 (m, 1H), 7.50-7.41 (m, 1H), 7.24-7.15 (m, 1H), 7.08 (t, J = 9.2 Hz, 1H), 6.95-6.60 (m, 1H), 6.59-6.43 (m, 1H), 5.60-5.34 (m, 1H), 4.59 (s, 1H), 3.52-3.33 (m, 1H), 3.11- 2.96 (m, 1H), 2.05-2.00 (m, 1H), 1.26-1.18 (m, 2H), 0.90-0.74 (m, 2H).

[0431] (1R)-3-azido-1-(6-bromo-2-cyclopropyl-3-fluorophenyl)-7-chloro-2,3-dihydro-1H- benzo[d]pyrrolo[1,2-a]imidazole

[0432] To a solution of (1R)-1-(6-bromo-2-cyclopropyl-3-fluoro-phenyl)-7-chloro-2,3- dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol (2 g, 4.7 mmol, 1 eq) in THF (20 mL) was added 114 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO DPPA (1.7 g, 6.2 mmol, 1.3 mL, 1.3 eq) and DBU (1 g, 6.6 mmol, 1 mL, 1.4 eq) at 0°C, and the reaction mixture was stirred at 50°C for 2 hr under N2. The reaction mixture was poured into H2O (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow oil (1.8 g, crude).

[0433] (1R)-1-(6-bromo-2-cyclopropyl-3-fluorophenyl)-7-chloro-2,3-dihydro-1H-benzo[d] pyrrolo[1,2-a]imidazol-3-amine

[0434] To a solution of(1R)-3-azido-1-(6-bromo-2-cyclopropyl-3-fluoro-phenyl)-7-chloro- 2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole (1.8 g, 4 mmol, 1 eq) in THF (18 mL) and H2O (1.8 mL) was added trimethylphosphane (1 M, 6 mL, 1.5 eq) and the reaction mixture was stirred at 25°C for 2 hr under N2. The reaction mixture was poured into H2O (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 0 / 1) to give the title compound as a yellow oil (1 g, 53% yield, 90% purity).1H NMR (400 MHz, MeOD-d4) δ = 7.59 (dd, J = 4.0, 8.4 Hz, 1H), 7.50-7.41 (m, 1H), 7.21-7.15 (m, 1H), 7.12-7.04 (m, 1H), 6.95- 6.62 (m, 1H), 6.59-6.42 (m, 1H), 4.79-4.67 (m, 1H), 3.54-3.32 (m, 1H), 2.97-2.74 (m, 1H), 2.07- 1.98 (m, 1H), 1.29-1.19 (m, 2H), 0.87-0.76 (m, 2H).

[0435] (7R,14R)-11-chloro-1-cyclopropyl-2-fluoro-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0436] To a solution of (1R)-1-(6-bromo-2-cyclopropyl-3-fluoro-phenyl)-7-chloro-2,3- dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-amine (1 g, 2.4 mmol, 1 eq) in DMSO (20 mL) was added K2CO3(986 mg,7 mmol, 3 eq), PhOH (492 mg, 5 mmol, 459μL, 2.2 eq), dichloropalladium;(5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (180 mg, 238 μmol, 0.1 eq), and 4A MS (330 mg). The reaction mixture was degassed and purged with CO 3 times and the reaction mixture was stirred under CO (15 psi) at 100°C for 16 hr. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate =1:0 to 0:1) to give the title compound as a brown oil (250 mg, 29% yield).1H NMR (400 MHz, MeOD-d4) δ = 8.41-8.27 (m, 1H), 7.59-7.53 (m, 1H), 7.37-7.30 (m, 115 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO 1H), 7.24-7.18 (m, 1H), 7.10 (t, J = 9.2 Hz, 1H), 6.95-6.90 (m, 1H), 4.93-4.89 (m, 1H), 3.58-3.43 (m, 1H), 2.83 (d, J = 13.6 Hz, 1H), 2.29-2.19 (m, 1H), 1.46-1.30 (m, 2H), 1.04-0.96 (m, 1H), 0.72 -0.66 (m, 1H).

[0437] (7R,14R)-11-chloro-1-cyclopropyl-2-fluoro-6-methyl-6,7-dihydro-7,14- methanobenzo[f] benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0438] To a solution of (7R,14R)-11-chloro-1-cyclopropyl-2-fluoro-6,7-dihydro-7,14- methanobenzo[f] benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (250 mg, 680 μmol, 1 eq) in THF (2.5 mL) was added KHMDS (1 M, 815 μL, 1.2 eq) at -78°C under N2 and the reaction mixture was stirred at -78°C for 1 hr. Iodomethane (145 mg, 1 mmol, 1.5 eq) was added and the reaction mixture stirred for 0.5 hr and then at 25°C for 1 hr. The reaction was quenched with sat. NH4Cl (5 mL) at 0°C, diluted with H2O (5 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 0 / 1) to give the title compound as a brown solid (100 mg, 34% yield, 90% purity).1H NMR (400 MHz, CDCl3) δ = 8.52-8.48 (m, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.24-7.19 (m, 2H), 7.04 (t, J = 9.2 Hz, 1H), 6.71 (d, J = 7.6 Hz, 1H), 4.91 (d, J = 7.2 Hz, 1H), 3.48-3.45 (m, 3H), 3.46 -3.42 (m, 1H), 2.84 (d, J = 13.6 Hz, 1H), 2.15-2.06 (m, 1H), 1.44-1.36 (m, 2H), 1.17-1.09 (m, 1H), 0.68-0.60 (m, 1H).

[0439] tert-Butyl (1-(5-((7R,14R)-1-cyclopropyl-2-fluoro-6-methyl-5-oxo-5,6,7,14-tetrahydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2- yl)cyclobutyl)carbamate

[0440] To a solution of (7R,14R)-11-chloro-1-cyclopropyl-2-fluoro-6-methyl-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (80 mg, 209 μmol, 1 eq) and [2-[1-(tert-butoxycarbonylamino)cyclobutyl]pyrimidin-5-yl]boronic acid (92 mg, 314 μmol, 1.5 eq) in THF (2 mL) was added K3PO4 (0.5 M, 838 μL, 2 eq) and XPHOS-PD-G2 (16 mg, 21 μmol, 0.1 eq) under N2and the reaction mixture was stirred at 90°C for 1 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a brown solid (90 mg, crude).

[0441] (7R,14R)-11-(2-(1-Aminocyclobutyl)pyrimidin-5-yl)-1-cyclopropyl-2-fluoro-6-methyl- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one 116 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0442] A solution of (1-(5-((7R,14R)-1-cyclopropyl-2-fluoro-6-methyl-5-oxo-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2- yl)cyclobutyl)carbamate (90 mg, 151 μmol, 1 eq) in HCl / EtOAc (4 M, 1 mL) was stirred at 25°C for 0.5 hr. The reaction mixture was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: Phenomenex Luna C18100*40 mm*5µm;mobile phase: [H2O(0.04% HCl)-ACN];gradient:15%-30% B over 8.0 minn) to give the title compound as a white solid (20 mg, 26% yield, 99% purity).1H NMR (400 MHz, DMSO-d6) δ = 9.25 (s, 2H), 8.96 (b, 3H), 8.26 (dd, J = 6.0, 9.2 Hz, 1H), 7.88-7.76 (m, 2H), 7.72-7.69 (m, 1H), 7.18 (t, J = 9.2 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 5.29 (d, J = 6.8 Hz, 1H), 3.63-3.51 (m, 1H), 3.32 (s, 3H), 2.88 (d, J = 13.6 Hz, 1H), 2.72-2.58 (m, 4H), 2.49-2.42 (m, 1H), 2.26-2.12 (m, 2H), 1.44-1.32 (m, 1H), 1.41-1.26 (m, 1H), 0.99-0.90 (m, 1H), 0.77-0.69 (m, 1H).

[0443] Example 50: Synthesis of (7R,14R)-11-(6-(1-aminocyclobutyl)pyridin-3-yl)-1- cyclopropyl-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (56) Br N H2N N N O

[0444] Aramethyl-1,3,2- dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (20 mg, 44 μmol, 1 eq), 1-(5-bromo-2-pyridyl)cyclobutanamine (10 mg, 44 μmol, 1 eq), K3PO4(0.5 M, 176 μL, 2 eq), and [2-(2-aminophenyl)phenyl]-chloro- palladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (3 mg, 4 μmol, 0.1 eq) in THF (1 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 100°C for 4 hr under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: Phenomenex Luna C18100*30mm*5µm; mobile phase: [H2O(0.2% FA)-ACN];gradient:5%-38% B over 8.0 min) to give the title compound as a white solid (3 mg, 14% yield, 99% purity).1H NMR (400 MHz, DMSO-d6) δ = 8.80 (d, J = 1.6 Hz, 1H), 8.17 (dd, J = 1.4, 7.7 Hz, 1H), 8.01 (dd, J = 2.2, 8.2 Hz, 1H), 7.79-7.64 (m, 3H), 7.52 (dd, J = 1.5, 8.5 Hz, 1H), 7.36-7.19 (m, 2H), 6.67 (d, J = 7.4 Hz, 117 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO 1H), 5.19 (d, J = 7.0 Hz, 1H), 3.55-3.49 (m, 1H), 3.30 (s, 3H), 2.84-2.74 (m, 2H), 2.62-2.51 (m, 2H), 2.18-2.08 (m, 2H), 2.07-1.95 (m, 1H), 1.84-1.70 (m, 1H), 1.31-1.21 (m, 2H), 1.04-0.94 (m, 1H), 0.82-0.74 (m, 1H).

[0445] Example 51: Synthesis of (7R,14R)-11-(2-(1-aminocyclobutyl) pyrimidin-5-yl)-1- ((1S,2R)-2-fluorocyclopropyl)-6,7-dihydro-7,14-methanobenzo[f] benzo [4,5] imidazo[1,2-a] [1,4] diazocin-5(14H)-one (57) trans cisNHPI (1.2 eq) O DIC (1.2 O O O CO2H eq)N CODMAP (0.1 eq)2EtBpin H O

[0447] To a mixture of 2-fluorocyclopropanecarboxylic acid (5.5 g, 52 mmol, 1 eq) and 2- hydroxyisoindoline-1,3-dione (10 g, 63 mmol, 1.2 eq) in DCM (50 mL) was added DIC (8 g, 63 mmol, 1.2 eq) and DMAP (645 mg, 5 mmol, 0.1 eq) under N2and the reaction mixture was stirred at 20°C for 12 hr under N2. The reaction mixture was filtered and the filter cake was washed with saturated NaHCO3 (50 mL) and 10% aq. NaHSO4 (50 mL). The filtrate was extracted with EtOAc (80 mL x 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, eluent of 0~15% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give the title compound (8.0 g).1H NMR (400 MHz, CDCl3) δ = 7.93- 7.88 (m, 2H), 7.82-7.80 (m, 2H), 5.09-4.91 (m, 1H), 2.48-2.42 (m, 1H), 1.84-1.74 (m, 1H), 1.62- 118 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO 1.53 (m, 1H) and 7.95-7.89 (m, 2H), 7.83-7.78 (m, 2H), 5.06-4.86 (m, 1H), 2.22-2.16 (m, 1H), 2.03-1.93 (m, 1H), 1.53-1.44 (m, 1H).

