Modulators of TNF-alpha activity

Abstract

Provided herein are inhibitors of TNF-alpha, pharmaceutical compositions comprising the inhibitory compounds, and methods for using the TNF-alpha inhibitory compounds for the treatment of diseases or disorders.

Description

WSGR Ref: 53699-720.601 MODULATORS OF TNF-ALPHA ACTIVITY CROSS REFERENCE

[0001] This application claims the benefit of US Provisional Application No. 63 / 613,623, filedDecember 21, 2023, which is incorporated herein by reference in its entirety. BACKGROUND

[0002] Tumor necrosis factor alpha (TNF-^) is an inflammatory cytokine that is responsible fora wide range of signaling events within cells. Aberrant TNF-^ signaling gives rise to inflammatory conditions and is thought to be an important component of inflammatory disease, such as rheumatoid arthritis. BRIEF SUMMARY OF THE INVENTION

[0003] Provided herein are inhibitors of TNF-^, pharmaceutical compositions comprising saidinhibitory compounds, and methods for using said inhibitory compounds for the treatment of inflammatory or autoimmune disease or disorder.

[0004] One embodiment provides a compound of Formula (I), or pharmaceutically acceptablesalt, solvate, N-oxide, or deuteroisotope thereof:wherein, W is N or C-R10; X is N or C-R11; Y is N or C-R12; Z is N or C-R13; R is selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted heterocyclyl, optionally substituted C1-C6 alkoxy, - PO(R8)(R9), -S(O)(NH)R8, or -CH2-PO(R8)(R9); R1is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl; R2is hydrogen, optionally substituted C1 alkyl, or halogen; R3is hydrogen, or halogen;WSGR Ref: 53699-720.601 R4is hydrogen, optionally substituted C1 alkyl, or halogen; R5is independently selected from hydrogen, or optionally substituted C1-C6 alkyl; R6is hydrogen, or halogen; R7is hydrogen, or halogen; R8and R9are each independently selected from optionally substituted C1-C6 alkyl; or R8and R9join to form a phosphorous-containing heterocyclic ring; R10is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; R11is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; R12is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; and R13is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl.

[0005] One embodiment provides a compound of Formula (Ia), or pharmaceutically acceptablesalt, solvate, N-oxide, or deuteroisotope thereof:wherein, W is N or C-R10; X is N or C-R11; Y is N or C-R12; Z is N or C-R13; R is selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted heterocyclyl, optionally substituted C1-C6 alkoxy, or - PO(R8)(R9); R1is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl; R2is hydrogen, optionally substituted C1 alkyl, or halogen; R3is hydrogen, or halogen; R4is hydrogen, optionally substituted C1 alkyl, or halogen; R5is independently selected from hydrogen, or optionally substituted C1-C6 alkyl; R6is hydrogen, or halogen; R7is hydrogen, or halogen;WSGR Ref: 53699-720.601 R8and R9are each independently selected from optionally substituted C1-C6 alkyl; or R8and R9join to form a phosphorous-containing heterocyclic ring; R10is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; R11is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; R12is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; and R13is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl.

[0006] One embodiment provides a compound of Formula (II), or pharmaceutically acceptablesalt, solvate, N-oxide, or deuteroisotope thereof:wherein, Ring A is an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms selected from N, O or S; R is selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted heterocyclyl, optionally substituted C1-C6 alkoxy, - PO(R8)(R9), -S(O)(NH)R8, or -CH2-PO(R8)(R9); R1is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl; R2is hydrogen, optionally substituted C1 alkyl, or halogen; R3is hydrogen, or halogen; R4is hydrogen, optionally substituted C1 alkyl, or halogen; R5is independently selected from hydrogen, or optionally substituted C1-C6 alkyl; R6is hydrogen, or halogen; R7is hydrogen, or halogen; and R8and R9are each independently selected from optionally substituted C1-C6 alkyl; or R8and R9join to form a phosphorous-containing heterocyclic ring.

[0007] One embodiment provides a compound of Formula (III), or pharmaceutically acceptablesalt, solvate, N-oxide, or deuteroisotope thereof:WSGR Ref: 53699-720.601wherein, G is -CN, halogen, optionally substituted C1-C6 alkoxy, optionally substituted heteroarylalkoxy, optionally substituted C2-C6 alkynyl, (optionally substituted C2-C6 alkynylene)-NH-(optionally substituted C3-C6 cycloalkyl), or (optionally substituted C2-C6 alkynylene)-O-(optionally substituted C3-C6 cycloalkyl); R1is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl; R2is hydrogen, optionally substituted C1 alkyl, or halogen; R3is hydrogen, or halogen; R4is hydrogen, optionally substituted C1 alkyl, or halogen; R5is independently selected from hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted heterocyclyl; R6is hydrogen, or halogen; and R7is hydrogen, or halogen.

[0008] One embodiment provides a pharmaceutical composition comprising a compound ofFormula (I), (Ia), (II), or (III), or pharmaceutically acceptable salt, solvate, or N-oxide thereof, and at least one pharmaceutically acceptable excipient.

[0009] One embodiment provides a method of treating a disease or disorder in a patient in needthereof comprising administering to the patient a compound of Formula (I), (Ia), (II), or (III), or pharmaceutically acceptable salt, solvate, or N-oxide thereof. Another embodiment provides the method wherein the disease or disorder is rheumatoid arthritis. INCORPORATION BY REFERENCE

[0010] All publications, patents, and patent applications mentioned in this specification areherein incorporated by reference for the specific purposes identified herein. DETAILED DESCRIPTION OF THE INVENTION

[0011] As used herein and in the appended claims, the singular forms "a," "and," and "the"include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includesWSGR Ref: 53699-720.601 reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, "consist of" or "consist essentially of" the described features. Definitions

[0012] As used in the specification and appended claims, unless specified to the contrary, thefollowing terms have the meaning indicated below.

[0013] "Amino" refers to the –NH2 radical.

[0014] "Cyano" refers to the -CN radical.

[0015] "Nitro" refers to the -NO2 radical.

[0016] "Oxa" refers to the -O- radical.

[0017] "Oxo" refers to the =O radical.

[0018] "Thioxo" refers to the =S radical.

[0019] "Imino" refers to the =N-H radical.

[0020] "Oximo" refers to the =N-OH radical.

[0021] "Hydrazino" refers to the =N-NH2 radical.

[0022] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely ofcarbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C1-C8alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1- C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C1alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, an alkylWSGR Ref: 53699-720.601 comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). In certain embodiments, an optionally substituted alkyl is a haloalkyl. In other embodiments, an optionally substituted alkyl is a fluoroalkyl. In other embodiments, an optionally substituted alkyl is a -CF3group.

[0023] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula –O-alkyl,where alkyl is an alkyl chain as defined above.

[0024] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consistingsolely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where eachWSGR Ref: 53699-720.601 Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0025] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consistingsolely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl comprises two to six carbon atoms. In other embodiments, an alkynyl comprises two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0026] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbonchain linking the rest of the molecule to a radical group, consisting solely of carbon andhydrogen, containing no unsaturation, and having from one to twelve carbon atoms, forexample, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain isWSGR Ref: 53699-720.601 attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., C1-C8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C1alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C5-C8 alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0027] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbonchain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkenylene comprises two to eight carbon atoms (e.g., C2-C8alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (e.g., C2-C4 alkenylene). In otherWSGR Ref: 53699-720.601 embodiments, an alkenylene comprises two to three carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (e.g., C2alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., C5-C8alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C3-C5 alkenylene). Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0028] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbonchain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C2-C8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C2-C5alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C2alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C3-C5 alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2),WSGR Ref: 53699-720.601 -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0029] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclichydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb- OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, - Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene orWSGR Ref: 53699-720.601 alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0030] "Aralkyl" refers to a radical of the formula -Rc-aryl where Rc is an alkylene chain asdefined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0031] "Aralkenyl" refers to a radical of the formula –Rd-aryl where Rd is an alkenylene chain asdefined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0032] "Aralkynyl" refers to a radical of the formula -Re-aryl, where Re is an alkynylene chainas defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0033] "Aralkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc-arylwhere Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0034] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbonradical consisting solely of carbon and hydrogen atoms, which includes spiro, fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds). A fully saturated carbocyclyl radical is also referred to as "cycloalkyl." Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo,WSGR Ref: 53699-720.601 oxo, thioxo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb- N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb- S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0035] "Carbocyclylalkyl" refers to a radical of the formula –Rc-carbocyclyl where Rc is analkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0036] "Carbocyclylalkynyl" refers to a radical of the formula –Rc-carbocyclyl where Rc is analkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0037] "Carbocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula –O-Rc-carbocyclyl where Rcis an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0038] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.

[0039] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one ormore fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl,fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0040] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical thatcomprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includesWSGR Ref: 53699-720.601 spiro, fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are notlimited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl,isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, - Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb- C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb- N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0041] "N-heterocyclyl" or “N-attached heterocyclyl” refers to a heterocyclyl radical as definedabove containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, and imidazolidinyl.WSGR Ref: 53699-720.601

[0042] "C-heterocyclyl" or “C-attached heterocyclyl” refers to a heterocyclyl radical as definedabove containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. A C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0043] "Heterocyclylalkyl" refers to a radical of the formula –Rc-heterocyclyl where Rc is analkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0044] "Heterocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula–O-Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0045] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radicalthat comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl,WSGR Ref: 53699-720.601 furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, optionally substituted fluoroalkyl, optionally substituted haloalkenyl, optionally substituted haloalkynyl, oxo, thioxo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, - Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc- C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb- S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.WSGR Ref: 53699-720.601

[0046] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least onenitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0047] "C-heteroaryl" refers to a heteroaryl radical as defined above and where the point ofattachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0048] "Heteroarylalkyl" refers to a radical of the formula –Rc-heteroaryl, where Rc is analkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0049] "Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula –O-Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0050] The compounds disclosed herein, in some embodiments, contain one or moreasymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Zgeometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemicand optically pure forms, and all tautomeric forms are also intended to be included. The term“geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans) of an alkene doublebond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0051] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule toanother atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on severalWSGR Ref: 53699-720.601 factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0052] The compounds disclosed herein, in some embodiments, are used in different enrichedisotopic forms, e.g., enriched in the content of2H,3H,11C,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos.5,846,514 and 6,334,997. As described in U.S. Patent Nos.5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0053] Unless otherwise stated, structures depicted herein are intended to include compoundswhich differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0054] The compounds of the present disclosure optionally contain unnatural proportions ofatomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,11C,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35Cl,37Cl,79Br,81Br,125I are all contemplated. In some embodiments, isotopic substitution with18F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0055] In certain embodiments, the compounds disclosed herein have some or all of the 1Hatoms replaced with2H atoms. The methods of synthesis for deuterium-containing compoundsWSGR Ref: 53699-720.601 are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0056] Deuterium substituted compounds are synthesized using various methods such asdescribed in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0057] Deuterated starting materials are readily available and are subjected to the syntheticmethods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0058] Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, suchas iodomethane-d3 (CD3I), are readily available and may be employed to transfer a deuterium- substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD3I is illustrated, by way of example only, in the reaction schemes below.

[0059] Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAlD4), areemployed to transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD4 is illustrated, by way of example only, in the reaction schemes below.

[0060] Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbonlinkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.WSGR Ref: 53699-720.601

[0061] In one embodiment, the compounds disclosed herein contain one deuterium atom. Inanother embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable1H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.

[0062] "Pharmaceutically acceptable salt" includes both acid and base addition salts. Apharmaceutically acceptable salt of any one of the TNF-^ inhibitory compounds describedherein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0063] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain thebiological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates,WSGR Ref: 53699-720.601 benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1- 19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0064] "Pharmaceutically acceptable base addition salt" refers to those salts that retain thebiological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N- dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0065] "Pharmaceutically acceptable solvate" refers to a composition of matter that is thesolvent addition form. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein exist in either unsolvated or solvated forms.

[0066] The term “subject” or “patient” encompasses mammals. Examples of mammals include,but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.WSGR Ref: 53699-720.601

[0067] As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are usedinterchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and / or a prophylactic benefit. By “therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made. Tumor Necrosis Factor alpha (TNFα) Protein and Function

[0068] Tumor necrosis factor alpha (TNFα) proteins are members of the TNF superfamily,comprising various transmembrane proteins with a homologous TNF domain forming trimers. The TNF superfamily comprises 19 family members, including, but not limited to tumor necrosis factor alpha (also known as tumor necrosis factor, or TNF), lymphotoxin alpha (TNFβ), lymphotoxin beta (TNFγ), OX40 ligand, CD40 ligand, Fas ligand, CD27 ligand, CD30 ligand, CD137 ligand, CD137 ligand, and TNF-related apoptosis-inducing ligand. TNFα proteins are cytokines and adipokines (cytokines secreted by adipose tissue).

[0069] TNFα is a transmembrane protein, with soluble TNFα (sTNFα) released via proteincleavage. The sTNFα can propagate signaling by binding to two receptors, TNFR1 and TNFR2. TNFα is a regulator of immune responses for cell signaling and can mediate cell survival and cell death inducing signaling. There are two receptors for TNF signaling, TNFR1 and TNFR2. sTNFα – TNFR1 signaling promotes immune cell activation and drives acute and chronic inflammation. Membrane TNFα – TNFR2 signaling promotes inflammation resolution, immune cell regulatory functions and cell survival.

[0070] The extracellular region of both TNFR1 and TNFR2 have four homologous cysteine-richdomains, but they have structurally different intracellular regions. TNFR1 has a protein binding region called a death domain which allows homo- and hetero-typic interactions with other death domain-containing proteins. In contrast, TNFR2 has a TNF Receptor Associated Factor TRAF) that interacts with TRAF family of signaling adaptors. The distinct profiles and differences of the two TNF receptors influence the cellular activity and physiological roles. TNFR1 can activate NF-κB and MAPK signaling, and cell death, and is important to regulate for inflammatory diseases. TNFR2 is highly regulated and restricted to specific cell types such as endothelial cells and T cells. TNFR1 primarily promotes tissue degeneration and inflammationWSGR Ref: 53699-720.601 and TNFR2 typically mediates local homestatic effects such as tissue regeneration and cell survival (D. Fresegna et al., Cells, 2020, 9, 2290).

[0071] Binding of TNFα to TNFR1 can activate NF-κB for mediating transcription of variousproteins involved in cell survival and proliferation, anti-apoptotic factors, and inflammatory response. Further, the MAPK pathway can also be activated by binding of TNFα to TNFR1, which is involved in cell differentiation and proliferation. When TNF binds to TNFR1, it triggers receptor trimerization, leading to the assembly of a TNFR1-associated signaling complex. This complex recruits the receptor interacting protein 1 (RIP2) and TNF receptor associated death domain (TRADD) to the TNFR1 through the receptive death domains. TRADD then recruits adaptor proteins TRAF2 and TRAF5, which can engage the E3 ligases cellular inhibitors of apoptosis (c-IAP1, c-IAP2). C-IAP1 / 2 are important for TNFR1 complex signaling, which can eventually lead to the recruitment of the signaling kinase complexes of kinase IKKα and IKKβ, which are inhibitors of kappa B kinase 1 and 2, and transforming growth factor beta- activated kinase 1 (TAK1) leading to activation of NF- κB and MAPK signaling. Activation of these signaling pathways can result in gene activation and expression of pro-inflammatory cytokines and pro-survival proteins.

[0072] TNF signaling is regulated by post-translational ubiquitination, which is essential for mybiological processes. Post-translational modifications of TNFR1-associated signaling complexes can result in a change from inflammatory gene signaling to cell death. This switch is dependent upon the ubiquitination status of RIP1, which is formed as part of the TNFR1-associated signaling complex from TNFα binding.

[0073] TNF has long been known to be a key regulator of the inflammatory response, andrecently has been known to be involved n brain functioning (D. Fresegna et al., Cells, 2020, 9, 2290). As a regulator of the inflammatory response, TNF can regulate many aspects of T cell biology including, but not limited to proliferation, survival, priming, and apoptotic fate. TNF is also known to play a role in conclusion of lymphocyte response, by the ability to promote cell death in both CD4 and CD8P T cells, through TNFR1. Specific inflammatory conditions can also result in TNFR2 promoting or supporting T cell apoptosis.

[0074] In normal adult brains, TNF is expressed at low levels, and it is believed that theexpression could be influenced by presence or absence of cytokines that can cross the blood brain barrier. TNFRs in the brain are expressed by glia and neurons cells, and have regulatory functions, including, but not limited to homeostatic synaptic plasticity, astrocyte-mediated synaptic transmission, and neurogenesis. These functions are useful for regulating learning and memory functions amongst other roles.WSGR Ref: 53699-720.601

[0075] TNF is recognized to be physiological gliotransmitter for the communication betweenneurons and glial cells, which in turn affects synaptic regulation. Glial TNF is important for maintenance of normal surface expression of AMPA receptors, and for homeostatic synaptic scaling, which allows for adjustment of the strength of all synapses on a neuron. Prior Art Small Molecules Inhibitors

[0076] Diseases treated with biologic TNFα inhibitors include, but are not limited to rheumatoidarthritis, inflammatory bowel disease, psoriatic arthritis, psoriasis, and ankylosing spondylitis. Patients with neuroinflammatory conditions and degenerative disease, including, but not limited to Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, treatment resistant depression, and tinnitus, may benefit from treatment with oral CNS sTNFα inhibitors by disrupting the sTNFα signaling and sparing the mTNFα signaling. Previous reports have also indicated targeting TNFR2 for treating Alzheimer’s Disease (N. Orti-Casañ et al., Front Neurosci.2019; 13: 49).

[0077] Small molecules have been developed for treatment of rheumatoid arthritis as somepatients have responded poorly to monotherapy of approved anti-TNFα drugs (J. D. Dietrich et al., J. Med. Chem.2021, 64, 417-429). Anti-TNFα drugs have also been expanded for use in other chronic autoimmune diseases, including, but not limited to, Crohn’s disease, psoriasis, psoriatic arthritis, ulcerative colitis inflammatory bowel disease, ankylosing spondylitis, and juvenile rheumatoid arthritis. Small molecules have been developed as an alternative to anti- TNFα biologics since the long-term clinical response rate is generally around 60-70% for rheumatoid arthritis.

[0078] Previous research has also indicated that TNFα inhibitors can be therapeutic fortreatment of multiple sclerosis (D. Fresegna et al., Cells, 2020, 9, 2290). There has been evidence of the involvement of TNF in various pathological issues of multiple sclerosis, including immune dysregulation, demylination, synaptopathy, and neuroinflammation. TNFα inhibitors have the potential for treatment of multiple sclerosis, other potential chronic neurodegenerative diseases of the central nervous system.

[0079] More than 50 million Americans struggle with tinnitus, which is the hearing of a soundwith no external source. It has been shown that TNFα is necessary for noise-induced neuroinflammation and synaptic imbalance (W. Wang et al., PLoS Biol.2019 Jun 18; 17(6):e3000307; A. Shulman et al., Curr Top Behav Neurosci.2021;51:161-174). It is believed that certain inhibitors of TNFα have activities for treating tinnitus.

[0080] Recent reports also indicate that TNFα inhibitors can be used alone or in combination fortreatment with inflammatory bowel disease (S. F. Fowler Braga and K. J. Clark, US Pharm. 2021; 46(5):34-37). TNFα is a mediator of the abnormal immune response of inflammatoryWSGR Ref: 53699-720.601 bowel disease, which leads to disruption of the intestinal mucosa and epithelial wall barrier. The anti-TNF agents can block TNF-mediated activation of the proinflammatory pathways to result in decreased immune-mediated inflammation.

[0081] Small molecule sTNF α inhibitors are active in pharmacology models of sTNFα / TNFR1signaling in addition to demonstrating efficacy in a model of collagen antibody induced arthritis. There is currently limited data in the public domain for small molecule sTNF α inhibitors. Some TNFα inhibitors include, but are not limited to XPro1595, Etanercept, Infliximab, Adalimumab, Certolizumab pegol, Golimumamb, and other inhibitors described in “TNF-α: The Shape of Small Molecules to Come?” (A. Dömling and X. Li, Drug Discov Today 2022 Jan; 27(1):3-7) and “Small Molecules that Inhibit TNF Signalling by Stabilising an Asymmetric Form of the Trimer (J. O’Connell et al., Nature Communications 10, 5795 (2019)). Additional small molecule inhibitors of TNFα include, but are not limited to the inhibitors described in “Biologic- like In Vivo Efficacy with Small Molecule Inhibitors of TNFα Identified Using Scaffold Hopping and Structure-Based Drug Design Approaches” (H-Y Xiao et al., J. Med. Chem.2020, 15050-15071), “Development of Orally Efficacious Allosteric Inhibitors of TNFα via Fragment- Based Drug Design” (J. D. Dietrich et al., J. Med. Chem.2021, 64, 417-429), and “Small- Molecule Inhibition of TNF-α” (M.M. He et al., Science, 310 (2015), 1022-1025).

[0082] Small molecule sTNFα inhibitors have potential as a valuable therapy for patientscurrently treated with biologic TNFα inhibitors which affect mTNFα with the ability to fine tune oral dosing requirements and avoid anti-drug antibody responses, thereby improving short and long responses (A. Dömling and X. Li, Drug Discov Today 2022 Jan; 27(1):3-7). Novel Compounds Inhibiting TNF-^

[0083] In one aspect, provided herein are TNF-^ inhibitory compounds.

[0084] One embodiment provides a compound of Formula (I), or pharmaceutically acceptablesalt, solvate, N-oxide, or deuteroisotope thereof:wherein, W is N or C-R10; X is N or C-R11; Y is N or C-R12;WSGR Ref: 53699-720.601 Z is N or C-R13; R is selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted heterocyclyl, optionally substituted C1-C6 alkoxy, - PO(R8)(R9), -S(O)(NH)R8, or -CH2-PO(R8)(R9); R1is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl; R2is hydrogen, optionally substituted C1 alkyl, or halogen; R3is hydrogen, or halogen; R4is hydrogen, optionally substituted C1 alkyl, or halogen; R5is independently selected from hydrogen, or optionally substituted C1-C6 alkyl; R6is hydrogen, or halogen; R7is hydrogen, or halogen; R8and R9are each independently selected from optionally substituted C1-C6 alkyl; or R8and R9join to form a phosphorous-containing heterocyclic ring; R10is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; R11is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; R12is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; and R13is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl.

[0085] One embodiment provides a compound of Formula (Ia), or pharmaceutically acceptablesalt, solvate, N-oxide, or deuteroisotope thereof:wherein, W is N or C-R10; X is N or C-R11; Y is N or C-R12; Z is N or C-R13; R is selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted heterocyclyl, optionally substituted C1-C6 alkoxy, or - PO(R8)(R9);WSGR Ref: 53699-720.601 R1is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl; R2is hydrogen, optionally substituted C1 alkyl, or halogen; R3is hydrogen, or halogen; R4is hydrogen, optionally substituted C1 alkyl, or halogen; R5is independently selected from hydrogen, or optionally substituted C1-C6 alkyl; R6is hydrogen, or halogen; R7is hydrogen, or halogen; R8and R9are each independently selected from optionally substituted C1-C6 alkyl; or R8and R9join to form a phosphorous-containing heterocyclic ring; R10is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; R11is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; R12is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; and R13is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl.

[0086] Another embodiment provides the compound of Formula (I) or (Ia), or pharmaceuticallyacceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein W is N.

[0087] Another embodiment provides the compound of Formula (I) or (Ia), or pharmaceuticallyacceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein X is N.

[0088] Another embodiment provides the compound of Formula (I) or (Ia), or pharmaceuticallyacceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein Y is N.

[0089] Another embodiment provides the compound of Formula (I) or (Ia), or pharmaceuticallyacceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein Z is N.

[0090] Another embodiment provides the compound of Formula (I) or (Ia), or pharmaceuticallyacceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein W is C-R10.

[0091] Another embodiment provides the compound of Formula (I) or (Ia), or pharmaceuticallyacceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein X is C-R11.

[0092] Another embodiment provides the compound of Formula (I) or (Ia), or pharmaceuticallyacceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein Y is C-R12.

[0093] Another embodiment provides the compound of Formula (I) or (Ia), or pharmaceuticallyacceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein Z is C-R13.

[0094] Another embodiment provides the compound of Formula (I) or (Ia), or pharmaceuticallyacceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein each R10, R11, R12, and R13is independently selected from hydrogen or halogen.

[0095] Another embodiment provides the compound of Formula (I) or (Ia), or pharmaceuticallyacceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein W is N, Z is N, X is C-R11,WSGR Ref: 53699-720.601 and Y is C-R12. Another embodiment provides the compound of Formula (I) or (Ia), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein W is N, Z is C-R13, X is C-R11, and Y is C-R12. Another embodiment provides the compound of Formula (I) or (Ia), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein W is C-R10, Z is C-R13, X is C-R11, and Y is C-R12.

[0096] One embodiment provides a compound of Formula (II), or pharmaceutically acceptablesalt, solvate, N-oxide, or deuteroisotope thereof:wherein, Ring A is an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms selected from N, O or S; R is selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted heterocyclyl, optionally substituted C1-C6 alkoxy, - PO(R8)(R9), -S(O)(NH)R8, or -CH2-PO(R8)(R9); R1is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl; R2is hydrogen, optionally substituted C1 alkyl, or halogen; R3is hydrogen, or halogen; R4is hydrogen, optionally substituted C1 alkyl, or halogen; R5is independently selected from hydrogen, or optionally substituted C1-C6 alkyl; R6is hydrogen, or halogen; R7is hydrogen, or halogen; and R8and R9are each independently selected from optionally substituted C1-C6 alkyl; or R8and R9join to form a phosphorous-containing heterocyclic ring.

[0097] Another embodiment provides the compound of Formula (II), or pharmaceuticallyacceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein Ring A is selected from an optionally substituted imidazole, oxazole, thiazole, pyrazole, isoxazole, isothiazole, or triazole.

[0098] Another embodiment provides the compound of Formula (I), (Ia), or (II), orpharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R1is selected from hydrogen, or optionally substituted C1-C6 alkyl.WSGR Ref: 53699-720.601

[0099] Another embodiment provides the compound of Formula (I), (Ia), or (II), orpharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R1is CH3or CD3.

[0100] Another embodiment provides the compound of Formula (I), (Ia), or (II), orpharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R2is hydrogen or halogen.

[0101] Another embodiment provides the compound of Formula (I), (Ia), or (II), orpharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R3is hydrogen or halogen.

[0102] Another embodiment provides the compound of Formula (I), (Ia), or (II), orpharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R4is hydrogen or halogen.

[0103] Another embodiment provides the compound of Formula (I), (Ia), or (II), orpharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R5is hydrogen. Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R5is optionally substituted C1-C6 alkyl. Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R5is optionally substituted C1 alkyl. Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R5is CH3.

[0104] Another embodiment provides the compound of Formula (I), (Ia), or (II), orpharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R is optionally substituted C1-C6 alkyl. Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R is optionally substituted C1-C3 alkyl. Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein the optionally substituted alkyl is substituted with at least an - OH or -NH2group.

[0105] Another embodiment provides the compound of Formula (I), (Ia), or (II), orpharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R is optionally substituted C3-C6 carbocyclyl. Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R is optionally substituted C5 carbocyclyl. Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, orWSGR Ref: 53699-720.601 deuteroisotope thereof, wherein R is optionally substituted C4 carbocyclyl. Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein the optionally substituted carbocyclyl is substituted with at least one group selected from -OH, -NH2, -CH3, -CN, or a halogen.

[0106] Another embodiment provides the compound of Formula (I), (Ia), or (II), orpharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R is optionally substituted heterocyclyl.

[0107] Another embodiment provides the compound of Formula (I), (Ia), or (II), orpharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R is optionally substituted 4- or 5-membered oxygen-containing heterocyclyl.

[0108] Another embodiment provides the compound of Formula (I), (Ia), or (II), orpharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R is optionally substituted oxetanyl. Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein the optionally substituted heterocyclyl is substituted with at least one group selected from -OH, -NH2, -CH3, -CN, or a halogen. Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R is 3-aminooxetan-3-yl.

[0109] Another embodiment provides the compound of Formula (I), (Ia), or (II), orpharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R is optionally substituted C1-C6 alkoxy.

[0110] Another embodiment provides the compound of Formula (I), (Ia), or (II), orpharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R is optionally substituted C1-C2 alkoxy. Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein the optionally substituted alkoxy is substituted with at least one halogen. Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein the optionally substituted alkoxy is substituted with at least one fluoro.

[0111] Another embodiment provides the compound of Formula (I), (Ia), or (II), orpharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R is - PO(R8)(R9). Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R8and R9are each independently selected from optionally substituted C1-C6 alkyl. Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate,WSGR Ref: 53699-720.601 N-oxide, or deuteroisotope thereof, wherein R8and R9are each independently selected from optionally substituted C1-C3 alkyl. Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R8and R9are each CH3. Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R8and R9join to form a phosphorous-containing heterocyclic ring.

[0112] One embodiment provides a compound of Formula (III), or pharmaceutically acceptablesalt, solvate, N-oxide, or deuteroisotope thereof:wherein, G is -CN, halogen, optionally substituted C1-C6 alkoxy, optionally substituted heteroarylalkoxy, optionally substituted C2-C6 alkynyl, (optionally substituted C2-C6 alkynylene)-NH-(optionally substituted C3-C6 cycloalkyl), or (optionally substituted C2-C6 alkynylene)-O-(optionally substituted C3-C6 cycloalkyl); R1is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl; R2is hydrogen, optionally substituted C1 alkyl, or halogen; R3is hydrogen, or halogen; R4is hydrogen, optionally substituted C1 alkyl, or halogen; R5is independently selected from hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted heterocyclyl; R6is hydrogen, or halogen; and R7is hydrogen, or halogen.

