Modulators of TNF-alpha activity

Abstract

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

Description

MODULATORS OF TNF-ALPHA ACTIVITYCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Patent Application No.63 / 739,439 filed on December 27, 2024, U.S. Provisional Patent Application No. 63 / 686,540 filed on August 23, 2024, and U.S. Provisional Patent Application No. 63 / 649,845 filed on May 20, 2024, each of which is incorporated by reference in its entirety.BACKGROUND

[0002] Tumor necrosis factor alpha (TNFa) is an inflammatory cytokine that is responsible for a wide range of signaling events within cells. Aberrant TNFa 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 TNFa, pharmaceutical compositions comprising said inhibitory 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 acceptable salt, solvate, deuteroisotope, or N-oxi de thereofwherein,B is C-R15or N;R15is H, D, -OH, -NH2, or optionally substituted C1-C6 alkyl;W-XRing A is selected fromZ-Y, wherein the * denotes point of attachment to phosphorous, or an optionally substituted heteroarylene selected from pyrazolene, imidazoline, oxazolene, or thiazolene;W is N or C-R11;X is N or C-R12;Y is N or C-R13;Z is N or C-R14;R2is selected from H, D, Cl, F, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl;R3, and R4are selected from H, D, Cl, or F;R5is selected from H, -OH, -CN, -©(optionally substituted C1-C6 alkyl), - □(optionally substituted C3-C6 cycloalkyl), optionally substituted C2-C6 alkynyl, or halogen;R6is selected from H, D, halogen, or optionally substituted C1-C6 alkyl;R7is selected from H, D, or halogen;R8is selected from H, D, or halogen;R9and R10are independently optionally substituted C1-C6 alkyl; or R9and R10join to form optionally substituted phosphorus-containing 3- to 8-membered ring; and R11, R12, R13, and R14are independently selected from H, D, halogen, -CN, -NH2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, or - NH(optionally substituted C1-C3 alkyl).

[0005] One embodiment provides a compound of Formula (II), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxi de thereof:wherein,Q-T is selected from -CO-N=, -O-CH=, -O-N=, -S-CH=, or -S-N=;* w-xH?='HRing A is selected fromz Y, wherein the * denotes point of attachment to phosphorous, or an optionally substituted heteroarylene selected from pyrazolene, imidazoline, oxazolene, or thiazolene;W is N or C-R11;X is N or C-R12;Y is N or C-R13;Z is N or C-R14;R2is selected from H, D, Cl, F, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl;R3, and R4are selected from H, D, Cl, or F;R5is selected from H, -OH, -©(optionally substituted C1-C6 alkyl), -©(optionally substituted C3-C6 cycloalkyl), optionally substituted C2-C6 alkynyl, or halogen;R6is selected from H, D, halogen, or optionally substituted C1-C6 alkyl;R7is selected from H, D, or halogen;R8is selected from H, D, or halogen;R9and R10are independently optionally substituted C1-C6 alkyl; or R9and R10join to form optionally substituted phosphorus-containing 3- to 8-membered ring; and R11, R12, R13, and R14are independently selected from H, D, halogen, -CN, -NH2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, or -NH(optionally substituted C1-C3 alkyl).

[0006] One embodiment provides a compound of Formula (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxi de thereof:wherein,U-V is selected from =N-NR16-, =N-O-, =N-S-, =CH-NR16-, =CH-O-, =CH-S-;R16is H or optionally substituted C1-C6 alkyl;W-XRing A is selected from, wherein the * denotes point of attachment to phosphorous, or an optionally substituted heteroarylene selected from pyrazolene, imidazoline, oxazolene, or thiazolene;W is N or C-R11;X is N or C-R12;Y is N or C-R13;Z is N or C-R14;R2is selected from H, D, Cl, F, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl;R3, and R4are selected from H, D, Cl, or F;R5is selected from H, -OH, -©(optionally substituted C1-C6 alkyl), -©(optionally substituted C3-C6 cycloalkyl), optionally substituted C2-C6 alkynyl, or halogen; R6is selected from H, D, halogen, or optionally substituted C1-C6 alkyl;R7is selected from H, D, or halogen;R8is selected from H, D, or halogen;R9and R10are independently optionally substituted C1-C6 alkyl; or R9and R10join to form optionally substituted phosphorus-containing 3- to 8-membered ring; and R11, R12, R13, and R14are independently selected from H, D, halogen, -CN, -NH2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, or - NH(optionally substituted C1-C3 alkyl).