[0448] 2-((1R,2R)-2-Fluorocyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0449] A solution of (1,3-dioxoisoindolin-2-yl) (1R,2R)-2-fluorocyclopropanecarboxylate (3.9 g, 15 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (4.4 g, 17 mmol, 1.1 eq) and ethylpyridine-4-carboxylate (473 mg, 3 mmol, 428 μL, 0.2 eq) in EtOAc (40 mL) was degassed and purged with N2for 3 times. The reaction mixture was stirred at 90°C for 12 hr under N2. The reaction mixture was filtered and the filter cake was washed with sat. NaHCO3(20 mL). The filtrate was extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by flash silica gel chromatography (ISCO®; 2 g SepaFlash® Silica Flash Column, eluent of 0~15% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give the title compound as a colorless oil (0.71 g, 24% yield).1H NMR (400 MHz, DMSO-d6) δ = 4.78-4.59 (m, 1H), 1.16 (s, 12H), 1.13-1.07 (m, 1H), 0.66-0.59 (m, 1H), 0.38-0.26 (m, 1H).

[0450] Potassium; trifluoro((1R,2R)-2-fluorocyclopropyl) borate

[0451] To a solution of 2-[(1R,2R)-2-fluorocyclopropyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (0.67 g, 3.60 mmol, 1 eq) in MeOH (7 mL) was added H2O (454 mg, 25 mmol, 454 μL, 7 eq) and KHF2(4.5 M, 4.40 mL, 5.5 eq) under N2and the reaction mixture was stirred at 20°C for 12 hr under N2. The resulting suspension was concentrated in vacuo to give a residue which was resuspended in hot acetone (30 mL). The suspension was filtered and the filtrate was concentrated to about 5 mL. Cold hexanes (30 mL) was added and the mixture was filtered and the filter cake was washed with cold hexanes (30 mL), then the filter cake was dried in vacuo to give the title compound as a white solid (0.45 g, 75% yield).1H NMR (400 MHz, DMSO-d6) δ = 4.35-4.17 (m, 1H), 0.45-0.37 (m, 1H), 0.09 (m, 1H), -0.17--0.26 (m, 1H).

[0452] (7R,14R)-11-chloro-1-((1S,2R)-2-fluorocyclopropyl)-6,7-dihydro-7,14-methanobenzo [f]benzo [4,5] imidazo[1,2-a] [1,4] diazocin-5(14H)-one

[0453] A mixture of potassium; trifluoro-[(1R,2R)-2-fluorocyclopropyl] borate (120 mg, 720 μmol, 1 eq), (7R,14R)-11-chloro-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-1-yl trifluoromethanesulfonate (330 mg, 720 μmol, 1 eq), Cs2CO3 (706 mg, 2 mmol, 3 eq), and Pd(dppf)Cl2 (53 mg, 72 μmol, 0.1 eq) in 119 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO toluene (2 mL) and H2O (0.1 mL) was degassed and purged with N2 for 3 times. The reaction mixture was stirred at 100°C for 12 hr under N2. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep- HPLC (column: Waters X bridge BEH C18 100*30mm*10µm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient:40%-70% B over 8.0 min to give the title compound as a white solid (32 mg, 6% yield, 99% purity). MS: [M+H]+= 368.0.

[0454] (7R,14R)-11-chloro-1-((1S,2R)-2-fluorocyclopropyl)-6,7-dihydro-7,14-methanobenzo [f]benzo [4,5]imidazo[1,2-a] [1,4] diazocin-5(14H)-one

[0455] (7R,14R)-11-chloro-1-((1S,2R)-2-fluorocyclopropyl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (25 mg, 68 μmol, 1 eq) was separated by SFC (column: DAICEL CHIRALPAK IG (250mm*30mm,10µm);mobile phase: [CO2-MeOH(0.1%NH3H2O)];B%:50%, isocratic elution mode) to give the title compound as a white solid (13 mg, 50% yield, 97% purity).

[0456] tert-Butyl (1-(5-((7R,14R)-1-((1S,2R)-2-fluorocyclopropyl)-5-oxo-5,6,7,14-tetrahydro- 7,14-methanobenzo[f]benzo[4,5imidazo[1,2-a[1,4diazocin-11-ylpyrimidin-2-ylcyclobutyl) carbamate

[0457] To a mixture of (7R,14R)-11-chloro-1-((1S,2R)-2-fluorocyclopropyl)-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (5 mg, 13 μmol, 1 eq) and [2-[1-(tert-butoxycarbonylamino)cyclobutyl]pyrimidin-5-yl]boronic acid (6 mg, 20 μmol, 1.5 eq) in THF (0.5 mL) was added K3PO4 (0.5 M, 54 μL, 2 eq) and [2-(2-aminophenyl)phenyl]- chloro-palladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (1 mg, 1.3 μmol, 0.1 eq) and the reaction mixture was stirred at 100°C for 4 hr under N2. The reaction mixture (combined with another batch at 8 mg scale) was filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow solid (20 mg, crude). MS: [M+H]+= 581.4.

[0458] (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-1-((1S,2R)-2-fluorocyclopropyl)- 6,7-dihydro-7,14-methanobenzo[f] benzo [4,5] imidazo[1,2-a] [1,4] diazocin-5(14H)-one

[0459] A solution of tert-butyl (1-(5-((7R,14R)-1-((1S,2R)-2-fluorocyclopropyl)-5-oxo- 5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11- yl)pyrimidin-2-yl)cyclobutyl)carbamate (20 mg, 34 μmol, 1 eq) in HCl / EtOAc (4 M, 0.5 mL) was stirred at 25°C for 1 hr. The reaction mixture was concentrated in vacuo to give a residue which 120 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO was purified by prep-HPLC (column: Phenomenex Luna C18 100*40mm*5µm;mobile phase: [H2O(0.2% FA)-ACN];gradient:1%-40% B over 10.0 min) to give the title compound as a white solid (5 mg, 27% yield, 98% purity.1H NMR (400 MHz, DMSO-d6) δ = 9.08 (s, 2H), 8.98 (d, J = 6.4 Hz, 1H), 8.21 (d, J = 7.2 Hz, 1H), 7.77-7.73 (m, 2H), 7.57 (dd, J = 1.6 Hz, 8.4 Hz, 1H), 7.34- 7.30 (m, 1H), 7.23-7.21 (m, 1H), 6.58 (d, J = 7.6 Hz, 1H), 5.15-4.98 (m, 1H), 4.87 (t, J = 6.4 Hz, 1H), 3.56-3.49 (m, 1H), 3.48-3.38 (m, 1H), 2.77 (d, J = 13.2 Hz, 1H), 2.65-2.60 (m, 2H), 2.17- 2.10 (m, 2H), 2.04-1.80 (m, 3H), 1.50-1.42 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ = -202.49 (s, 1F). MS: [M+H]+= 481.2.

[0460] Example 52: Synthesis of (7R,14R)-11-(2-((1r,3R)-1-amino-3-(hydroxymethyl)-3- methylcyclobutyl)pyrimidin-5-yl)-1-cyclopropyl-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one and (7R,14R)-11-(2- ((1s,3S)-1-amino-3-(hydroxymethyl)-3-methylcyclobutyl)pyrimidin-5-yl)-1-cyclopropyl-6- methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (58 and 59) Br N O O

[0462] To a solution of 3-(hydroxymethyl)-3-methyl-cyclobutanone (1.5 g, 13 mmol, 1 eq) in DMF (15 mL) was added TBSCl (3 g, 20 mmol, 1.5 eq) and imidazole (1.8 g, 26 mmol, 2 eq) and the reaction mixture was stirred at 25°C for 12 hr. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine 121 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO (25 mL x 2), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 10 / 1) to give the title compound as a colorless oil (1.6 g, 53% yield).1H NMR (400 MHz, CDCl3) δ = 3.59 (s, 2H), 3.09-3.04 (m, 1H), 3.03-2.99 (m, 1H), 2.67-2.62 (m, 1H), 2.61-2.57 (m, 1H), 1.31 (s, 3H), 0.89 (s, 9H), 0.06 (s, 6H).

[0463] N-(3-(((tert-Butyldimethylsilyl)oxy)methyl)-3-methylcyclobutylidene)-2- methylpropane-2-sulfinamide

[0464] To a solution of 3-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-methyl-cyclobutanone (1 g, 4 mmol, 1 eq) in THF (10 mL) was added 2-methylpropane-2-sulfinamide (636 mg, 5 mmol, 1.2 eq) and Ti(OEt)4(2 g, 8 mmol, 1.8 mL, 2 eq) and the reaction mixture was stirred at 20°C for 12 hr under N2. The reaction mixture was treated with ACN (50 mL) and H2O (50 mL) and filtered and the filtrate was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=50 / 1 to 1 / 1) give the title compound as a colorless oil (1 g, 68% yield, 99% purity).1H NMR (400 MHz, CDCl3) δ = 3.50 (s, 2H), 3.26-2.83 (m, 3H), 2.72-2.56 (m, 1H), 1.26- 1.22 (m, 12H), 0.90 (s, 9H), 0.06 (s, 6H).

[0465] N-((1r,3r)-1-(5-bromopyrimidin-2-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-3- methylcyclobutyl)-2-methylpropane-2-sulfinamide (1a) and N-((1s,3s)-1-(5-bromopyrimidin-2- yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide (1b)

[0466] To a solution of 5-bromo-2-iodo-pyrimidine (309 mg, 1.1 mmol, 1.2 eq) in DCM (6 mL) was added n-BuLi (2.5 M, 477 μL, 1.3 eq) dropwise at -78°C and the reaction mixture was stirred at -78°C for 30 min under N2. A solution of N-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-3- methyl-cyclobutylidene]-2-methyl-propane-2-sulfinamide (300 mg, 904 μmol, 1 eq) in DCM (6 mL) was added dropwise and stirred at -78°C for 30 mins under N2and then at 40°C for 11 hr under N2. The reaction mixture was poured into sat. NH4Cl (20 mL) at 0°C under N2 and stirred for 5 mins. H2O (20 mL) was added and the aqueous layer was extracted with DCM (15 mL x 2). The combined organic layers were washed with brine (30 mL) and dried (Na2S04), then the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: WePure Biotech XP tC18150*40*7µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:65%-95% 122 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO B over 8.0 min) to give title compound 1a as a white solid (30 mg, 6% yield, 92% purity) and title compound 1b as a white solid (35 mg, 7% yield, 87% purity).1a:1H NMR (400 MHz, CDCl3) δ = 8.74 (s, 2H), 4.37 (s, 1H), 3.38-3.28 (m, 2H), 2.64 (d, J = 12.4 Hz, 1H), 2.25-2.17 (m, 1H), 2.14- 2.01 (m, 2H), 1.28 (s, 3H), 1.23 (s, 9H), 0.77 (s, 9H), -0.05 (d, J = 3.2 Hz, 6H).1b:1H NMR (400 MHz, CDCl3) δ = 8.78 (s, 2H), 4.42 (s, 1H), 3.62-3.49 (m, 2H), 2.85 (d, J = 12.4 Hz, 1H), 2.54- 2.40 (m, 2H), 2.34-2.27 (m, 1H), 1.21 (s, 9H), 1.04 (s, 3H), 0.92 (s, 9H), 0.07 (s, 6H).