[0113] Another embodiment provides the compound of Formula (III), or pharmaceuticallyacceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein G is -CN. Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein G is halogen. Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein G is optionally substituted C1-C6 alkoxy.

[0114] Another embodiment provides the compound of Formula (III), or pharmaceuticallyacceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein G is optionally substitutedWSGR Ref: 53699-720.601 heteroarylalkoxy. Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein G is - CH2-heteroaryl. Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein G is - CH2-pyrazole.

[0115] Another embodiment provides the compound of Formula (III), or pharmaceuticallyacceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein G is optionally substituted C2-C6 alkynyl.

[0116] Another embodiment provides the compound of Formula (III), or pharmaceuticallyacceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein G is (optionally substituted C2-C6 alkynylene)-NH-(optionally substituted C3-C6 cycloalkyl), or (optionally substituted C2- C6 alkynylene)-O-(optionally substituted C3-C6 cycloalkyl).

[0117] Another embodiment provides the compound of Formula (III), or pharmaceuticallyacceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R1is selected from hydrogen, or optionally substituted C1-C6 alkyl. Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R1is CH3 or CD3.

[0118] Another embodiment provides the compound of Formula (III), or pharmaceuticallyacceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R2is hydrogen or halogen.

[0119] Another embodiment provides the compound of Formula (III), or pharmaceuticallyacceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R3is hydrogen or halogen.

[0120] Another embodiment provides the compound of Formula (III), or pharmaceuticallyacceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R4is hydrogen or halogen.

[0121] Another embodiment provides the compound of Formula (III), or pharmaceuticallyacceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R5is hydrogen. Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R5is optionally substituted C1-C6 alkyl. Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R5is optionally substituted C1 alkyl. Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R5is CH3. Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R5is optionally substituted heterocyclyl. Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R5is optionally substituted azetidine.WSGR Ref: 53699-720.601

[0122] One embodiment provides a TNF-^ inhibitory compound, or pharmaceuticallyacceptable salt, solvate, N-oxide, or deuteroisotope thereof, having a structure presented in Table 1. Table 1WSGR Ref: 53699-720.601WSGR Ref: 53699-720.601WSGR Ref: 53699-720.601WSGR Ref: 53699-720.601WSGR Ref: 53699-720.601WSGR Ref: 53699-720.601WSGR Ref: 53699-720.601WSGR Ref: 53699-720.601WSGR Ref: 53699-720.601WSGR Ref: 53699-720.601WSGR Ref: 53699-720.601WSGR Ref: 53699-720.601WSGR Ref: 53699-720.601WSGR Ref: 53699-720.601WSGR Ref: 53699-720.601WSGR Ref: 53699-720.601WSGR Ref: 53699-720.601WSGR Ref: 53699-720.601WSGR Ref: 53699-720.601WSGR Ref: 53699-720.601WSGR Ref: 53699-720.601WSGR Ref: 53699-720.601WSGR Ref: 53699-720.601

[0123] Another embodiment provides a TNF-^ inhibitory compound, or pharmaceuticallyacceptable salt, solvate, N-oxide, or deuteroisotope thereof, having a structure presented in Table 2.WSGR Ref: 53699-720.601 Table 2WSGR Ref: 53699-720.601WSGR Ref: 53699-720.601WSGR Ref: 53699-720.601Preparation of Compounds

[0124] The compounds used in the synthetic chemistry reactions described herein are madeaccording to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and / or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak CompanyWSGR Ref: 53699-720.601 (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0125] Suitable reference books and treatise that detail the synthesis of reactants useful in thepreparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif.1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527- 29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471- 57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[0126] Specific and analogous reactants are optionally identified through the indices of knownchemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databasesWSGR Ref: 53699-720.601 (contact the American Chemical Society, Washington, D.C. for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference useful for the preparation andselection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G.Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002. Pharmaceutical Compositions

[0127] In certain embodiments, the TNF-^ inhibitory compound described herein isadministered as a pure chemical. In other embodiments, the TNF-^ inhibitory compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0128] Provided herein is a pharmaceutical composition comprising at least one TNF-^inhibitory compound as described herein, or pharmaceutically acceptable salt, solvate, or N- oxide thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or the patient) of the composition.

[0129] One embodiment provides a pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and a compound of Formula (I), (Ia), (II), or (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof.

[0130] One embodiment provides a method of preparing a pharmaceutical compositioncomprising mixing a compound of Formula (I), (Ia), (II), or (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, and a pharmaceutically acceptable carrier.

[0131] In certain embodiments, the TNF-^ inhibitory compound as described by Formula (I),(Ia), (II), or (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.WSGR Ref: 53699-720.601

[0132] One embodiment provides a pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and a compound of Table 1 or Table 2, or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof.

[0133] One embodiment provides a method of preparing a pharmaceutical compositioncomprising mixing a compound of Table 1 or Table 2, or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, and a pharmaceutically acceptable carrier.

[0134] In certain embodiments, the TNF-^ inhibitory compound as described by Table 1 orTable 2, or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0135] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules ofhard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0136] In some embodiments, the TNF-^ inhibitory compound as described by Formula (I) orTable 1 or Table 2, or pharmaceutically acceptable salt or solvate thereof, is formulated for administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a non-aqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like.

[0137] The dose of the composition comprising at least one TNF-^ inhibitory compound asdescribed herein differs depending upon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors.

[0138] Pharmaceutical compositions are administered in a manner appropriate to the disease tobe treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity. Optimal doses areWSGR Ref: 53699-720.601 generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0139] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, ormore, per day. Methods of Treatment

[0140] One embodiment provides a compound of Formula (I), (Ia), (II), or (III), orpharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, for use in a method of treatment of the human or animal body.

[0141] One embodiment provides a compound of Formula (I), (Ia), (II), or (III), orpharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, for use in a method of treatment of inflammatory or autoimmune disease or disorder. Another embodiment provides a compound of Formula (I), (Ia), (II), or (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, for use in a method of treatment of inflammatory disease or disorder. Yet another embodiment provides a compound of Formula (I), (Ia), (II), or (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, for use in a method of treatment of autoimmune disease or disorder.

[0142] One embodiment provides a pharmaceutical composition comprising a compound ofFormula (I), (Ia), (II), or (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of inflammatory or autoimmune disease or disorder.

[0143] One embodiment provides a use of a compound of Formula (I), (Ia), (II), or (III), orpharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, in the manufacture of a medicament for the treatment of inflammatory or autoimmune disease or disorder.

[0144] In some embodiments is provided a method of treating an inflammatory or autoimmunedisease or disorder, in a patient in need thereof, comprising administering to the patient a compound of Formula (I), (Ia), (II), or (III), or a pharmaceutically acceptable salt, solvate, or N- oxide thereof. In some embodiments is provided a method of treating inflammatory or autoimmune disease or disorder, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I), (Ia), (II), or (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, and a pharmaceutically acceptable excipient. One embodiment provides a method of treating an inflammatory disease or disorder. Another embodiment provides a method of treating an autoimmune disease or disorder.WSGR Ref: 53699-720.601

[0145] One embodiment provides a compound of Table 1 or Table 2, or pharmaceuticallyacceptable salt, solvate, N-oxide, or deuteroisotope thereof, for use in a method of treatment of the human or animal body.

[0146] One embodiment provides a compound of Table 1 or Table 2, or pharmaceuticallyacceptable salt, solvate, N-oxide, or deuteroisotope thereof, for use in a method of treatment of inflammatory or autoimmune disease or disorder.

[0147] One embodiment provides a pharmaceutical composition comprising a compound ofTable 1 or Table 2, or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of inflammatory or autoimmune disease or disorder.

[0148] One embodiment provides a use of a compound of Table 1 or Table 2, orpharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, in the manufacture of a medicament for the treatment of inflammatory or autoimmune disease or disorder.

[0149] In some embodiments is provided a method of treating an inflammatory or autoimmunedisease or disorder in a patient in need thereof, comprising administering to the patient a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt, solvate, or N-oxide thereof. In some embodiments is provided a method of treating an inflammatory or autoimmune disease or disorder, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Table 1 or Table 2, or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, and a pharmaceutically acceptable excipient.

[0150] In some embodiments the inflammatory and autoimmune disease or disorder is selectedfrom, but are not limited to: rheumatoid arthritis, psoriatic arthritis, systemic onset juvenile idiopathic arthritis, multiple sclerosis, lupus nephritis, systemic lupus erythematosus, psoriasis, Crohn's disease, colitis, asthma, graft versus host disease, allograft rejection, chronic obstructive pulmonary disease, multiple sclerosis, Alzheimer’s disease, Graves' disease, cutaneous lupus, ankylosing spondylitis, cryopyrin-associated periodic syndromes (CAPS), gout, and gouty arthritis, ulcerative TNF receptor associated periodic syndrome (TRAPS), Wegener’s granulomatosis, sarcoidosis, familial Mediterranean fever (FMF), neuropathic pain, and adult onset stills.

[0151] Provided herein is the method wherein the pharmaceutical composition is administeredorally. Provided herein is the method wherein the pharmaceutical composition is administered by injection.

[0152] One embodiment provides a method of inhibiting TNF-^ activity comprising contactingthe TNF-^ protein with a compound of Formula (I), (Ia), (II), or (III), or Table 1, or Table 2.WSGR Ref: 53699-720.601 Another embodiment provides the method of inhibiting TNF-^ activity, wherein the TNF-^ protein is contacted in an in vivo setting. Another embodiment provides the method of inhibiting TNF-^ activity, wherein the TNF-^ protein is contacted in an in vitro setting.

[0153] Other embodiments and uses will be apparent to one skilled in the art in light of thepresent disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way. EXAMPLES I. Chemical Synthesis

[0154] In some embodiments, the TNF-^ inhibitory compounds disclosed herein aresynthesized according to the following examples. As used below, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: ACN acetonitrileoC degrees Celsius δH chemical shift in parts per million downfield from tetramethylsilane DCM dichloromethane (CH2Cl2) DIAD diisopropyl azodicarboxylate DIEA diisopropylethylamine DMF dimethylformamide DMSO dimethylsulfoxide EA ethyl acetate EtOAc ethyl acetate ESI electrospray ionization Et ethyl g gram(s) h hour(s) HPLC high performance liquid chromatography Hz hertzJ coupling constant (in NMR spectrometry)LCMS liquid chromatography mass spectrometryμ microm multiplet (spectral); meter(s); milli M molar M+parent molecular ionWSGR Ref: 53699-720.601 Me methyl MsCl methanesulfonyl chloride MHz megahertz min minute(s) mol mole(s); molecular (as in mol wt) mL milliliter MS mass spectrometry nm nanometer(s) NMR nuclear magnetic resonance pH potential of hydrogen; a measure of the acidity or basicity of an aqueous solution PE petroleum ether RT room temperature s singlet (spectral) t triplet (spectral) SFC Supercritical fluid chromatography T temperature TFA trifluoroacetic acid THF tetrahydrofuran TPP Triphenylphosphine

[0155] Example 1: (7R,14R)-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-onePreparation 1A: (7R,14R)-11-chloro-6-(methyl-d3)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one A mixture of (7R,14R)-11-chloro-6-(methyl-d3)-5-oxo-5,6,7,14-tetrahydro-7,14-WSGR Ref: 53699-720.601 methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-1-yl trifluoromethanesulfonate (220 mg, 0.463 mmol), ethynyltriisopropylsilane (88 mg, 0.486 mmol), SPhos Pd Gen.3 (36 mg, 0.046 mmol), SPhos (19 mg, 0.046 mmol) and K2CO3(192 mg, 1.389 mmol) in ACN (5 mL) was stirred for 3 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) to followed by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 75% to 95% gradient in 20 min. This resulted in (7R,14R)-11-chloro-6-(methyl- d3)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (162 mg, 68%) as a white solid. MS ESI calculated for C29H31D3ClN3OSi [M + H]+, 507.23, found 507.35.1H NMR (300 MHz, Chloroform-d) δ 8.64 – 8.57 (m, 1H), 7.80 – 7.72 (m, 2H), 7.64 (d, J = 8.7 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.26 – 7.19 (m, 1H), 6.54 (d, J = 7.2 Hz, 1H), 4.98 (d, J = 7.0 Hz, 1H), 3.54 – 3.42 (m, 1H), 2.92 (d, J = 13.6 Hz, 1H), 1.40 – 1.19 (m, 21H). Preparation 1B: (7R,14R)-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one A mixture of (7R,14R)-11-chloro-6-(methyl-d3)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (60 mg, 0.118 mmol), 2-[4-(dimethylphosphoryl)-3-fluorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (53 mg, 0.177 mmol), SPhos Pd Gen.3 (5 mg, 0.006 mmol), SPhos (5 mg, 0.012 mmol) and K3PO4 (505 mg, 0.236 mmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL) was stirred for 1 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) to afford (7R,14R)-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (68 mg, 89%) as a yellow oil. MS ESI calculated for C37H40D3FN3O2PSi [M + H]+, 643.30, found 643.40.1H NMR (400 MHz, Chloroform-d) δ 8.59 – 8.48 (m, 1H), 7.97 – 7.85 (m, 1H), 7.80 – 7.69 (m, 3H), 7.48 – 7.42 (m, 1H), 7.41 – 7.32 (m, 2H), 7.25 – 7.16 (m, 1H), 6.62 – 6.54 (m, 1H), 4.96 (d, J = 6.9 Hz, 1H), 3.51 – 3.41 (m, 1H), 2.89 (d, J = 13.6 Hz, 1H), 1.83 – 1.80 (m, 3H), 1.79 – 1.76 (m, 3H), 1.24 – 1.07 (m, 21H). Example 1: (7R,14R)-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-1-ethynyl-6-(methyl-d3)- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one To a solution of (7R,14R)-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-WSGR Ref: 53699-720.601 a][1,4]diazocin-5(14H)-one (50 mg, 0.078 mmol) in THF (2 mL) was added TBAF (93 uL, 0.094 mmol, 1 M in THF) at room temperature. The resulting mixture was stirred for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) to followed by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 25% to 50% gradient in 20 min. This resulted in (7R,14R)-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (8 mg, 22%) as a white solid. MS ESI calculated for C28H20D3FN3O2P [M + H]+, 487.17, found 487.20.1H NMR (400 MHz, Chloroform-d) δ 8.70 – 8.61 (m, 1H), 8.07 – 7.97 (m, 2H), 7.81 (d, J = 8.5 Hz, 1H), 7.78 – 7.73 (m, 1H), 7.60 – 7.48 (m, 2H), 7.42 (d, J = 7.9 Hz, 1H), 7.36 – 7.30 (m, 1H), 6.53 (d, J = 7.1 Hz, 1H), 5.03 (d, J = 6.9 Hz, 1H), 3.72 (s, 1H), 3.55 – 3.45 (m, 1H), 2.93 (d, J = 13.5 Hz, 1H), 1.86 (s, 3H), 1.82 (s, 3H).19F NMR (377 MHz, Chloroform-d) δ -105.71.31P NMR (162 MHz, Chloroform-d) δ 30.42.

[0156] Example 2: (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-onePreparation 2A: tert-butyl (1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-((triisopropylsilyl)ethynyl)- 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 A mixture of (7R,14R)-11-chloro-6-(methyl-d3)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (90 mg, 0.177 mmol), tert- butyl N-{1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2- yl]cyclobutyl}carbamate (99 mg, 0.265 mmol), SPhos (7 mg, 0.018 mmol), SPhos Pd Gen.3 (7 mg, 0.009 mmol) and K3PO4(75 mg, 0.354 mmol) in 1,4-dioxane (2 mL) and H2O (0.4 mL) was stirred for 1 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) to afford tert-butyl (1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-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 (95 mg, 74%) as a yellow solid. MS ESI calculated for C42H49D3N6O3Si [M + H]+, 720.41, found 720.35.1H NMR (400 MHz, Chloroform-d) δ 8.87 (s, 2H), 8.59 (m, 1H), 7.89 – 7.82 (m, 2H), 7.74 (m, 1H), 7.43 – 7.36 (m,WSGR Ref: 53699-720.601 2H), 6.61 (t, J = 8.3 Hz, 2H), 5.01 (d, J = 7.0 Hz, 1H), 3.69 (d, J = 9.1 Hz, 3H), 3.55 – 3.45 (m, 1H), 2.94 (d, J = 13.6 Hz, 1H), 2.21 – 2.08 (m, 3H), 1.28 – 1.25 (m, 3H), 1.24 (s, 9H), 1.14 – 1.07 (m, 18H). Example 2: (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-1-ethynyl-6-(methyl-d3)-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one To a solution of tert-butyl (1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-((triisopropylsilyl)ethynyl)- 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 (85 mg, 0.118 mmol) in DCM (2 mL) was TFA (400 uL, 9.151 mmol) dropwise at 0 °C. The solution was stirred for 1 h at room temperature. The resulting mixture was diluted with water (2 mL). The mixture neutralized to pH 7 with saturated NaHCO3 (aq.). The aqueous layer was extracted with DCM (3 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The above residue dissolved in THF (2 mL) was added TBAF (141 uL, 0.142 mmol, 1M in THF) at room temperature. The resulting mixture was stirred for 1 h. Then the resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) to followed by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 25% to 50% gradient in 20 min. This resulted in (7R,14R)-11-(2-(1- aminocyclobutyl)pyrimidin-5-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (26 mg, 47%) as a white solid. MS ESI calculated for C28H21D3N6O [M + H]+, 464.22 found 464.20.1H NMR (400 MHz, Chloroform-d) δ 8.95 (s, 2H), 8.66 - 8.61 (m, 1H), 7.96 (d, J = 1.7 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.76 - 7.70 (m, 1H), 7.51 – 7.35 (m, 2H), 6.52 (d, J = 7.2 Hz, 1H), 4.98 (d, J = 7.0 Hz, 1H), 3.73 (s, 1H), 3.53 - 3.44 (m, 1H), 2.92 (d, J = 13.6 Hz, 1H), 2.86 - 2.77 (m, 2H), 2.31 – 1.97 (m, 4H).

[0157] Example 3: (7R,14R)-1-ethynyl-11-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- onePreparation 3A: (7R,14R)-11-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-WSGR Ref: 53699-720.601 a][1,4]diazocin-5(14H)-one A mixture of (7R,14R)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (130 mg, 0.217 mmol), 2-(5-bromopyrimidin-2-yl)propan-2-ol (71 mg, 0.326 mmol), Pd(dppf)Cl2 (18 mg, 0.022 mmol) and K2CO3 (90 mg, 0.651 mmol) in 1,4- dioxane (2 mL) and H2O (0.4 mL) was stirred for 2 h at 80 °C under nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) to afford (7R,14R)-11-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (121 mg, 92%) as a brown oil. MS ESI calculated for C36H40D3N5O2Si [M + H]+, 609.34 found 609.40.1H NMR (400 MHz, Chloroform-d) δ 8.84 (s, 1H), 8.77 (s, 2H), 8.63 – 8.57 (m, 1H), 7.89 – 7.82 (m, 1H), 7.77 – 7.70 (m, 1H), 7.44 – 7.35 (m, 2H), 6.64 – 6.57 (m, 1H), 5.02 (d, J = 6.9 Hz, 1H), 4.30 (s, 1H), 3.57 – 3.41 (m, 1H), 2.95 (d, J = 13.6 Hz, 1H), 1.59 (s, 6H), 1.23 – 1.03 (m, 21H). Example 3: (7R,14R)-1-ethynyl-11-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-6-(methyl-d3)- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one A solution of (7R,14R)-11-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (150 mg, 0.246 mmol) in THF (2 mL) was added TBAF (0.37 mL, 0.369 mmol, 1 M in THF) stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) followed by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30*150 mm, 5m; Mobile Phase A: Water(10 mmol / L NH4HCO3+0.05% NH3.H2O), Mobile Phase B: CH3CN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 1.5 min, 5% B to 23% B in 2 min, 23% to 34% B in 10 min; Wave Length: 254 / 220 nm; RT1(min): 11.57) to afford (7R,14R)-1-ethynyl-11-(2-(2-hydroxypropan-2-yl)pyrimidin-5- yl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (134 mg, 12%). MS ESI calculated for C27H20D3N5O2 [M + H]+, 453.20 found 453.20.1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 2H), 8.49 – 8.39 (m, 1H), 8.02 (d, J = 1.9 Hz, 1H), 7.86 – 7.74 (m, 2H), 7.66 – 7.59 (m, 1H), 7.46 (t, J = 8.0 Hz, 1H), 6.48 (d, J = 7.1 Hz, 1H), 5.27 (d, J = 7.1 Hz, 1H), 5.15 (s, 1H), 5.10 (s, 1H), 3.65 – 3.50 (m, 1H), 2.89 (d, J = 13.8 Hz, 1H), 1.55 (s, 6H).

[0158] Example 4: (7R,14R)-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-6-(methyl-d3)-1-(prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-oneWSGR Ref: 53699-720.601To a stirred mixture of (7R,14R)-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-6-(methyl-d3)-5- oxo-5,6,7,14-tetrahydro-7,14-methanobenzo [f] benzo [4,5] imidazo [1,2-a] [1,4] diazocin-1-yltrifluoromethanesulfonate (20 mg, 0.033 mmol), CuI (1 mg, 0.007 mmol), KF (6 mg, 0.099mmol), Pd(PPh3)2Cl2(7 mg, 0.010 mmol) and trimethyl(prop-1-yn-1-yl) silane (11 mg, 0.099 mmol) in DMF (0.2 mL) was added TEA (17 mg, 0.165 mmol) at room temperature. The mixture was stirred for 4 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (8:1) followed by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in water (10 mmol / L NH4HCO3), 35% to 50% gradient in 20 min; detector, 254 nm to afford (7R,14R)-11-(4- (dimethylphosphoryl)-3-fluorophenyl)-6-(methyl-d3)-1-(prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (5 mg, 28%). MS ESIcalculated for C29H22D3FN3O2P [M + H]+, 501.19 found 501.20.1H NMR (400 MHz, DMSO-d6) δ 8.41 – 8.33 (m, 1H), 8.00 (d, J = 1.8 Hz, 1H), 7.94 – 7.84 (m, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.71 – 7.66 (m, 1H), 7.66 – 7.62 (m, 1H), 7.62 – 7.53 (m, 2H), 7.40 (t, J = 7.9 Hz, 1H), 6.49 (d, J = 7.0 Hz, 1H), 5.25 (d, J = 7.0 Hz, 1H), 3.59 – 3.47 (m, 1H), 2.86 (d, J = 13.8 Hz, 1H), 2.37 (s,3H), 1.77 (s, 3H), 1.73 (d, J = 2.8 Hz, 3H). 19F NMR (377 MHz, DMSO-d6) δ -105.60.31P NMR(162 MHz, DMSO-d6) δ 28.36.

[0159] Example 5: (7R,14R)-11-(6-(1-aminocyclobutyl)pyridin-3-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-oneWSGR Ref: 53699-720.601Preparation 5A: N-(1-(5-bromopyridin-2-yl)cyclobutyl)-2-methylpropane-2-sulfinamide A solution of 2,5-dibromopyridine (8.20 g, 34.628 mmol) in Toluene (100 mL) was treated with n-BuLi (15 mL, 38.091 mmol, 2.5 M in THF) for 30 min at -78°C under nitrogen atmosphere followed by the addition of N-cyclobutylidene-2-methylpropane-2-sulfinamide (6.00 g, 34.628 mmol) at -78°C. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of Water (100 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 2) to afford N-[1-(5-bromopyridin-2-yl)cyclobutyl]-2-methylpropane-2- sulfinamide (6.01 g, 52%) as a yellow oil. MS ESI calculated for C13H19BrN2OS [M + H]+,331.04 found 331.00. 1H NMR (400 MHz, Chloroform-d) δ 8.59 – 8.53 (m, 1H), 7.79 – 7.71 (m,1H), 7.37 – 7.31 (m, 1H), 4.22 (s, 1H), 2.64 – 2.52 (m, 3H), 2.49 – 2.37 (m, 1H), 2.08 – 1.99 (m, 1H), 1.84 – 1.71 (m, 1H), 1.14 (s, 9H). Preparation 5B: 2-methyl-N-(1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-((triisopropylsilyl)ethynyl)- 5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyridin- 2-yl)cyclobutyl)propane-2-sulfinamide To a stirred mixture of (7R,14R)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (120 mg, 0.200 mmol) and N-[1-(5-bromopyridin-2-yl)cyclobutyl]- 2-methylpropane-2-sulfinamide (79 mg, 0.240 mmol in 1,4-dioxane (3 mL) and H2O (0.6 mL)WSGR Ref: 53699-720.601 were added Pd(dppf)Cl2 (16 mg, 0.020 mmol) and K2CO3 (83 mg, 0.600 mmol) at room temperature. The resulting mixture was stirred for 2 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) to afford 2-methyl-N-(1-(5- ((7R,14R)-6-(methyl-d3)-5-oxo-1-((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyridin-2-yl)cyclobutyl)propane- 2-sulfinamide (120 mg, 82%) as a yellow oil. MS ESI calculated for C42H50D3N5O2SSi [M + H]+, 723.39 found 723.35. Preparation 5C: N-(1-(5-((7R,14R)-1-ethynyl-6-(methyl-d3)-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)cyclobutyl)-2- methylpropane-2-sulfinamide To a stirred mixture of 2-methyl-N-(1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)pyridin-2-yl)cyclobutyl)propane-2-sulfinamide (200 mg, 0.277 mmol) in THF (2 mL) was added TBAF (0.33 mL, 0.332 mmol, 1M in THF) dropwise at room temperature. The resulting mixture was stirred for 1 h at room temperature. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) to afford N-(1- (5-((7R,14R)-1-ethynyl-6-(methyl-d3)-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)cyclobutyl)-2- methylpropane-2-sulfinamide (100 mg, 63%) as a yellow oil. MS ESI calculated for C33H30D3N5O2S [M + H]+, 567.25 found 567.20. Example 5: (7R,14R)-11-(6-(1-aminocyclobutyl)pyridin-3-yl)-1-ethynyl-6-(methyl-d3)-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one To a stirred solution of N-(1-(5-((7R,14R)-1-ethynyl-6-(methyl-d3)-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)cyclobutyl)-2- methylpropane-2-sulfinamide (100 mg, 0.176 mmol) in 1,4-dioxane (1 mL) was added 4 M HCl(gas) in 1,4-dioxane (1 mL) dropwise at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure and purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30*150 mm, 5m; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: MeOH; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 1.5 min, 5% B to 45% B in 2 min, 45% to 62% B in 12 min; Wave Length: 254nm; RT1(min): 10.58) to afford (7R,14R)-11-(6-(1- aminocyclobutyl)pyridin-3-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (5 mg, 5%). MS ESI calculated for C29H22D3N5O [M + H]+, 463.22 found 463.25.1H NMR (400 MHz, DMSO-d6) δWSGR Ref: 53699-720.601 8.79 (d, J = 2.4 Hz, 1H), 8.49 – 8.42 (m, 1H), 8.01 – 7.94 (m, 2H), 7.82 – 7.77 (m, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.58 – 7.52 (m, 1H), 7.46 (t, J = 7.9 Hz, 1H), 6.47 (d, J = 7.1 Hz, 1H), 5.25 (d, J = 7.1 Hz, 1H), 5.13 (s, 1H), 3.62 – 3.51 (m, 1H), 2.87 (d, J = 13.7 Hz, 1H), 2.63 – 2.54 (m, 2H), 2.42 – 2.22 (m, 2H), 2.11 – 1.93 (m, 3H), 1.81 – 1.71 (m, 1H).

[0160] Example 6: (7R,14R)-11-(1-cyclopropyl-1H-pyrazol-4-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-onePreparation 6A: (7R,14R)-11-(1-cyclopropyl-1H-pyrazol-4-yl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one A mixture of (7R,14R)-11-chloro-6-(methyl-d3)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (60 mg, 0.118 mmol), 1- cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (33 mg, 0.142 mmol), SPhos Pd Gen.3 (9 mg, 0.012 mmol), SPhos (4 mg, 0.012 mmol) and K3PO4(75.34 mg, 0.354 mmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL) was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford (7R,14R)-11-(1- cyclopropyl-1H-pyrazol-4-yl)-6-(methyl-d3)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (62 mg, 90%) as a yellow oil. MS ESI calculated for C35H38D3N5OSi [M + H]+, 579.33 found.579.25. Example 6: (7R,14R)-11-(1-cyclopropyl-1H-pyrazol-4-yl)-1-ethynyl-6-(methyl-d3)-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one To a stirred solution of (7R,14R)-11-(1-cyclopropyl-1H-pyrazol-4-yl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (50 mg, 0.086 mmol) in THF (2 mL) was added TBAF (103 uL, 0.103 mmol, 1 M in THF) dropwise at room temperature. The resulting mixture was stirred for additional 1 h at room temperature. The resulting mixture was concentrated under vacuum and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) followed by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (10mmol / L NH4HCO3), 20% to 50% gradient in 20 min;WSGR Ref: 53699-720.601 detector, 254 nm. This resulted in (7R,14R)-11-(1-cyclopropyl-1H-pyrazol-4-yl)-1-ethynyl-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- one (6 mg, 17%). MS ESI calculated for C26H18D3N5O [M + H]+, 423.19 found 423.25.1H NMR (400 MHz, Chloroform-d) δ 8.66 – 8.60 (m, 1H), 7.83 (d, J = 1.8 Hz, 1H), 7.75 – 7.65 (m, 4H), 7.43 – 7.31 (m, 2H), 6.45 (d, J = 7.2 Hz, 1H), 4.93 (d, J = 7.0 Hz, 1H), 3.71 (s, 1H), 3.66 – 3.59 (m, 1H), 3.49 – 3.40 (m, 1H), 2.88 (d, J = 13.5 Hz, 1H), 1.20 – 1.13 (m, 2H), 1.10 – 1.02 (m, 2H).