[0007] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N- oxide thereof, and at least one pharmaceutically acceptable excipient.

[0008] One embodiment provides a method of treating a disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof. Another embodiment provides the method wherein the disease or disorder is rheumatoid arthritis.INCORPORATION BY REFERENCE

[0009] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein.DETAILED DESCRIPTION OF THE INVENTION

[0010] 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" includes 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 intendedto 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

[0011] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0012] " Amino" refers to the -NH2 radical.

[0013] "Cyano" refers to the -CN radical.

[0014] "Nitro" refers to the -NO2 radical.

[0015] " Oxa" refers to the -O- radical.

[0016] " Oxo" refers to the =0 radical.

[0017] " Thioxo" refers to the =S radical.

[0018] " Imino" refers to the =N-H radical.

[0019] " Oximo" refers to the =N-0H radical.

[0020] "Hydrazino" refers to the =N-NH2 radical.

[0021] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon 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., Ci-Cs alkyl). 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., Ci- 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-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., Ci alkyl). 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., Cs-Cs alkyl). In other embodiments, an alkyl 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-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl ( / / -propyl), 1 -methylethyl ( / .w-propyl), 1 -butyl ( / / -butyl), 1 -methylpropyl (sec-butyl), 2-m ethylpropyl ( / .w-butyl), 1,1 -dimethylethyl (tert-butyl), 1 -pentyl ( / / -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, trimethyl silanyl, -ORa, -SIU, -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 -CF3 group.

[0022] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0023] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely 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 (z.e., vinyl), prop-l-enyl (z.e., allyl), but-l-enyl, pent-l-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, trimethyl silanyl, -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, ortrifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0024] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely 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, -SIU, -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 trifluorom ethyl).

[0025] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, ^-butylene, and the like. The alkylene chain is 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., Ci-C8alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). 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-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., Cs-Cs 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-C5 alkylene). 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, -SIU, -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] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain 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-C8 alkenylene). 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 other 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., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms e.g., Cs-Cs alkenylene). 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).

[0027] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain 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-C5 alkynylene). 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., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., Cs-Cs 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), -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, ortrifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0028] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon 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, z.e., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Huckel 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 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.

[0029] "Aralkyl" refers to a radical of the formula -Rc-aryl where 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.

[0030] "Aralkenyl" refers to a radical of the formula -Rd-aryl where Rdis an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described abovefor an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0031] "Aralkynyl" refers to a radical of the formula -Re-aryl, where Reis an alkynylene chain as 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.

[0032] "Aralkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc-aryl where 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.

[0033] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes 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 (z.e., containing single C-C bonds only) or unsaturated (z.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, norbomyl (z.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, oxo, thioxo, cyano, nitro, -Rb-0Ra, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-0C(0)-N(Ra)2, -Rb- N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)0Ra, -Rb-N(Ra)C(0)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, ortrifluoromethyl), 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.

[0034] "Carbocyclylalkyl" refers to a radical of the formula -Rc-carbocyclyl where Rcis an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0035] "Carbocyclylalkynyl" refers to a radical of the formula -Rc-carbocyclyl where Rcis an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0036] "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.

[0037] " Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.

[0038] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-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.

[0039] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical that comprises 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 includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. 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 not limited to, dioxolanyl, thienyl[l,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.

[0040] 'W-heterocyclyl" or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above 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 / f-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such A-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1- piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, and imidazolidinyl.

[0041] " C-heterocyclyl" or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined above 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.

[0042] "Heterocyclylalkyl" refers to a radical of the formula -Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, theheterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclyl alkyl 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.

[0043] "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.

[0044] "Heteroaryl" refers to a radical derived from a 3 - to 18-membered aromatic ring radical that 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, z.e., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Hiickel 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 quatemized. 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[Z>][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotri azolyl, benzo[4,6]imidazo[l,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[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, 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-naphthyri dinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1 -phenyl- UT-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.