[0467] N-((1r,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-(5-((7R,14R)-1-cyclopropyl-6- methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4] diazocin- 11-yl)pyrimidin-2-yl)-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide

[0468] To a solution of N-[1-(5-bromopyrimidin-2-yl)-3-[[tert- butyl(dimethyl)silyl]oxymethyl]-3-methyl-cyclobutyl]-2-methyl-propane-2-sulfinamide (30 mg, 61 μmol, 1 eq) and (7R,14R)-1-cyclopropyl-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (27 mg, 61 μmol, 1 eq) in THF (1 mL) was added K3PO4 (0.5 M, 244 μL, 2 eq) and [2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3-(2,4,6- triisopropylphenyl)phenyl]phosphane (5 mg, 6 μmol, 0.1 eq) and the reaction mixture was stirred at 100°C for 2 hr under N2. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuo to give a residue which was purified by prep-TLC (SiO2, PE: EtOAc = 0:1) to give the title compound as a yellow solid (30 mg, 54% yield, 82% purity).1H NMR (400 MHz, CDCl3) δ = 8.88 (s, 2H), 8.49-8.42 (m, 1H), 7.87-7.81 (m, 1H), 7.50 (s, 1H), 7.44-7.40 (m, 1H), 7.36-7.32 (m, 2H), 6.66 (d, J = 7.2 Hz, 1H), 4.99 (d, J = 6.8 Hz, 1H), 4.46 (d, J = 4.0 Hz, 1H), 3.52-3.48 (m, 4H), 3.40-3.30 (m, 2H), 3.21 (d, J = 12.8 Hz, 1H), 2.89 (d, J = 12.8 Hz, 1H), 2.72 (d, J = 12.4 Hz, 1H), 2.51-2.40 (m, 1H), 2.33-2.23 (m, 1H), 2.16-2.09 (m, 1H), 1.31 (s, 3H), 1.25 (s, 9H), 1.18-1.07 (m, 2H), 0.80-0.63 (m, 11H), -0.06 (s, 6H).

[0469] (7R,14R)-11-(2-((1r,3R)-1-amino-3-(hydroxymethyl)-3-methylcyclobutyl)pyrimidin-5- yl)-1-cyclopropyl-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4] diazocin-5(14H)-one

[0470] A solution of N-((1r,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-(5-((7R,14R)-1- cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)pyrimidin-2-yl)-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide (20 mg, 27 μmol, 1 eq) in HCl / EtOAc (4 M, 0.5 mL) was stirred at 20°C for 1 hr. The reaction mixture 123 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: Phenomenex Luna C18100*40mm*5µm;mobile phase: [H2O(0.2% FA)-ACN];gradient:3%-30% B over 10.0 min) to give the title compound as a white solid (3 mg, 20% yield, 100% purity).1H NMR (400 MHz, DMSO-d6) δ = 9.05 (s, 2H), 8.17 (dd, J = 2.8 Hz, J = 6.4 Hz, 1H), 7.79-7.77 (m, 2H), 7.58 (d, J = 8.4 Hz, 1H), 7.30-7.29 (m, 2H), 6.67 (d, J = 7.6 Hz, 1H), 5.21 (d, J = 7.2 Hz, 1H), 4.48-4.45 (m, 1H), 3.54-3.49 (m, 1H), 3.31 (s, 3H), 3.23 (br d, J = 4.4 Hz, 2H), 2.82-2.76 (m, 2H), 2.64 (d, J = 11.2 Hz, 2H), 1.76 (d, J = 12.0 Hz, 2H), 1.31 (s, 3H), 1.26-1.24 (m, 2H), 1.00 (m, 1H), 0.75 (m, 1H).

[0471] N-((1s,3S)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-(5-((7R,14R)-1-cyclopropyl-6- methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4] diazocin- 11-yl)pyrimidin-2-yl)-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide

[0472] To a solution of N-[1-(5-bromopyrimidin-2-yl)-3-[[tert- butyl(dimethyl)silyl]oxymethyl]-3-methyl-cyclobutyl]-2-methyl-propane-2-sulfinamide (35 mg, 71 μmol, 1 eq) and (7R,14R)-1-cyclopropyl-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (32 mg, 71 μmol, 1 eq) in THF (1.5 mL) was added K3PO4(0.5 M, 285 μL, 2 eq) and [2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3-(2,4,6- triisopropylphenyl)phenyl]phosphane (5 mg, 7 μmol, 0.1 eq) and the reaction mixture was stirred at 100°C for 2 hr under N2. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuum to give the title compound as a yellow solid (35 mg, 61% yield, 92% purity).1H NMR (400 MHz, CDCl3) δ = 8.92 (s, 2H), 8.49-8.42 (m, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.38-7.30 (m, 2H), 6.67 (d, J = 7.6 Hz, 1H), 5.01 (d, J = 6.8 Hz, 1H), 4.57 (d, J = 6.0 Hz, 1H), 3.64-3.55 (m, 2H), 2.91 (t, J = 13.2 Hz, 2H), 2.55 (d, J = 12.8 Hz, 1H), 2.50-2.43 (m, 2H), 2.41-2.35 (m, 1H), 1.37-1.31 (m, 2H), 1.23 (s, 9H), 1.18-1.10 (m, 2H), 1.08 (s, 3H), 0.93 (s, 9H), 0.73-0.66 (m, 1H), 0.09 (s, 6H).

[0473] (7R,14R)-11-(2-((1s,3S)-1-amino-3-(hydroxymethyl)-3-methylcyclobutyl)pyrimidin-5- yl)-1-cyclopropyl-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4] diazocin-5(14H)-one

[0474] A solution of N-((1s,3S)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-(5-((7R,14R)-1- cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)pyrimidin-2-yl)-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide (25 124 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO mg, 34 μmol, 1 eq) in HCl / EtOAc (4 M, 0.5 mL) was stirred at 20°C for 1 hr. The reaction mixture was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: Phenomenex Luna C18100*40mm*5µm;mobile phase: [H2O(0.2% FA)-ACN];gradient:5%-35% B over 8.0 min) to give the title compound as a white solid (5 mg, 25% yield, 99% purity).1H NMR (400 MHz, DMSO-d6) δ = 9.08 (s, 2H), 8.18-8.16 (m, 1H), 7.79-7.74 (m, 2H), 7.60-7.58 (m, 1H), 7.32-7.29 (m, 2H), 6.68 (d, J = 7.6 Hz, 1H), 5.21 (d, J = 7.2 Hz, 1H), 3.56-3.49 (m, 1H), 3.44 (s, 2H), 3.31 (s, 3H), 2.84-2.76 (m, 2H), 2.44 (s, 2H), 2.09 (d, J = 12.8 Hz, 2H), 1.30-1.19 (m, 2H), 1.07 (s, 3H), 1.04-0.98 (m, 1H), 0.79-0.70 (m, 1H).

[0475] Example 53: Synthesis of (7R,14R)-11-(2-(6-amino-2-oxaspiro[3.3]heptan-6- yl)pyrimidin-5-yl)-1-cyclopropyl-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (60) N OO N N S NH NNH NNN NO [00.

[0477] A solution of 2-oxaspiro[3.3]heptan-6-one (1 g, 9 mmol, 1 eq), 2-methylpropane-2- sulfinamide (1.1 g, 9 mmol, 1 eq), and Ti(i-PrO)4 (2.5 g, 9 mmol, 2.6 mL, 1 eq) in EtOH (20 mL) was degassed and purged with N2 for 3 times, and the reaction mixture was stirred at 80°C for 12 hr under N2. The reaction was quenched with H2O (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 0 / 1) to give the title compound as a white solid (500 mg, 23% 125 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO yield, 90% purity).1H NMR (400 MHz, DMSO-d6) δ= 4.68-4.62 (m, 4 H), 3.63-3.35 (m, 4 H), 1.12 (s, 9 H).

[0478] N-[6-(5-Bromopyrimidin-2-yl)-2-oxaspiro[3.3]heptan-6-yl]-2-methyl-propane-2- sulfinamide

[0479] To a solution of 5-bromo-2-iodo-pyrimidine (741 mg, 2.6 mmol, 1.4 eq) in DCM (14 mL) was added n-BuLi (2.5 M, 966 μL, 1.3 eq) dropwise at -75°C under N2. After 30 mins, 2- methyl-N-(2-oxaspiro[3.3]heptan-6-ylidene)propane-2-sulfinamide (400 mg, 1.9 mmol, 1 eq) in DCM (4 mL) was added dropwise at -75°C and the reaction mixture was stirred at -75°C for 30 mins and then sat. NH4Cl (30 mL) was added dropwise under N2. The reaction mixture was stirred for 20 min and then poured into H2O (30 mL) and extracted with DCM (20 mL x 3). The combined organics layer were concentrated in vacuo to give a residue which was purified by prep-HPLC (neutral condition; column: WePure Biotech XP tC18150*40*10µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:10%-40% B over 8.0 min) to give the title compound as a yellow solid (70 mg, 10% yield, 100% purity).1H NMR (400 MHz, DMSO-d6) δ =8.98 (s, 2 H), 6.05 (b, 1 H), 4.62 (s, 2 H), 4.47-4.42 (m, 2 H), 2.90-2.95 (m, 1 H), 2.78-2.83 (m, 1 H), 2.68-2.73 (m, 2 H), 1.07 (s, 9 H).

[0480] N-(6-(5-((7R,14R)-1-Cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2-yl)-2- oxaspiro[3.3]heptan-6-yl)-2-methylpropane-2-sulfinamide

[0481] A solution of N-[6-(5-bromopyrimidin-2-yl)-2-oxaspiro[3.3]heptan-6-yl]-2-methyl- propane-2-sulfinamide (60 mg, 160 μmol, 1 eq), (7R,14R)-1-cyclopropyl-6-methyl-11-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (73 mg, 160 μmol, 1 eq), K3PO4(0.5 M, 641 μL, 2 eq), and XPHOS- PD-G2 (12 mg, 16 μmol, 0.1 eq) in THF (4 mL) was degassed and purged with N2 for 3 times, and the reaction mixture was stirred at 100°C for 4 hr under N2. The reaction mixture was partitioned between H2O (20 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give the title compound as a black oil (150 mg, crude).