[0161] Example 7: (7R,14R)-1-ethynyl-11-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-onePreparation 7A: (7R,14R)-11-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one To a stirred solution of (7R,14R)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (100 mg, 0.167 mmol) and 2-(5-bromopyridin-2-yl)propan-2-ol (72 mg, 0.334 mmol) in 1,4-dioxane (1 mL) and H2O (0.25 mL) were added K3PO4 (106 mg, 0.501 mmol), SPhos (14 mg, 0.033 mmol) and SPhos Pd Gen.3 (13 mg, 0.017 mmol) at room temperature. The resulting mixture was stirred for 2 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (9:1) to afford (7R,14R)-11-(6-(2-hydroxypropan- 2-yl)pyridin-3-yl)-6-(methyl-d3)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (75 mg, 74%) as an off- white solid. MS ESI calculated for C37H41D3N4O2Si [M + H]+, 608.34 found 608.35.1H NMR (400 MHz, Chloroform-d) δ 8.69 – 8.53 (m, 1H), 7.97 – 7.64 (m, 3H), 7.59 – 7.10 (m, 5H), 6.66 – 6.56 (m, 1H), 4.96 (d, J = 12.1 Hz, 1H), 3.56 – 3.31 (m, 1H), 2.92 (d, J = 13.4 Hz, 1H), 1.77 – 1.53 (m, 9H), 1.35 – 0.89 (m, 18H). Example 7: (7R,14R)-1-ethynyl-11-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-6-(methyl-d3)-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one A solution of (7R,14R)-11-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-6-(methyl-d3)-1-WSGR Ref: 53699-720.601 ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (65 mg, 0.107 mmol) and TBAF (130 uL, 0.019 mmol, 1 M in THF) in THF (1 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (9:1) followed by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm,; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 9% B to 29% B in 10 min; Wave Length: 254 / 220 nm; RT1(min): 10.03) to afford (7R,14R)-1-ethynyl-11-(6-(2-hydroxypropan-2- yl)pyridin-3-yl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (5 mg, 10%). MS ESI calculated for C28H21D3N4O2 [M + H]+, 452.21 found 452.15.1H NMR (400 MHz, Chloroform-d) δ 8.76 (d, J = 2.2 Hz, 1H), 8.64 (d, J = 8.2 Hz, 1H), 7.97 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.50 – 7.43 (m, 2H), 7.40 (t, J = 7.9 Hz, 1H), 6.52 (d, J = 7.1 Hz, 1H), 4.99 (d, J = 7.0 Hz, 1H), 3.74 (s, 1H), 3.54 – 3.38 (m, 1H), 2.92 (d, J = 13.5 Hz, 1H), 1.61 (s, 6H).

[0162] Example 8: tert-butyl (1-(4-((7R,14R)-1-ethynyl-6-(methyl-d3)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11- yl)phenyl)ethyl)carbamatePreparation 8A: tert-butyl (1-(4-((7R,14R)-6-(methyl-d3)-5-oxo-1-((triisopropylsilyl)ethynyl)- 5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11- yl)phenyl)ethyl)carbamate To a solution of (7R,14R)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (200 mg, 0.200 mmol) and tert-butyl N-[1-(4- bromophenyl)ethyl]carbamate (78 mg, 0.260 mmol) in 1,4-dioxane (1 mL) and H2O (0.2 mL) were added K2CO3(83 mg, 0.600 mmol) and Pd(dppf)Cl2(16 mg, 0.020 mmol) at room temperature. After stirring for 1 h at 80 °C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) to afford tert-butyl (1-(4-((7R,14R)-6- (methyl-d3)-5-oxo-1-((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)phenyl)ethyl)carbamate (123 mg, 89%) as a yellow solid. MS ESI calculated for C42H49D3N4O3Si [M + H]+, 692.40 found 692.40.WSGR Ref: 53699-720.601 Preparation 8B: tert-butyl (1-(4-((7R,14R)-1-ethynyl-6-(methyl-d3)-5-oxo-5,6,7,14-tetrahydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)phenyl)ethyl)carbamate To a stirred solution of tert-butyl (1-(4-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)phenyl)ethyl)carbamate (123 mg, 0.178 mmol) in THF (2 mL) was added TBAF (56 mg, 0.214 mmol) dropwise at 0 °C. The resulting mixture was stirred for additional 30 min at room temperature. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) to afford tert- butyl (1-(4-((7R,14R)-1-ethynyl-6-(methyl-d3)-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)phenyl)ethyl)carbamate (93 mg, 88%) as a yellow solid. MS ESI calculated for C33H29D3N4O3 [M + H]+, 536.27 found 535.15. Example 8: (7R,14R)-11-(4-(1-aminoethyl)phenyl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one To a stirred solution of tert-butyl (1-(4-((7R,14R)-1-ethynyl-6-(methyl-d3)-5-oxo-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11- yl)phenyl)ethyl)carbamate (93 mg, 0.174 mmol) in DCM (2 mL) was added TFA (0.5 mL) dropwise at room temperature. The resulting mixture was stirred for additional 30 min at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 30% to 40% gradient in 10 min; detector, 254 nm. This resulted in (7R,14R)-11-(4-(1-aminoethyl)phenyl)-1-ethynyl-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- one (19 mg, 26%). MS ESI calculated for C28H21D3N4O [M + H]+, 436.21 found 436.15.1H NMR (400 MHz, Chloroform-d) δ 8.67 – 8.57 (m, 1H), 7.94 – 7.84 (m, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.71 – 7.66 (m, 1H), 7.59 (s, 1H), 7.57 – 7.55 (m, 1H), 7.51 – 7.43 (m, 3H), 7.40 – 7.33 (m, 1H), 6.43 – 6.32 (m, 1H), 4.94 (d, J = 7.1 Hz, 1H), 4.36 – 4.24 (m, 1H), 3.62 (d, J = 16.8 Hz, 1H), 3.55 – 3.41 (m, 1H), 2.94 – 2.82 (m, 1H), 1.53 (d, J = 6.7 Hz, 3H).

[0163] Example 9: (7R,14R)-11-(5-(aminomethyl)pyridin-2-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-onePreparation 9A: tert-butyl ((6-((7R,14R)-6-(methyl-d3)-5-oxo-1-((triisopropylsilyl)ethynyl)- 5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyridin-WSGR Ref: 53699-720.601 3-yl)methyl)carbamate To a solution of (7R,14R)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (120 mg, 0.120 mmol) and tert-butyl N-[(6-bromopyridin-3- yl)methyl]carbamate (45 mg, 0.156 mmol) in 1,4-dioxane (2 mL) and H2O (0.4 mL) were added K2CO3(50 mg, 0.360 mmol) and Pd(dppf)Cl2(9 mg, 0.012 mmol). The resulting mixture was stirred for 3 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) to afford tert-butyl ((6-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)pyridin-3-yl)methyl)carbamate (55 mg, 67%) as a yellow solid. MS ESI calculated for C40H46D3N5O3Si [M + H]+, 679.38 found 679.35.1H NMR (400 MHz, Chloroform-d) δ 8.70 – 8.50 (m, 2H), 8.20 (s, 1H), 7.98 – 7.62 (m, 5H), 7.44 – 7.32 (m, 1H), 6.65 (d, J = 7.0 Hz, 1H), 5.00 (d, J = 6.6 Hz, 1H), 4.91 (s, 1H), 4.37 (s, 2H), 3.56 – 3.44 (m, 1H), 2.92 (d, J = 13.3 Hz, 1H), 1.42 (s, 9H), 1.31 – 0.99 (m, 21H). Preparation 9B: (7R,14R)-11-(5-(aminomethyl)pyridin-2-yl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one To a stirred solution of tert-butyl ((6-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)pyridin-3-yl)methyl)carbamate (55 mg, 0.081 mmol) in DCM (2 mL) was added TFA (0.5 mL) dropwise at room temperature. The resulting mixture was stirred for additional 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. This resulted in (7R,14R)-11-(5-(aminomethyl)pyridin-2-yl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one as a brown solid (43 mg, crude). MS ESI calculated for C35H38D3N5OSi [M + H]+, 579.33 found 579.35. Example 9: (7R,14R)-11-(5-(aminomethyl)pyridin-2-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one To a stirred solution of (7R,14R)-11-(5-(aminomethyl)pyridin-2-yl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (43 mg, 0.074 mmol) in THF (1 mL) was added TBAF (23 mg, 0.089 mmol) at 0 °C. The resulting mixture was stirred for 30 min at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel;WSGR Ref: 53699-720.601 mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 35% to 45% gradient in 10 min; detector, 254 nm. This resulted in (7R,14R)-11-(5-(aminomethyl)pyridin-2-yl)-1-ethynyl-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- one (6 mg, 19%). MS ESI calculated for C26H18D3N5O [M + H]+, 423.19 found 423.15.1H NMR (400 MHz, Chloroform-d) δ 8.69 – 8.58 (m, 2H), 8.38 (s, 1H), 7.94 – 7.85 (m, 1H), 7.80 – 7.65 (m, 4H), 7.38 (t, J = 7.9 Hz, 1H), 6.52 (d, J = 7.2 Hz, 1H), 4.95 (d, J = 7.0 Hz, 1H), 3.95 (s, 2H), 3.76 (s, 1H), 3.52 – 3.43 (m, 1H), 2.89 (d, J = 13.5 Hz, 1H).

[0164] Example 10: (7R,14R)-11-(4-(aminomethyl)-3-fluorophenyl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-onePreparation 10A: tert-butyl (2-fluoro-4-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)benzyl)carbamate To a stirred mixture of (7R,14R)-11-chloro-6-(methyl-d3)-1-((triisopropylsilyl)ethynyl)-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (80 mg, 0.158 mmol) and (4-(((tert-butoxycarbonyl)amino)methyl)-3-fluorophenyl)boronic acid (50 mg, 0.190 mmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL) were added K3PO4 (100 mg, 0.474 mmol), SPhos (6 mg, 0.016 mmol) and SPhos Pd Gen.3 (12 mg, 0.016 mmol) at room temperature. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (12:1) to afford tert-butyl (2-fluoro-4-((7R,14R)-6- (methyl-d3)-5-oxo-1-((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)benzyl)carbamate (100 mg, 91%) as a white solid. MS ESI calculated for C41H46D3FN4O3Si [M + H]+, 696.37 found 696.25.1H NMR (400 MHz, Chloroform-d) δ 8.63 – 8.53 (m, 1H), 7.84 – 7.71 (m, 3H), 7.43 – 7.27 (m, 4H), 7.22 – 7.14 (m, 1H), 6.60 (d, J = 7.8 Hz, 1H), 4.97 (d, J = 7.0 Hz, 1H), 4.91 (s, 1H), 4.39 (d, J = 6.2 Hz, 2H), 3.55 – 3.41 (m, 1H), 2.91 (d, J = 13.5 Hz, 1H), 1.46 (s, 9H), 1.24 – 0.91 (m, 21H). Example 10: (7R,14R)-11-(4-(aminomethyl)-3-fluorophenyl)-1-ethynyl-6-(methyl-d3)-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one To a stirred solution of tert-butyl (2-fluoro-4-((7R,14R)-6-(methyl-d3)-5-oxo-1-WSGR Ref: 53699-720.601 ((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)benzyl)carbamate (100 mg, 0.144 mmol) in DCM (2.5 mL) was added TFA (0.5 mL) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue (110 mg) in THF (2 mL) was added TBAF (221 uL, 0.222 mmol) at room temperature. The resulting mixture was stirred for 0.5 h at room temperature. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (12:1) followed by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 10% to 38% gradient in 10 min; detector, 254 nm to afford (7R,14R)-11-(4-(aminomethyl)-3- fluorophenyl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (13 mg, 16%). MS ESIcalculated for C27H18D3FN4O [M + H]+, 440.19 found 440.20.1H NMR (400 MHz, Chloroform-d) δ 8.50 – 8.40 (m, 1H), 7.96 (d, J = 1.8 Hz, 1H), 7.85 – 7.77 (m, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.54 – 7.50 (m, 1H), 7.49 – 7.31 (m, 3H), 6.45 (d, J = 7.1 Hz, 1H), 5.24 (d, J = 7.1 Hz, 1H), 5.09 (s, 1H), 3.79 (s, 2H), 3.62 – 3.50 (m, 1H), 2.87 (d, J = 13.8 Hz, 1H).19F NMR (377 MHz, Chloroform-d) δ -119.43.

[0165] Example 11: (7R,14R)-1-ethynyl-6-(methyl-d3)-11-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-onePreparation 11A: (7R,14R)-6-(methyl-d3)-11-(1-methyl-1H-pyrazol-4-yl)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one A mixture of (7R,14R)-11-chloro-6-(methyl-d3)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (50 mg, 0.099 mmol), 1- methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (103 mg, 0.495 mmol), SPhos (4 mg, 0.010 mmol), SPhos Pd G3 (8 mg, 0.010 mmol) and K3PO4 (63 mg, 0.297 mmol) in 1,4-dioxane (1 mL) and H2O (0.1 mL) was stirred for 2 h at 100 °C under nitrogen atmosphere. The reaction was diluted by the addition of water (10 mL) at room temperature and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate wasWSGR Ref: 53699-720.601 concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1:9) to afford (7R,14R)-6-(methyl-d3)-11-(1-methyl-1H-pyrazol-4-yl)-1-((triisopropylsilyl)ethynyl)- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (50 mg, 92%) as a white solid. MS ESI calculated for C33H36D3N5OSi [M + H]+, 553.31 found 553.40.1H NMR (400 MHz, Chloroform-d) δ 8.59 – 8.52 (m, 1H), 7.75 – 7.71 (m, 1H), 7.70 (s, 1H), 7.69 – 7.66 (m, 2H), 7.42 (s, 1H), 7.40 – 7.31 (m, 2H), 6.58 (d, J = 7.4 Hz, 1H), 4.93 (d, J = 6.9 Hz, 1H), 3.92 (s, 3H), 3.49 – 3.39 (m, 1H), 2.89 (d, J = 13.5 Hz, 1H), 1.29 – 1.14 (m, 21H). Example 11: (7R,14R)-1-ethynyl-6-(methyl-d3)-11-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one A solution of (7R,14R)-6-(methyl-d3)-11-(1-methyl-1H-pyrazol-4-yl)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (40 mg, 0.072 mmol) in THF (1 mL) was treated with TBAF (23 mg, 0.086 mmol) for 1 h at room temperature. The reaction was quenched by the addition of water (5 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (3 x 15 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2) followed by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5 m; Mobile Phase A: Water (10 mmol / L NH4HCO3+ 0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 23% B to 38% B in 10 min; Wave Length: 254 / 220 nm; RT1 (min): 12.34) to afford (7R,14R)-1-ethynyl-6-(methyl-d3)-11-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (9 mg, 32%). MS ESI calculated for C24H16D3N5O [M + H]+, 397.18 found 397.15.1H NMR (400 MHz, Chloroform- d) δ 8.66 – 8.59 (m, 1H), 7.83 (d, J = 1.7 Hz, 1H), 7.78 – 7.71 (m, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.57 (s, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.35 – 7.30 (m, 1H), 6.45 (d, J = 7.2 Hz, 1H), 4.92 (d, J = 7.0 Hz, 1H), 3.95 (s, 3H), 3.71 (s, 1H), 3.50 – 3.38 (m, 1H), 2.87 (d, J = 13.5 Hz, 1H).

[0166] Example 12: (7R,14R)-1-ethynyl-6-(methyl-d3)-11-(1-methyl-1H-pyrazol-3-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-onePreparation 12A: (7R,14R)-6-(methyl-d3)-11-(1-methyl-1H-pyrazol-3-yl)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-WSGR Ref: 53699-720.601 a][1,4]diazocin-5(14H)-one To a stirred solution of (7R,14R)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (50 mg, 0.084 mmol) and 3-iodo-1-methylpyrazole (26 mg, 0.126 mmol) in 1,4-dioxane (2 mL) and H2O (0.4 mL) were added Pd(PPh3)4 (4 mg, 0.004 mmol) and K2CO3(46 mg, 0.336 mmol) at room temperature. The resulting mixture was stirred for 2 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford (7R,14R)-6-(methyl-d3)-11-(1-methyl-1H-pyrazol-3-yl)-1-((triisopropylsilyl)ethynyl)- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (40 mg, 86%) as a yellow oil. MS ESI calculated for C33H36D3N5OSi [M + H]+, 553.31 found 553.45.1H NMR (400 MHz, Chloroform-d) δ 8.59 – 8.51 (m, 1H), 7.98 (s, 1H), 7.76 – 7.68 (m, 3H), 7.41 – 7.34 (m, 2H), 6.64 (d, J = 7.3 Hz, 1H), 6.50 (d, J = 2.2 Hz, 1H), 4.99 (d, J = 6.9 Hz, 1H), 3.93 (s, 3H), 3.55 – 3.40 (m, 1H), 2.96 – 2.83 (m, 1H), 1.34 – 1.13 (m, 21H). Example 12: (7R,14R)-1-ethynyl-6-(methyl-d3)-11-(1-methyl-1H-pyrazol-3-yl)-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one To a stirred solution of (7R,14R)-6-(methyl-d3)-11-(1-methyl-1H-pyrazol-3-yl)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (40 mg, 0.072 mmol) in THF (2 mL) was added TBAF (22 mg, 0.086 mmol) dropwise at 0 °C. The resulting mixture was stirred for additional 30 min at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 54% B to 63% B in 10 min; Wave Length: 254 nm; RT1(min): 2.35) to afford (7R,14R)-1-ethynyl-6-(methyl-d3)- 11-(1-methyl-1H-pyrazol-3-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (9 mg, 33%). MS ESI calculated for C24H16D3N5O [M + H]+, 397.18found 397.20.1H NMR (400 MHz, Chloroform-d) δ 8.67 – 8.60 (m, 1H), 8.17 (s, 1H), 7.82 – 7.70 (m, 3H), 7.44 – 7.35 (m, 2H), 6.55 – 6.49 (m, 2H), 5.04 (d, J = 7.1 Hz, 1H), 3.96 (s, 3H), 3.77 (s, 1H), 3.54 – 3.42 (m, 1H), 2.91 (d, J = 13.5 Hz, 1H).

[0167] Example 13: (7R,14R)-11-(4-(3-aminooxetan-3-yl)phenyl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f] benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-oneWSGR Ref: 53699-720.601Preparation 13A: N-[3-(4-bromophenyl) oxetan-3-yl]-2-methylpropane-2-sulfinamide To a solution of 4-bromoiodobenzene (7.26 g, 25.677 mmol) in THF (70 mL) was added dropwise n-butyllithium solution (8 mL, 20.000 mmol, 2.5 M in THF) at -78 °C under nitrogen atmosphere. The reaction mixture was stirred at -78 °C for 30 min. Then a solution of 2-methyl- N-(oxetan-3-ylidene) propane-2-sulfinamide (3.00 g, 17.118 mmol) in THF (10 mL) was added and the mixture was stirred for additional 1 h. The reaction was quenched with sat. NH4Cl (50 mL) and extracted with EtOAc (3 x 80 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under vacuum and purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford N-[3-(4-bromophenyl) oxetan-3-yl]-2-methylpropane-2-sulfinamide (2.01 g, 35%) as a brown oil. MS ESI calculatedfor C13H18BrNO2S [M + H]+, 332.02334.02 found 331.90333.90.1H NMR (400 MHz,Chloroform-d) δ 7.65 – 7.58 (m, 2H), 7.49 – 7.42 (m, 2H), 5.02 – 4.68 (m, 4H), 1.13 (s, 9H).Preparation 13B: 3-(4-bromophenyl) oxetan-3-amine To a stirred solution of N-[3-(4-bromophenyl) oxetan-3-yl]-2-methylpropane-2-sulfinamide (500 mg, 1.505 mmol) in THF (2 mL) and H2O (0.2 mL) was added I2(95 mg, 0.376 mmol) at room temperature. The resulting mixture was stirred for 3 h at 50 °C under nitrogen atmosphere. The mixture was basified to pH 7 with saturated NaHCO3 (aq.). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (12:1) to afford 3-(4-bromophenyl) oxetan-3-amine (170 mg, 50%) as a brown solid. MS ESI calculated for C9H10BrNO [M + H]+, 227.99229.99 found 228.05230.05. 1H NMR (400 MHz, DMSO-d6) δ 7.60 – 7.51 (m, 4H), 4.72 – 4.56 (m, 4H).Preparation 13C: (7R,14R)-11-(4-(3-aminooxetan-3-yl) phenyl)-6-(methyl-d3)-1-WSGR Ref: 53699-720.601 ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one To a stirred mixture of (7R,14R)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (70 mg, 0.117 mmol) and 3-(4-bromophenyl) oxetan-3-amine (27 mg, 0.117 mmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL) were added Pd(dppf)Cl2.CH2Cl2(10 mg, 0.012 mmol) and K2CO3 (48 mg, 0.351 mmol) at room temperature. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford (7R,14R)-11-(4-(3-aminooxetan-3-yl) phenyl)-6-(methyl- d3)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo [1,2- a][1,4]diazocin-5(14H)-one (40 mg, 55%) as a brown solid. MS ESI calculated for C38H41D3N4O2Si [M + H]+, 620.34 found 620.10.1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 8.2 Hz, 1H), 7.84 – 7.38 (m, 9H), 6.47 (d, J = 7.0 Hz, 1H), 5.25 (d, J = 6.9 Hz, 1H), 4.76 – 4.64 (m, 4H), 3.67 – 3.54 (m, 1H), 2.92 (d, J = 13.8 Hz, 1H), 2.86 – 2.61 (m, 2H),1.29 – 0.87 (m, 21H). Example 13: (7R,14R)-11-(4-(3-aminooxetan-3-yl)phenyl)-1-ethynyl-6-(methyl-d3)-6,7- dihydro-7,14-methanobenzo[f] benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one A solution of (7R,14R)-11-(4-(3-aminooxetan-3-yl)phenyl)-6-(methyl-d3)-1-((triisopropylsilyl) ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (35 mg, 0.056 mmol) in THF (1 mL) was added TBAF (68 uL, 0.067 mmol, 1M in THF) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (5 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5m; Mobile Phase A: water (10 mmol / L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 14% B to 28% B in 12 min; Wave Length: 254 nm) to afford (7R,14R)-11-(4-(3-aminooxetan-3- yl)phenyl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (8 mg, 29%). MS ESI calculated for C29H21D3N4O2 [M + H]+,464.21 found 464.25.1H NMR (400 MHz, DMSO-d6) δ 8.49 – 8.42 (m, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.83 – 7.77 (m, 1H), 7.72 – 7.61 (m, 5H), 7.56 – 7.42 (m, 2H), 6.45 (d, J = 7.1 Hz, 1H), 5.24 (d, J = 7.0 Hz, 1H), 5.09 (s, 1H), 4.78 – 4.72 (m, 2H), 4.68 (d, J = 5.9 Hz, 2H), 3.64 – 3.47 (m, 1H), 2.87 (d, J = 13.8 Hz, 1H), 2.58 (s, 2H).WSGR Ref: 53699-720.601

[0168] Example 14: (7R,14R)-11-(4-(3-aminooxetan-3-yl)-3-fluorophenyl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- onePreparation 14A: N-(3-(4-bromo-2-fluorophenyl) oxetan-3-yl)-2-methylpropane-2-sulfinamide To a solution of 4-bromo-2-fluoro-1-iodobenzene (10.30 g, 34.237 mmol) in THF (100 mL) was added dropwise n-butyllithium solution (13 mL, 32.500 mmol, 2.5 M in THF) at -78 °C undernitrogen atmosphere. The reaction mixture was stirred at -78 °C for 30 min. Then a solutionof 2-methyl-N-(oxetan-3-ylidene) propane-2-sulfinamide (5.00 g, 28.531 mmol) in THF (10 mL) was added and stirred for additional 1 h. The reaction was quenched with sat. NH4Cl (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, concentrated under vacuum and purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford N-(3-(4-bromo-2- fluorophenyl) oxetan-3-yl)-2-methylpropane-2-sulfinamide (3.50 g, 35%) as a brown oil. MSESI calculated for C13H17BrFNO2S [M + H]+, 350.01352.01 found 349.90351.90.1H NMR(400 MHz, Chloroform-d) δ 7.59 – 7.53 (m, 1H), 7.51 – 7.45 (m, 1H), 7.45 – 7.38 (m, 1H), 5.12– 4.87 (m, 4H), 1.07 (s, 9H). Preparation 14B: 3-(4-bromo-2-fluorophenyl) oxetan-3-amine To a stirred mixture of N-(3-(4-bromo-2-fluorophenyl) oxetan-3-yl)-2-methylpropane-2- sulfinamide (500 mg, 1.428 mmol) in THF (2 mL) and H2O (0.2 mL) was added I2 (90 mg, 0.357 mmol) at room temperature. The resulting mixture was stirred for 3 h at 50 °C under nitrogen atmosphere. The mixture was basified to pH 7 with saturated NaHCO3 (aq.). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (12:1) to afford 3-(4-bromo-2-fluorophenyl)WSGR Ref: 53699-720.601oxetan-3-amine (200 mg, 57%) as a brown solid. MS ESI calculated for C9H9BrFNO [M + H]+,245.99247.99 found 246.05248.05. 1H NMR (400 MHz, DMSO-d6) δ 7.56 – 7.48 (m, 1H),7.45 – 7.37 (m, 1H), 7.37 – 7.28 (m, 1H), 4.90 (d, J = 6.4 Hz, 2H), 4.56 (d, J = 6.4 Hz, 2H), 2.93 – 2.56 (m, 2H). Preparation 14C: (7R,14R)-11-(4-(3-aminooxetan-3-yl)-3-fluorophenyl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-oneTo a stirred solution of (7R,14R)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (70 mg, 0.117 mmol) and 3-(4-bromo-2-fluorophenyl) oxetan-3- amine (43 mg, 0.176 mmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL) were added Pd(dppf)Cl2.CH2Cl2(10 mg, 0.012 mmol) and K2CO3(48 mg, 0.351 mmol) at room temperature. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford (7R,14R)-11-(4-(3-aminooxetan-3- yl)-3-fluorophenyl)-6-(methyl-d3)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (50 mg, 67%) as a brown solid. MS ESI calculated for C38H40D3FN4O2Si [M + H]+, 638.33 found 638.35.1H NMR (400 MHz, DMSO-d6) δ 8.48 – 8.33 (m, 1H), 7.83 – 7.78 (m, 1H), 7.75 (d, J = 1.8 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.50 – 7.36 (m, 3H), 7.34 – 7.21 (m, 2H), 6.47 (d, J = 7.1 Hz, 1H), 5.25 (d, J = 7.0 Hz, 1H), 4.94 (d, J = 6.2 Hz, 2H), 4.66 – 4.57 (m, 2H), 3.66 – 3.54 (m, 1H), 2.92 (d, J = 13.8 Hz, 1H), 2.72 (s, 2H), 1.14 – 1.03 (m, 21H). Example 14: (7R,14R)-11-(4-(3-aminooxetan-3-yl)-3-fluorophenyl)-1-ethynyl-6-(methyl-d3)- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one A solution of (7R,14R)-11-(4-(3-aminooxetan-3-yl)-3-fluorophenyl)-6-(methyl-d3)-1- ((triisopropylsilyl) ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-on (50 mg, 0.081 mmol) in THF (1 mL) was added TBAF (96 uL, 0.097 mmol, 1M in THF) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (5 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30*150 mm, 5m; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient:19% to 36% B in 12 min; Wave Length: 254 nm) to afford (7R,14R)-11-(4-(3-aminooxetan-3-yl)-3-fluorophenyl)-1-ethynyl-6-WSGR Ref: 53699-720.601 (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (7 mg, 19%). MS ESI calculated for C29H20D3FN4O2 [M + H]+, 482.20 found 482.25. 1HNMR (400 MHz, DMSO-d6) δ 8.49 – 8.40 (m, 1H), 7.97 (d, J = 1.7 Hz, 1H), 7.84 – 7.78 (m, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.58 – 7.51 (m, 1H), 7.49 – 7.36 (m, 4H), 6.46 (d, J = 7.1 Hz, 1H), 5.25 (d, J = 7.1 Hz, 1H), 5.10 (s, 1H), 4.97 (d, J = 6.2 Hz, 2H), 4.61 (d, J = 6.2 Hz, 2H), 3.61 – 3.48 (m, 1H), 2.87 (d, J = 13.7 Hz, 1H), 2.59 (s, 2H).19F NMR (377 MHz, DMSO-d6) δ -115.89.