[0045] "A-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen 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 A-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0046] " C-heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment 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.

[0047] "Heteroarylalkyl" refers to a radical of the formula -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 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.

[0048] "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 heteroaryl alkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0049] The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (5)-. 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 Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and 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 double bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0050] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another 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 several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0051] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,nC,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.

[0052] Unless otherwise stated, structures depicted herein are intended to include compounds which 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.

[0053] The compounds of the present disclosure optionally contain unnatural proportions of atomic 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,nC,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35C1,37C1,79Br,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.

[0054] In certain embodiments, the compounds disclosed herein have some or all of theJH atoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0055] Deuterium substituted compounds are synthesized using various methods such as described 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.

[0056] Deuterated starting materials are readily available and are subjected to the synthetic methods 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.

[0057] Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-ds (CD3I), are readily available and may be employed to transfer a deuteriumsubstituted 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.

[0058] Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAlD4), are employed 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.

[0059] Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.

[0060] In one embodiment, the compounds disclosed herein contain one deuterium atom. In another 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-exchangeableJH 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.

[0061] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the TNFa inhibitory compounds described herein 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.

[0062] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological 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, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenyl acetates, 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 bycontacting 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.

[0063] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological 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, isopropyl amine, 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, A-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0064] "Pharmaceutically acceptable solvate" refers to a composition of matter that is the solvent 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.

[0065] 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.

[0066] As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably. 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 isobserved 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 (TNFa) Protein and Function

[0067] Tumor necrosis factor alpha (TNFa) 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 (TNFP), lymphotoxin beta (TNFy), 0X40 ligand, CD40 ligand, Fas ligand, CD27 ligand, CD30 ligand, CD137 ligand, CD137 ligand, and TNF-related apoptosis-inducing ligand. TNFa proteins are cytokines and adipokines (cytokines secreted by adipose tissue).

[0068] TNFa is a transmembrane protein, with soluble TNFa (sTNFa) released via protein cleavage. The sTNFa can propagate signaling by binding to two receptors, TNFR1 and TNFR2. TNFa 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. sTNFa - TNFR1 signaling promotes immune cell activation and drives acute and chronic inflammation. Membrane TNFa - TNFR2 signaling promotes inflammation resolution, immune cell regulatory functions and cell survival.

[0069] The extracellular region of both TNFR1 and TNFR2 have four homologous cysteine-rich domains, 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-KB and MAPK signaling, and cell death, and is important to regulate 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 inflammation, while TNFR2 typically mediates local homeostatic effects such as tissue regeneration and cell survival (D. Fresegna et al., Cells, 2020, 9, 2290).

[0070] Binding of TNFa to TNFR1 can activate NF-KB for mediating transcription of various proteins involved in cell survival and proliferation, anti-apoptotic factors, and inflammatory response. Further, the MAPK pathway can also be activated by binding of TNFa to TNFR1, which is involved in cell differentiation and proliferation. When TNFa binds to TNFR1, it triggers receptor trimerization, leading to the assembly of a TNFR1 -associated signalingcomplex. This complex recruits the receptor interacting protein 1 (RIP1) 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-IAPl, C-IAP2). c-IAPl / 2 are important for TNFR1 complex signaling, which can eventually lead to the recruitment of the signaling kinase complexes of kinase IKKa and IKKP, which are inhibitors of kappa B kinase 1 and 2, and transforming growth factor betaactivated kinase 1 (TAK1) leading to activation of NF-KB and MAPK signaling. Activation of these signaling pathways can result in gene activation and expression of pro-inflammatory cytokines and pro-survival proteins.

[0071] TNF signaling is regulated by post-translational ubiquitination, which is essential for my biological 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 RIP 1, which is formed as part of the TNFR1 -associated signaling complex from TNFa binding.

[0072] TNF has long been known to be a key regulator of the inflammatory response, and recently has been known to be involved in 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.

[0073] In normal adult brains, TNF is expressed at low levels, and it is believed that the expression 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.