[0482] (7R,14R)-11-(2-(6-Amino-2-oxaspiro[3.3]heptan-6-yl)pyrimidin-5-yl)-1-cyclopropyl- 6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one 126 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0483] A solution of N-(6-(5-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2-yl)-2- oxaspiro[3.3]heptan-6-yl)-2-methylpropane-2-sulfinamide (170 mg, 273 μmol, 1 eq) in TFA (2 mL) and DCM (2 mL) was degassed and purged with N2 for 3 times, and the reaction mixture was stirred at 25°C for 12 hr under N2. The reaction mixture was concentrated in vacuo to give a residue which was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18 75*30mm*3µm;mobile phase: [H2O(0.1%TFA)-ACN];gradient:1%-30% B over 8.0 min) to give the title compound as a yellow oil (2 mg, 8% yield, 98% purity).1H NMR (400 MHz, DMSO-d6) δ =9.84-9.65 (m, 2H), 8.17-8.08 (m, 1H), 7.93-7.82 (m, 2H), 7.74-7.66 (m, 1H), 7.33-7.25 (m, 2H), 6.73 (d, J = 7.2 Hz, 1H), 5.20 (d, J = 6.8 Hz, 1H), 4.9-4.7 (m, 2H), 3.61 (m, 2H), 3.57-3.49 (m, 1H), 3.29 (s, 3H), 2.81-2.70 (m, 2H), 2.69-2.66 (m, 2H), 2.32-2.26 (m, 2H), 1.30-1.18 (m, 2H), 1.04-0.95 (m, 1H), 0.77-0.66 (m, 1H).

[0484] Example 54: Synthesis of (7R,14R)-11-(6-(1-amino-3,3-difluorocyclobutyl)-5- fluoropyridin-3-yl)-1-cyclopropyl-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (61) N3NBr N F N Pd / C(0.1 eq) N B iF NN HNH2NNOopyl- 6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0486] To a solution of 2-(1-azido-3,3-difluorocyclobutyl)-5-bromo-3-fluoropyridine (81 mg, 264 μmol, 1.5 eq) and (7R,14R)-1-cyclopropyl-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (80 mg, 176 μmol, 1 eq) in THF (8 mL) was added K3PO4(0.5 M, 700 μL, 2 eq) and [2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3-(2,4,6- triisopropylphenyl)phenyl]phosphane (41 mg, 53 μmol,0.3 eq) and the reaction mixture was stirred at 100°C for 4 hr under N2. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (25 mL x 2). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue (combined with another batch with 10 mg scale) which 127 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO was purified by prep-TLC (SiO2, DCM: MeOH =10:1) to give the title compound as a yellow oil (50 mg, 43% yield). MS: [M+H]+= 557.4.

[0487] (7R,14R)-11-(6-(1-amino-3,3-difluorocyclobutyl)-5-fluoropyridin-3-yl)-1-cyclopropyl- 6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0488] To a solution of (7R,14R)-11-(6-(1-azido-3,3-difluorocyclobutyl)-5-fluoropyridin-3- yl)-1-cyclopropyl-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (40 mg, 72 μmol, 1 eq) in DMF (8 mL) was added TEA (22 mg, 216 μmol, 30 μL, 3 eq) and Pd / C (8mg, 10% purity, 7 μmol 0.1 eq) and the reaction mixture was degassed and purged with H2for 3 times. The reaction mixture was stirred under H2(15 psi) at 20°C for 1 hr. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue (combined with another batch with 10 mg scale) which was purified by prep-HPLC (column: WePure Biotech XP tC18 150*40*7µm;mobile phase: [H2O(10 mM NH4HCO3)- ACN];gradient:30%-60% B over 8.0 min) to give the title compound as a white solid (15 mg, 39% yield, 99% purity).1H NMR (400 MHz, DMSO-d6) δ = 8.64 (m, 1H), 8.17 (dd, J = 2.4, 7.2 Hz, 1H), 8.01 (dd, J = 1.6, 12.4 Hz, 1H), 7.77-7.74 (m, 2H) , 7.57 (dd, J = 1.2, 8.4 Hz, 1H), 7.32-7.26 (m, 2H), 6.67 (d, J = 7.6 Hz, 1H), 5.20 (d, J = 7.2 Hz, 1H), 3.56-3.49 (m, 1H), 3.39-3.45 (m, 2H), 3.31 (s, 3H), 2.83-2.73 (m, 4H), 2.45 (s, 2H), 1.28-1.23 (m, 2H), 1.04-0.99 (m, 1H), 0.78-0.75 (m, 1H).

[0489] Example 55: Synthesis of (1R,3r)-3-(5-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo- 5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)-3- fluoropyridin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carbonitrile and (1S,3s)-3-(5-((7R,14R)-1- cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)-3-fluoropyridin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carbonitrile (62 and 63) N ODate of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0490] (1r,3r)-3-(5-Bromo-3-fluoropyridin-2-yl)-3-hydroxy-1-methylcyclobutane-1- carbonitrile and (1s,3s)-3-(5-bromo-3-fluoropyridin-2-yl)-3-hydroxy-1-methylcyclobutane-1- carbonitrile

[0491] To a solution of 2,5-dibromo-3-fluoropyridine (2 g, 9 mmol, 1 eq) in DCM (10 mL) was added n-BuLi (2.5 M, 4 mL, 1.1 eq) at -78°C under N2. After 30 min, 1-methyl-3-oxocyclobutane- 1-carbonitrile (1 g, 9 mmol, 1 eq) was added at -78°C and the reaction mixture was stirred at 20°C for 1.5 hr under N2. The reaction was quenched with water (20 mL) at 0°C and extracted with DCM (15 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (FA condition;column: Phenomenex Luna C18100*40mm*5 µm;mobile phase: [H2O(0.2% FA)-ACN];gradient:20%-50% B over 12.0 min) to give the (r,r) title compound as a white solid (500 mg) and the (s,s) title compound as a white solid (400 mg).1H NMR (400 MHz, DMSO-d6r,r) δ = 8.57 (s, 1H), 8.20 (dd, J = 1.6, 10.0 Hz, 1H), 6.18 (s,1H), 3.29 (d, J = 12.4 Hz, 2H), 2.42 (d, J = 13.2 Hz, 2H), 1.61 (s, 3H).1H NMR (400 MHz, DMSO-d6 s,s) δ = 8.54 (s, 1H), 8.18 (dd, J = 2.0, 10.0 Hz, 1H), 6.23 (s, 1H), 2.89 (d, J = 12.4 Hz, 2H), 2.76 (d, J = 13.2 Hz, 2H), 1.29 (s, 3H).

[0492] (1R,3r)-3-(5-((7R,14R)-1-cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)-3-fluoropyridin-2-yl)-3-hydroxy- 1-methylcyclobutane-1-carbonitrile

[0493] To a solution of (1r,3r)-3-(5-bromo-3-fluoropyridin-2-yl)-3-hydroxy-1- methylcyclobutane-1-carbonitrile (25 mg, 88 μmol, 1 eq) and (7R,14R)-1-cyclopropyl-6-methyl- 11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (40 mg, 88 μmol, 1 eq) in THF (2 mL) was added XPHOS-PD-G2 (7 mg, 9 μmol, 0.1 eq) and K3PO4 (0.5 M, 351 μL, 2 eq) and the reaction mixture was stirred at 100°C for 2 hr under N2. ACN (10 mL) was added, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (neutral condition; column: WePure Biotech XP tC18150*40*7µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:32%-62% B over 8.0 min) to give the title compound as a white solid (5 mg, 97% purity).1H NMR (400 MHz, DMSO-d6) δ = 8.17 (dd, J = 1.6, 7.6 Hz, 1H), 8.01 (dd, J = 1.6, 12.0 Hz, 1H), 7.77-7.75 (m, 2H), 7.59 (dd, J = 1.2, 8.4 Hz, 1H), 7.32-7.25 (m, 2H), 6.67 (d, J = 7.2 Hz, 1H), 6.12 (s, 1H), 5.21 (d, J = 6.8 Hz, 1H), 3.57-3.50 (m, 1H), 3.38-3.34 (m, 2H), 129 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO 3.31 (s, 3H), 2.86-2.77 (m, 2H), 2.48-2.44 (m, 2H), 1.64 (s, 3H), 1.31-1.21 (m, 2H), 1.06-0.99 (m, 1H), 0.78-0.74 (m, 1H). BrOHNN N O

[0494] ( o-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)-3-fluoropyridin-2-yl)-3-hydroxy- 1-methylcyclobutane-1-carbonitrile

[0495] To a solution of (7R,14R)-1-cyclopropyl-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (20 mg, 44 μmol, 1 eq) and (1s,3s)-3-(5-bromo-3-fluoropyridin-2-yl)-3-hydroxy-1- methylcyclobutane-1-carbonitrile (12 mg, 44 μmol, 1 eq) in THF (1 mL) was added K3PO4 (0.5 M, 175 μL, 2 eq) and [2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3-(2,4,6- triisopropylphenyl)phenyl]phosphane (3.5 mg, 4.4 μmol, 0.1 eq) and the reaction mixture was stirred at 100°C for 2 hr under N2. The reaction mixture (combined with another batch with 20 mg scale) was filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: We Pure Biotech XP tC18150*40*7µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:30%-70% B over 8.0 min) to give the title compound as a white solid (5 mg, 99% purity).1H NMR (400 MHz, DMSO-d6) δ = 8.66 (s, 1H), 8.17 (dd, J = 2.0, 7.2 Hz, 1H), 8.00 (dd, J = 1.6, 12.0 Hz, 1H), 7.76-7.74 (m, 2H), 7.58 (dd, J = 1.6, 8.8 Hz, 1H), 7.32-7.25 (m, 2H), 6.66 (d, J = 7.6 Hz, 1H), 6.16 (s, 1H), 5.20 (d, J = 6.8 Hz, 1H), 3.56-3.49 (m, 1H), 3.31 (s, 3H), 2.95 (d, J = 12.8 Hz, 2H), 2.82-2.77 (m, 4H), 1.32 (s, 3H), 1.28-1.23 (m, 2H), 1.03-0.98 (m, 1H), 0.79-0.74 (m, 1H).

[0496] Example 56: Synthesis of (7R,14R)-11-(2-((1R,2R,3R)-1-amino-2-fluoro-3- (hydroxymethyl)-3-methylcyclobutyl)pyrimidin-5-yl)-1-cyclopropyl-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one and (7R,14R)-11-(2- ((1S,2S,3S)-1-amino-2-fluoro-3-(hydroxymethyl)-3-methylcyclobutyl)pyrimidin-5-yl)-1- 130 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO cyclopropyl-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (64 and 65) 1)LDA(1.5 eq),OTHF(10 V), Select-F(1.5 eq St-BuO t-Bu O0 o) C, 0.5 h,MS O S OT MeCN(10 V)NH2(1.1 eq) N TBSOoTBSO One

[0498] To a solution of 3-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-methyl-cyclobutanone (3.5 g, 15 mmol, 1 eq) in THF (73 mL) was added LDA (2 M, 11.5 mL, 1.5 eq) dropwise at -78°C under N2. After addition, the internal temperature was allowed to warm to 0°C and stirred for 30 min and then TMSCl (2.50 g, 23 mmol, 3 mL, 1.5 eq) was added dropwise and the reaction mixture was stirred at 0°C for 1 hr under N2. The reaction was quenched with sat. aq. NH4Cl (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow oil (9 g, crude).1H NMR (400 MHz, CDCl3) δ = 4.67 (s, 1H), 3.48 (s, 2H), 2.36 (d, J = 12.8 Hz, 2H), 2.18 (d, J = 12.8 Hz, 2H), 1.17 (s, 3H), 0.90 (s, 9H), 0.23 (s, 9H), 0.04 (s, 6H).