[0169] Example 15: (7R,14R)-1-ethynyl-6-(methyl-d3)-11-(2-methyl-2H-1,2,3-triazol-4-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-onePreparation 15A: (7R,14R)-6-(methyl-d3)-11-(2-methyl-2H-1,2,3-triazol-4-yl)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one A mixture of (7R,14R)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (60 mg, 0.100 mmol), 4-bromo-2-methyl-1,2,3-triazole (49 mg, 0.300 mmol), Pd(PPh3)4 (6 mg, 0.005 mmol), K2CO3 (55 mg, 0.400 mmol) and H2O (0.5 mL) in 1,4-dioxane (0.5 mL) was stirred for 2 h at 100 °C under nitrogen atmosphere. The reaction was diluted with water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1:9) to afford (7R,14R)-6-(methyl-d3)-11-(2-methyl-2H-1,2,3-triazol-4-yl)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (80 mg, crude) as a white solid. MS ESI calculated for C32H35D3N6OSi [M + H]+, 554.31 found 554.45. Example 15: (7R,14R)-1-ethynyl-6-(methyl-d3)-11-(2-methyl-2H-1,2,3-triazol-4-yl)-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one A solution of (7R,14R)-6-(methyl-d3)-11-(2-methyl-2H-1,2,3-triazol-4-yl)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (50 mg, 0.090 mmol) in THF (1 mL) was treated with TBAF (108 uL, 0.108 mmol) for 1 h at room temperature. The reaction was diluted with water (5 mL) at room temperature and extracted with EtOAc (3 x 10 mL). The combined organic layers wereWSGR Ref: 53699-720.601 washed with brine (3 x 15 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1:1) followed by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30*150 mm, 5 m; Mobile Phase A: Water (10 mmol / L NH4HCO3 + 0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 21% B to 38% B in 12 min; Wave Length: 254 / 220 nm; RT1 (min): 13.02) to afford (7R,14R)-1-ethynyl-6-(methyl-d3)-11-(2- methyl-2H-1,2,3-triazol-4-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (6 mg, 15%). MS ESI calculated for C23H15D3N6O [M + H]+, 398.17 found 398.15.1H NMR (400 MHz, Chloroform-d) δ 8.68 – 8.57 (m, 1H), 8.12 (d, J = 1.6 Hz, 1H), 7.78 (s, 1H), 7.77 – 7.71 (m, 2H), 7.70 – 7.65 (m, 1H), 7.38 (t, J = 7.9 Hz, 1H), 6.47 (d, J = 7.2 Hz, 1H), 4.94 (d, J = 7.0 Hz, 1H), 4.24 (s, 3H), 3.76 (s, 1H), 3.49 – 3.38 (m, 1H), 2.88 (d, J = 13.5 Hz, 1H).

[0170] Example 16: (7R,14R)-11-(4-(aminomethyl)phenyl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-onePreparation 16A: tert-butyl (4-((7R,14R)-6-(methyl-d3)-5-oxo-1-((triisopropylsilyl)ethynyl)- 5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11- yl)benzyl)carbamate A mixture of (7R,14R)-11-chloro-6-(methyl-d3)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (80 mg, 0.158 mmol), (4- (((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (42 mg, 0.166 mmol), SPhos (6 mg, 0.016 mmol), SPhos Pd Gen.3 (12 mg, 0.016 mmol) and K3PO4(100 mg, 0.474 mmol) in 1,4- dioxane (1 mL) and H2O (0.2 mL) was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) followed by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 55% to 65% gradient in 10 min; detector, 254 nm. This resulted in tert-butyl (4-((7R,14R)-6-(methyl-d3)-5-oxo-1-((triisopropylsilyl)ethynyl)-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)benzyl)carbamate (54 mg, 50%) as a yellow oil. MS ESI calculated for C41H47D3N4O3Si [M + H]+, 678.38 found 678.20.WSGR Ref: 53699-720.601 Example 16: (7R,14R)-11-(4-(aminomethyl)phenyl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one To a solution of tert-butyl (4-((7R,14R)-6-(methyl-d3)-5-oxo-1-((triisopropylsilyl)ethynyl)- 5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11- yl)benzyl)carbamate (54 mg, 0.080 mmol) in DCM (1 mL) was added TFA (0.2 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was neutralized to pH 7 with saturated NaHCO3 (aq.). The resulting mixture was extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were washed with water (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The above residue in THF (1 mL) was added TBAF (95 uL, 0.096 mmol, 1 mol / L) at 0 °C. The solution was stirred for additional 1 h at room temperature. The resulting mixture was concentrated under vacuum and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) followed by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 80% to 90% gradient in 10 min; detector, 254 nm. This resulted in (7R,14R)-11-(4- (aminomethyl)phenyl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (8 mg, 24%). MS ESI calculated for C27H19D3N4O [M + H]+, 422.20 found 422.15.1H NMR (400 MHz, DMSO-d6) δ 8.51 – 8.40 (m, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.86 – 7.77 (m, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 7.9 Hz, 2H), 7.50 – 7.39 (m, 4H), 6.45 (d, J = 7.1 Hz, 1H), 5.24 (d, J = 7.1 Hz, 1H), 5.08 (s, 1H), 3.75 (s, 2H), 3.65 – 3.49 (m, 1H), 2.86 (d, J = 13.8 Hz, 1H), 2.07 (s, 2H).

[0171] Example 17: (7R,14R)-11-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-onePreparation 17A: (7R,14R)-11-(1-(difluoromethyl)-1H-pyrazol-4-yl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one A mixture of (7R,14R)-11-chloro-6-(methyl-d3)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (60 mg, 0.111 mmol), 1- (difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (81 mg, 0.333 mmol),WSGR Ref: 53699-720.601 SPhos (5 mg, 0.011 mmol), SPhos Pd Gen.3 (9 mg, 0.011 mmol) and K3PO4 (47 mg, 0.222 mmol) in 1,4-dioxane (1 mL) and H2O (0.2 mL) was stirred for 16 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) followed by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 70% to 80% gradient in 10 min; detector, 254 nm. This resulted in (7R,14R)-11-(1-(difluoromethyl)-1H-pyrazol-4-yl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (51 mg, 74%) as a light yellow solid. MS ESI calculated for C33H34D3F2N5OSi [M + H]+, 589.29 found 589.25.1H NMR (400 MHz, Chloroform-d) δ 8.61 – 8.54 (m, 1H), 7.96 (s, 1H), 7.87 (s, 1H), 7.79 – 7.72 (m, 3H), 7.42 – 7.35 (m, 2H), 7.14 (t, J = 60.6 Hz, 1H), 6.63 (d, J = 7.3 Hz, 1H), 5.04 (d, J = 6.9 Hz, 1H), 3.57 – 3.41 (m, 1H), 2.93 (d, J = 13.6 Hz, 1H), 1.31 – 1.02 (m, 21H). Example 17: (7R,14R)-11-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-ethynyl-6-(methyl-d3)-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one To a solution of (7R,14R)-11-(1-(difluoromethyl)-1H-pyrazol-4-yl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (45 mg, 0.076 mmol) in THF (1 mL) was added TBAF (92 uL, 0.091 mmol, 1 mol / L). The solution was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) followed by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 80% to 90% gradient in 10 min; detector, 254 nm. This resulted in (7R,14R)-11-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (20 mg, 60%). MS ESI calculated for C24H14D3F2N5O [M + H]+, 433.16 found 433.00.1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.45 (d, J = 8.2 Hz, 1H), 8.14 (s, 1H), 8.03 – 7.71 (m, 3H), 7.66 (d, J = 8.5 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 6.42 (d, J = 7.0 Hz, 1H), 5.22 (d, J = 7.1 Hz, 1H), 5.18 (s, 1H), 3.62 – 3.48 (m, 1H), 2.86 (d, J = 13.8 Hz, 1H).19F NMR (377 MHz, DMSO-d6) δ -94.06.

[0172] Example 18: (7R,14R)-11-(2-(2-aminospiro[3.3]heptan-2-yl)pyrimidin-5-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-oneWSGR Ref: 53699-720.601Preparation 18A: 2-methyl-N-{spiro[3.3]heptan-2-ylidene}propane-2-sulfinamide To a stirred mixture of spiro[3.3]heptan-2-one (500 mg, 4.539 mmol) and tert-butanesulfinamide (660 mg, 5.447 mmol) in THF (10 mL) was added Ti(Oi-Pr)4 (1.93 g, 6.808 mmol) at room temperature. The resulting mixture was stirred for 16 h at room temperature. The reaction was diluted with water at room temperature. The aqueous layer was extracted with EtOAc (3 x 50 mL). The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 2-methyl-N-{spiro[3.3]heptan-2- ylidene}propane-2-sulfinamide (500 mg, 52%) as a colorless oil. MS ESI calculated for C11H19NOS [M + H]+, 214.12 found 214.05.1H NMR (400 MHz, Chloroform-d) δ 3.51 – 3.42 (m, 1H), 3.29 – 3.22 (m, 1H), 3.10 – 3.05 (m, 2H), 2.17 – 2.09 (m, 4H), 1.94 – 1.84 (m, 2H), 1.23 (s, 9H). Preparation 18B: N-[2-(5-bromopyrimidin-2-yl)spiro[3.3]heptan-2-yl]-2-methylpropane-2- sulfinamide To a stirred mixture of 5-bromo-2-iodopyrimidine (641 mg, 2.250 mmol) in Toluene (8 mL) was added n-BuLi (0.82 mL, 2.063 mmol, 2.5 M in THF) at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at -78 °C under nitrogen atmosphere. To the above mixture was added 2-methyl-N-{spiro[3.3]heptan-2-ylidene}propane-2-sulfinamide (400 mg, 1.875 mmol) at -78 °C. The resulting mixture was stirred for additional 1 h at room temperature. The resulting mixture was concentrated under vacuum and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (20:1) to afford N-[2-(5-bromopyrimidin-2- yl)spiro[3.3]heptan-2-yl]-2-methylpropane-2-sulfinamide (110 mg, 16%) as a white solid. MS ESI calculated for C15H22BrN3OS [M + H]+, 372.07374.07 found 372.05374.05.1H NMR (400 MHz, Chloroform-d) δ 8.74 (s, 2H), 3.05 – 2.95 (m, 1H), 2.68 – 2.59 (m, 2H), 2.51 – 2.43 (m, 1H), 2.17 – 2.11 (m, 2H), 2.02 – 1.88 (m, 2H), 1.86 – 1.80 (m, 2H), 1.21 (s, 9H). Preparation 18C: 2-methyl-N-(2-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-WSGR Ref: 53699-720.601 ((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)pyrimidin-2-yl)spiro[3.3]heptan-2-yl)propane-2-sulfinamide To a stirred mixture of (7R,14R)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (128 mg, 0.128 mmol) and N-[2-(5-bromopyrimidin-2- yl)spiro[3.3]heptan-2-yl]-2-methylpropane-2-sulfinamide (48 mg, 0.128 mmol) in 1,4-dioxane (1.5 mL) and H2O (0.3 mL) were added K2CO3 (53 mg, 0.384 mmol) and Pd(dppf)Cl2.CH2Cl2 (11 mg, 0.013 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 2-methyl-N-(2-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)pyrimidin-2-yl)spiro[3.3]heptan-2-yl)propane-2-sulfinamide (95 mg, 97%) as a white solid. MS ESI calculated for C44H53D3N6O2SSi [M + H]+, 764.41, found 764.30. Example 18: (7R,14R)-11-(2-(2-aminospiro[3.3]heptan-2-yl)pyrimidin-5-yl)-1-ethynyl-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- one To a stirred mixture of 2-methyl-N-(2-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)pyrimidin-2-yl)spiro[3.3]heptan-2-yl)propane-2-sulfinamide (85 mg, 0.111 mmol) in 1,4-dioxane (1 mL) was added 4 M HCl(gas) in 1,4-dioxane (1 mL, 4.000 mmol) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. To the above mixture was added THF (1 mL), 1 M TBAF in THF (267 uL, 0.266 mmol) at room temperature. The resulting mixture was stirred for additional 2 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) followed by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 30% to 60% gradient in 25 min; detector, 254 nm. This resulted in (7R,14R)-11-(2-(2- aminospiro[3.3]heptan-2-yl)pyrimidin-5-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (13 mg, 22%). MS ESI calculated for C31H25D3N6O [M + H]+, 504.25 found 504.25.1H NMR (400 MHz, Chloroform- d) δ 8.92 (s, 2H), 8.68 – 8.60 (m, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.76 – 7.70 (m, 1H), 7.47 – 7.43 (m, 1H), 7.40 (t, J = 7.9 Hz, 1H), 6.52 (d, J = 7.2 Hz, 1H), 4.98 (d, J =WSGR Ref: 53699-720.601 7.0 Hz, 1H), 3.72 (s, 1H), 3.53 – 3.41 (m, 1H), 3.01 – 2.85 (m, 3H), 2.29 – 2.20 (m, 4H), 2.08 – 1.80 (m, 4H).

[0173] Example 19: (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-6-(methyl-d3)-1-(prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-onePreparation 19A: tert-butyl (1-(5-((7R,14R)-1-hydroxy-6-(methyl-d3)-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 To a stirred mixture of (7R,14R)-11-chloro-1-hydroxy-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f] benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (150 mg, 0.438 mmol), K3PO4 (278 mg, 1.314 mmol) and tert-butylN-{1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrimidin-2-yl]cyclobutyl}carbamate (246 mg, 0.657 mmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL) were added SPhos (36 mg, 0.088 mmol) and SPhos Pd Gen.3 (34 mg, 0.044 mmol) at room temperature. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (9:1) to afford tert-butyl(1-(5-((7R,14R)-1-hydroxy-6-(methyl-d3)-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, 62%) as a brown solid. MS ESI calculated for C31H29D3N6O4[M + H]+, 556.27 found 556.40. Preparation 19B: (7R,14R)-11-(2-(1-((tert-butoxycarbonyl)amino)cyclobutyl)pyrimidin-5-yl)-6- (methyl-d3)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-1-yl trifluoromethanesulfonate To a stirred mixture of tert-butyl (1-(5-((7R,14R)-1-hydroxy-6-(methyl-d3)-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-WSGR Ref: 53699-720.601 yl)cyclobutyl)carbamate (130 mg, 0.234 mmol), 1,1,1-trifluoro-N-phenyl-N-(trifluoromethane) sulfonylmethanesulfonamide (133 mg, 0.374 mmol) and DMAP (3 mg, 0.023 mmol) in DCM (3 mL) was added TEA (47 mg, 0.468 mmol) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (8:1) to (7R,14R)-11-(2-(1-((tert-butoxycarbonyl)amino)cyclobutyl)pyrimidin-5-yl) -6-(methyl-d3)-5- oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-1-yl trifluoromethanesulfonate (88 mg, 55%) as a brown solid. MS ESI calculated forC32H28D3F3N6O6S [M + H]+, 688.22 found 688.40. 1H NMR (400 MHz, Chloroform-d) δ 8.92(s, 2H), 8.74 – 8.61 (m, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.57 – 7.50 (m, 3H), 7.49 – 7.45 (m, 1H), 6.12 (d, J = 7.2 Hz, 1H), 5.02 (d, J = 7.0 Hz, 1H), 3.65 – 3.49 (m, 1H), 2.97 (d, J = 13.8 Hz, 1H), 2.85 – 2.57 (m, 4H), 2.25 – 2.14 (m, 2H), 1.55 – 1.33 (m, 9H). Preparation 19C: tert-butyl(1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-(prop-1-yn-1-yl)-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 To a stirred mixture of tert-butyl (7R,14R)-11-(2-(1-((tert- butoxycarbonyl)amino)cyclobutyl)pyrimidin-5-yl) -6-(methyl-d3)-5-oxo-5,6,7,14-tetrahydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-1-yl trifluoromethanesulfonate (80 mg, 0.116 mmol), CuI (5 mg, 0.023 mmol), Pd(PPh3)2Cl2(24 mg, 0.035 mmol) and trimethyl (prop-1-yn-1-yl) silane (39 mg, 0.348 mmol) in DMF (3 mL) was added KF (20 mg, 0.348 mmol) and TEA (59 mg, 0.580 mmol) at room temperature. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (9:1) to afford tert-butyl(1-(5- ((7R,14R)-6-(methyl-d3)-5-oxo-1-(prop-1-yn-1-yl)-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 (32 mg, 48%) as a brown oil. MS ESI calculated for C34H31D3N6O3[M + H]+, 578.29 found 578.30.1H NMR (400 MHz, Chloroform-d) δ 8.90 – 8.80 (m, 2H), 8.51– 8.43(m, 1H), 7.87 (d, J = 1.8 Hz, 1H), 7.78 – 7.73 (m, 1H), 7.57 – 7.53 (m, 1H), 7.39 – 7.35 (m, 1H), 7.31 – 7.24 (m, 1H), 6.51 – 6.40 (m, 1H), 4.90 (d, J = 7.2 Hz, 1H), 3.47 – 3.31 (m, 1H), 2.73 – 2.58 (m, 4H), 2.32 (s, 1H), 2.25 – 2.17 (m, 3H), 2.12 – 2.02 (m, 2H), 1.36 (s, 9H). Example 19: (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-6-(methyl-d3)-1-(prop-1-yn- 1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-oneWSGR Ref: 53699-720.601 To a stirred solution of tert-butyl(1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-(prop-1-yn-1-yl)- 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 (35 mg, 0.061 mmol) in DCM (1 mL) was added TFA (35 uL, 0.471 mmol) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure and purified by Prep-HPLC with the following conditions: (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient: 4%B to 24%B in 10 min; Wave Length: 254 / 220 nm) to afford (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-6-(methyl-d3)-1-(prop-1-yn-1-yl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one(7 mg, 22%). MS ESIcalculated for C29H23D3N6O [M + H]+, 478.24 found 478.05. 1H NMR (400 MHz, DMSO-d6) δ9.05 (s, 2H), 8.41 – 8.34 (m, 1H), 7.94 (d, J = 1.8 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.73 – 7.66 (m, 1H), 7.65 – 7.55 (m, 1H), 7.40 (t, J = 7.9 Hz, 1H), 6.51 (d, J = 7.1 Hz, 1H), 5.26 (d, J = 7.1 Hz, 1H), 3.59 – 3.51 (m, 1H), 2.86 (d, J = 13.8 Hz, 1H), 2.70 – 2.61 (m, 2H), 2.34 (s, 3H), 2.21 – 2.11 (m, 2H), 2.06 – 1.95 (m, 1H), 1.92 – 1.80 (m, 1H).

[0174] Example 20: (7R,14R)-11-(6-(1-aminocyclobutyl)-5-fluoropyridin-3-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- onePreparation 20A: N-cyclobutylidene-2-methylpropane-2-sulfinamide To a stirred solution of cyclobutanone (10.00 g, 142.672 mmol) and tert-butanesulfinamide (14.41 g, 118.893 mmol) in THF (100 mL) was added Ti(Oi-Pr)4(67.58 g, 237.787 mmol) dropwise at room temperature. The resulting mixture was stirred for 16 h at 60 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (8:1) to afford N-cyclobutylidene-2-methylpropane-2- sulfinamide (10.01 g, 48%) as a yellow oil. MS ESI calculated for C8H15NOS [M + H]+, 174.09WSGR Ref: 53699-720.601 found 174.20.1H NMR (400 MHz, Chloroform-d) δ 3.57 – 3.44 (m, 1H), 3.35 – 3.20 (m, 1H), 3.17 – 3.08 (m, 2H), 2.19 – 2.06 (m, 2H), 1.24 (s, 9H). Preparation 20B: N-[1-(5-bromo-3-fluoropyridin-2-yl)cyclobutyl]-2-methylpropane-2- sulfinamide A solution of 2,5-dibromo-3-fluoropyridine (1.47 g, 5.771 mmol) in DCM (20 mL) was treated with n-BuLi (3.00 mL, 7.502 mmol, 2.5 M in THF) for 30 min at -78 °C under nitrogen atmosphere followed by the addition of N-cyclobutylidene-2-methylpropane-2-sulfinamide (1.00 g, 5.771 mmol) in DCM (5 mL) dropwise at -78 °C. The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4Cl (aq.) at room temperature. The resulting mixture was extracted with CH2Cl2 (3 x 40 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford N-[1-(5-bromo- 3-fluoropyridin-2-yl)cyclobutyl]-2-methylpropane-2-sulfinamide (930 mg, 46%) as a yellow oil. MS ESI calculated for C13H18BrFN2OS [M + H]+, 349.03351.03 found 348.90350.90.19F NMR (377 MHz, Chloroform-d) δ -118.78. Preparation 20C: 1-(5-bromo-3-fluoropyridin-2-yl)cyclobutan-1-amine To a stirred solution of N-[1-(5-bromo-3-fluoropyridin-2-yl)cyclobutyl]-2-methylpropane-2- sulfinamide (500 mg, 1.432 mmol) in 1,4-dioxane (1.5 mL) was added HCl (gas) in 1,4-dioxane (1.5 mL) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The reaction was quenched by the addition of sat. NaHCO3 (aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 1-(5-bromo-3-fluoropyridin-2- yl)cyclobutan-1-amine (190 mg, 54%) as a yellow oil. MS ESI calculated for C9H10BrFN2[M + H]+, 245.00247.00 found 244.90246.90.1H NMR (400 MHz, Chloroform-d) δ 8.41 (s, 1H),7.59 – 7.51 (m, 1H), 2.77 – 2.66 (m, 2H), 2.27 – 2.11 (m, 3H), 1.87 – 1.77 (m, 1H). 19F NMR(377 MHz, Chloroform-d) δ -119.69. Preparation 20D: (7R,14R)-11-(6-(1-aminocyclobutyl)-5-fluoropyridin-3-yl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one To a stirred solution of (7R,14R)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (70 mg, 0.117 mmol) and 1-(5-bromo-3-fluoropyridin-2-WSGR Ref: 53699-720.601 yl)cyclobutan-1-amine (43 mg, 0.176 mmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL) were added Pd(dppf)Cl2(10 mg, 0.012 mmol) and K2CO3(48 mg, 0.351 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, 254 nm to afford (7R,14R)-11-(6-(1-aminocyclobutyl)-5-fluoropyridin-3-yl)-6- (methyl-d3)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (40 mg, 54%) as an off- white solid. MS ESI calculated for C38H41D3FN5OSi [M + H]+637.35 found 637.20. Example 20: (7R,14R)-11-(6-(1-aminocyclobutyl)-5-fluoropyridin-3-yl)-1-ethynyl-6-(methyl- d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one To a stirred solution of (7R,14R)-11-(6-(1-aminocyclobutyl)-5-fluoropyridin-3-yl)-6-(methyl- d3)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (38 mg, 0.060 mmol) in THF (800 uL) was added TBAF (72 uL, 0.072 mmol, 1 M in THF) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (4 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in water (10 mmol / L NH4HCO3), 10% to 40% gradient in 25 min; detector, 254 nm to afford (7R,14R)-11-(6-(1- aminocyclobutyl)-5-fluoropyridin-3-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (7 mg, 26%). MS ESI calculated for C29H21D3FN5O [M + H]+, 481.22 found 481.20.1H NMR (400 MHz, Chloroform- d) δ 8.67 – 8.60 (m, 1H), 8.59 (t, J = 1.8 Hz, 1H), 7.98 – 7.92 (m, 1H), 7.83 – 7.76 (m, 1H), 7.76 – 7.70 (m, 1H), 7.60 – 7.52 (m, 1H), 7.46 – 7.36 (m, 2H), 6.51 (d, J = 7.3 Hz, 1H), 4.97 (d, J = 7.0 Hz, 1H), 3.73 (s, 1H), 3.54 – 3.42 (m, 1H), 2.91 (d, J = 13.5 Hz, 1H), 2.87 – 2.76 (m, 2H), 2.37 – 2.24 (m, 3H), 1.95 – 1.86 (m, 1H).19F NMR (377 MHz, Chloroform-d) δ -123.60.

[0175] Example 21: (7R,14R)-11-(4-(1-aminocyclobutyl)-3-fluorophenyl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-oneWSGR Ref: 53699-720.601Preparation 21A: N-[1-(4-bromo-2-fluorophenyl)cyclobutyl]-2-methylpropane-2-sulfinamide A solution of 4-bromo-2-fluoro-1-iodobenzene (1.74 g, 5.771 mmol) in THF (20 mL) was treated with n-BuLi (407 mg, 6.348 mmol) for 30 min at -78 °C under nitrogen atmosphere followed by the addition of N-cyclobutylidene-2-methylpropane-2-sulfinamide (1.00 g, 5.771 mmol) in THF (5 mL) dropwise at -78 °C. The resulting mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4Cl (aq.) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:2) to afford N-[1-(4-bromo-2- fluorophenyl)cyclobutyl]-2-methylpropane-2-sulfinamide (410 mg, 20%) as a yellow oil. MS ESI calculated for C14H19BrFNOS [M + H]+, 348.04350.04 found 347.80349.80.19F NMR (377 MHz, DMSO-d6) δ -109.84. Preparation 21B: 1-(4-bromo-2-fluorophenyl)cyclobutan-1-amine To a solution of N-[1-(4-bromo-2-fluorophenyl)cyclobutyl]-2-methylpropane-2-sulfinamide (400 mg, 1.149 mmol) in 1,4-dioxane (5 mL) was added HCl (gas) in 1,4-dioxane (2.5 mL) dropwise at room temperature. The resulting mixture was stirred for 1 h at room temperature. The reaction was quenched by the addition of sat. NaHCO3 (aq.) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 1-(4-bromo-2-fluorophenyl)cyclobutan-1-amine (100 mg, 36%) as a yellow oil. MS ESI calculated for C10H11BrFN [M + H]+, 244.01246.01 found 243.95 245.95.1H NMR (400 MHz, Chloroform-d) δ 7.25 – 7.18 (m, 2H), 7.12 (t, J = 8.3 Hz, 1H), 2.60 – 2.47 (m, 2H), 2.38 – 2.13 (m, 3H), 1.88 – 1.69 (m, 1H).19F NMR (377 MHz, Chloroform-d) δWSGR Ref: 53699-720.601 -113.23. Preparation 21C: (7R,14R)-11-(4-(1-aminocyclobutyl)-3-fluorophenyl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one To a stirred solution of (7R,14R)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (70 mg, 0.117 mmol) and 1-(4-bromo-2-fluorophenyl)cyclobutan-1- amine (51 mg, 0.211 mmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL) were added Pd(dppf)Cl2 (10 mg, 0.012 mmol) and K2CO3(49 mg, 0.351 mmol) at room temperature. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (12:1) to afford (7R,14R)-11-(4-(1-aminocyclobutyl)-3-fluorophenyl)-6- (methyl-d3)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (45 mg, 60%) as a yellow oil. MS ESI calculated for C39H42D3FN4OSi [M + H]+, 636.35 found 636.50. Example 21: (7R,14R)-11-(4-(1-aminocyclobutyl)-3-fluorophenyl)-1-ethynyl-6-(methyl-d3)- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one To a stirred solution of (7R,14R)-11-(4-(1-aminocyclobutyl)-3-fluorophenyl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (45 mg, 0.071 mmol) in THF (1 mL) was added TBAF (85 uL, 0.085 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (4 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in water (10 mmol / L NH4HCO3), 10% to 40% gradient in 25 min; detector, 254 nm to afford (7R,14R)-11-(4-(1- aminocyclobutyl)-3-fluorophenyl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (3 mg, 9%). MS ESI calculated for C30H22D3FN4O [M + H]+, 480.22 found 480.20.1H NMR (400 MHz, Chloroform- d) δ 8.66 – 8.57 (m, 1H), 7.86 (s, 1H), 7.77 – 7.67 (m, 2H), 7.48 – 7.29 (m, 5H), 6.41 (d, J = 7.2 Hz, 1H), 4.94 (d, J = 7.1 Hz, 1H), 3.68 (s, 1H), 3.55 – 3.44 (m, 1H), 2.88 (d, J = 13.6 Hz, 1H), 2.74 – 2.56 (m, 2H), 2.52 – 2.29 (m, 3H), 1.93 – 1.81 (m, 1H).19F NMR (377 MHz, Chloroform-d) δ -113.83.WSGR Ref: 53699-720.601

[0176] Example 22: (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-1-ethynyl-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-onePreparation 22A: (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 To a stirred 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 (910 mg, 2.335 mmol) in THF (10 mL) was added KHMDS (9.34 mL, 9.340 mmol, 1.0 M in THF) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 3 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) to afford (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 (600 mg, 75%) as a white solid. MS ESI calculated for C18H14ClN3O2[M + H]+, 340.08 found 340.05.1H NMR (400 MHz, Chloroform-d) δ 8.17 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.31 – 7.18 (m, 2H), 7.12 (d, J = 8.0 Hz, 1H), 6.41 (d, J = 7.2 Hz, 1H), 5.10 (d, J = 7.2 Hz, 1H), 3.56 (s, 3H), 3.52 – 3.39 (m, 1H), 2.91 (d, J = 13.5 Hz, 1H). Preparation 22B: (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 To a stirred 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 (120 mg, 0.353 mmol) and TEA (98 uL, 0.706 mmol) in DCM (3 mL) were added DMAP (4 mg, 0.035 mmol) and 1,1,1- trifluoro-N-phenyl-N-(trifluoromethane)sulfonylmethanesulfonamide (202 mg, 0.565 mmol) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) to afford (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 (160 mg, 96%) as a pink solid. MS ESI calculated forWSGR Ref: 53699-720.601 C19H13ClF3N3O4S [M + H]+, 472.03, found 472.05.1H NMR (400 MHz, Chloroform-d) δ 8.74 – 8.65 (m, 1H), 7.68 (d, J = 8.7 Hz, 1H), 7.60 – 7.49 (m, 2H), 7.41 – 7.36 (m, 1H), 7.32 – 7.27 (m, 1H), 6.07 (d, J = 7.1 Hz, 1H), 5.14 (d, J = 7.1 Hz, 1H), 3.63 – 3.57 (m, 1H), 3.56 (s, 3H), 2.97 (d, J = 13.8 Hz, 1H).19F NMR (377 MHz, Chloroform-d) δ -72.80. Preparation 22C: (7R,14R)-11-chloro-6-methyl-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one To a stirred 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 (160 mg, 0.339 mmol) and Pd(PPh3)2Cl2(24 mg, 0.034 mmol) in DMF (3 mL) were added CuI (6 mg, 0.034 mmol), TEA (236 uL, 1.695 mmol) and ethynyltriisopropylsilane (68 mg, 0.373 mmol) at room temperature. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was diluted with EtOAc (100 mL). The resulting mixture was washed with 3 x 20 mL of water. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) to afford (7R,14R)-11- chloro-6-methyl-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (135 mg, 79%) as a yellowsolid. MS ESI calculated for C29H34ClN3OSi [M + H]+, 504.22 found 504.25. 1H NMR (400MHz, Chloroform-d) δ 8.62 – 8.52 (m, 1H), 7.78 – 7.66 (m, 2H), 7.63 (d, J = 8.7 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.24 – 7.18 (m, 1H), 6.54 (d, J = 7.2 Hz, 1H), 5.00 (d, J = 7.0 Hz, 1H), 3.52 (s, 3H), 3.49 – 3.42 (m, 1H), 2.91 (d, J = 13.6 Hz, 1H), 1.26 – 1.25 (m, 3H), 1.25 – 1.18 (m, 18H). Preparation 22D: tert-butyl (1-(5-((7R,14R)-6-methyl-5-oxo-1-((triisopropylsilyl)ethynyl)- 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 To a stirred mixture of (7R,14R)-11-chloro-6-methyl-1-((triisopropylsilyl)ethynyl)-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (135 mg, 0.268 mmol) and K3PO4 (170 mg, 0.804 mmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL) were added SPhos Pd Gen.3 (21 mg, 0.027 mmol), SPhos (22 mg, 0.054 mmol) and tert-butyl N-{1-[5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]cyclobutyl}carbamate (201 mg, 0.536 mmol) at room temperature. The resulting mixture was stirred for 16 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) to afford tert- butyl (1-(5-((7R,14R)-6-methyl-5-oxo-1-((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2-WSGR Ref: 53699-720.601 yl)cyclobutyl)carbamate (150 mg, 78%) as a white solid. MS ESI calculated for C42H52N6O3Si[M + H]+, 717.39 found 717.40. 1H NMR (400 MHz, Chloroform-d) δ 8.87 (s, 2H), 8.61 – 8.55(m, 1H), 7.90 – 7.86 (m, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.76 – 7.72 (m, 1H), 7.43 – 7.36 (m, 2H), 6.62 (d, J = 7.3 Hz, 1H), 6.25 – 5.95 (m, 1H), 5.01 (d, J = 7.0 Hz, 1H), 3.52 (s, 3H), 3.51 – 3.45 (m, 1H), 2.94 (d, J = 13.6 Hz, 1H), 2.89 – 2.61 (m, 4H), 2.21 – 2.10 (m, 2H), 1.45 (s, 9H), 1.22 – 1.15 (m, 3H), 1.14 – 1.08 (m, 18H). Example 22: (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-1-ethynyl-6-methyl-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one To a stirred solution of tert-butyl (1-(5-((7R,14R)-6-methyl-5-oxo-1-((triisopropylsilyl)ethynyl)- 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, 0.209 mmol) in DCM (2 mL) was added TFA (0.4 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (2 mL). The mixture was basified to pH 8 with TEA. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) to afford crude intermediate. The residue was dissolved in THF (2 mL). To the above mixture was added TBAF (251 uL, 0.251 mmol, 1 M in THF) at room temperature. The resulting mixture was stirred at room temperature for additional 2 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) followed by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 30% to 50% gradient in 20 min. This resulted in (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-1-ethynyl-6-methyl- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (30 mg,31%). MS ESI calculated for C28H24N6O [M + H]+, 461.20 found 461.25. 1H NMR (400 MHz,Chloroform-d) δ 8.95 (s, 2H), 8.67 – 8.61 (m, 1H), 7.99 – 7.94 (m, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.76 – 7.70 (m, 1H), 7.49 – 7.36 (m, 2H), 6.53 (d, J = 7.2 Hz, 1H), 4.99 (d, J = 7.1 Hz, 1H), 3.73 (s, 1H), 3.53 (s, 3H), 3.51 – 3.44 (m, 1H), 2.92 (d, J = 13.6 Hz, 1H), 2.86 – 2.75 (m, 2H), 2.28 – 2.14 (m, 3H), 2.09 – 1.94 (m, 1H).