[0074] TNF is recognized to be physiological gliotransmitter for the communication between neurons 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

[0075] Diseases treated with biologic TNFa inhibitors include, but are not limited to rheumatoid arthritis, inflammatory bowel disease, psoriatic arthritis, psoriasis, and ankylosing spondylitis. Patients with neuroinflammatory conditions and degenerative disease, including, but not limitedto Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, treatment resistant depression, and tinnitus, may benefit from treatment with oral CNS sTNFa inhibitors by disrupting the sTNFa signaling and sparing the mTNFa signaling. Previous reports have also indicated targeting TNFR2 for treating Alzheimer’s Disease (N. Orti-Casan et al., Front Neurosci. 2019; 13: 49).

[0076] Small molecules have been developed for treatment of rheumatoid arthritis as some patients have responded poorly to monotherapy of approved anti-TNFa drugs (J. D. Dietrich et al., J. Med. Chem. 2021, 64, 417-429). Anti-TNFa 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- TNFa biologies since the long-term clinical response rate is generally around 60-70% for rheumatoid arthritis.

[0077] Previous research has also indicated that TNFa inhibitors can be therapeutic for treatment 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. TNFa inhibitors have the potential for treatment of multiple sclerosis, other potential chronic neurodegenerative diseases of the central nervous system.

[0078] More than 50 million Americans struggle with tinnitus, which is the hearing of a sound with no external source. It has been shown that TNFa 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 TNFa have activities for treating tinnitus.

[0079] Recent reports also indicate that TNFa inhibitors can be used alone or in combination for treatment with inflammatory bowel disease (S. F. Fowler Braga and K. J. Clark, US Pharm. 2021; 46(5):34-37). TNFa is a mediator of the abnormal immune response of inflammatory 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.

[0080] Small molecule sTNFa inhibitors are active in pharmacology models of sTNFa / TNFR1 signaling 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 a inhibitors. Some TNFa inhibitors include, but are not limited to XProl595, Etanercept, Infliximab, Adalimumab, Certolizumab pegol, Golimumamb, and other inhibitors described in “TNF-a: The Shape ofSmall Molecules to Come?” (A. Dbmling and X. Li, Drug Discov Today 2022 Jan; 27(l):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 TNFa include, but are not limited to the inhibitors described in “Biologiclike In Vivo Efficacy with Small Molecule Inhibitors of TNFa 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 TNFa via Fragment- Based Drug Design” (J. D. Dietrich et al., J. Med. Chem. 2021, 64, 417-429), and “Small- Molecule Inhibition of TNF-a” (M.M. He et al., Science, 310 (2015), 1022-1025).

[0081] Small molecule sTNFa inhibitors have potential as a valuable therapy for patients currently treated with biologic TNFa inhibitors which affect mTNFa with the ability to fine tune oral dosing requirements and avoid anti-drug antibody responses, thereby improving short and long responses (A. Dbmling and X. Li, Drug Discov Today 2022 Jan; 27(l):3-7).Novel Compounds Inhibiting TNFa

[0082] In one aspect, provided herein are TNFa inhibitory compounds.

[0083] One embodiment provides a compound of Formula (I), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxi de thereof:wherein,B is C-R15or N;R15is H, D, -OH, -NH2, or optionally substituted C1-C6 alkyl;* W-X = HRing A is selected fromz Y, wherein the * denotes point of attachment to phosphorous, or an optionally substituted heteroarylene selected from pyrazolene, imidazoline, oxazolene, or thiazolene;W is N or C-R11;X is N or C-R12;Y is N or C-R13;Z is N or C-R14;R2is selected from H, D, Cl, F, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl;R3, and R4are selected from H, D, Cl, or F;R5is selected from H, -OH, -©(optionally substituted C1-C6 alkyl), -©(optionally substituted C3-C6 cycloalkyl), optionally substituted C2-C6 alkynyl, or halogen; R6is selected from H, D, halogen, or optionally substituted C1-C6 alkyl;R7is selected from H, D, or halogen;R8is selected from H, D, or halogen;R9and R10are independently optionally substituted C1-C6 alkyl; or R9and R10join to form optionally substituted phosphorus-containing 3- to 8-membered ring; and R11, R12, R13, and R14are independently selected from H, D, halogen, -CN, -NH2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, or - NH(optionally substituted C1-C3 alkyl).