[0499] 3-(((tert-Butyldimethylsilyl)oxy)methyl)-2-fluoro-3-methylcyclobutan-1-one

[0500] To a solution of 1-(chloromethyl)-4-fluoro-1,4- diazoniabicyclo[2.2.2]octane;ditetrafluoroborate (5.3 g, 15 mmol, 1.5 eq) in ACN (70 mL) was added a solution of tert-butyl-dimethyl-[(1-methyl-3-trimethylsilyloxy-cyclobut-2-en-1- yl)methoxy]silane (3 g, 10 mmol, 1 eq) in ACN (30 mL) dropwise at 0°C under N2 and the reaction mixture was stirred at 0°C for 12 hr. The reaction was quenched with H2O (500 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (300 mL), 131 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by silica gel column chromatography (ethyl acetate in hexanes, from 1% to 2%) to give the title compound as a colorless oil (4 g, 54% yield, 90% purity).1H NMR (400 MHz, CDCl3) δ = 5.53-5.38 (m, 1H), 3.76 (d, J = 10.0 Hz, 1H), 3.63 (d, J = 10.0 Hz, 1H), 3.00-2.95 (m, 1H), 2.32-2.24 (m, 1H), 1.14 (d, J = 1.6 Hz, 3H), 0.91(s, 9H), 0.10 (d, J = 3.6 Hz, 6H).

[0501] (E)-N-(3-(((tert-Butyldimethylsilyl)oxy)methyl)-2-fluoro-3-methylcyclobutylidene)-2- methylpropane-2-sulfinamide

[0502] To a solution of 3-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluoro-3- methylcyclobutan-1-one (2 g, 8.1 mmol, 1 eq) and 2-methylpropane-2-sulfinamide (1.1 g, 8.9 mmol, 1.1 eq) in THF (20 mL) was added Ti(OEt)4(2.8 g, 12 mmol, 2.5 mL, 1.5 eq) and the reaction mixture was stirred at 40°C and 12 hr under N2. The reaction was quenched with H2O (100 mL) and filtered through a pad of celite® and washed with ethyl acetate (200 mL). The aqueous layer was extracted with ethyl acetate (200 mL x 3) and the combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by silica gel column chromatography (ethyl acetate in hexanes, from 2% to 5%) to give the title compound as a colorless oil (4.5 g, 78% yield, 98% purity). MS: [M+H]+= 350.3.

[0503] N-((1R,2R,3R)-1-(5-bromopyrimidin-2-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-2- fluoro-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide and N-((1S,2S,3S)-1-(5- bromopyrimidin-2-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluoro-3-methylcyclobutyl)-2- methylpropane-2-sulfinamide

[0504] To a solution of 5-bromo-2-iodo-pyrimidine (3.9 g, 14 mmol, 1.2 eq) in DCM (50 mL) was added n-BuLi (2.5 M, 5.50 mL, 1.2 eq) dropwise at -78°C under N2and the reaction mixture was stirred at -78°C for 30 min. (E)-N-(3-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluoro- 3-methylcyclobutylidene)-2-methylpropane-2-sulfinamide (4 g, 11 mmol, 1 eq) was then added at -78°C and the reaction was stirred at -78°C under N2for 2 hr. The reaction was quenched with sat. aq. NH4Cl (100 mL) and extracted with DCM (100 mL x 3), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by silica gel column chromatography (ethyl acetate in hexanes, from 5% to 25%) to give the (1R,2R,3R) title compound as a yellow solid (1 g, 100% purity) and the (1S,2S,3S) title compound as a yellow solid (0.5 g, 100% purity). MS: [M+H]+= (1R,2R,3R) 508.2 and (1S,2S,3S) 508.2. 132 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0505] N-((1R,2R,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-(5-((7R,14R)-1-cyclopropyl- 6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)pyrimidin-2-yl)-2-fluoro-3-methylcyclobutyl)-2-methylpropane-2- sulfinamide

[0506] To a solution of (7R,14R)-1-cyclopropyl-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (40 mg, 88 μmol, 1 eq) in THF (2 mL) was added K3PO4(0.5 M, 350 μL, 2 eq), N- [(1R,2R,3R)-1-(5-bromopyrimidin-2-yl)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-fluoro-3- methyl-cyclobutyl]-2-methyl-propane-2-sulfinamide (54 mg, 105 μmol, 1.2 eq) and [2-(2- aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3-(2,4,6- triisopropylphenyl)phenyl]phosphane (14 mg, 17.6 μmol, 0.2 eq) and the reaction mixture was stirred at 80°C for 6 hr under N2. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc 15 mL (5 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-TLC (SiO2, EtOAc:MeOH = 20:1) to give the title compound as a white solid (30 mg, 40% yield, 90% purity). MS: [M+H]+= 758.5.

[0507] (7R,14R)-11-(2-((1R,2R,3R)-1-amino-2-fluoro-3-(hydroxymethyl)-3-methylcyclobutyl) pyrimidin-5-yl)-1-cyclopropyl-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5] imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0508] A solution of N-((1R,2R,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-(5- ((7R,14R)-1-cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2-yl)-2-fluoro-3- methylcyclobutyl)-2-methylpropane-2-sulfinamide (30 mg, 40 μmol, 1 eq) in HCl / EtOAc (4M, 0.5 mL) was stirred at 20°C for 6 hr. The reaction mixture was concentrated in vacuo to give a residue which was purified by prep-HPLC (FA condition; column: WePure Biotech XP tC18 150*40*7µm;mobile phase: [H2O (10 mM NH4HCO3)-ACN];gradient:20%-55% B over 8.0 min) to give the title compound as a yellow solid (5 mg, 23% yield, 99% purity).1H NMR (400 MHz, DMSO-d6) δ = 9.07 (s, 2H), 8.18-8.15 (m, 1H), 7.79-7.77 (m, 2H), 7.60-7.57 (m, 1H), 7.30-7.28 (m, 2H), 6.67 (d, J = 7.2 Hz, 1H), 5.21-5.07 (m, 2H), 4.77 (t , J = 5.2 Hz, 1H), 3.54-3.50 (m, 1H), 3.29 (s, 3H), 3.27 (s, 2H), 2.79-2.76 (m, 2H), 2.33-2.30 (m, 3H), 1.68-1.63 (m, 1H), 1.34 (s, 3H), 1.26-1.24 (m, 2H),1.20-1.00 (m, 1H), 0.77-0.74 (m, 1H). 133 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO N Bpin N Nt-Bu O N N B N O yl-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)pyrimidin-2-yl)-2-fluoro-3-methylcyclobutyl)-2-methylpropane-2- sulfinamide

[0510] To a solution of (7R,14R)-1-cyclopropyl-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (40 mg, 88 μmol, 1 eq) in THF (2 mL) was added K3PO4 (0.5 M, 350 μL, 2 eq), N- [(1R,2R,3R)-1-(5-bromopyrimidin-2-yl)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-fluoro-3- methyl-cyclobutyl]-2-methyl-propane-2-sulfinamide (54 mg, 105 μmol, 1.2 eq) and [2-(2- aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3-(2,4,6- triisopropylphenyl)phenyl]phosphane (14 mg, 17.6 μmol, 0.2 eq) and the reaction mixture was stirred at 80°C for 6 hr under N2. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc 15 mL (5 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-TLC (SiO2, EtOAc: MeOH = 20:1) to give the title compound as a white solid (30 mg, 40% yield, 90% purity). MS: [M+H]+= 758.5.

[0511] (7R,14R)-11-(2-((1S,2S,3S)-1-amino-2-fluoro-3-(hydroxymethyl)-3-methylcyclobutyl) pyrimidin-5-yl)-1-cyclopropyl-6-methyl-6,7-dihydro-7,14-methanobenzo[f] benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0512] A solution of N-((1S,2S,3S)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-(5-((7R,14R)- 1-cyclopropyl-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)pyrimidin-2-yl)-2-fluoro-3-methylcyclobutyl)-2-methylpropane-2- sulfinamide (30 mg, 40 μmol, 1 eq) in HCl / EtOAc (4M, 0.5 mL) was stirred at 20°C for 6 hr. The reaction mixture was concentrated in vacuo to give a residue which was purified by prep-HPLC (FA condition; column: WePure Biotech XP tC18 150*40*7µm;mobile phase: [H2O (10 mM NH4HCO3)-ACN];gradient:20%-55% B over 8.0 min) to give the title compound as a yellow solid (5 mg, 23% yield, 99% purity).1H NMR (400 MHz, DMSO-d6) δ = 9.08 (s, 2H), 8.18-8.16 134 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO (m, 1H), 7.80-7.77 (m, 2H), 7.60-7.58 (m, 1H), 7.30-7.29 (m, 2H), 6.67 (d, J = 7.2 Hz, 1H), 5.22- 5.08 (m, 2H), 4.78 (t , J = 5.2 Hz, 1H), 3.55 -3.51 (m, 1H), 3.29 (s, 3H), 3.28 (s, 2H), 2.80-2.76 (m, 2H), 2.33-2.26 (m, 3H), 1.68-1.63 (m, 1H), 1.35 (s, 3H), 1.26-1.25 (m, 2H),1.20-1.00 (m, 1H), 0.77-0.74 (m, 1H).

[0513] Example 57: Synthesis of (7R,14R)-11-(2-((1s,3S)-1-amino-3-(difluoromethyl)-3- (hydroxymethyl)cyclobutyl)pyrimidin-5-yl)-1-cyclopropyl-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4] diazocin-5(14H)-one (66) BrMsCl (3.6 eq),Br BrTBSO HON) TBSO MsONN3TBSO NNTEA (4.5 eq aN3N DCM (10 V) N N DMSO (4V): H2O

[0514] )-3- (difluoromethyl)cyclobutyl methanesulfonate

[0515] To a solution of 1-(5-bromopyrimidin-2-yl)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]- 3-(difluoromethyl)cyclobutanol (200 mg, 472 μmol, 1 eq) and TEA (215 mg, 2 mmol, 295 μL, 4.5 eq) in DCM (2 mL) was added MsCl (194 mg, 1.7 mmol, 131 μL, 3.6 eq) drop-wise at 0°C under N2, then the reaction mixture was warmed to 20°C and stirred for 30 min under N2. The reaction was quenched with sat. NaHCO3(10 mL) at 0°C, diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow oil (240 mg, crude).