[0177] Example 23: (7R,14R)-11-(2-(1-amino-3,3-dimethylcyclobutyl)pyrimidin-5-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-oneWSGR Ref: 53699-720.601Preparation 23A: N-(3,3-dimethylcyclobutylidene)-2-methylpropane-2-sulfinamide To a stirred mixture of tert-butanesulfinamide (1.00 g, 8.251 mmol) and 3,3- dimethylcyclobutan-1-one (0.97 g, 9.901 mmol) in THF (30 mL) was added Ti(Oi-Pr)4 (5.86 g, 20.627 mmol) dropwise at room temperature. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (5 x 30 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford N- (3,3-dimethylcyclobutylidene)-2-methylpropane-2-sulfinamide (634 mg, 38%) as a yellow oil. MS ESI calculated for C10H19NOS [M + H]+, 202.12 found 202.00.1H NMR (400 MHz, Chloroform-d) δ 3.28 – 3.20 (m, 1H), 3.03 – 2.96 (m, 1H), 2.85 – 2.80 (m, 2H), 1.29 (s, 3H), 1.27 (s, 3H), 1.25 (s, 9H). Preparation 23B: N-(1-(5-bromopyrimidin-2-yl)-3,3-dimethylcyclobutyl)-2-methylpropane-2- sulfinamide To a stirred solution of 5-bromo-2-iodopyrimidine (467 mg, 1.639 mmol) in DCM (10 mL) was added n-BuLi (0.65 mL, 2.50 mol / L) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at -78 °C. To the above mixture was added N-(3,3- dimethylcyclobutylidene)-2-methylpropane-2-sulfinamide (300 mg, 1.490 mmol) in DCM (2 mL) dropwise at -78 °C. The resulting mixture was stirred for additional 3 h at room temperature. The reaction was quenched by the addition of Water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (20:1) to afford N-(1-(5-bromopyrimidin-2-yl)-3,3- dimethylcyclobutyl)-2-methylpropane-2-sulfinamide (124 mg, 23%) as a yellow oil. MS ESIcalculated for C14H22BrN3OS [M + H]+, 360.07362.07 found 360.20362.20.1H NMR (400WSGR Ref: 53699-720.601 MHz, Chloroform-d) δ 8.75 (s, 2H), 4.48 (s, 1H), 3.04 – 2.90 (m, 1H), 2.48 – 2.39 (m, 2H), 2.35 – 2.25 (m, 1H), 1.31 (s, 3H), 1.22 (s, 9H), 1.08 (s, 3H). Preparation 23C: N-(3,3-dimethyl-1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-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)-2-methylpropane-2-sulfinamide To a stirred mixture of (7R,14R)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (90 mg, 0.150 mmol) and N-[1-(5-bromopyrimidin-2-yl)-3,3- dimethylcyclobutyl]-2-methylpropane-2-sulfinamide (70 mg, 0.195 mmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL) were added Pd(dppf)Cl2.CH2Cl2 (12 mg, 0.015 mmol) and K2CO3 (62 mg, 0.450 mmol) at room temperature. The resulting mixture was stirred for 1 h at 80 °C under nitrogen atmosphere. The resulting mixture was diluted with water (25 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (3 x 15 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 20:1) to afford N-(3,3-dimethyl-1-(5- ((7R,14R)-6-(methyl-d3)-5-oxo-1-((triisopropylsilyl)ethynyl)-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)-2- methylpropane-2-sulfinamide (100 mg, 88%) as a yellow oil. MS ESI calculated for C43H53D3N6O2SSi [M + H]+, 752.41 found 752.50.1H NMR (400 MHz, Chloroform-d) δ 8.87 (s, 2H), 8.60 – 8.56 (m, 1H), 7.87 – 7.84 (m, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.76 – 7.72 (m, 1H), 7.43 – 7.39 (m, 2H), 6.62 (d, J = 7.1 Hz, 1H), 5.00 (d, J = 6.9 Hz, 1H), 3.54 – 3.44 (m, 1H), 2.95 (d, 1H), 2.64 – 2.33 (m, 4H), 1.35 (s, 3H), 1.24 (s, 9H), 1.19 – 1.15 (m, 6H), 1.14 – 1.10 (m, 19H). Example 23: (7R,14R)-11-(2-(1-amino-3,3-dimethylcyclobutyl)pyrimidin-5-yl)-1-ethynyl-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- one To a stirred solution of N-(3,3-dimethyl-1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-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)-2-methylpropane-2-sulfinamide (90 mg, 0.120 mmol) in 1,4-dioxane (0.5 mL) was added HCl(gas) in 1,4-dioxane (0.5 mL, 4.00 mol / L) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in THF (1.0 mL). To the above mixture was added TBAF (42 uL, 1.00 mol / L) dropwise at room temperature. The resulting mixture was stirred at room temperature for additional 1 h. The resulting mixture was diluted with water (5 mL) and extracted with EtOAc / MeOH(10:1) (3 x 15WSGR Ref: 53699-720.601 mL). The combined organic layers were washed with water (5 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5m; Mobile Phase A: Water(10 mmol / L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 34% B to 51 % B in 10 min; Wave Length: 254nm / 220nm; RT1(min): 9.08) to afford (7R,14R)-11-(2-(1- amino-3,3-dimethylcyclobutyl)pyrimidin-5-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (7 mg, 12%). MS ESI calculated for C30H25D3N6O [M + H]+, 492.25 found 492.20.1H NMR (400 MHz, Chloroform- d) δ 8.94 (s, 2H), 8.66 – 8.61 (m, 1H), 7.98 – 7.94 (m, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.75 – 7.71 (m, 1H), 7.47 – 7.43 (m, 1H), 7.40 (t, J = 7.9 Hz, 1H), 6.53 (d, J = 7.2 Hz, 1H), 4.98 (d, J = 7.0 Hz, 1H), 3.73 (s, 1H), 3.54 – 3.44 (m, 1H), 2.92 (d, J = 13.6 Hz, 1H), 2.78 – 2.70 (m, 2H), 2.15 – 2.07 (m, 2H), 1.40 (s, 3H), 1.16 (s, 3H).

[0178] Example 24: (7R,14R)-11-(2-((1s,3S)-1-amino-3-methylcyclobutyl)pyrimidin-5-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-onePreparation 24A: 2-methyl-N-(3-methylcyclobutylidene)propane-2-sulfinamide To a stirred mixture of 3-methylcyclobutan-1-one (1.50 g, 17.832 mmol) and tert- butanesulfinamide (2.60 g, 21.398 mmol) in THF (30 mL) was added Ti(Oi-Pr)4 (12.70 g, 44.580 mmol) dropwise at room temperature. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (5 x 30 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 2- methyl-N-(3-methylcyclobutylidene)propane-2-sulfinamide (1.90 g, 57%) as a yellow oil. MSWSGR Ref: 53699-720.601 ESI calculated for C9H17NOS [M + H]+, 188.10 found 188.05.1H NMR (400 MHz, Chloroform- d) δ 3.69 – 3.37 (m, 1H), 3.29 – 3.16 (m, 1H), 3.09 – 2.75 (m, 1H), 2.72 – 2.54 (m, 2H), 1.27 – 1.21 (m, 12H). Preparation 24B and 26S: N-((1s,3s)-1-(5-bromopyrimidin-2-yl)-3-methylcyclobutyl)-2- methylpropane-2-sulfinamide and N-((1r,3r)-1-(5-bromopyrimidin-2-yl)-3-methylcyclobutyl)-2- methylpropane-2-sulfinamide To a stirred solution of 5-bromo-2-iodopyrimidine (1.83 g, 6.407 mmol) in DCM (20 mL) was added n-BuLi (2.4 mL, 2.50 mol / L) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at -78 °C. To the above mixture was added 2-methyl-N- (3-methylcyclobutylidene)propane-2-sulfinamide (1.00 g, 5.339 mmol) in DCM (10 mL) dropwise at -78 °C. The resulting mixture was stirred for additional 2 h at room temperature. The reaction was quenched by the addition of water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (20:1). The first peak afforded N-((1s,3s)-1-(5-bromopyrimidin-2-yl)-3- methylcyclobutyl)-2-methylpropane-2-sulfinamide (144 mg, 8%) as a yellow solid. MS ESIcalculated for C13H20BrN3OS [M + H]+, 346.05348.05, found 345.90347.90.1H NMR (400MHz, Chloroform-d) δ 8.74 (s, 2H), 2.94 – 2.84 (m, 1H), 2.37 – 2.28 (m, 2H), 2.22 – 2.13 (m, 2H), 1.24 (s, 9H), 1.13 (d, J = 4.8 Hz, 3H). The second peak afforded N-((1r,3r)-1-(5- bromopyrimidin-2-yl)-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide (347 mg, 19%) as ayellow solid. MS ESI calculated for C13H20BrN3OS [M + H]+, 346.05348.05, found 345.90347.85.1H NMR (400 MHz, Chloroform-d) δ 8.76 (s, 2H), 3.02 – 2.94 (m, 1H), 2.78 – 2.69 (m, 1H), 2.43 – 2.32 (m, 2H), 2.19 – 2.12 (m, 1H), 1.24 (s, 9H), 1.19 (d, J = 6.4 Hz, 3H). Preparation 24C: 2-methyl-N-((1s,3S)-3-methyl-1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-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)propane-2-sulfinamide To a stirred mixture of (7R,14R)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (50 mg, 0.084 mmol) and N-((1s,3s)-1-(5-bromopyrimidin-2-yl)-3- methylcyclobutyl)-2-methylpropane-2-sulfinamide (38 mg, 0.109 mmol) in 1,4-dioxane (1.25 mL) and H2O (0.25 mL) were added Pd(dppf)Cl2.CH2Cl2(7 mg, 0.008 mmol) and K2CO3(35 mg, 0.252 mmol) at room temperature. The resulting mixture was stirred for 1 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (20:1) toWSGR Ref: 53699-720.601 afford 2-methyl-N-((1s,3S)-3-methyl-1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-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)propane-2-sulfinamide (42 mg, 68%) as a yellow solid. MS ESI calculated for C42H51D3N6O2SSi [M + H]+, 738.40 found 738.35. Example 24: (7R,14R)-11-(2-((1s,3S)-1-amino-3-methylcyclobutyl)pyrimidin-5-yl)-1-ethynyl- 6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- one To a stirred solution of 2-methyl-N-((1s,3S)-3-methyl-1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-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)propane-2-sulfinamide (37 mg, 0.050 mmol) in 1,4-dioxane (0.5 mL) was added HCl(gas) in 1,4-dioxane (0.5 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in THF (1 mL). To the above mixture was added TBAF (46 uL, 1 mol / L in THF) dropwise at room temperature. The resulting mixture was stirred at room temperature for additional 1 h. The resulting mixture was diluted with water (5 mL) and extracted with EtOAc / MeOH (10:1) (3 x 5 mL). The combined organic layers were washed with water (5 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5m; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 7% B to 27% B in 10 min; Wave Length: 254 nm; RT1(min): 9.93) to afford (7R,14R)-11-(2-((1s,3S)-1-amino-3-methylcyclobutyl)pyrimidin-5-yl)-1-ethynyl-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- one (6 mg, 25%). MS ESI calculated for C29H23D3N6O [M + H]+, 478.24 found 478.20.1H NMR (400 MHz, Methanol-d4) δ 9.06 (s, 2H), 8.52 (d, J = 9.3 Hz, 1H), 8.12 (s, 1H), 7.87 – 7.70 (m, 2H), 7.66 – 7.53 (m, 1H), 7.50 – 7.33 (m, 1H), 6.64 (d, J = 5.4 Hz, 1H), 5.22 (d, J = 6.5 Hz, 1H), 4.82 (s, 1H), 3.72 – 3.52 (m, 1H), 2.93 (d, J = 13.3 Hz, 1H), 2.89 – 2.74 (m, 1H), 2.68 – 2.39 (m, 4H), 1.27 (d, J = 6.8 Hz, 3H).

[0179] Example 25: (7R,14R)-11-(2-((1r,3R)-1-amino-3-methylcyclobutyl)pyrimidin-5-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-oneWSGR Ref: 53699-720.601Preparation 25A: 2-methyl-N-((1r,3R)-3-methyl-1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-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)propane-2-sulfinamide To a stirred mixture of (7R,14R)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (50 mg, 0.084 mmol) and N-((1r,3r)-1-(5-bromopyrimidin-2-yl)-3- methylcyclobutyl)-2-methylpropane-2-sulfinamide (38 mg, 0.109 mmol) in H2O (0.25 mL) and 1,4-dioxane (1.25 mL) were added Pd(dppf)Cl2.CH2Cl2 (7 mg, 0.008 mmol) and K2CO3 (35 mg, 0.252 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 1 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 20:1) to afford 2-methyl-N-((1r,3R)-3- methyl-1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-((triisopropylsilyl)ethynyl)-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)propane-2-sulfinamide (59 mg, 96%) as a brown oil. MS ESI calculated for C42H51D3N6O2SSi [M + H]+, 738.40, found 738.30.1H NMR (400 MHz, Chloroform-d) δ 8.87 (d, J = 1.8 Hz, 2H), 8.64 – 8.54 (m, 1H), 7.90 – 7.79 (m, 2H), 7.79 – 7.70 (m, 1H), 7.43 – 7.34 (m, 2H), 6.60 (d, J = 7.3 Hz, 1H), 4.99 (d, J = 6.9 Hz, 1H), 3.57 – 3.45 (m, 1H), 2.93 (d, J = 13.6 Hz, 1H), 2.91 – 2.82 (m, 2H), 2.60 – 2.46 (m, 2H), 2.31 – 2.20 (m, 1H), 1.29 – 1.07 (m, 33H). Example 25: (7R,14R)-11-(2-((1r,3R)-1-amino-3-methylcyclobutyl)pyrimidin-5-yl)-1-ethynyl- 6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one To a stirred solution of 2-methyl-N-((1r,3R)-3-methyl-1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-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)propane-2-sulfinamide (54 mg, 0.073 mmol) in 1,4-dioxane (0.5 mL) was added HCl(gas)in 1,4-dioxane (0.5 mL, 4 M in THF) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in THF (1.0 mL). To the above mixture was added TBAF (47 uL, 1 M in THF) dropwise at room temperature. The resulting mixture was stirred at room temperature for additional 1 h. The resulting mixture wasWSGR Ref: 53699-720.601 diluted with water (10 mL) and extracted with EtOAc / MeOH (3 x 5 mL). The combined organic layers were washed with water (5 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5m; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 7% B to 27% B in 10 min; Wave Length: 254 nm; RT1(min): 9.97) to afford (7R,14R)-11-(2- ((1r,3R)-1-amino-3-methylcyclobutyl)pyrimidin-5-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (9 mg, 25%). MS ESI calculated for C29H23D3N6O [M + H]+, 478.24 found 478.20.1H NMR (400 MHz, Chloroform- d) δ 8.94 (s, 2H), 8.66 – 8.59 (m, 1H), 7.95 (d, J = 1.7 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.77 – 7.68 (m, 1H), 7.48 – 7.34 (m, 2H), 6.51 (d, J = 7.2 Hz, 1H), 4.98 (d, J = 7.0 Hz, 1H), 3.76 (s, 1H), 3.54 – 3.40 (m, 1H), 2.97 – 2.84 (m, 3H), 2.59 – 2.43 (m, 1H), 2.15 – 2.00 (m, 2H), 1.23 (d, J = 6.7 Hz, 3H).

[0180] Example 26: (7R,14R)-1-ethynyl-6-(methyl-d3)-11-(1-methyl-1H-imidazol-4-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-onePreparation 26A: (7R,14R)-6-(methyl-d3)-11-(1-methyl-1H-imidazol-4-yl)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one A solution of (7R,14R)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (50 mg, 0.084 mmol) and 4-iodo-1-methyl-1H-imidazole (21 mg, 0.101 mmol) in EtOH (0.5 mL) and Toluene (0.5 mL) was treated with Na2CO3(27 mg, 0.252 mmol) in H2O (0.3 mL) and Pd(dppf)Cl2 (6 mg, 0.008 mmol) for 2 h at 100 °C under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford (7R,14R)-6-(methyl-d3)-11-(1-methyl-1H- imidazol-4-yl)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (60 mg, crude) as a black oil. MS ESI calculated for C33H36D3N5OSi [M + H]+, 553.31 found 553.30.WSGR Ref: 53699-720.601 Example 26: (7R,14R)-1-ethynyl-6-(methyl-d3)-11-(1-methyl-1H-imidazol-4-yl)-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one A solution of (7R,14R)-6-(methyl-d3)-11-(1-methyl-1H-imidazol-4-yl)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (40 mg, 0.072 mmol) in THF (0.8 mL) was treated with TBAF (87 uL, 0.086 mmol, 1 M in THF) at room temperature for 1 h. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (5 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 20:1) followed by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3+ 0.05% NH3H2O), Mobile Phase B: MeOH; Flow rate: 60 mL / min; Gradient: 36% B to 53% B in 10 min; Wave Length: 254 / 220 nm; RT1 (min): 12.1) to afford (7R,14R)-1-ethynyl- 6-(methyl-d3)-11-(1-methyl-1H-imidazol-4-yl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (4 mg, 12%). MS ESI calculated for C24H16D3N5O [M + H]+, 397.18 found 397.20.1H NMR (400 MHz, Chloroform- d) δ 8.65 – 8.58 (m, 1H), 8.12 (d, J = 1.6 Hz, 1H), 7.74 – 7.65 (m, 2H), 7.64 – 7.57 (m, 1H), 7.48 (s, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.12 (d, J = 1.4 Hz, 1H), 6.48 (d, J = 7.2 Hz, 1H), 4.92 (d, J = 7.0 Hz, 1H), 3.82 (s, 1H), 3.72 (s, 3H), 3.50 – 3.38 (m, 1H), 2.86 (d, J = 13.5 Hz, 1H).

[0181] Example 27: (7R,14R)-1-ethynyl-6-(methyl-d3)-11-(2-(piperazin-1-yl)pyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-onePreparation 27A: tert-butyl 4-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-((triisopropylsilyl)ethynyl)- 5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11- yl)pyrimidin-2-yl)piperazine-1-carboxylate To a stirred mixture of (7R,14R)-11-chloro-6-(methyl-d3)-1-((triisopropylsilyl)ethynyl)-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (100 mg, 0.197 mmol) and tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2- yl]piperazine-1-carboxylate (115 mg, 0.295 mmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL) were added SPhos (8 mg, 0.020 mmol) and SPhos Pd Gen.3 (15 mg) at room temperatureWSGR Ref: 53699-720.601 under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 16 h. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (12:1) to afford tert-butyl 4-(5-((7R,14R)-6- (methyl-d3)-5-oxo-1-((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2-yl)piperazine-1- carboxylate (128 mg, 88%) as an orange solid. MS ESI calculated for C42H50D3N7O3Si [M + H]+, 735.42 found 735.40.1H NMR (400 MHz, Chloroform-d) δ 8.61 – 8.55 (m, 1H), 8.48 (s, 2H), 7.79 – 7.70 (m, 3H), 7.37 (t, J = 8.0 Hz, 1H), 7.34 – 7.29 (m, 1H), 6.58 (d, J = 7.3 Hz, 1H), 4.97 (d, J = 7.0 Hz, 1H), 3.86 (t, J = 5.3 Hz, 4H), 3.52 (t, J = 5.3 Hz, 4H), 3.49 – 3.43 (m, 1H), 2.91 (d, J = 13.5 Hz, 1H), 1.50 (s, 9H), 1.26 – 1.09 (m, 21H). Example 27: (7R,14R)-1-ethynyl-6-(methyl-d3)-11-(2-(piperazin-1-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 stirred solution of tert-butyl 4-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)pyrimidin-2-yl)piperazine-1-carboxylate (120 mg, 0.163 mmol) in DCM (1 mL) was added TFA (0.2 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure. This result in the crude product (168 mg). The above residue in THF (2.5 mL) was added TBAF (208 uL, 0.209 mmol, 1M in THF) at room temperature. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (5:1) followed by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; flow rate: 60 mL / min; Gradient: 27% B to 42% B in 10 min; wave Length: 254 nm; RT1(min): 5.102) to afford (7R,14R)-1-ethynyl-6-(methyl-d3)-11-(2-(piperazin-1-yl)pyrimidin-5-yl)-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (19 mg, 23%). MSESI calculated for C28H22D3N7O [M + H]+, 479.23 found 479.25.1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 2H), 8.48 – 8.42 (m, 1H), 7.86 (d, J = 1.8 Hz, 1H), 7.81 – 7.77 (m, 1H), 7.69 (d, J =8.5 Hz, 1H), 7.50 – 7.42 (m, 2H), 6.44 (d, J = 7.1 Hz, 1H), 5.23 (d, J = 7.0 Hz, 1H), 5.13 (s, 1H), 3.78 – 3.66 (m, 4H), 3.60 – 3.49 (m, 1H), 2.86 (d, J = 13.8 Hz, 1H), 2.79 – 2.70 (m, 4H), 1.23 (s, 1H).

[0182] Example 28 and 29: (1S,3s)-3-amino-3-(5-((7R,14R)-1-ethynyl-6-(methyl-d3)-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 and (1R,3r)-3-amino-3-(5-((7R,14R)-1-WSGR Ref: 53699-720.601 ethynyl-6-(methyl-d3)-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-carbonitrilePreparation 28A: N-(3-cyano-3-methylcyclobutylidene)-2-methylpropane-2-sulfinamide To a stirred solution of 1-methyl-3-oxocyclobutane-1-carbonitrile (2.00 g, 18.327 mmol) and tert-butanesulfinamide (2.67 g, 21.992 mmol) in THF (20 mL) was added Ti(Oi-Pr)4 (8.22 mL, 27.491 mmol) dropwise at room temperature. The resulting mixture was stirred for 2 h at 60 °C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford N-(3-cyano-3- methylcyclobutylidene)-2-methylpropane-2-sulfinamide (2.48 g, 63%) as a light yellow solid. MS ESI calculated for C10H16N2OS [M + H]+, 213.10 found 213.25.1H NMR (400 MHz, Chloroform-d) δ 4.13 – 3.84 (m, 1H), 3.73 – 3.42 (m, 2H), 3.16 – 3.07 (m, 1H), 1.67 (d, J = 5.1 Hz, 3H), 1.25 (d, J = 1.6 Hz, 9H). Preparation 28B: N-(1-(5-bromopyrimidin-2-yl)-3-cyano-3-methylcyclobutyl)-2- methylpropane-2-sulfinamide To a stirred solution of 5-bromo-2-iodopyrimidine (2.79 g, 9.797 mmol) in DCM (20 mL) was added n-BuLi (3.62 mL, 9.043 mmol, 2.5 M in THF) dropwise at -76 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at -76 °C under nitrogen atmosphere. To the above mixture was added N-(3-cyano-3-methylcyclobutylidene)-2-methylpropane-2- sulfinamide (1.60 g, 7.536 mmol) in DCM (20 mL) dropwise at -76 °C. The resulting mixture was stirred for additional 2 h at -76 °C under nitrogen atmosphere. The reaction was quenchedWSGR Ref: 53699-720.601 with water at 0 °C. The resulting mixture was extracted with CH2Cl2 (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (PE / EA) (2:1) followed by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 10% to 30% gradient in 30 min; detector, 254 nm. This resulted in N-[1-(5-bromopyrimidin-2-yl)-3-cyano-3-methylcyclobutyl]-2-methylpropane- 2-sulfinamide (324 mg, 11%) as a white solid. MS ESI calculated for C14H19BrN4OS [M + H]+, 371.05373.05 found 370.90372.85.1H NMR (400 MHz, Chloroform-d) δ 8.84 – 8.73 (m, 2H), 4.93 – 4.57 (m, 1H), 3.62 – 3.27 (m, 1H), 3.26 – 3.12 (m, 1H), 3.00 – 2.81 (m, 1H), 2.67 – 2.52 (m, 1H), 1.73 – 1.53 (m, 3H), 1.34 – 1.22 (m, 9H). Preparation 28C: N-(3-cyano-3-methyl-1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-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)-2-methylpropane-2-sulfinamide A mixture of (7R,14R)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (200 mg, 0.334 mmol), N-[1-(5-bromopyrimidin-2-yl)-3-cyano-3- methylcyclobutyl]-2-methylpropane-2-sulfinamide (103 mg, 0.278 mmol), Pd(dppf)Cl2.CH2Cl2 (22 mg, 0.028 mmol) and K2CO3(115 mg, 0.835 mmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL) was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford N-(3-cyano-3-methyl-1-(5-((7R,14R)-6-(methyl-d3)- 5-oxo-1-((triisopropylsilyl)ethynyl)-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)-2- methylpropane-2-sulfinamide (170 mg, 80%) as a white solid. MS ESI calculated for C43H50D3N7O2SSi [M + H]+, 763.39 found 763.30.1H NMR (400 MHz, Chloroform-d) δ 8.99 – 8.84 (m, 2H), 8.58 (d, J = 8.2 Hz, 1H), 7.90 – 7.79 (m, 2H), 7.79 – 7.70 (m, 1H), 7.45 – 7.33 (m, 2H), 6.62 (t, J = 6.5 Hz, 1H), 5.39 – 5.22 (m, 1H), 5.05 – 4.92 (m, 1H), 3.57 – 3.42 (m, 2H), 3.37 – 3.17 (m, 1H), 3.08 – 2.98 (m, 1H), 2.93 (d, J = 13.4 Hz, 1H), 2.81 – 2.63 (m, 1H), 1.78 (d, J = 2.5 Hz, 3H), 1.34 – 1.07 (m, 30H). Preparation 28D: 3-amino-1-methyl-3-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-5,6,7,14 tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)pyrimidin-2-yl)cyclobutane-1-carbonitrile To a stirred solution of N-(3-cyano-3-methyl-1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-WSGR Ref: 53699-720.601 a][1,4]diazocin-11-yl)pyrimidin-2-yl)cyclobutyl)-2-methylpropane-2-sulfinamide (160 mg, 0.210 mmol) in 1,4-dioxane (2 mL) was added HCl(gas) in 1,4-dioxane (0.5 mL, 2.000 mmol, 4M in THF) dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was basified and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 3-amino-1-methyl-3-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-((triisopropylsilyl)ethynyl)- 5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11- yl)pyrimidin-2-yl)cyclobutane-1-carbonitrile (102 mg, 73%) as a white solid. MS ESI calculated for C39H42D3N7OSi [M + H]+, 659.36 found 659.30. Preparation 28E: 3-amino-3-(5-((7R,14R)-1-ethynyl-6-(methyl-d3)-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 A mixture of 3-amino-1-methyl-3-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)pyrimidin-2-yl)cyclobutane-1-carbonitrile (102 mg, 0.155 mmol) and KF (38 mg, 0.668 mmol) in MeOH (3 mL) was stirred at 60 °C for 16 h. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 20% to 50% gradient in 20 min; detector, 254 nm. This resulted in 3- amino-3-(5-((7R,14R)-1-ethynyl-6-(methyl-d3)-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 (70 mg, 83%) as a white solid. MS ESI calculated for C30H22D3N7O [M + H]+, 503.23 found 503.20. Example 28 and 29: (1S,3s)-3-amino-3-(5-((7R,14R)-1-ethynyl-6-(methyl-d3)-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 and (1R,3r)-3-amino-3-(5-((7R,14R)-1-ethynyl-6-(methyl- d3)-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 3-amino-3-(5-((7R,14R)-1-ethynyl-6-(methyl-d3)-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 (70 mg) was purified by Prep-HPLC with the following conditions ( Column: CHIRAL ART Cellulose-SZ, 2.0*25cm, 5um; Mobile Phase A: Hex(10mM NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: isocratic 50; Wave Length: 220 / 254 nm; RT1(min): 13.5; RT2(min): 20.6). The first peak afforded 28 mg (40%). MS ESI calculated for C30H22D3N7O [M + H]+, 503.23 found 503.15.1H NMR (400WSGR Ref: 53699-720.601 MHz, Chloroform-d) δ 8.96 (s, 2H), 8.68 – 8.61 (m, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.78 – 7.71 (m, 1H), 7.48 – 7.36 (m, 2H), 6.53 (d, J = 7.2 Hz, 1H), 4.99 (d, J = 7.0 Hz, 1H), 3.75 (s, 1H), 3.55 – 3.41 (m, 3H), 2.93 (d, J = 13.6 Hz, 1H), 2.45 – 2.37 (m, 2H), 1.83 (s, 3H). The second peak afforded 15 mg (22%). MS ESI calculated for C30H22D3N7O [M + H]+, 503.23 found 503.15.1H NMR (400 MHz, Chloroform-d) δ 8.94 (s, 2H), 8.68 – 8.61 (m, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.79 – 7.70 (m, 1H), 7.46 – 7.37 (m, 2H), 6.52 (d, J = 7.2 Hz, 1H), 4.99 (d, J = 7.0 Hz, 1H), 3.73 (s, 1H), 3.55 – 3.43 (m, 1H), 3.01 – 2.82 (m, 5H), 1.63 (s, 3H).

[0183] Example 30: (7R,14R)-11-(6-(2-aminospiro[3.3]heptan-2-yl)pyridin-3-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- onePreparation 30A: N-[2-(5-bromopyridin-2-yl)spiro[3.3]heptan-2-yl]-2-methylpropane-2- sulfinamide To a stirred solution of 5-bromo-2-iodopyridine (527 mg, 1.856 mmol) in Toluene (7 mL) was added 2.5M n-BuLi (0.74 mL, 1.856 mmol) at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 30 min. To the above solution was added 2-methyl-N- {spiro[3.3]heptan-2-ylidene}propane-2-sulfinamide (330 mg, 1.547 mmol) at -78 °C. The resulting mixture was stirred at room temperature for additional 1 h. The reaction was quenched with water at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (20:1) to afford N-[2-(5-bromopyridin-2-yl)spiro[3.3]heptan-2-yl]-2-methylpropane-2-sulfinamide (470 mg, 82%) as a yellow oil. MS ESI calculated for C16H23BrN2OS [M + H]+, 371.07373.07 found 371.10373.05.1H NMR (400 MHz, Chloroform-d) δ 8.63 – 8.58 (m, 1H), 7.81 – 7.75 (m, 1H), 7.36 – 7.31 (m, 1H), 2.68 – 2.51 (m, 2H), 2.15 – 2.12 (m, 2H), 1.91 – 1.81 (m, 6H), 1.17 (s, 9H). Preparation 30B: 2-methyl-N-(2-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-WSGR Ref: 53699-720.601 ((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)pyridin-2-yl)spiro[3.3]heptan-2-yl)propane-2-sulfinamide To a stirred solution of N-[2-(5-bromopyridin-2-yl)spiro[3.3]heptan-2-yl]-2-methylpropane-2- sulfinamide (65 mg, 0.176 mmol) and (7R,14R)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (70 mg, 0.117 mmol) in 1,4-dioxane (1.5 mL), H2O (0.3 mL) were added Pd(dppf)Cl2.CH2Cl2 (11 mg, 0.014 mmol) and K2CO3 (48 mg, 0.351 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 2-methyl-N-(2-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)pyridin-2-yl)spiro[3.3]heptan-2-yl)propane-2-sulfinamide (60 mg, 67%) as a white solid. MS ESI calculated for C45H54D3N5O2SSi [M + H]+, 763.42 found 763.40. Example 30: (7R,14R)-11-(6-(2-aminospiro[3.3]heptan-2-yl)pyridin-3-yl)-1-ethynyl-6-(methyl- d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one To a stirred solution of 2-methyl-N-(2-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)pyridin-2-yl)spiro[3.3]heptan-2-yl)propane-2-sulfinamide (60 mg, 0.079 mmol) in THF (2 mL) was added 1M TBAF in THF (90 uL, 0.095 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with EtOAc (50 mL) and washed with water (3 x 20 mL). The combined organic layer was concentrated under vacuum. To the above residue in 1,4-dioxane (1 mL) was added 4 M HCl(gas) in 1,4-dioxane (1 mL, 4.000 mmol) at room temperature. The resulting mixture was stirred at room temperature for additional 30 min. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 25% to 55% gradient in 25 min; detector, 254 nm. This resulted in (7R,14R)-11-(6- (2-aminospiro[3.3]heptan-2-yl)pyridin-3-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (15 mg, 37%). MS ESI calculated for C32H26D3N5O [M + H]+, 503.26 found 503.20.1H NMR (400 MHz, Chloroform- d) δ 8.80 (d, J = 2.3 Hz, 1H), 8.68 – 8.57 (m, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.88 – 7.84 (m, 1H), 7.81 – 7.77 (m, 1H), 7.74 – 7.70 (m, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.47 – 7.43 (m, 1H), 7.39 (t, J = 7.9 Hz, 1H), 6.51 (d, J = 7.2 Hz, 1H), 4.97 (d, J = 7.0 Hz, 1H), 3.71 (s, 1H), 3.54 – 3.42 (m, 1H), 2.90 (d, J = 13.5 Hz, 1H), 2.80 – 2.71 (m, 2H), 2.38 – 2.29 (m, 2H), 2.26 – 2.19 (m, 2H),WSGR Ref: 53699-720.601 2.00 – 1.93 (m, 2H), 1.93 – 1.80 (m, 2H).

[0184] Example 31 and 32: (7R,14R)-11-(2-((1S,2R)-1-amino-2-methylcyclobutyl)pyrimidin-5-yl)-1-ethynyl-6-(methyl-d3)-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-((1R,2S)-1-amino-2- methylcyclobutyl)pyrimidin-5-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-onePreparation 31A: 2-methyl-N-(2-methylcyclobutylidene)propane-2-sulfinamide To a stirred mixture of 2-methylcyclobutan-1-one (500 mg, 5.944 mmol) and tert- butanesulfinamide (865 mg, 7.133 mmol) in THF (10 mL) was added tetrakis(propan-2- yloxy)titanium (4.22 g, 14.860 mmol) slowly at room temperature. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of sat. NaHCO3 aq. (10 mL). The mixture was diluted with ethyl acetate (10 mL), stirred for 10 min. and filtered, the filter cake was washed with ethyl acetate (20 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 2-methyl-N-(2- methylcyclobutylidene)propane-2-sulfinamide (200 mg, 18%) as a colorless oil. MS ESI calculated for C9H17NOS [M + H]+, 188.11 found 188.15.1H NMR (400 MHz, Chloroform-d) δ 3.57 – 3.04 (m, 3H), 2.38 – 2.19 (m, 1H), 1.75 – 1.59 (m, 1H), 1.26 – 1.17 (m, 12H). Preparation 31B: N-(1-(5-bromopyrimidin-2-yl)-2-methylcyclobutyl)-2-methylpropane-2-WSGR Ref: 53699-720.601 sulfinamide To a stirred solution of 5-bromo-2-iodopyrimidine (237 mg, 0.833 mmol) in DCM (2.5 mL) was added butyllithium (0.31 mL, 0.763 mmol, 2.5 mol / L in hexane) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at -78 °C under nitrogen atmosphere. To the above mixture was added 2-methyl-N-(2-methylcyclobutylidene)propane-2- sulfinamide (130 mg, 0.694 mmol). The resulting mixture was allowed to warm to room temperature slowly and stirred for additional 1 h at room temperature. The reaction was quenched with sat. NH4Cl (aq.) at room temperature. The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, 254 nm. This resulted in N-[1-(5-bromopyrimidin-2-yl)-2- methylcyclobutyl]-2-methylpropane-2-sulfinamide (119 mg, 50%) as a red solid. MS ESI calculated for C13H20BrN3OS [M + H]+, 346.06348.06 found 346.00348.00.1H NMR (400 MHz, Chloroform-d) δ 8.72 (s, 2H), 3.08 – 2.96 (m, 1H), 2.61 – 2.49 (m, 2H), 2.17 – 2.04 (m, 1H), 1.79 – 1.68 (m, 1H), 1.29 (s, 9H), 1.15 (d, J = 6.9 Hz, 3H). Preparation 31C: 2-methyl-N-(2-methyl-1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-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)propane-2-sulfinamide To a stirred solution of N-[1-(5-bromopyrimidin-2-yl)-2-methylcyclobutyl]-2-methylpropane-2- sulfinamide (110 mg, 0.318 mmol) and (7R,14R)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (228 mg, 0.382 mmol) in 1,4-dioxane (2 mL) and H2O (0.4 mL) were added Pd(dppf)Cl2.CH2Cl2 (26 mg, 0.032 mmol) and K2CO3(132 mg, 0.954 mmol). The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The reaction was quenched with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 2-methyl-N-(2-methyl-1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-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)propane-2-sulfinamide (200 mg, crude) as a brown oil. The crude product was used in the next step directly without further purification. MS ESI calculated for C42H51D3N6O2SSi [M + H]+, 738.41 found 738.45. Preparation 31D: (7R,14R)-11-(2-(1-amino-2-methylcyclobutyl)pyrimidin-5-yl)-6-(methyl-d3)-WSGR Ref: 53699-720.601 1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one To a stirred solution of 2-methyl-N-(2-methyl-1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-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)propane-2-sulfinamide (200 mg, crude) in 1,4- dioxane (1 mL) was added HCl (1 mL, 4.000 mmol, 4 mol / L in 1,4-dioxane) dropwise at room temperature. The resulting mixture was stirred for 1 h at room temperature. The mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, 254 nm. This resulted in (7R,14R)-11-(2-(1-amino-2-methylcyclobutyl)pyrimidin-5-yl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (60 mg) as a brown solid. MS ESI calculated for C38H43D3N6OSi [M + H]+, 634.38 found 634.40. Preparation 31E: (7R,14R)-11-(2-(1-amino-2-methylcyclobutyl)pyrimidin-5-yl)-1-ethynyl-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- one To a stirred solution of (7R,14R)-11-(2-(1-amino-2-methylcyclobutyl)pyrimidin-5-yl)-6- (methyl-d3)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (60 mg, 0.057 mmol) in THF (1 mL) was added TBAF (0.07 mL, 0.068 mmol, 1 mol / L in THF) dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated under vacuum. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 10:1) followed by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5m; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 22% B in 10 min; Wave Length: 254 nm; RT1(min): 11.45) to afford (7R,14R)-11-(2-(1-amino-2-methylcyclobutyl)pyrimidin-5-yl)-1-ethynyl-6-(methyl-d3)- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (20 mg, 74%) as a light yellow solid. MS ESI calculated for C29H23D3N6O [M + H]+, 478.24 found 478.20. Example 31 and 32: (7R,14R)-11-(2-((1S,2R)-1-amino-2-methylcyclobutyl)pyrimidin-5-yl)-1- ethynyl-6-(methyl-d3)-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-((1R,2S)-1-amino-2- methylcyclobutyl)pyrimidin-5-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-oneWSGR Ref: 53699-720.601 (7R,14R)-11-(2-(1-amino-2-methylcyclobutyl)pyrimidin-5-yl)-1-ethynyl-6-(methyl-d3)-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (20 mg) was purified by Prep-Chiral HPLC with the following conditions (Column: Lux 5u Cellulose-2, 30*250 mm, 5.0 um; Mobile Phase A: Hex(10 mM NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient: isocratic 50; Wave Length: 222 / 282 nm; RT1(min): 19.3; RT2(min): 22.5). The first peak afforded 6 mg (31%). MS ESI calculated for C29H23D3N6O [M + H]+, 478.24 found 478.30.1H NMR (400 MHz, Methanol-d4) δ 9.02 (s, 2H), 8.53 (dd, J = 8.2, 1.4 Hz, 1H), 8.11 (s, 1H), 7.83 – 7.71 (m, 2H), 7.59 (dd, J = 8.6, 1.8 Hz, 1H), 7.43 (t, J = 7.9 Hz, 1H), 6.66 (d, J = 7.1 Hz, 1H), 5.23 (d, J = 7.2 Hz, 1H), 4.45 (s, 1H), 3.66 – 3.52 (m, 1H), 3.00 – 2.80 (m, 3H), 2.24 – 2.10 (m, 1H), 2.11 – 2.00 (m, 1H), 1.91 – 1.76 (m, 1H), 1.13 (d, J = 7.1 Hz, 3H). The second peak afforded 8 mg (39%). MS ESI calculated for C29H23D3N6O [M + H]+, 478.24 found 478.35.1H NMR (400 MHz, Methanol-d4) δ 9.02 (s, 2H), 8.53 (d, J = 8.9 Hz, 1H), 8.11 (s, 1H), 7.82 – 7.73 (m, 2H), 7.64 – 7.55 (m, 1H), 7.48 – 7.38 (m, 1H), 6.69 – 6.62 (m, 1H), 5.22 (d, J = 7.2 Hz, 1H), 4.45 (s, 1H), 3.67 – 3.54 (m, 1H), 2.99 – 2.78 (m, 3H), 2.23 – 2.10 (m, 1H), 2.10 – 1.98 (m, 1H), 1.91 – 1.75 (m, 1H), 1.13 (d, J = 6.9 Hz, 3H).

[0185] Example 33: (7R,14R)-11-(2-(6-amino-2-oxaspiro[3.3]heptan-6-yl)pyrimidin-5-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-onePreparation 33A: 6-(5-bromopyrimidin-2-yl)-2-oxaspiro[3.3]heptan-6-ol To a stirred solution of 5-bromo-2-iodopyrimidine (1.40 g, 4.905 mmol) in DCM (10 mL) was added 2.5 M n-BuLi in hexane (1.96 mL, 4.905 mmol) at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 30 min under nitrogen atmosphere followed by addition of 2-oxaspiro[3.3]heptan-6-one (500 mg, 4.459 mmol) at -78 °C. The resulting mixture was stirred at room temperature for additional 1 h. The reaction was quenched with water atWSGR Ref: 53699-720.601 room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 6-(5- bromopyrimidin-2-yl)-2-oxaspiro[3.3]heptan-6-ol (700 mg, 58%) as a yellow solid. MS ESI calculated for C10H11BrN2O2 [M + H]+, 271.00273.00 found 270.90272.90.1H NMR (400 MHz, Chloroform-d) δ 8.75 (s, 2H), 4.87 (s, 2H), 4.75 (s, 2H), 4.69 (s, 1H), 2.91 – 2.83 (m, 2H), 2.72 – 2.64 (m, 2H). Preparation 33B: 6-(5-bromopyrimidin-2-yl)-2-oxaspiro[3.3]heptan-6-yl methanesulfonate To a stirred solution of 6-(5-bromopyrimidin-2-yl)-2-oxaspiro[3.3]heptan-6-ol (200 mg, 0.738 mmol) and TEA (205 uL, 1.476 mmol) in DCM (4 mL) was added MsCl (101 mg, 0.886 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction was quenched with water and extracted with CH2Cl2 (3 x 50 mL). The resulting mixture was concentrated under vacuum. This resulted in 6-(5- bromopyrimidin-2-yl)-2-oxaspiro[3.3]heptan-6-yl methanesulfonate (250 mg, 97%) as a yellow oil. MS ESI calculated for C11H13BrN2O4S [M + H]+, 348.98350.98, found 348.75350.75.1H NMR (400 MHz, Chloroform-d) δ 8.79 (s, 2H), 4.78 – 4.74 (m, 4H), 3.19 (s, 3H), 3.15 – 3.03 (m, 4H). Preparation 33C: 2-{6-azido-2-oxaspiro[3.3]heptan-6-yl}-5-bromopyrimidine To a stirred solution of 6-(5-bromopyrimidin-2-yl)-2-oxaspiro[3.3]heptan-6-yl methanesulfonate (200 mg, 0.573 mmol) in DMSO (3.2 mL) and H2O (0.8 mL) was added NaN3(45 mg, 0.688 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. The resulting mixture was diluted with EtOAc (20 mL). The resulting mixture was washed with 3 x 20 mL of water. The organic layer was concentrated under vacuum. This resulted in 2-{6-azido-2- oxaspiro[3.3]heptan-6-yl}-5-bromopyrimidine (120 mg, 71%) as a yellow oil. MS ESI calculated for C10H10BrN5O [M + H]+, 296.01298.00, found 295.80297.85.1H NMR (400 MHz, Chloroform-d) δ 8.80 (s, 2H), 4.81 (s, 2H), 4.70 (s, 2H), 3.06 – 2.91 (m, 2H), 2.77 – 2.61 (m, 2H). Preparation 33D: 6-(5-bromopyrimidin-2-yl)-2-oxaspiro[3.3]heptan-6-amine To a stirred solution of 2-{6-azido-2-oxaspiro[3.3]heptan-6-yl}-5-bromopyrimidine (120 mg, 0.405 mmol) and PPh3(128 mg, 0.486 mmol) in THF (1.2 mL), H2O (1.2 mL) was added KOH (57 mg, 1.013 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 6-(5-bromopyrimidin-2-yl)-2-oxaspiro[3.3]heptan-6-amine (40 mg, 36%) as a white solid. MS ESI calculated for C10H12BrN3O [M + H]+, 270.02272.01 found 269.75271.90. Preparation 33E: (7R,14R)-11-(2-(6-amino-2-oxaspiro[3.3]heptan-6-yl)pyrimidin-5-yl)-6-WSGR Ref: 53699-720.601 (methyl-d3)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one To a stirred solution of (7R,14R)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (50 mg, 0.084 mmol) and 6-(5-bromopyrimidin-2-yl)-2- oxaspiro[3.3]heptan-6-amine (23 mg, 0.084 mmol) in 1,4-dioxane (1.5 mL) and H2O (0.3 mL) were added K2CO3 (35 mg, 0.252 mmol) and Pd(dppf)Cl2.CH2Cl2 (7 mg, 0.008 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 3 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford (7R,14R)-11-(2-(6-amino-2- oxaspiro[3.3]heptan-6-yl)pyrimidin-5-yl)-6-(methyl-d3)-1-((triisopropylsilyl)ethynyl)-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (30 mg, 54%) as a yellow solid. MS ESI calculated for C39H43D3N6O2Si [M + H]+, 662.36 found 662.25. Example 33: (7R,14R)-11-(2-(6-amino-2-oxaspiro[3.3]heptan-6-yl)pyrimidin-5-yl)-1-ethynyl-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- one To a stirred solution of (7R,14R)-11-(2-(6-amino-2-oxaspiro[3.3]heptan-6-yl)pyrimidin-5-yl)-6- (methyl-d3)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (30 mg, 0.045 mmol) in MeOH (1 mL) was added KF (13 mg, 0.225 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 16 h. The resulting mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 20% to 55% gradient in 25 min; detector, 254 nm. This resulted in (7R,14R)-11-(2-(6-amino-2-oxaspiro[3.3]heptan-6-yl)pyrimidin-5-yl)-1-ethynyl-6-(methyl- d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (3 mg, 11%). MS ESI calculated for C30H23D3N6O2[M + H]+, 506.23 found 506.15.1H NMR (400 MHz, Chloroform-d) δ 8.90 (s, 2H), 8.67 – 8.61 (m, 1H), 7.95 – 7.91 (m, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.76 – 7.70 (m, 1H), 7.47 – 7.35 (m, 2H), 6.51 (d, J = 7.2 Hz, 1H), 4.98 (d, J = 7.0 Hz, 1H), 4.86 (s, 2H), 4.81 (s, 2H), 3.72 (s, 1H), 3.59 – 3.43 (m, 1H), 2.99 (d, J = 12.2 Hz, 2H), 2.92 (d, J = 13.6 Hz, 1H), 2.51 (d, J = 13.2 Hz, 2H).

[0186] Example 34: (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-1-(but-1-yn-1-yl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- oneWSGR Ref: 53699-720.601Preparation 34A: tert-butyl (1-(5-((7R,14R)-1-(but-1-yn-1-yl)-6-(methyl-d3)-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 To a stirred mixture of (7R,14R)-11-(2-(1-((tert-butoxycarbonyl)amino)cyclobutyl)pyrimidin-5- yl)-6-(methyl-d3)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-1-yl trifluoromethanesulfonate (100 mg, 0.145 mmol), Pd(PPh3)2Cl2 (31 mg, 0.043 mmol), CuI (6 mg, 0.029 mmol) and KF (25 mg, 0.435 mmol) in DMF (5 mL) were added TEA (74 mg, 0.725 mmol) and but-1-yn-1-yltrimethylsilane (22 mg, 0.174 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford tert-butyl (1-(5- ((7R,14R)-1-(but-1-yn-1-yl)-6-(methyl-d3)-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 (50 mg, 58%) as a brown solid. MS ESI calculated for C35H33D3N6O3[M + H]+, 592.30 found 592.20.Example 34: (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-1-(but-1-yn-1-yl)-6-(methyl- d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one To a stirred solution of tert-butyl (1-(5-((7R,14R)-1-(but-1-yn-1-yl)-6-(methyl-d3)-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, 0.051 mmol) in DCM (1 mL) was added TFA (0.2 mL) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure and purified by Prep-HPLC with the following conditions: (Column: Xselect CSH C18 OBD Column 30*150mm 5μm; Mobile Phase A: water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient: 4%B to 24%B in 10 min; Wave Length: 254 / 220 nm) to afford (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-1-(but-1-yn-1-yl)-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (4 mg, 17%). MS ESIcalculated for C30H25D3N6O [M + H]+, 492.25 found 492.25. 1H NMR (400 MHz, DMSO-d6) δ9.16 (s, 2H), 8.40 – 8.33 (m, 1H), 7.96 (d, J = 1.8 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.73 – 7.62 (m, 2H), 7.41 (t, J = 7.9 Hz, 1H), 6.51 (d, J = 7.1 Hz, 1H), 5.28 (d, J = 7.1 Hz, 1H), 3.46 – 3.34WSGR Ref: 53699-720.601 (m, 3H), 2.88 (d, J = 13.8 Hz, 1H), 2.80 – 2.66 (m, 4H), 2.62 – 2.52 (m, 2H), 2.26 – 2.09 (m, 2H), 1.29 (t, J = 7.5 Hz, 3H).

[0187] Example 35: (7R,14R)-11-(2-(1-aminocyclopentyl)pyrimidin-5-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-onePreparation 35A: N-cyclopentylidene-2-methylpropane-2-sulfinamide To a stirred solution of cyclopentanone (3.00 g, 35.664 mmol) and tert-butanesulfinamide (5.19 g, 42.797 mmol) in THF (50 mL) was added Ti(Oi-Pr)4(21.3 mL, 71.328 mmol) at room temperature. The resulting mixture was stirred for overnight at room temperature. The reaction was quenched by the addition of sat. NaHCO3 (aq.) (30 mL). The mixture was filtered, the filter cake was washed with ethyl acetate (30 mL). The aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford N- cyclopentylidene-2-methylpropane-2-sulfinamide (3.40 g, 51%) as a yellow oil. MS ESI calculated for C9H17NOS [M + H]+, 188.11 found 188.15. Preparation 35B: N-(1-(5-bromopyrimidin-2-yl)cyclopentyl)-2-methylpropane-2-sulfinamide To a stirred mixture of 5-bromo-2-iodopyrimidine (6.39 g, 22.424 mmol) in toluene (30 mL) was added butyllithium (8.97 mL, 22.424 mmol, 2.5 mol / L in hexanes) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at -78 °C under nitrogen atmosphere. To a stirred solution of N-cyclopentylidene-2-methylpropane-2-sulfinamide (2.00 g, 10.678 mmol) in toluene (10 mL) was added AlMe3(5.87 mL, 11.746 mmol, 2 mol / L inWSGR Ref: 53699-720.601 toluene) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 20 min, and then added to the aryl lithium mixture dropwise at -78 °C. The reaction was allowed to warm to room temperature slowly and stirred overnight at room temperature under nitrogen atmosphere. The reaction was quenched with sat. NH4Cl (aq.). The mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, 254 nm. This resulted in N-(1-(5-bromopyrimidin-2- yl)cyclopentyl)-2-methylpropane-2-sulfinamide (1.01 g, 27%) as a brown solid. MS ESI calculated for C13H20BrN3OS [M + H]+, 346.06348.06 found 346.10348.10.1H NMR (400 MHz, Chloroform-d) δ 8.72 (s, 2H), 2.61 – 2.49 (m, 1H), 2.42 – 2.30 (m, 1H), 2.24 – 2.07 (m, 2H), 1.94 – 1.75 (m, 4H), 1.22 (s, 9H). Preparation 35C: 2-methyl-N-(1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)pyrimidin-2-yl)cyclopentyl)propane-2-sulfinamide To a stirred solution of (7R,14R)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (166 mg, 0.277 mmol) and N-(1-(5-bromopyrimidin-2- yl)cyclopentyl)-2-methylpropane-2-sulfinamide (80 mg, 0.231 mmol) in 1,4-dioxane (1.6 mL) and H2O (0.3 mL) were added Pd(dppf)Cl2.CH2Cl2 (19 mg, 0.023 mmol) and K2CO3 (96 mg, 0.693 mmol). The resulting mixture was stirred for overnight at 100 °C under nitrogen atmosphere. The mixture was quenched with water (10 mL), and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 2- methyl-N-(1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-((triisopropylsilyl)ethynyl)-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2- yl)cyclopentyl)propane-2-sulfinamide (150 mg) as a brown oil. The crude product was used in the next step directly without further purification. MS ESI calculated for C42H51D3N6O2SSi [M + H]+, 738.41 found 738.40. Preparation 35D: (7R,14R)-11-(2-(1-aminocyclopentyl)pyrimidin-5-yl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one To a stirred solution of 2-methyl-N-(1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-WSGR Ref: 53699-720.601 a][1,4]diazocin-11-yl)pyrimidin-2-yl)cyclopentyl)propane-2-sulfinamide (200 mg) in 1,4- dioxane (2 mL) was added 4M HCl(gas) in 1,4-dioxane (2 mL) slowly. The resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, 254 nm. This resulted in (7R,14R)-11-(2-(1- aminocyclopentyl)pyrimidin-5-yl)-6-(methyl-d3)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (110 mg, 77%) as a brown oil. MS ESI calculated for C38H43D3N6OSi [M + H]+, 634.38 found 634.45. Example 35: (7R,14R)-11-(2-(1-aminocyclopentyl)pyrimidin-5-yl)-1-ethynyl-6-(methyl-d3)- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one To a stirred solution of (7R,14R)-11-(2-(1-aminocyclopentyl)pyrimidin-5-yl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (110 mg, 0.174 mmol) in DMF (3 mL) was added CsF (264 mg, 1.736 mmol). The resulting mixture was stirred at room temperature for 2 h. The mixture was filtered, the filter cake was washed with ethyl acetate (2 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: Xselect CSH F-Phenyl OBD column 30*250 mm, 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: MeOH; Flow rate: 60 mL / min; Gradient: 43% B to 62% B in 10 min; Wave Length: 254 nm; RT1(min): 5.42) to afford (7R,14R)-11-(2-(1- aminocyclopentyl)pyrimidin-5-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (27 mg, 33%). MS ESI calculated for C29H23D3N6O [M + H]+, 478.24 found 478.30.1H NMR (400 MHz, Methanol-d4) δ 9.13 – 9.02 (m, 2H), 8.58 – 8.44 (m, 1H), 8.13 (s, 1H), 7.86 – 7.72 (m, 2H), 7.65 – 7.51 (m, 1H), 7.48 – 7.34 (m, 1H), 6.66 (dd, J = 6.9, 3.1 Hz, 1H), 5.24 (dd, J = 7.2, 2.5 Hz, 1H), 4.42 (s, 1H), 3.67 – 3.53 (m, 1H), 2.99 – 2.88 (m, 1H), 2.59 – 2.46 (m, 2H), 2.20 – 1.95 (m, 6H).