[0516] 2-((1s,3s)-1-azido-3-(((tert-Butyldimethylsilyl)oxy)methyl)-3- (difluoromethyl)cyclobutyl)-5-bromopyrimidine 135 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0517] To a solution of [1-(5-bromopyrimidin-2-yl)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]- 3-(difluoromethyl)cyclobutyl]methanesulfonate (240 mg, 478 μmol, 1 eq) in DMSO (0.96 mL) and H2O (0.24 mL) was added NaN3(110 mg, 1.7 mmol, 3.5 eq) at 80°C under N2and the reaction mixture was stirred at 80°C for 4 hr. The reaction was quenched with sat. Na2CO3 (10 mL) at 0°C, diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-TLC (SiO2, hexanes:ethyl acetate = 15:1) to give the title compound as a colorless oil (40 mg, 18% yield, 96% purity).1H NMR (400 MHz, CDCl3) δ = 8.84 (s, 2H), 6.00 (t, J = 57.2 Hz, 1H), 3.65 (s, 2H), 2.80 (d, J = 14 Hz, 2H), 2.66 (d, J = 14.4 Hz, 2H), 0.82 (s, 9H), -0.02 (s, 6H).

[0518] (7R,14R)-11-(2-((1s,3S)-1-azido-3-(((tert-butyldimethylsilyl)oxy)methyl)-3- (difluoromethyl)cyclobutyl)pyrimidin-5-yl)-1-cyclopropyl-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a] [1,4] diazocin-5(14H)-one

[0519] To a solution of (7R,14R)-1-cyclopropyl-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (60 mg, 131 μmol, 1 eq) and [3-azido-3-(5-bromopyrimidin-2-yl)-1- (difluoromethyl)cyclobutyl]methoxy-tert-butyl-dimethyl-silane (59 mg, 131 μmol, 1 eq) in dioxane (1 mL) was added K3PO4 (0.5 M, 527 μL, 2 eq) and [2-(2-aminophenyl)phenyl]-chloro- palladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl] phosphane (10 mg, 13 μmol, 0.1 eq) and the reaction mixture was heated to 100°C and stirred for 3 hr under N2. The reaction mixture was filtered through a pad of celite® and the filtrate was concentrated in vacuo to give a residue which was purified prep-TLC (SiO2, EtOAc:MeOH = 20:1) to give the title compound as a colorless oil (10 mg, 77% purity).

[0520] (7R,14R)-11-(2-((1s,3S)-1-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-3- (difluoromethyl)cyclobutyl)pyrimidin-5-yl)-1-cyclopropyl-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0521] To a solution of (7R,14R)-11-(2-((1s,3S)-1-azido-3-(((tert- butyldimethylsilyl)oxy)methyl)-3-(difluoromethyl)cyclobutyl)pyrimidin-5-yl)-1-cyclopropyl-6- methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (10 mg, 14 μmol, 1 eq) in DMF (1 mL) was added TEA (4 mg, 43 μmol, 6 μL, 3 eq) followed by Pd / C (3 mg, 10% purity). The reaction mixture was degassed and purged with H2 for 3 times and 136 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO stirred at 20°C for 1 hr under H2 (15 psi). The reaction mixture was filtered through a pad of celite® and the filtrate was concentrated in vacuo to give the title compound as a yellow oil (10 mg, 68% purity).

[0522] (7R,14R)-11-(2-((1s,3S)-1-amino-3-(difluoromethyl)-3-(hydroxymethyl)cyclobutyl) pyrimidin-5-yl)-1-cyclopropyl-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5] imidazo[1,2-a] [1,4] diazocin-5(14H)-one

[0523] A solution of (7R,14R)-11-(2-((1s,3S)-1-amino-3-(((tert- butyldimethylsilyl)oxy)methyl)-3-(difluoromethyl)cyclobutyl) pyrimidin-5-yl)-1-cyclopropyl-6- methyl-6,7-dihydro-7,14-methanobenzo[f] benzo[4,5]imidazo[1,2-a][1,4] diazocin-5(14H)-one (5 mg, 7 μmol, 1 eq) in HCl / dioxane (4 M, 0.5 mL) was stirred at 20°C for 1 hr. The reaction mixture was concentrated in vacuo to give a residue (combined with another batch with 4 mg scale) which was purified by prep-HPLC (column: Phenomenex Luna C18 100*40mm*5µm;mobile phase: [H2O(0.2% FA)-ACN];gradient:5%-35% B over 8.0 min) to give the title compound as a white solid (1.2 mg, 99% purity).1H NMR (400 MHz, DMSO-d6) δ = 9.09 ( s, 2H), 8.17 (dd, J = 2.8, 6.0 Hz, 1H), 7.80-7.78 (m, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.32-7.29 (m, 2H), 6.68 (d, J = 7.2 Hz, 1H), 6.26 (t, J = 57.6 Hz, 1H), 5.21 (d, J = 6.8 Hz, 1H), 4.86 (s, 1H), 3.57-3.52 (m, 3H), 3.31 (s, 3H), 2.80-1.77 (m, 2H), 2.71-2.67 (m, 2H), 2.17-2.15 (m, 2H), 1.25 (d, J = 7.6 Hz, 2H), 1.01 (m, 1H), 0.76 (m, 1H).

[0524] Example 58: Synthesis of (7R,14R)-1-cyclopropyl-11-(2-((1s,3S)-1,3-dihydroxy-3- methylcyclobutyl)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one and (7R,14R)-1- cyclopropyl-11-(2-((1s,3S)-1,3-dihydroxy-3-methylcyclobutyl)pyrimidin-5-yl)-6-methyl-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (67 and 68) 137 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO N Br OHONBrHO NBrI N N N N Omethylcyclobutan-1-ol and (1s,3s)-1-(5-bromopyrimidin-2-yl)-3-((tert-butyldimethylsilyl)oxy)-3- methylcyclobutan-1-ol

[0526] To a solution of 3-[tert-butyl(dimethyl)silyl]oxy-3-methyl-cyclobutanone (2 g, 9.3 mmol, 1 eq) in DCM (40 mL) was added 5-bromo-2-iodo-pyrimidine (2.9 g, 10 mmol, 1.1 eq) under N2at -78°C and the reaction mixture was stirred at -78°C for 10 min. A solution of n-BuLi (2.5 M, 4.5 mL, 1.2 eq) was added slowly at -78°C and stirred for 1 hr under N2. The reaction mixture was allowed to warm to 20°C and stirred for 1 hr under N2. The reaction was quenched with sat. NaHCO3(30 mL) at 0°C, diluted with H2O (50 mL) and extracted with DCM (40 mL x 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by column chromatography (SiO2, Petroleum ether / ethyl acetate=5 / 1 to 0 / 1) to give the title (1r, 3r) compound as a yellow oil (0.3 g, 94% purity) and the title (1s, 3s) compound as a yellow oil (0.12 g, 94% purity).1H NMR (400 MHz, CDCl3) δ = 8.79 (s, 2H), 4.42 (s, 1H), 2.98-2.95 (m, 2H), 2.40-2.37 (m, 2H), 1.71 (s, 3H), 0.92 (s, 9H), 0.11 (s, 6H);1H NMR (400 MHz, DMSO-d6) δ = 9.00 (s, 2H), 5.80 (s, 1H), 2.93-2.90 (m, 2H), 2.46 -2.42 (m, 2H), 1.08 (s, 3H), 0.87 (s, 9H), 0.07 (s, 6H).

[0527] (7R,14R)-11-(2-((1s,3S)-3-((tert-butyldimethylsilyl)oxy)-1-hydroxy-3- methylcyclobutyl)pyrimidin-5-yl)-1-cyclopropyl-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5] imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0528] To a solution of (7R,14R)-1-cyclopropyl-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (20 mg, 44 μmol, 1 eq) in THF (1 mL) was added K3PO4(0.5 M, 175 μL, 2 eq), (1r,3r)-1-(5-bromopyrimidin-2-yl)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutan-1-ol (18 138 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO mg, 48 μmol, 1.1 eq) and [2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3-(2,4,6- triisopropylphenyl)phenyl]phosphane (10 mg, 13 μmol, 0.3 eq) and the reaction mixture was stirred at 80°C for 8 hr under N2. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc 20 mL (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-TLC (SiO2, hexanes:ethyl acetate = 1:0) to give the title compound as a white solid (0.015 g, 22% yield, 80% purity). MS: [M+H]+= 622.5.

[0529] (7R,14R)-1-Cyclopropyl-11-(2-((1r,3R)-1,3-dihydroxy-3-methylcyclobutyl)pyrimidin- 5-yl)-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one

[0530] To a solution of (7R,14R)-11-(2-((1s,3S)-3-((tert-butyldimethylsilyl)oxy)-1-hydroxy- 3-methylcyclobutyl)pyrimidin-5-yl)-1-cyclopropyl-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (15 mg, 24 μmol, 1 eq) in THF (0.5 mL) was added N,N-diethylethanamine;trihydrofluoride (155 mg, 965 μmol, 157 μL, 40 eq) and the reaction mixture was stirred at 25°C for 6 hr under N2. The reaction was quenched with sat. NaHCO3(50 mL), diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: WePure Biotech XP tC18150*40*7µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:20%-50% B over 8.0 min) to give the title compound as a white solid (3 mg, 99% purity).1H NMR (400 MHz, DMSO-d6) δ = 9.07 (s, 2H), 8.16 (dd, J = 2.0, 7.6 Hz, 1H), 7.79-7.77 (m, 2H), 7.59 (d, J = 8.4 Hz, 1H), 7.29-7.27 (m, 2H), 6.67 (d, J = 7.6 Hz, 1H), 5.44 (s, 1H), 5.20 (J = 6.8 Hz, 1H), 4.90 (s, 1H), 3.54-3.49 (m, 1H), 3.30 (s, 3H), 2.79-2.72 (m, 4H), 2.25-2.22 (m, 2H), 1.50 (s, 3H), 1.28- 1.22 (m, 2H), 1.00-0.98 (m, 1H), 0.77-0.75 (m, 1H). HONBrN N N N O, , y y y y y y methylcyclobutyl)pyrimidin-5-yl)-1-cyclopropyl-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5] imidazo[1,2-a][1,4]diazocin-5(14H)-one 139 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0532] To a solution of (7R,14R)-1-cyclopropyl-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (0.02 g, 44 μmol, 1 eq) in THF (1 mL) was added K3PO4(0.5 M, 193 μL, 2.2 eq), (1s,3s)-1-(5-bromopyrimidin-2-yl)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutan-1-ol (18 mg, 48 μmol, 1.1 eq) and [2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3-(2,4,6- triisopropylphenyl)phenyl]phosphane (10 mg, 13 μmol, 0.3 eq) and the reaction mixture was stirred at 80°C for 4 hr under N2. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc 20 mL (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-TLC (SiO2, hexanes:ethyl acetate = 1:0) to give the title compound as a white solid (0.015 g, 22% yield, 80% purity). MS: [M+H]+= 622.3.