[0188] Example 36 and 37: (7R,14R)-11-(6-((1S,2R)-1-amino-2-methylcyclobutyl)pyridin-3-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one and (7R,14R)-11-(6-((1R,2S)-1-amino-2-methylcyclobutyl)pyridin- 3-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-oneWSGR Ref: 53699-720.601Preparation 36A: 2-methyl-N-(2-methylcyclobutylidene)propane-2-sulfinamide To a stirred solution of 2-methylcyclobutan-1-one (1.00 g, 11.888 mmol) and tert- butanesulfinamide (1.73 g, 14.266 mmol) in THF (20 mL) was added Ti(Oi-Pr)4(8.45 g, 29.720 mmol) dropwise at room temperature. The resulting mixture was stirred at room temperature for 12 h. The reaction was quenched with water at room temperature. The resulting mixture was filtered, the filter cake was washed with ethyl acetate (5 x 20 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford 2-methyl-N-(2-methylcyclobutylidene)propane-2-sulfinamide (440 mg, 20%) as a yellow oil. MS ESI calculated for C9H17NOS [M + H]+, 188.10 found 188.00.1H NMR (400 MHz, Chloroform-d) δ 3.59 – 3.11 (m, 3H), 2.36 – 2.21 (m, 1H), 1.76 – 1.64 (m, 1H), 1.26 – 1.21 (m, 12H). Preparation 36B: N-(1-(5-bromopyridin-2-yl)-2-methylcyclobutyl)-2-methylpropane-2- sulfinamide To a stirred solution of 5-bromo-2-iodopyridine (364 mg, 1.282 mmol) in DCM (5 mL) wasWSGR Ref: 53699-720.601 added n-BuLi (0.4 mL, 2.5 mol / L) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 30 min. To the above mixture was added 2-methyl-N-[(1Z)-2- methylcyclobutylidene]propane-2-sulfinamide (200 mg, 1.068 mmol) in DCM (2 mL) dropwise at -78 °C. The resulting mixture was stirred at room temperature for additional 2 h. The reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with CH2Cl2(3 x 10 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (20:1) to afford N-[1-(5-bromopyridin-2-yl)-2-methylcyclobutyl]-2- methylpropane-2-sulfinamide (270 mg, 73%) as a yellow solid. MS ESI calculated forC14H21BrN2OS [M + H]+, 345.06347.06, found 344.95346.95.1H NMR (400 MHz,Chloroform-d) δ 8.70 – 8.55 (m, 1H), 7.86 – 7.71 (m, 1H), 7.46 – 7.31 (m, 1H), 2.88 – 2.49 (m, 3H), 2.06 – 1.98 (m, 1H), 1.83 – 1.67 (m, 1H), 1.26 (d, J = 6.1 Hz, 9H), 1.17 (d, J = 7.1 Hz, 3H). Preparation 36C: 2-methyl-N-(2-methyl-1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)pyridin-2-yl)cyclobutyl)propane-2-sulfinamide To a stirred mixture of (7R,14R)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (100 mg, 0.167 mmol) and N-[1-(5-bromopyridin-2-yl)-2- methylcyclobutyl]-2-methylpropane-2-sulfinamide (69 mg, 0.200 mmol) in H2O (0.25 mL) and 1,4-dioxane (2.5 mL) were added Pd(dppf)Cl2.CH2Cl2 (14 mg, 0.017 mmol) and K2CO3 (69 mg, 0.501 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 1 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 2-methyl-N-(2-methyl-1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-((triisopropylsilyl)ethynyl)- 5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyridin- 2-yl)cyclobutyl)propane-2-sulfinamide (98 mg, 80%) as a yellow solid. MS ESI calculated for C43H52D3N5O2SSi [M + H]+, 737.40 found 737.50.1H NMR (400 MHz, Chloroform-d) δ 8.84 – 8.67 (m, 1H), 8.58 (d, J = 8.3 Hz, 1H), 7.94 – 7.71 (m, 4H), 7.62 – 7.33 (m, 4H), 6.69 – 6.57 (m, 1H), 5.03 – 4.92 (m, 1H), 3.55 – 3.41 (m, 1H), 2.96 – 2.89 (m, 1H), 2.88 – 2.64 (m, 2H), 2.12 – 2.03 (m, 1H), 1.80 – 1.60 (m, 2H), 1.33 – 1.05 (m, 33H). Preparation 36D: (7R,14R)-11-(6-(1-amino-2-methylcyclobutyl)pyridin-3-yl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one To a stirred solution of 2-methyl-N-(2-methyl-1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-WSGR Ref: 53699-720.601 ((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)pyridin-2-yl)cyclobutyl)propane-2-sulfinamide (88 mg, 0.119 mmol) in 1,4-dioxane (1 mL) was added 4M HCl(gas)in 1,4-dioxane (1 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DMF (2 mL). To the above mixture was added CsF (181 mg, 1.190 mmol) at room temperature. The resulting mixture was stirred at room temperature for additional 1 h. The resulting solution was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 20% to 50% gradient in 30 min; detector, 254 nm to (7R,14R)-11-(6-(1-amino-2-methylcyclobutyl)pyridin-3-yl)-1-ethynyl-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- one (54 mg, 95%) as a yellow solid. MS ESI calculated for C30H24D3N5O [M + H]+, 477.24 found 477.20. Example 36 and 37: (7R,14R)-11-(6-((1S,2R)-1-amino-2-methylcyclobutyl)pyridin-3-yl)-1- ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one and (7R,14R)-11-(6-((1R,2S)-1-amino-2-methylcyclobutyl)pyridin- 3-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one The mixture (30 mg) was purified by Prep-Chiral HPLC with the following conditions (Column: Lux 5u Cellulose-2, 4.6*250mm, 5um; Mobile Phase A: Hex(10mM NH3-MeOH), Mobile Phase B:EtOH; Flow rate: 40 mL / min; Gradient: isocratic 50; Wave Length: 220 / 290 nm; RT1(min): 18.161; RT2(min): 22.403). The first peak afforded 8 mg (25%). MS ESI calculated for C30H24D3N5O [M + H]+, 477.24, found 477.25.1H NMR (400 MHz, Chloroform-d) δ 8.81 (d, J = 2.4 Hz, 1H), 8.65 – 8.60 (m, 1H), 7.97 – 7.92 (m, 1H), 7.89 – 7.84 (m, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.74 – 7.68 (m, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.47 – 7.42 (m, 1H), 7.39 (t, J = 7.9 Hz, 1H), 6.50 (d, J = 7.2 Hz, 1H), 4.97 (d, J = 7.0 Hz, 1H), 3.71 (s, 1H), 3.54 – 3.43 (m, 1H), 2.90 (d, J = 13.6 Hz, 1H), 2.88 – 2.79 (m, 1H), 2.66 – 2.57 (m, 1H), 2.19 – 2.03 (m, 2H), 1.92 – 1.77 (m, 1H), 1.18 (d, J = 7.0 Hz, 3H). The second peak afforded 5 mg (18%). MS ESI calculated for C30H24D3N5O [M + H]+, 477.24 found 477.25.1H NMR (400 MHz, Chloroform- d) δ 8.84 – 8.80 (m, 1H), 8.66 – 8.60 (m, 1H), 7.95 (d, J = 1.7 Hz, 1H), 7.89 – 7.83 (m, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.75 – 7.70 (m, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.47 – 7.42 (m, 1H), 7.39 (t, J = 7.9 Hz, 1H), 6.50 (d, J = 7.2 Hz, 1H), 4.97 (d, J = 7.0 Hz, 1H), 3.72 (s, 1H), 3.52 – 3.43 (m, 1H), 2.90 (d, J = 13.5 Hz, 1H), 2.88 – 2.80 (m, 1H), 2.65 – 2.54 (m, 1H), 2.14 – 2.04 (m, 2H), 1.88 – 1.80 (m, 1H), 1.18 (d, J = 7.0 Hz, 3H).WSGR Ref: 53699-720.601

[0189] Example 38: (7R,14R)-11-(2-(1-amino-3,3-difluorocyclobutyl)pyrimidin-5-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-onePreparation 38A: 1-(5-bromopyrimidin-2-yl)-3,3-difluorocyclobutan-1-ol To a stirred solution of 5-bromo-2-iodopyrimidine (1477 mg, 5.185 mmol) in DCM (15 mL) was added 2.5 M n-BuLi in hexane (2.07 mL, 5.185 mmol) at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 30 min. To the above solution was added 3,3-difluorocyclobutan-1-one (500 mg, 4.714 mmol) at -78 °C. The resulting mixture was stirred at room temperature for additional 1 h. The reaction was quenched with water at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (20:1) to afford 1-(5- bromopyrimidin-2-yl)-3,3-difluorocyclobutan-1-ol (330 mg, 26%) as a white solid. MS ESI calculated for C8H7BrF2N2O [M + H]+, 264.97266.97 found 264.75266.75.1H NMR (400 MHz, Chloroform-d) δ 8.83 (s, 2H), 3.43 – 3.27 (m, 2H), 3.07 – 2.91 (m, 2H).19F NMR (377 MHz, Chloroform-d) δ -90.33, -90.85, -92.67, -93.19. Preparation 38B: 1-(5-bromopyrimidin-2-yl)-3,3-difluorocyclobutyl methanesulfonate To a stirred solution of 1-(5-bromopyrimidin-2-yl)-3,3-difluorocyclobutan-1-ol (330 mg, 1.245 mmol) and TEA (0.35 mL, 2.490 mmol) in DCM (6 mL) was added MsCl (171 mg, 1.494 mmol) at 0 °C under nitrogen atmosphere. The resulting solution was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction was quenched with water at room temperature. The aqueous layer was extracted with CH2Cl2 (3 x 20 mL). The resulting mixture was concentrated under vacuum. This resulted in 1-(5-bromopyrimidin-2-yl)-3,3- difluorocyclobutyl methanesulfonate (400 mg, 94%) as a yellow oil. MS ESI calculated for C9H9BrF2N2O3S [M + H]+, 342.95344.95 found 342.95344.95.1H NMR (400 MHz,WSGR Ref: 53699-720.601 Chloroform-d) δ 8.86 (s, 2H), 3.67 – 3.55 (m, 2H), 3.46 – 3.37 (m, 2H), 3.19 (s, 3H).19F NMR (377 MHz, Chloroform-d) δ -90.68, -91.21, -92.07, -92.60. Preparation 38C: 2-(1-azido-3,3-difluorocyclobutyl)-5-bromopyrimidine To a stirred mixture of 1-(5-bromopyrimidin-2-yl)-3,3-difluorocyclobutyl methanesulfonate (360 mg, 1.049 mmol) in DMSO (5.6 mL) and H2O (1.4 mL) was added NaN3 (102 mg, 1.573 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 24 h under argon atmosphere. The resulting mixture was diluted with EtOAc (50 mL). The residue was washed with water (5 x 50 mL). The organic layer was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 2-(1-azido- 3,3-difluorocyclobutyl)-5-bromopyrimidine (130 mg, 43%) as a yellow oil. MS ESI calculated for C8H6BrF2N5 [M + H]+, 289.98291.98 found 290.10292.10.1H NMR (400 MHz, Chloroform-d) δ 8.85 (s, 2H), 3.51 – 3.37 (m, 2H), 3.13 – 2.98 (m, 2H).19F NMR (377 MHz, Chloroform-d) δ -89.95, -90.47, -91.26, -91.79. Preparation 38D: 1-(5-bromopyrimidin-2-yl)-3,3-difluorocyclobutan-1-amine To a stirred solution of 2-(1-azido-3,3-difluorocyclobutyl)-5-bromopyrimidine (120 mg, 0.414 mmol) and PPh3(130 mg, 0.497 mmol) in THF (1.5 mL), H2O (1.5 mL) was added KOH (58 mg, 1.035 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h under argon atmosphere. The organic layer was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 1-(5- bromopyrimidin-2-yl)-3,3-difluorocyclobutan-1-amine (70 mg, 64%) as a white solid. MS ESI calculated for C8H8BrF2N3 [M + H]+, 263.99265.98 found 264.10266.05.1H NMR (400 MHz, Chloroform-d) δ 8.78 (s, 2H), 3.44 –3.29 (m, 2H), 2.84 –2.71 (m, 2H).19F NMR (377 MHz, Chloroform-d) δ -88.33, -88.85, -90.86, -91.38. Preparation 38E: (7R,14R)-11-(2-(1-amino-3,3-difluorocyclobutyl)pyrimidin-5-yl)-6-(methyl- d3)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one To a stirred mixture of 1-(5-bromopyrimidin-2-yl)-3,3-difluorocyclobutan-1-amine (66 mg, 0.100 mmol) and (7R,14R)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (60 mg, 0.100 mmol) in 1,4-dioxane (1.5 mL) and H2O (0.3 mL) were added K2CO3 (42 mg, 0.300 mmol) and Pd(dppf)Cl2.CH2Cl2 (8 mg, 0.010 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 3 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford (7R,14R)-11-(2-(1-amino-3,3- difluorocyclobutyl)pyrimidin-5-yl)-6-(methyl-d3)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-WSGR Ref: 53699-720.601 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (30 mg, 46%) as a yellow solid. MS ESI calculated for C37H39D3F2N6OSi [M + H]+, 656.33 found 656.35. Example 38: (7R,14R)-11-(2-(1-amino-3,3-difluorocyclobutyl)pyrimidin-5-yl)-1-ethynyl-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- one To a stirred solution of (7R,14R)-11-(2-(1-amino-3,3-difluorocyclobutyl)pyrimidin-5-yl)-6- (methyl-d3)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (30 mg, 0.046 mmol) in MeOH (1 mL) was added KF (11 mg, 0.184 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 6 h. The resulting mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 25% to 55% gradient in 30 min; detector, 254 nm. The resulting mixture was concentrated under vacuum. This resulted in (7R,14R)-11-(2-(1-amino-3,3- difluorocyclobutyl)pyrimidin-5-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (4 mg, 19%). MS ESI calculated for C28H19D3F2N6O [M + H]+, 500.20 found 500.20.1H NMR (400 MHz, Chloroform-d) δ 8.95 (s, 2H), 8.68 – 8.61 (m, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.88 – 7.81 (m, 1H), 7.77 – 7.70 (m, 1H), 7.49 – 7.37 (m, 2H), 6.53 (d, J = 7.2 Hz, 1H), 4.99 (d, J = 7.0 Hz, 1H), 3.73 (s, 1H), 3.56 – 3.39 (m, 3H), 2.93 (d, J = 13.6 Hz, 1H), 2.85 – 2.71 (m, 2H).19F NMR (377 MHz, Chloroform-d) δ -87.97, -88.49, -90.88, -91.41.

[0190] Example 39: (7R,14R)-1-ethynyl-11-(3-fluoro-4-(S-methylsulfonimidoyl)phenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- onePreparation 39A: (4-bromo-2-fluorophenyl)(imino)methyl-lambda6-sulfanone A mixture of 4-bromo-2-fluoro-1-(methylsulfanyl)benzene (1.90 g, 8.594 mmol), (Diacetoxyiodo)benzene (8.30 g, 25.782 mmol) and NH4OAc (2.65 g, 34.376 mmol) in EtOHWSGR Ref: 53699-720.601 (19 mL) was stirred at room temperature for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with MeOH (0.1% NH3.H2O) in DCM (0~8%) to afford (4-bromo-2- fluorophenyl)(imino)methyl-lambda6-sulfanone (1.70 g, 78%) as a colorless oil. MS ESI calculated for C7H7BrFNOS [M + H]+, 251.94253.94 found 251.95253.95.1H NMR (400 MHz, Chloroform-d) δ 7.83 (t, J = 8.0 Hz, 1H), 7.51 – 7.39 (m, 2H), 3.25 (s, 3H).19F NMR (377 MHz, Chloroform-d) δ -106.47. Preparation 39B: (7R,14R)-11-(3-fluoro-4-(S-methylsulfonimidoyl)phenyl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one A mixture of (7R,14R)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (80 mg, 0.134 mmol), (4-bromo-2-fluorophenyl)(imino)methyl- lambda6-sulfanone (50 mg, 0.201 mmol), K3PO4 (85 mg, 0.402 mmol) and Pd(dppf)Cl2 (11 mg, 0.013 mmol) in 1,4-dioxane (1 mL) and H2O (0.1 mL) was stirred at 80 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum and purified by silica gel column chromatography, eluted with MeOH in DCM (0~10%) followed purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 50% to 80% gradient in 30 min; detector, 254 nm. This resulted in (7R,14R)-11-(3-fluoro-4-(S-methylsulfonimidoyl)phenyl)-6- (methyl-d3)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (55 mg, 64%) as a lightyellow solid. MS ESI calculated for C36H38D3FN4O2SSi [M + H]+, 644.29 found 644.30. 1HNMR (400 MHz, Chloroform-d) δ 8.62 – 8.54 (m, 1H), 7.96 (t, J = 7.9 Hz, 1H), 7.87 – 7.79 (m, 2H), 7.79 – 7.71 (m, 1H), 7.48 – 7.32 (m, 4H), 6.62 (d, J = 7.2 Hz, 1H), 5.01 (d, J = 7.0 Hz, 1H), 3.56 – 3.43 (m, 1H), 3.30 (s, 3H), 2.94 (d, J = 13.6 Hz, 1H), 1.31 – 1.01 (m, 21H). Example 39: (7R,14R)-1-ethynyl-11-(3-fluoro-4-(S-methylsulfonimidoyl)phenyl)-6-(methyl- d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one To a stirred mixture of (7R,14R)-11-(3-fluoro-4-(S-methylsulfonimidoyl)phenyl)-6-(methyl-d3)- 1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (50 mg, 0.078 mmol) in THF (1 mL) was added TBAF (0.1 mL, 0.094 mmol, 1M in THF) dropwise at room temperature. The mixture was stirred for 30 min at room temperature. The resulting mixture was concentrated under vacuum and purified by silica gel column chromatography, eluted with MeOH in DCM (0~10%) followed by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase,WSGR Ref: 53699-720.601 CH3CN in Water (10 mmol / L NH4HCO3), 40% to 50% gradient in 20 min; detector, 254 nm. This resulted in (7R,14R)-1-ethynyl-11-(3-fluoro-4-(S-methylsulfonimidoyl)phenyl)-6-(methyl- d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (19mg, 50%). MS ESI calculated for C27H18D3FN4O2S [M + H]+, 488.16 found 488.00. 1H NMR(400 MHz, Chloroform-d) δ 8.68 – 8.61 (m, 1H), 8.05 – 7.96 (m, 2H), 7.81 (d, J = 8.5 Hz, 1H), 7.78 – 7.73 (m, 1H), 7.55 – 7.37 (m, 4H), 6.52 (d, J = 7.2 Hz, 1H), 5.01 (d, J = 7.0 Hz, 1H), 3.72 (s, 1H), 3.55 – 3.44 (m, 1H), 3.32 (s, 3H), 2.93 (d, J = 13.6 Hz, 1H).19F NMR (377 MHz, Chloroform-d) δ -108.75.

[0191] Example 40: (7R,14R)-1-ethynyl-6-(methyl-d3)-11-(2-(pyrrolidin-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 formatePreparation 40A: 3-(dimethylamino)-2-iodoprop-2-enal To a solution of 3-(dimethylamino)prop-2-enal (5.00 g, 50.437 mmol) in DCM (200 mL) was added NIS (11.35 g, 50.437 mmol) at room temperature. The reaction was stirred for 1 h at room temperature. The reaction mixture was washed with sat aqueous Na2S2O3 (150 mL) and water (2 x 50 mL). The organic phase was dried over Na2SO4 and concentrated to give a black solid. The crude product was re-crystallized from ethyl acetate / hexane (1 / 4, 40mL) to afford 3- (dimethylamino)-2-iodoprop-2-enal (8.30 g, 73%) as a dark yellow solid.1H NMR (400 MHz,WSGR Ref: 53699-720.601 Chloroform-d) δ 8.29 (s, 1H), 7.36 (s, 1H), 3.34 (s, 6H). Preparation 40B: tert-butyl 2-carbamimidoylpyrrolidine-1-carboxylate To a solution of tert-butyl 2-carbamoylpyrrolidine-1-carboxylate (3.00 g, 14.001 mmol) in DCM (50 mL) was added tetrafluoroboranuide (3.59 g, 18.901 mmol) at room temperature. The reaction mixture was stirred for 3 h. The solvent was distilled off in a vacuum at < 40 °C. The oily residue was treated with 7M NH3(g) in MeOH (40 mL, 280.000 mmol) for 24 h at room temperature. After the removal of methanol the residue was triturated with diethyl ether, then ether was decanted, and the residue was dried at room temperature. The crude tert-butyl 2- carbamimidoylpyrrolidine-1-carboxylate (4.30 g) was used in the next step without further purification. MS ESI calculated for C10H19N3O2 [M + H]+, 214.15 found 214.20. Preparation 40C: tert-butyl 2-(5-iodopyrimidin-2-yl)pyrrolidine-1-carboxylate A solution of tert-butyl 2-carbamimidoylpyrrolidine-1-carboxylate (1.30 g, 6.095 mmol) and t- BuONa (0.64 g, 6.705 mmol) in EtOH (18 mL) was stirred at room temperature for 10 min. To the above solution was added 3-(dimethylamino)-2-iodoprop-2-enal (1.65 g, 7.314 mmol) at room temperature. The resulting mixture was stirred at 80 °C for additional 16 h. The resulting mixture was concentrated under vacuum and purified by silica gel column chromatography, eluted with PE / EA (1 / 1) to afford tert-butyl 2-(5-iodopyrimidin-2-yl)pyrrolidine-1-carboxylate (660 mg, 28%) as a white solid. MS ESI calculated for C13H18IN3O2 [M + H]+, 376.04 found 376.05.1H NMR (300 MHz, Chloroform-d) δ 8.87 (s, 1H), 8.86 (s, 1H), 5.05 – 4.79 (m, 1H), 3.86 – 3.44 (m, 2H), 2.42 (d, J = 9.0 Hz, 1H), 2.12 – 1.76 (m, 3H), 1.45 (s, 4H), 1.20 (s, 5H). Preparation 40D: tert-butyl 2-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-((triisopropylsilyl)ethynyl)- 5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11- yl)pyrimidin-2-yl)pyrrolidine-1-carboxylate To a solution of (7R,14R)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (160 mg, 0.267 mmol) and tert-butyl 2-(5-iodopyrimidin-2- yl)pyrrolidine-1-carboxylate (120 mg, 0.320 mmol) in 1,4-dioxane (1.5 mL) and H2O (0.3 mL) were added K3PO4 (170 mg, 0.801 mmol) and Pd(dppf)Cl2 (22 mg, 0.027 mmol) at room temperature. After stirring for 3 h at 100 °C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (19 / 1) to afford tert-butyl 2-(5-((7R,14R)-6- (methyl-d3)-5-oxo-1-((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2-yl)pyrrolidine-1- carboxylate (100 mg, 51%) as a light yellow solid. MS ESI calculated for C42H49D3N6O3Si [M + H]+, 720.41 found 720.40.WSGR Ref: 53699-720.601 Preparation 40E: tert-butyl 2-(5-((7R,14R)-1-ethynyl-6-(methyl-d3)-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)pyrrolidine- 1-carboxylate To a stirred solution of tert-butyl 2-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)pyrimidin-2-yl)pyrrolidine-1-carboxylate (247 mg, 0.343 mmol) in THF (5 mL) was added TBAF (0.41 mL, 0.412 mmol, 1M in THF) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (19 / 1) to afford tert-butyl 2-(5-((7R,14R)-1-ethynyl-6-(methyl-d3)-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)pyrrolidine-1-carboxylate (100 mg, 51%) as a yellow solid. MS ESI calculated for C33H29D3N6O3[M + H]+, 564.27 found 564.35. Example 40: (7R,14R)-1-ethynyl-6-(methyl-d3)-11-(2-(pyrrolidin-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 formate To a stirred solution of tert-butyl 2-(5-((7R,14R)-1-ethynyl-6-(methyl-d3)-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)pyrrolidine-1-carboxylate (100 mg, 0.177 mmol) in DCM (2 mL) was added TFA (0.2 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was basified to pH 8 with saturated Na2CO3 (aq.) and extracted with CH2Cl2 (4 x 50 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (5% to 18%) followed by Prep-HPLC with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (0.1% FA), 5% to 45% gradient in 25 min; detector, 254 nm to afford (7R,14R)-1-ethynyl-6-(methyl-d3)-11-(2- (pyrrolidin-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 formate (60 mg, 66%). MS ESI calculated for C28H21D3N6O [M + H]+, 464.22 found 464.15.1H NMR (400 MHz, Chloroform-d) δ 8.93 (d, J = 3.3 Hz, 2H), 8.69 – 8.60 (m, 1H), 8.44 (s, 1H), 7.95 (t, J = 2.2 Hz, 1H), 7.88 – 7.80 (m, 1H), 7.79 – 7.71 (m, 1H), 7.47 – 7.37 (m, 2H), 6.56 – 6.48 (m, 1H), 5.07 (t, J = 6.9 Hz, 1H), 5.02 – 4.95 (m, 1H), 3.78 (d, J = 4.2 Hz, 1H), 3.64 – 3.35 (m, 3H), 2.93 (d, J = 13.5 Hz, 1H), 2.73 – 2.55 (m, 1H), 2.32 – 2.08 (m, 2H), 2.03 – 1.87 (m, 1H).WSGR Ref: 53699-720.601

[0192] Example 41: (7R,14R)-11-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-6-(methyl-d3)-1-(prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-onePreparation 41A: (7R,14R)-1-chloro-11-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-6-(methyl- d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one To a stirred solution of (7R,14R)-1-chloro-6-(methyl-d3)-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, 0.133 mmol) and 2-(5-bromopyrimidin-2-yl)propan-2-ol (43 mg, 0.200 mmol) in 1,4-dioxane (2.5 mL) and H2O (0.5 mL) were added Pd(dppf)Cl2(9 mg, 0.013 mmol) and K2CO3(36 mg, 0.266 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 10:1) to afford (7R,14R)-1-chloro-11-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-6-(methyl-d3)- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (40 mg, 66%) as a brown oil. MS ESI calculated for C25H19D3ClN5O2 [M + H]+, 463.17 found 463.00.1H NMR (400 MHz, Chloroform-d) δ 8.94 (s, 2H), 8.64 – 8.54 (m, 1H), 7.90 (t, J = 4.3 Hz, 2H), 7.70 – 7.61 (m, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.40 (t, J = 8.1 Hz, 1H), 6.60 – 6.48 (m, 1H), 5.21 – 5.04 (m, 1H), 3.63 – 3.45 (m, 1H), 2.96 (d, J = 11.7 Hz, 1H), 1.66 (s, 6H). Example 41: (7R,14R)-11-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-6-(methyl-d3)-1-(prop-1- yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one To a stirred solution of (7R,14R)-1-chloro-11-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- one (50 mg, 0.108 mmol) and trimethyl(prop-2-yn-1-yl)silane (24 mg, 0.216 mmol) in ACN (2 mL) were added SPhos (8 mg, 0.022 mmol), SPhos Pd Gen.3 (16 mg, 0.022 mmol) and K2CO3(74 mg, 0.540 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (20 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: Water (10WSGR Ref: 53699-720.601 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 26% B to 41 % B in 10 min; Wave Length: 254 nm; RT1(min): 10.51) to afford (7R,14R)-11-(2-(2- hydroxypropan-2-yl)pyrimidin-5-yl)-6-(methyl-d3)-1-(prop-1-yn-1-yl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (7 mg, 14%). MS ESI calculated for C28H22D3N5O2 [M + H]+, 467.22 found 467.10.1H NMR (400 MHz, Chloroform- d) δ 8.93 (s, 2H), 8.60 – 8.53 (m, 1H), 7.97 (d, J = 1.7 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.66 – 7.61 (m, 1H), 7.51 – 7.46 (m, 1H), 7.36 (t, J = 7.9 Hz, 1H), 6.56 (d, J = 6.9 Hz, 1H), 5.04 (d, J = 6.8 Hz, 1H), 4.65 (s, 1H), 3.57 – 3.42 (m, 1H), 2.93 (d, J = 13.4 Hz, 1H), 2.30 (s, 3H), 1.66 (s, 6H).

[0193] Example 42: (7R,14R)-11-(6-(3-aminooxetan-3-yl)pyridin-3-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-onePreparation 42A: N-(3-(5-bromopyridin-2-yl)oxetan-3-yl)-2-methylpropane-2-sulfinamide To a solution of 2-bromo-5-iodopyridine (5.83 g, 20.542 mmol) in THF (40 mL) was added n- butyllithium solution (8 mL, 20.00 mmol, 2.5M in THF) dropwise at -78 °C under nitrogen atmosphere. The reaction mixture was stirred at -78 °C for 30 min. Then a solution of 2-methyl- N-(oxetan-3-ylidene)propane-2-sulfinamide (3.00 g, 17.118 mmol) in 10 mL THF was added to above reaction dropwise and the mixture was stirred for another 1 h. The reaction was quenched with sat. NH4Cl (50 mL), extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4and concentratedWSGR Ref: 53699-720.601 under vacuum to yield a crude product which was directly purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (12:1) to afford N-(3-(5-bromopyridin-2-yl)oxetan- 3-yl)-2-methylpropane-2-sulfinamide (2.50 g, 44%) as a brown solid. MS ESI calculated for C12H17BrN2O2S [M + H]+, 333.02335.02 found 333.10335.10. Preparation 42B: 2-methyl-N-(3-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)pyridin-2-yl)oxetan-3-yl)propane-2-sulfinamide To a stirred mixture of N-(3-(5-bromopyridin-2-yl)oxetan-3-yl)-2-methylpropane-2-sulfinamide (100 mg, 0.300 mmol) and (7R,14R)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (179 mg, 0.300 mmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL) were added K2CO3(124 mg, 0.900 mmol) and Pd(dppf)Cl2(24 mg, 0.030 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 2-methyl-N-(3-(5- ((7R,14R)-6-(methyl-d3)-5-oxo-1-((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyridin-2-yl)oxetan-3-yl)propane- 2-sulfinamide (110 mg, 51%) as a brown solid. MS ESI calculated for C41H48D3N5O3SSi [M + H]+, 725.37 found 725.40. Preparation 42C: (7R,14R)-11-(6-(3-aminooxetan-3-yl)pyridin-3-yl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one To a stirred mixture of 2-methyl-N-(3-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)pyridin-2-yl)oxetan-3-yl)propane-2-sulfinamide (100 mg, 0.138 mmol) in THF (2 mL) and H2O (0.5 mL) was added I2(9 mg, 0.035 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The residue was basified to pH 10 with 10 mL saturated NaHCO3 (aq.). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (9:1) to afford (7R,14R)-11-(6-(3-aminooxetan-3-yl)pyridin-3-yl)-6- (methyl-d3)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (40 mg, 47%) as an off- white solid. MS ESI calculated for C37H40D3N5O2Si [M + H]+, 621.34 found 621.35.WSGR Ref: 53699-720.601 Example 42: (7R,14R)-11-(6-(3-aminooxetan-3-yl)pyridin-3-yl)-1-ethynyl-6-(methyl-d3)-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one To a stirred solution of (7R,14R)-11-(6-(3-aminooxetan-3-yl)pyridin-3-yl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (35 mg, 0.056 mmol) in THF (0.5 mL) was added TBAF (67.65 uL, 0.067 mmol, 1 M in THF) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (5 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30*150 mm, 5m; Mobile Phase A: water (10 mmol / L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% to 48% B in 10 min; Wave Length: 254nm / 220nm) to afford (7R,14R)- 11-(6-(3-aminooxetan-3-yl)pyridin-3-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (4 mg, 15%). MS ESIcalculated for C28H20D3N5O2 [M + H]+, 465.20 found 465.25. 1H NMR (400 MHz, DMSO-d6) δ8.89 (d, J = 2.4 Hz, 1H), 8.49 – 8.39 (m, 2H), 8.08 – 8.02 (m, 1H), 7.97 – 7.92 (m, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.83 – 7.79 (m, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 6.48 (d, J = 7.1 Hz, 1H), 5.25 (d, J = 7.1 Hz, 1H), 5.08 (s, 1H), 4.76 (t, J = 6.2 Hz, 2H), 4.73 – 4.67 (m, 2H), 3.62 – 3.51 (m, 1H), 2.87 (d, J = 13.7 Hz, 1H).

[0194] Example 43: (7R,14R)-11-(2-(1-aminocyclopentyl)pyrimidin-5-yl)-6-(methyl-d3)-1-(prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-onePreparation 43A: (7R,14R)-1-chloro-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-WSGR Ref: 53699-720.601 2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one To a stirred mixture of (7R,14R)-1-chloro-6-(methyl-d3)-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl trifluoromethanesulfonate (100 mg, 0.211 mmol) and BPD (80 mg, 0.317 mmol) in 1,4-dioxane (2.5 mL) were added Pd(dppf)Cl2.CH2Cl2 (34 mg, 0.042 mmol) and KOAc (62 mg, 0.633 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 1 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford (7R,14R)-1-chloro-6-(methyl-d3)- 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, 84%) as a yellow oil. MS ESI calculated for C24H22D3BClN3O3 [M + H]+, 453.19 found 453.15.1H NMR (400 MHz, Chloroform-d) δ 8.60 – 8.52 (m, 1H), 8.09 (s, 1H), 7.77 – 7.67 (m, 2H), 7.66 – 7.59 (m, 1H), 7.35 (t, J = 8.1 Hz, 1H), 6.45 (d, J = 6.8 Hz, 1H), 4.95 (d, J = 6.4 Hz, 1H), 3.51 – 3.38 (m, 1H), 2.87 (d, J = 13.3 Hz, 1H), 1.35 (s, 12H). Preparation 43B: N-(1-(5-((7R,14R)-1-chloro-6-(methyl-d3)-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)cyclopentyl)-2- methylpropane-2-sulfinamide To a stirred mixture of (7R,14R)-1-chloro-6-(methyl-d3)-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, 0.177 mmol) and N-[1-(5-bromopyrimidin-2-yl)cyclopentyl]-2- methylpropane-2-sulfinamide (122 mg, 0.354 mmol) in 1,4-dioxane (2.0 mL) and H2O (0.2 mL) were added Pd(dppf)Cl2·CH2Cl2(14 mg, 0.018 mmol) and K2CO3(73 mg, 0.531 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 12 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford N-(1-(5-((7R,14R)-1- chloro-6-(methyl-d3)-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)cyclopentyl)-2-methylpropane-2-sulfinamide (50 mg,48%) as a yellow solid. MS ESI calculated for C31H30D3ClN6O2S [M + H]+, 592.23 found592.35.1H NMR (400 MHz, Chloroform-d) δ 8.93 (s, 2H), 8.62 – 8.55 (m, 1H), 7.91 – 7.78 (m, 2H), 7.66 – 7.32 (m, 3H), 6.48 (d, J = 7.1 Hz, 1H), 4.97 (d, J = 7.0 Hz, 1H), 3.56 – 3.45 (m, 1H), 2.91 (d, J = 13.5 Hz, 1H), 2.70 – 2.55 (m, 1H), 2.55 – 2.44 (m, 1H), 2.31 – 2.16 (m, 1H), 2.21 – 2.07 (m, 1H), 1.98 – 1.76 (m, 4H), 1.24 (s, 9H). Preparation 43C: 2-methyl-N-(1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-(prop-1-yn-1-yl)-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2- yl)cyclopentyl)propane-2-sulfinamideWSGR Ref: 53699-720.601 To a stirred mixture of N-(1-(5-((7R,14R)-1-chloro-6-(methyl-d3)-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)cyclopentyl)- 2-methylpropane-2-sulfinamide (50 mg, 0.084 mmol) and trimethyl(prop-2-yn-1-yl)silane (19 mg, 0.168 mmol) in ACN (2 mL) were added SPhos (7 mg, 0.017 mmol), K2CO3 (58 mg, 0.420 mmol) and SPhos Pd Gen.3 (13 mg, 0.017 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 2-methyl-N-(1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-(prop- 1-yn-1-yl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11- yl)pyrimidin-2-yl)cyclopentyl)propane-2-sulfinamide (42 mg, 83%) as a yellow solid. MS ESI calculated for C34H33D3N6O2S [M + H]+, 596.28 found 596.30. Example 43: (7R,14R)-11-(2-(1-aminocyclopentyl)pyrimidin-5-yl)-6-(methyl-d3)-1-(prop-1-yn- 1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one To a stirred solution of 2-methyl-N-(1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-(prop-1-yn-1-yl)- 5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11- yl)pyrimidin-2-yl)cyclopentyl)propane-2-sulfinamide (42 mg, 0.070 mmol) in 1,4-dioxane (1 mL) was added HCl(gas) in 1,4-dioxane (1 mL, 4.00 mol / L) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by reverse phase flash with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: Water(10 mmol / L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 28% B to 41% B in 10 min; Wave Length: 254 nm; RT1(min): 10.26) to afford (7R,14R)-11-(2-(1-aminocyclopentyl)pyrimidin-5-yl)-6-(methyl-d3)-1-(prop-1- yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (8 mg, 23%). MS ESI calculated for C30H25D3N6O [M + H]+, 492.25 found 492.30.1H NMR (400 MHz, Methanol-d4) δ 8.97 (s, 2H), 8.47 – 8.40 (m, 1H), 8.05 (d, J = 1.7 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.70 – 7.64 (m, 1H), 7.59 – 7.52 (m, 1H), 7.35 (t, J = 7.9 Hz, 1H), 6.63 (d, J = 7.1 Hz, 1H), 5.20 (d, J = 7.1 Hz, 1H), 3.62 – 3.51 (m, 1H), 2.89 (d, J = 13.8 Hz, 1H), 2.46 – 2.33 (m, 2H), 2.32 (s, 3H), 2.04 – 1.81 (m, 6H).

[0195] Example 44 and 45: (7R,14R)-1-ethynyl-6-(methyl-d3)-11-(2-((R)-pyrrolidin-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 and (7R,14R)-1-ethynyl-6-(methyl-d3)-11-(2-((S)-pyrrolidin-2-yl)pyrimidin-5-yl)- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-oneWSGR Ref: 53699-720.601(7R,14R)-1-ethynyl-6-(methyl-d3)-11-(2-(pyrrolidin-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 (45 mg) was purified by SFC with the following conditions (Column: CHIRALPAK-IK, 3*25mm, 5μm; Mobile Phase A: CO2, Mobile Phase B: MeOH: DCM=1: 1(20 mM NH3); Flow rate: 90 mL / min; Gradient: isocratic 50% B; RT1(min): 6.28; RT2(min): 14.72.). The first peak afforded 12 mg (26%) as a white solid. MS ESI calculated for C28H21D3N6O [M + H]+, 464.22 found 464.25.1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 2H), 8.44 (d, J = 8.2 Hz, 1H), 8.01 (s, 1H), 7.79 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 8.4 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 6.47 (d, J = 7.0 Hz, 1H), 5.27 (d, J = 7.0 Hz, 1H), 5.13 (s, 1H), 4.41 (t, J = 7.3 Hz, 1H), 3.62 – 3.52 (m, 1H), 3.22 – 3.10 (m, 2H), 3.02 – 2.92 (m, 1H), 2.88 (d, J = 13.7 Hz, 1H), 2.32 – 2.20 (m, 1H), 1.97 – 1.68 (m, 3H). The second peak afforded 11 mg (24%). MS ESI calculated for C28H21D3N6O [M + H]+, 464.22 found 464.25.1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 2H), 8.44 (d, J = 8.2 Hz, 1H), 8.01 (s, 1H), 7.79 (d, J = 7.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 6.48 (d, J = 7.0 Hz, 1H), 5.27 (d, J = 7.1 Hz, 1H), 5.12 (s, 1H), 4.52 (t, J = 8.0 Hz, 1H), 3.64 – 3.50 (m, 1H), 3.27 – 3.14 (m, 2H), 3.11 – 2.99 (m, 1H), 2.89 (d, J = 13.7 Hz, 1H), 2.38 – 2.21 (m, 1H), 2.05 – 1.78 (m, 3H).

[0196] Example 46: (7R,14R)-11-(2-(4-hydroxytetrahydro-2H-pyran-4-yl)pyrimidin-5-yl)-6-(methyl-d3)-1-(prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-oneA mixture of (7R,14R)-1-chloro-11-(2-(4-hydroxytetrahydro-2H-pyran-4-yl)pyrimidin-5-yl)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- one (36 mg, 0.071 mmol), trimethyl(prop-2-yn-1-yl)silane (80 mg, 0.710 mmol), SPhos (6 mg, 0.014 mmol), SPhos Pd Gen.3 (11 mg, 0.014 mmol) and K2CO3 (49 mg, 0.355 mmol) in CH3CNWSGR Ref: 53699-720.601 (0.5 mL) was stirred at 80 °C for 16 h under nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) followed by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: Water (10 mmol / L NH4HCO3 + 0.1%NH3.H2O), Mobile Phase B: CH3CN; Flow rate: 60 mL / min; Gradient: 21% B to 36% B in 10 min; Wave Length: 254 nm; RT1(min): 16.62) to afford (7R,14R)-11-(2-(4-hydroxytetrahydro-2H-pyran-4-yl)pyrimidin-5-yl)-6- (methyl-d3)-1-(prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (12 mg, 33%). MS ESI calculated for C30H24D3N5O3 [M + H]+, 509.23 found 509.25.1H NMR (400 MHz, Methanol-d4) δ 9.04 (s, 2H), 8.50 – 8.39 (m, 1H), 8.08 (d, J = 1.8 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.72 – 7.66 (m, 1H), 7.63 – 7.57 (m, 1H), 7.37 (t, J = 8.0 Hz, 1H), 6.64 (d, J = 7.1 Hz, 1H), 5.21 (d, J = 7.2 Hz, 1H), 4.03 – 3.93 (m, 2H), 3.91 – 3.78 (m, 2H), 3.65 – 3.54 (m, 1H), 2.91 (d, J = 13.8 Hz, 1H), 2.51 – 2.38 (m, 2H), 2.33 (s, 3H), 1.79 – 1.69 (m, 2H).

[0197] Example 47 and 48: (7R,14R)-11-(2-((1s,3S)-1-amino-3-methoxycyclobutyl)pyrimidin-5-yl)-1-ethynyl-6-(methyl-d3)-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-((1r,3R)-1-amino-3- methoxycyclobutyl)pyrimidin-5-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-onePreparation 47A: N-(3-methoxy-1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-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)-2-methylpropane-2-sulfinamide To a stirred solution of (7R,14R)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-WSGR Ref: 53699-720.601 a][1,4]diazocin-5(14H)-one (90 mg, 0.150 mmol) and N-(1-(5-bromopyrimidin-2-yl)-3- methoxycyclobutyl)-2-methylpropane-2-sulfinamide (65 mg, 0.180 mmol) in 1,4-dioxane (3 mL) and H2O (0.6 mL) were added Pd(dppf)Cl2(11 mg, 0.015 mmol) and K2CO3(62 mg, 0.450 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford N-(3-methoxy-1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-((triisopropylsilyl)ethynyl)- 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)-2-methylpropane-2-sulfinamide (100 mg, 88%) as a brown oil. MS ESI calculated for C42H51D3N6O3SSi [M + H]+, 754.39 found 754.35. Preparation 47B: (7R,14R)-11-(2-(1-amino-3-methoxycyclobutyl)pyrimidin-5-yl)-6-(methyl- d3)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one To a stirred solution of N-(3-methoxy-1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-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)-2-methylpropane-2-sulfinamide (100 mg, 0.133 mmol) in 1,4-dioxane (1 mL) was added HCl (gas) in 1,4-dioxane (1 mL, 32.913 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched by the addition of Water (5 mL) at room temperature. The mixture was basified to pH 7 with saturated Na2CO3 (aq.). The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford (7R,14R)-11-(2-(1-amino-3- methoxycyclobutyl)pyrimidin-5-yl)-6-(methyl-d3)-1-((triisopropylsilyl)ethynyl)-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (60 mg, 69%) as abrown oil. MS ESI calculated for C38H43D3N6O2Si [M + H]+, 650.36, found 650.35.1H NMR(400 MHz, Chloroform-d) δ 8.85 (d, J = 4.1 Hz, 2H), 8.62 – 8.53 (m, 1H), 7.89 – 7.82 (m, 2H), 7.80 – 7.71 (m, 1H), 7.45 – 7.34 (m, 2H), 6.64 – 6.56 (m, 1H), 5.02 (d, J = 7.0 Hz, 1H), 4.17 – 4.07 (m, 1H), 3.54 – 3.44 (m, 3H), 3.33 (s, 3H), 3.10 – 3.01 (m, 1H), 2.94 (d, J = 13.6 Hz, 1H), 2.77 – 2.49 (m, 1H), 2.36 – 2.26 (m, 1H), 2.13 – 2.06 (m, 1H), 1.25 – 1.02 (m, 21H). Example 47 and 48: (7R,14R)-11-(2-((1s,3S)-1-amino-3-methoxycyclobutyl)pyrimidin-5-yl)-1- ethynyl-6-(methyl-d3)-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-((1r,3R)-1-amino-3- methoxycyclobutyl)pyrimidin-5-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-oneWSGR Ref: 53699-720.601 A mixture of (7R,14R)-11-(2-(1-amino-3-methoxycyclobutyl)pyrimidin-5-yl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (50 mg, 0.077 mmol) and CsF (116 mg, 0.770 mmol) in DMF (1 mL) was stirred at room temperature for 1 h. The resulting solution was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C1830*250 mm, 5m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 33% B to 47% B in 10 min; Wave Length: 254 nm; RT1(min): 10.51). The first peak afforded 3 mg (8%). MS ESI calculated for C29H23D3N6O2 [M + H]+, 494.23 found 494.20.1H NMR (400 MHz, Chloroform- d) δ 8.95 (s, 2H), 8.63 (d, J = 8.2 Hz, 1H), 7.95 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.48 – 7.35 (m, 2H), 6.50 (d, J = 7.2 Hz, 1H), 4.98 (d, J = 7.0 Hz, 1H), 4...

Claims

WSGR Ref: 53699-720.601 Claims We claim:

1. A compound of Formula (I), or pharmaceutically acceptable salt, solvate, N-oxide, ordeuteroisotope thereof:wherein, W is N or C-R10; X is N or C-R11; Y is N or C-R12; Z is N or C-R13; R is selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted heterocyclyl, optionally substituted C1-C6 alkoxy, - PO(R8)(R9), -S(O)(NH)R8, or -CH2-PO(R8)(R9); R1is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl; R2is hydrogen, optionally substituted C1 alkyl, or halogen; R3is hydrogen, or halogen; R4is hydrogen, optionally substituted C1 alkyl, or halogen; R5is independently selected from hydrogen, or optionally substituted C1-C6 alkyl; R6is hydrogen, or halogen; R7is hydrogen, or halogen; R8and R9are each independently selected from optionally substituted C1-C6 alkyl; or R8and R9join to form a phosphorous-containing heterocyclic ring; R10is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; R11is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; R12is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; and R13is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl.

2. A compound of Formula (Ia), or pharmaceutically acceptable salt, solvate, N-oxide, ordeuteroisotope thereof:WSGR Ref: 53699-720.601wherein, W is N or C-R10; X is N or C-R11; Y is N or C-R12; Z is N or C-R13; R is selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted heterocyclyl, optionally substituted C1-C6 alkoxy, or - PO(R8)(R9); R1is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl; R2is hydrogen, optionally substituted C1 alkyl, or halogen; R3is hydrogen, or halogen; R4is hydrogen, optionally substituted C1 alkyl, or halogen; R5is independently selected from hydrogen, or optionally substituted C1-C6 alkyl; R6is hydrogen, or halogen; R7is hydrogen, or halogen; R8and R9are each independently selected from optionally substituted C1-C6 alkyl; or R8and R9join to form a phosphorous-containing heterocyclic ring; R10is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; R11is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; R12is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; and R13is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl.

3. A compound of Formula (II), or pharmaceutically acceptable salt, solvate, N-oxide, ordeuteroisotope thereof:WSGR Ref: 53699-720.601wherein, Ring A is an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms selected from N, O or S; R is selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted heterocyclyl, optionally substituted C1-C6 alkoxy, - PO(R8)(R9), -S(O)(NH)R8, or -CH2-PO(R8)(R9); R1is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl; R2is hydrogen, optionally substituted C1 alkyl, or halogen; R3is hydrogen, or halogen; R4is hydrogen, optionally substituted C1 alkyl, or halogen; R5is independently selected from hydrogen, or optionally substituted C1-C6 alkyl; R6is hydrogen, or halogen; R7is hydrogen, or halogen; and R8and R9are each independently selected from optionally substituted C1-C6 alkyl; or R8and R9join to form a phosphorous-containing heterocyclic ring.

4. The compound of claim 3, or pharmaceutically acceptable salt, solvate, N-oxide, ordeuteroisotope thereof, wherein Ring A is selected from an optionally substituted imidazole, oxazole, thiazole, pyrazole, isoxazole, isothiazole, or triazole.

5. The compound of claim 1 or 2, or pharmaceutically acceptable salt, solvate, N-oxide, ordeuteroisotope thereof, wherein W is N.

6. The compound of claim 1, 2, or 3, or pharmaceutically acceptable salt, solvate, N-oxide,or deuteroisotope thereof, wherein X is N.

7. The compound of any one of claims 1-2, or 5-6, or pharmaceutically acceptable salt,solvate, N-oxide, or deuteroisotope thereof, wherein Y is N.

8. The compound of any one of claims 1-2, or 5-7, or pharmaceutically acceptable salt,solvate, N-oxide, or deuteroisotope thereof, wherein Z is N.

9. The compound of any one of claims 1, 2, or 6-8, or pharmaceutically acceptable salt,solvate, N-oxide, or deuteroisotope thereof, wherein W is C-R10.WSGR Ref: 53699-720.60110. The compound of any one of claims 1, 2, 5, or 7-9, or pharmaceutically acceptable salt,solvate, N-oxide, or deuteroisotope thereof, wherein X is C-R11.

11. The compound of any one of claims 1, 2, 5, 6, or 8-10, or pharmaceutically acceptablesalt, solvate, N-oxide, or deuteroisotope thereof, wherein Y is C-R12.

12. The compound of any one of claims 1, 2, 5-7, or 9-11, or pharmaceutically acceptablesalt, solvate, N-oxide, or deuteroisotope thereof, wherein Z is C-R13.

13. The compound of any one of claims 1, 2, or 5-12, or pharmaceutically acceptable salt,solvate, N-oxide, or deuteroisotope thereof, wherein each R10, R11, R12, and R13is independently selected from hydrogen or halogen.

14. The compound of claim 1 or 2, or pharmaceutically acceptable salt, solvate, N-oxide, ordeuteroisotope thereof, wherein W is N, Z is N, X is C-R11, and Y is C-R12.

15. The compound of any one of claims 1-14, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein R1is selected from hydrogen, or optionally substituted C1-C6 alkyl.

16. The compound of any one of claims 1-15, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein R1is CH3or CD3.

17. The compound of any one of claims 1-16, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein R2is hydrogen or halogen.

18. The compound of any one of claims 1-17, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein R3is hydrogen or halogen.

19. The compound of any one of claims 1-18, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein R4is hydrogen or halogen.

20. The compound of any one of claims 1-19, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein R5is hydrogen.

21. The compound of any one of claims 1-19, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein R5is optionally substituted C1-C6 alkyl.

22. The compound of any one of claims 1-19, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein R5is optionally substituted C1 alkyl.

23. The compound of any one of claims 1-19, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein R5is CH3.

24. The compound of any one of claims 1-23, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein R is optionally substituted C1-C6 alkyl.

25. The compound of any one of claims 1-23, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein R is optionally substituted C1-C3 alkyl.WSGR Ref: 53699-720.60126. The compound of claim 24 or 25, or pharmaceutically acceptable salt, solvate, N-oxide,or deuteroisotope thereof, wherein the optionally substituted alkyl is substituted with at least an - OH or -NH2group.

27. The compound of any one of claims 1-23, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein R is optionally substituted C3-C6 carbocyclyl.

28. The compound of any one of claims 1-23, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein R is optionally substituted C5 carbocyclyl.

29. The compound of any one of claims 1-23, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein R is optionally substituted C4 carbocyclyl.

30. The compound of any one of claims 27-29, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein the optionally substituted carbocyclyl is substituted with at least one group selected from -OH, -NH2, -CH3, -CN, or a halogen.

31. The compound of any one of claims 1-23, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein R is optionally substituted heterocyclyl.

32. The compound of any one of claims 1-23, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein R is optionally substituted 4- or 5-membered oxygen-containing heterocyclyl.

33. The compound of any one of claims 1-23, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein R is optionally substituted oxetanyl.

34. The compound of any one of claims 31-33, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein the optionally substituted heterocyclyl is substituted with at least one group selected from -OH, -NH2, -CH3, -CN, or a halogen.

35. The compound of claim 33, or pharmaceutically acceptable salt, solvate, N-oxide, ordeuteroisotope thereof, wherein R is 3-aminooxetan-3-yl.

36. The compound of any one of claims 1-23, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein R is optionally substituted C1-C6 alkoxy.

37. The compound of any one of claims 1-23, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein R is optionally substituted C1-C2 alkoxy.

38. The compound of any one of claims 36-37, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein the optionally substituted alkoxy is substituted with at least one halogen.

39. The compound of any one of claims 36-37, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein the optionally substituted alkoxy is substituted with at least one fluoro.WSGR Ref: 53699-720.60140. The compound of any one of claims 1-23, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein R is -PO(R8)(R9).

41. The compound of claim 40, or pharmaceutically acceptable salt, solvate, N-oxide, ordeuteroisotope thereof, wherein R8and R9are each independently selected from optionally substituted C1-C6 alkyl.

42. The compound of claim 40, or pharmaceutically acceptable salt, solvate, N-oxide, ordeuteroisotope thereof, wherein R8and R9are each independently selected from optionally substituted C1-C3 alkyl.

43. The compound of claim 40, or pharmaceutically acceptable salt, solvate, N-oxide, ordeuteroisotope thereof, wherein R8and R9are each CH3.

44. The compound of claim 40, or pharmaceutically acceptable salt, solvate, N-oxide, ordeuteroisotope thereof, wherein R8and R9join to form a phosphorous-containing heterocyclic ring.

45. A compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, ordeuteroisotope thereof:wherein, G is -CN, halogen, optionally substituted C1-C6 alkoxy, optionally substituted heteroarylalkoxy, optionally substituted C2-C6 alkynyl, (optionally substituted C2-C6 alkynylene)-NH-(optionally substituted C3-C6 cycloalkyl), or (optionally substituted C2-C6 alkynylene)-O-(optionally substituted C3-C6 cycloalkyl); R1is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl; R2is hydrogen, optionally substituted C1 alkyl, or halogen; R3is hydrogen, or halogen; R4is hydrogen, optionally substituted C1 alkyl, or halogen; R5is independently selected from hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted heterocyclyl; R6is hydrogen, or halogen; and R7is hydrogen, or halogen.WSGR Ref: 53699-720.60146. The compound of claim 45, or pharmaceutically acceptable salt, solvate, N-oxide, ordeuteroisotope thereof, wherein R1is selected from hydrogen, or optionally substituted C1-C6 alkyl.

47. The compound of claim 45, or pharmaceutically acceptable salt, solvate, N-oxide, ordeuteroisotope thereof, wherein R1is CH3 or CD3.

48. The compound of any one of claims 45-47, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein R2is hydrogen or halogen.

49. The compound of any one of claims 45-48, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein R3is hydrogen or halogen.

50. The compound of any one of claims 45-49, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein R4is hydrogen or halogen.

51. The compound of any one of claims 45-50, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein R5is hydrogen.

52. The compound of any one of claims 45-50, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein R5is optionally substituted C1-C6 alkyl.

53. The compound of any one of claims 45-50, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein R5is optionally substituted C1 alkyl.

54. The compound of any one of claims 45-50, or pharmaceutically acceptable salt, solvate,N-oxide, or deuteroisotope thereof, wherein R5is CH3.

55. A compound described in Table 1, or pharmaceutically acceptable salt, solvate, or N-oxide thereof.

56. A compound described in Table 2, or pharmaceutically acceptable salt, solvate, or N-oxide thereof.

57. A pharmaceutical composition comprising the compound, or pharmaceuticallyacceptable salt or solvate or N-oxide thereof, of any one of claims 1-56 and a pharmaceutically acceptable excipient or carrier.

58. A method of preparing a pharmaceutical composition comprising mixing the compound,or pharmaceutically acceptable salt or solvate or N-oxide thereof, of any one of claims 1-56, and a pharmaceutically acceptable excipient or carrier.

59. A compound, or pharmaceutically acceptable salt or solvate or N-oxide thereof, of anyone of claims 1-56, or the pharmaceutical composition of claim 57, for use in a method of treatment of the human or animal body.

60. A compound, or pharmaceutically acceptable salt or solvate or N-oxide thereof, of anyone of claims 1-56 or the pharmaceutical composition of claim 57, for use in a method of treatment of inflammatory or autoimmune disease or disorder.WSGR Ref: 53699-720.60161. Use of a compound, or pharmaceutically acceptable salt or solvate or N-oxide thereof, ofany one of claims 1-56 or the pharmaceutical composition of claim 57, in the manufacture of a medicament for the treatment of an inflammatory or autoimmune disease or disorder.

62. A pharmaceutical composition comprising the compound, or pharmaceuticallyacceptable salt or solvate or N-oxide thereof, of any one of claims 1-56, for use in an inflammatory or autoimmune disease or disorder in a patient in need thereof.

63. A method of treating an inflammatory or autoimmune disease or disorder in a patient inneed thereof, comprising administering to the patient a therapeutically effectively amount of the compound, or pharmaceutically acceptable salt or solvate or N-oxide thereof, of any one of claims 1-56, or the pharmaceutical composition of claim 57.

64. A method of inhibiting TNF-^ activity comprising contacting the TNF-^ protein withthe compound, or pharmaceutically acceptable salt or solvate or N-oxide thereof, of any one of claims 1-56, or the pharmaceutical composition of claim 57, wherein the TNF-^ protein is contacted in an in vitro setting.

65. A method of inhibiting TNF-^ activity comprising contacting the TNF-^ protein withthe compound, or pharmaceutically acceptable salt or solvate or N-oxide thereof, of any one of claims 1-56, or the pharmaceutical composition of claim 57, wherein the TNF-^ protein is contacted in an in vivo setting.

66. A method of treating or preventing a condition conducive to treatment or prevention byinhibition of TNF-^ in a patient comprising administering to the patient a therapeutically effective amount of the compound, or pharmaceutically acceptable salt or solvate or N-oxide thereof, of any one of claims 1-56, or the pharmaceutical composition of claim 57.

67. A pharmaceutical composition comprising the compound, or pharmaceuticallyacceptable salt or solvate or N-oxide thereof, of any one of claims 1-56, for use in treating or preventing a condition conducive to treatment or prevention by inhibition of TNF-^ in a patient.

68. The compound, or pharmaceutically acceptable salt or solvate or N-oxide thereof, of anyone of claims 1-56 or the pharmaceutical composition of claim 57, for use in treating or preventing a condition conducive to treatment or prevention by inhibition of TNF-^ in a patient.

69. Use of the compound, or pharmaceutically acceptable salt or solvate or N-oxide thereof,of any one of claims 1-56, or the pharmaceutical composition of claim 57, in the preparation of a medicament for treating or preventing a condition conducive to treatment or prevention by inhibition of TNF-^ in a patient.

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