[0533] (7R,14R)-1-cyclopropyl-11-(2-((1s,3S)-1,3-dihydroxy-3-methylcyclobutyl)pyrimidin-5- yl)-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- one

[0534] To a solution of (7R,14R)-11-(2-((1s,3S)-3-((tert-butyldimethylsilyl)oxy)-1-hydroxy- 3-methylcyclobutyl)pyrimidin-5-yl)-1-cyclopropyl-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (0.015 g, 24 μmol, 1 eq) in THF (0.2 mL) was added N,N-diethylethanamine;trihydrofluoride (155 mg, 965 μmol, 157 μL, 40 eq) and the reaction mixture was stirred at 25°C for 8 hr under N2. The reaction was quenched with sat. NaHCO3(50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC (column: WePure Biotech XP tC18 150*40*7µm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:25%-55% B over 8.0 min) to give the title compound as a white solid (3 mg, 99% purity).1H NMR (400 MHz, DMSO-d6) δ = 9.09 (s, 2H), 8.18-8.16 (m, 1H), 7.79-7.77 (m, 2H), 7.61 (d, J = 8.4 Hz, 1H), 7.32-7.28 (m, 2H), 6.67 (d, J = 7.6 Hz, 1H), 5.59 (s, 1H), 5.21 (d, J = 6.8 Hz, 1H), 4.96 (s, 1H), 3.55-3.52 (m, 1H), 3.31 (s, 3H), 2.91-2.88 (m, 2H), 2.80-2.76 (m, 2H), 2.42-2.39 (m, 2H), 1.26-1.24 (m, 2H), 1.08 (s, 3H), 1.01-0.99 (m, 1H), 0.79-0.74 (m, 1H).

[0535] Example 59: Synthesis of (7R,14R)-1-cyclopropyl-11-(6-((1s,3S)-3-(difluoromethyl)- 1-hydroxy-3-(hydroxymethyl)cyclobutyl)-5-fluoropyridin-3-yl)-6-methyl-6,7-dihydro-7,14- 140 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one and (7R,14R)-1- cyclopropyl-11-(6-((1r,3R)-3-(difluoromethyl)-1-hydroxy-3-(hydroxymethyl)cyclobutyl)-5- fluoropyridin-3-yl)-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (69 and 70) NBrBrBr Br TBSOON NFTBSOHOTBSOHONO-(difluoromethyl)cyclobutan-1-ol and (1r,3r)-1-(5-bromo-3-fluoropyridin-2-yl)-3-(((tert- butyldimethylsilyl)oxy)methyl)-3-(difluoromethyl)cyclobutan-1-ol

[0537] To a solution of 2,5-dibromo-3-fluoro-pyridine (2.1 g, 8.3 mmol, 1.1 eq) in DCM (35 mL) was added dropwise n-BuLi (2.5 M, 3.3 mL, 1.1 eq) at -78°C under N2. After 10 min, a solution of 3-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-(difluoromethyl)cyclobutanone (2 g, 7.5 mmol, 1 eq) in DCM (5 mL) was added dropwise at -78°C and the reaction mixture was warmed to 20°C and stirred for 2 hr under N2. The reaction was quenched with sat. NH4Cl (30 mL) at 0°C, diluted with water (15 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep-HPLC(column: Phenomenex Luna C18 (250*70mm,15µm);mobile phase: [H2O(0.2% FA)-ACN];gradient:70%-98% B over 22.0 min) to give the (1s,3s) title compound as a yellow solid (1.1 g) and the (1r,3r) title compound as a yellow solid (0.5 g).1H NMR (400 MHz, CDCl3) δ = 8.44 (s, 1H), 7.65-7.62 (m, 1H), 6.11 (t, J = 57.6 Hz, 1H), 3.61 (s, 2H), 3.40 (s, 1H), 2.88-2.85 (m, 2H), 2.50-2.46 (m, 2H), 0.82 (s, 9H), - 0.005 (s, 6H);1H NMR (400 MHz, CDCl3) δ = 8.44 (s, 1H), 7.64-7.61 (m, 1H), 6.11 (t, J = 57.2 Hz, 1H), 4.30 (s, 1H), 3.97 (s, 2H), 3.05-3.01 (m, 2H), 2.27-2.23 (m, 2H), 0.95 (s, 9H), 0.16 (s, 6H). 141 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO

[0538] (7R,14R)-11-(6-((1s,3S)-3-(((tert-butyldimethylsilyl)oxy)methyl)-3-(difluoromethyl)-1- hydroxycyclobutyl)-5-fluoropyridin-3-yl)-1-cyclopropyl-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0539] To a mixture of (7R,14R)-1-cyclopropyl-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (30 mg, 65 μmol, 1 eq) and 1-(5-bromo-3-fluoro-2-pyridyl)-3-[[tert- butyl(dimethyl)silyl]oxymethyl]-3-(difluoromethyl) cyclobutanol (52 mg, 118 μmol, 1.8 eq) in dioxane (1.2 mL) was added K3PO4 (0.5 M, 263 μL, 2 eq) and [2-(2-aminophenyl)phenyl]-chloro- palladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl] phosphane (5 mg, 6 μmol, 0.1 eq) and the reaction mixture was heated to 100°C and stirred for 3 hr under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue (combined with another batch with 20 mg scale) which was purified by prep-TLC (SiO2, EtOAc:MeOH=20:1) to give the title compound as a white solid (30 mg, 95% purity). MS: [M+H]+= 689.4.

[0540] (7R,14R)-1-cyclopropyl-11-(6-((1s,3S)-3-(difluoromethyl)-1-hydroxy-3- (hydroxymethyl)cyclobutyl)-5-fluoropyridin-3-yl)-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo [4,5] imidazo[1,2-a] [1,4] diazocin-5(14H)-one

[0541] A solution of (7R,14R)-11-(6-((1s,3S)-3-(((tert-butyldimethylsilyl)oxy)methyl)-3- (difluoromethyl)-1-hydroxycyclobutyl)-5-fluoropyridin-3-yl)-1-cyclopropyl-6-methyl-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (30 mg, 43 µmol, 1 eq) in HCl / dioxane (4 M, 2 mL) was stirred at 20°C for 1 hr. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prep- HPLC (column: Phenomenex Luna C18 100*40mm*5µm;mobile phase: [H2O(0.2% FA)- ACN];gradient:15%-50% B over 8.0 min) to give the title compound as a white solid (8 mg, 29% yield, 99% purity).1H NMR (400 MHz, DMSO-d6) δ = 8.66 (s, 1H), 8.17 (dd, J = 2.0, 7.6 Hz, 1H), 7.99 (dd, J = 1.6, 12.0 Hz, 1H), 7.77-7.75 (m, 2H), 7.59 (dd, J = 1.6, 8.8 Hz, 1H), 7.32-7.26 (m, 2H), 6.67 (d, J = 7.6 Hz, 1H), 6.11 (t, J = 57.2 Hz, 1H), 5.89-5.70 (m, 1H), 5.21 (d, J = 6.8 Hz, 1H), 4.83-4.74 (m, 1H), 3.57-3.50 (m, 1H), 3.31 (s, 3H), 3.26 (s, 2H), 2.86-2.77 (m, 4H), 2.34 (d, J = 13.6 Hz, 2H), 1.31-1.21 (m, 2H), 1.02-0.99 (m, 1H), 0.79-0.76 (m, 1H). 142 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO Br HO NN TBSO N N NN NN N F HCFHOTBSO OHCl / dioxaneNN NO-1-hydroxycyclobutyl)-5-fluoropyridin-3-yl)-1-cyclopropyl-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0543] A solution of (7R,14R)-1-cyclopropyl-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (50 mg, 110 μmol, 1 eq) and (1r,3r)-1-(5-bromo-3-fluoropyridin-2-yl)-3-(((tert- butyldimethylsilyl)oxy)methyl)-3-(difluoromethyl) cyclobutan-1-ol (87 mg, 197 μmol, 1.8 eq) in dioxane (2 mL) was d...

Claims

Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO What is claimed is:

1. A compound which is of formula I: R5R4N R1a pharmaceutically acceptable salt or stereoisomer thereof,X is CH, CF, CCl, CCN, or N; R1 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or (C3-C8) heterocycloalkyl, any of which groups can be optionally substituted by one or more substituents selected from fluoro, cyano, hydroxy, amino, (C3-C10) cycloalkyl or (C3-C10) heterocycloalkyl; R2 is (C3-C10) cycloalkyl or (C3-C10) heterocycloalkyl, either of which groups can be optionally substituted by one or more substituents selected from halo, hydroxy, (C1-C6) alkyl, (C1- C6) alkoxy, hydroxy(C1-C6) alkyl, amino, amino(C1-C6) alkyl, and amino-di(C1-C6) alkyl; R3 is hydrogen, halo, cyano, -CF3, -OCF3, -ORa, -SRa, -SORa, -SO2Ra, -NRbRc, -NRcCORd, -NRcCO2Rd, -NHCONRbRc, -NRcSO2Re, -CORd, -CO2Rd, -CONRbRc, -SO2NRbRc, - S(O)(N-Rb)Re, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C7) cycloalkyl, (C4-C7) cycloalkenyl, (C6-C14) aryl, (C6-C14) aryl(C1-C6)alkyl, (C3-C7) heterocycloalkyl, (C3-C7) heterocycloalkenyl, 5- to 14-membered heteroaryl, 5- to 14-membered heteroaryl(C1-C6)alkyl, (C3-C7) heterocycloalkyl(C1-C6)alkyl-(C6-C14) aryl, (C3-C7) heterocycloalkenyl-(C6-C14) aryl, (C3-C7) cycloalkyl-5- to 14-membered heteroaryl, (C3-C7) cycloalkyl-(C1-C6) alkyl-5- to 14- membered heteroaryl, (C4-C7) cycloalkenyl-5- to 14-membered heteroaryl, (C4-C9) bicycloalkyl- 5- to 14-membered heteroaryl, (C3-C7) heterocycloalkyl-5- to 14-membered heteroaryl, (C3-C7) heterocycloalkyl-(C1-C6) alkyl-5- to 14-membered heteroaryl, (C3-C7) heterocycloalkenyl-5- to 14-membered heteroaryl, (C4-C9) heterobicycloalkyl-5- to 14-membered heteroaryl, or (C4-C9) spiroheterocycloalkyl-5- to 14-membered heteroaryl, any of which groups can be optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (C1-C6) alkyl, (C3-C7) cycloalkyl, -CHF2, (C1-C6) alkoxy, hydroxy(C1-C6) alkyl, oxo, amino, amino(C1-C6) alkyl, amino- di(C1-C6) alkyl, -P(O)RfRg, -CO2Rh, -S(O)Rh, -S(O)2Rh, -CON(Rh)2, (C1-C6) alkyl-O-(C3-C7) 212 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO heterocyclyl, (C3-C7) heterocyclyl, (C3-C7) heterocyclyl-(C3-C7) cycloalkyl, (C3-C7) heterocyclyl- (C3-C7) heterocyclyl, 5- to 14-membered heteroaryl, and (C6-C14) aryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more substituents selected from cyano, hydroxy, (C1-C3) alkyl, amino, (C1-C3) alkylhydroxy, carboxyl, fluoro, (C1- C3) alkylhalo, and -P(O)RfRg; Rais (C1-C6) alkyl, (C3-C7) cycloalkyl, (C6-C14) aryl, (C6-C14) aryl-(C1-C6) alkyl, (C3-C7) heterocycloalkyl, 5- to 14-membered heteroaryl, 5- to 14-membered heteroaryl-(C1-C6) alkyl, any of which groups can be optionally substituted by one or more substituents selected from (C1-C6) alkoxy and oxo; Rbis hydrogen, (C1-C6) alkyl, (C6-C14) aryl-(C1-C6) alkyl, (C3-C7) heterocycloalkyl, or (C3-C7) heterocycloalkyl-(C1-C6) alkyl, any of which groups can be optionally substituted by one or more substituents selected from (C1-C6) alkoxy, (C1-C6) alkylthio, (C1-C6) alkylsulphinyl, (C1-C6) alkylsulphonyl, hydroxy, cyano, (C2-C6) alkoxycarbonyl, di(C1-C6)alkylamino, and (C2-C6) alkoxycarbonylamino; Rcis hydrogen, (C1-C6) alkyl, (C3-C7) cycloalkyl, or (C3-C7) heterocycloalkyl, any of which groups can be optionally substituted by one or more substituents selected from (C2-C6) alkylcarbonyl and (C2-C6) alkoxycarbonyl, or Rband Rc, taken together with the nitrogen atom to which they are attached, form azetidine-1-yl, pyrrolidine-1-yl, oxazolidine-3-yl, isoxazolidin-2-yl, thiazolidine- 3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholine-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl, homopiperazin-1-yl, (imino)(oxo)thiazinam-4-yl, (oxo)thiazinam-4-yl, and (dioxo)thiazinam-4-yl, any of which can be optionally substituted by one or more substituents selected from (C1-C6) alkyl, (C1-C6) alkylsulphonyl, hydroxy, hydroxy(C1-C6) alkyl, amino(C1- C6) alkyl, cyano, oxo, (C2-C6) alkylcarbonyl, carboxy, (C2-C6) alkoxycarbonyl, amino, (C2-C6) alkylcarbonyl-amino, (C2-C6) alkylcarbonylamino(C1-C6) alkyl, (C2-C6) alkoxycarbonylamino, (C1-C6) alkyl-sulphonylamino, and aminocarbonyl; Rdis hydrogen, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C6-C14) aryl, (C3-C7) heterocycloalkyl, or 5- to 14-membered heteroaryl, any which can be optionally 213 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO substituted by one or more substituents selected from halo, (C1-C6) alkyl, (C1-C6) alkoxy, oxo, (C2-C6) alkylcarbonyloxy, and di(C1-C6) alkylamino; Reis (C1-C6) alkyl, (C6-C14) aryl, or 5- to 14-membered heteroaryl, any of which can be optionally substituted by (C1-C6) alkyl; Rfis hydroxy, optionally substituted (C1-C3) alkoxy, or optionally substituted (C1- C6) alkyl; Rgis hydroxy, optionally substituted (C1-C3) alkoxy, or optionally substituted (C1- C6) alkyl; or Rfand Rg, taken together with the phosphorus atom to which they are attached, form an optionally substituted phosphorus-containing 3- to 8-membered aliphatic alkyl ring; and Rhis hydrogen, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C1-C6) alkylamino, or optionally substituted di(C1- C6) alkylamino, wherein the one or more optional substituents of Rf, Rg, and Rhare independently selected from (C1-C3) alkyl, fluoro, hydroxy, cyano, and amino; R4is hydrogen, halo, cyano, nitro, hydroxy, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -ORa, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl, or 5- to 14-membered heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl and heteroaryl can be optionally substituted by one or more substituents selected from hydroxy(C1-C6) alkyl and (C2-C6) alkoxycarbonyl; R5and R6are independently hydrogen, halo, cyano, hydroxy, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -ORa, (C1-C6) alkyl, (C3-C7) cycloalkyl, or (C3-C7) heterocycloalkyl, wherein said alkyl, cycloalkyl, and heterocycloalkyl can be optionally substituted by one or more substituents selected from hydroxy(C1-C6) alkyl and (C2-C6) alkoxycarbonyl; each R7 is independently hydrogen, halo, cyano, hydroxy, amino, -CF3, (C1-C6) alkyl, (C1- C6) alkoxy, or (C3-C7) cycloalkyl; and n is 0, 1, or 2.

2. The compound of claim 1, wherein the compound is of formula Ia: 214 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO R5R4N R1a pharmaceutically acceptable salt or stereoisomer thereof.

3. The compound of claim 1 or 2, wherein R1 is hydrogen or methyl. F 4. The compound of claim any one of claims 1-3, wherein R2 iF ,F OHFFNH2F F or5. The compound of any one of claims 1-4, wherein R3is 5- to 14-membered heteroaryl, 5- to 14-membered heteroaryl(C1-C6)alkyl, (C3-C7) cycloalkyl-5- to 14-membered heteroaryl, (C3- C7) cycloalkyl-(C1-C6) alkyl-5- to 14-membered heteroaryl, (C4-C7) cycloalkenyl-5- to 14- membered heteroaryl, (C4-C9) bicycloalkyl-5- to 14-membered heteroaryl, (C3-C7) heterocycloalkyl-5- to 14-membered heteroaryl, (C3-C7) heterocycloalkyl-(C1-C6) alkyl-5- to 14- membered heteroaryl, (C3-C7) heterocycloalkenyl-5- to 14-membered heteroaryl, (C4-C9) heterobicycloalkyl-5- to 14-membered heteroaryl, or (C4-C9) spiroheterocycloalkyl-5- to 14- membered heteroaryl, any of which groups can be optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (C1-C6) alkyl, (C3-C7) cycloalkyl, -CHF2, hydroxy(C1-C6) alkyl, oxo, amino, and amino(C1-C6) alkyl, wherein said alkyl and cycloalkyl is optionally substituted by one or more substituents selected from cyano, hydroxy, (C1-C3) alkyl, (C1-C3) alkylhydroxy, carboxyl, fluoro, (C1-C3) alkylhalo, and amino. 215 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO 6. The compound of any one of claims 1-5, wherein R4 is hydrogen, halo, cyano, methoxy, - CF3, -CHF2, -CH2F, -OCF3, -OCHF2, (C1-C4) alkyl, (C3-C7) cycloalkyl, or (C3-C7) heterocycloalkyl, wherein said alkyl, cycloalkyl, and heterocycloalkyl can be optionally substituted by one or more substituents selected from hydroxy(C1-C6) alkyl and (C2-C6) alkoxycarbonyl.

7. The compound of any one of claims 1-6, wherein R5is hydrogen, halo, cyano, methoxy, - CF3, -CHF2, -CH2F, -OCF3, -OCHF2, (C1-C4) alkyl, (C3-C7) cycloalkyl, or (C3-C7) heterocycloalkyl, wherein said alkyl, cycloalkyl, and heterocycloalkyl can be optionally substituted by one or more substituents selected from hydroxy(C1-C6) alkyl and (C2-C6) alkoxycarbonyl.

8. The compound of any one of claims 1-7, wherein R6is hydrogen, halo, cyano, methoxy, - CF3, -CHF2, -CH2F, -OCF3, -OCHF2, (C1-C4) alkyl, (C3-C7) cycloalkyl, or (C3-C7) heterocycloalkyl, wherein said alkyl, cycloalkyl, and heterocycloalkyl can be optionally substituted by one or more substituents selected from hydroxy(C1-C6) alkyl and (C2-C6) alkoxycarbonyl.

9. The compound of claim 1, which is of formula Ib: N R8N a pharmaceutically acceptable salt or stereoisomer thereof,Ring A is phenyl or 5- or 6-membered heteroaryl, wherein said phenyl and heteroaryl can be optionally substituted by one or more substituents selected from (C1-C4) alkyl and halo; R8 is hydrogen or methyl; NH2CN OH NH NH H2, AFSDOCDate of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO OH H N OH 2HOH2NHOHOH2N NH2, ,,10. The compound of claim 9, wherein Ring A is pyrimidinyl, pyridinyl, imidazole, thiazole, isothiazole, oxazole, isoxazole, triazole, thiadiazol, oxadiazole, pyrazine, or pyridazine. NH211. The compound of claim 9 or 10, wherein R9.

12. The compound of claim 1, which is of formula Ic: R5R4N of,Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO * Z1Z2Ring B is Z Z4, wherein * denotes point of attachment to L, or optionally substituted piperi lly substituted pyrazolene, optionally substituted imidazolene,optionally substituted oxazolene, or optionally substituted thiazolene; Z1 is N or CR11; Z2 is N or CR12; Z3is N or CR13; Z4 is N or CR14; R11, R12, R13, and R14 are independently hydrogen, halo, -CN, -NH2, optionally substituted (C1-C3) alkyl, optionally substituted (C1-C3) alkoxy, or -NH(optionally substituted (C1-C3) alkyl); L is a bond, -NH-, -(CH2)n-, -C(R’)(R”)-, -O(CH2)n-*, or -NH(CH2)n-*, wherein the * denotes the point of attachment to phosphorous; n is 1, 2, or 3; and R’ and R” are independently hydrogen, hydroxy, fluoro, or methyl. F 13. The compound of claim 12, wherein R2 i,FOHFFNH2F ,14. The compound of claim 12 or 13, wherein Rfand Rgare both methyl.

15. The compound of claim 1, which is 218 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO N N N NH N N N N HN O HN O (2),Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO N N NH NH N N N O O 2),Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO N N F N N N N O H N N 2 O P N O HO O O NC HO O NC H2NAFSDODate of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO N N N N N N N O NO, 8),Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO N N NH N N OH2NNN N),4), 6), ),Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO N N N N N N N N HOOHOO 2), 4), ),Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO N N N N N N N HNO8), 0),Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO N N N N N N O N N O lly16. A pharmaceutical composition, comprising the compound of any one of claims 1-15, or pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

17. The method of treating a disease or disorder that is characterized or mediated by aberrant tumor necrosis factor receptor 1 (TNFR1) signaling, comprising administering to a subject in need thereof the compound of any one of claims 1-15, or a pharmaceutically acceptable salt or stereoisomer thereof, or the pharmaceutical composition of claim 16. 226 AFSDOCS:302709159.1Date of Deposit: June 3, 2025 Attorney Docket No.046094-792001WO 18. The method of claim 17, wherein the disease or disorder is an inflammatory or neuroinflammatory disease.

19. The method of claim 18, wherein the inflammatory disease is rheumatoid arthritis, psoriasis, hidradenitis suppurativa, polyarticular juvenile idiopathic arthritis, non-infectious uveitis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, or psoriatic arthritis.

20. The method of claim 18, wherein the neuroinflammatory disease is multiple sclerosis, Alzheimer’s disease, or amyotrophic lateral sclerosis. 227 AFSDOCS:302709159.1

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