[0084] One embodiment provides a compound of Formula (I), having the structure of Formula (la), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof:wherein,B is C-R15or N;R15is H, D, -OH, -NH2, or optionally substituted C1-C6 alkyl;W-X7 — YRing A is selected from , wherein the * denotes point of attachment to phosphorous, or an optionally substituted heteroarylene selected from pyrazolene, imidazoline, oxazolene, or thiazolene;W is N or C-R11;X is N or C-R12;Y is N or C-R13;Z is N or C-R14;R2is selected from H, D, Cl, F, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl;R3, and R4are selected from H, D, Cl, or F;R5is selected from H, -OH, -©(optionally substituted C1-C6 alkyl), -©(optionally substituted C3-C6 cycloalkyl), optionally substituted C2-C6 alkynyl, or halogen; R6is selected from H, D, halogen, or optionally substituted C1-C6 alkyl;R7is selected from H, D, or halogen;R8is selected from H, D, or halogen;R9and R10are independently optionally substituted C1-C6 alkyl; or R9and R10join to form optionally substituted phosphorus-containing 3- to 8-membered ring; and R11, R12, R13, and R14are independently selected from H, D, halogen, -CN, -NH2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, or - NH(optionally substituted C1-C3 alkyl).

[0085] Another embodiment provides the compound of Formula (I) or (la), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein B is C-R15. Another embodiment provides the compound of Formula (I) or (la), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R15is optionally substituted C1-C6 alkyl. Another embodiment provides the compound of Formula (I) or (la), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R15is optionally substituted Cl alkyl. Another embodiment provides the compound of Formula (I) or (la), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R15is H or D.

[0086] Another embodiment provides the compound of Formula (I) or (la), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein B is N.

[0087] One embodiment provides a compound of Formula (II), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof:wherein,Q-T is selected from -CO-N=, -O-CH=, -O-N=, -S-CH=, or -S-N=;Ring A is selected from, wherein the * denotes point of attachment to phosphorous, or an optionally substituted heteroarylene selected from pyrazolene, imidazoline, oxazolene, or thiazolene;W is N or C-R11;X is N or C-R12;Y is N or C-R13;Z is N or C-R14;R2is selected from H, D, Cl, F, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl;R3, and R4are selected from H, D, Cl, or F;R5is selected from H, -OH, -©(optionally substituted C1-C6 alkyl), -©(optionally substituted C3-C6 cycloalkyl), optionally substituted C2-C6 alkynyl, or halogen;R6is selected from H, D, halogen, or optionally substituted C1-C6 alkyl;R7is selected from H, D, or halogen;R8is selected from H, D, or halogen;R9and R10are independently optionally substituted C1-C6 alkyl; or R9and R10join to form optionally substituted phosphorus-containing 3- to 8-membered ring; and R11, R12, R13, and R14are independently selected from H, D, halogen, -CN, -NH2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, or - NH(optionally substituted C1-C3 alkyl).

[0088] Another embodiment provides the compound of Formula (II), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein Q-T is selected from -CO- N=.

[0089] Another embodiment provides the compound of Formula (II), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein Q-T is selected from -O- CH=, or -S-CH=

[0090] Another embodiment provides the compound of Formula (II), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein Q-T is selected from -O- N=, or -S-N=.

[0091] One embodiment provides a compound of Formula (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof:wherein,U-V is selected from =N-NR16-, =N-O-, =N-S-, =CH-NR16-, =CH-O-, =CH-S-;R16is H or optionally substituted C1-C6 alkyl;Ring A is selected from, wherein the * denotes point of attachment to phosphorous, or an optionally substituted heteroarylene selected from pyrazolene, imidazoline, oxazolene, or thiazolene;W is N or C-R11;X is N or C-R12;Y is N or C-R13;Z is N or C-R14;R2is selected from H, D, Cl, F, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl;R3, and R4are selected from H, D, Cl, or F;R5is selected from H, -OH, -©(optionally substituted C1-C6 alkyl), -©(optionally substituted C3-C6 cycloalkyl), optionally substituted C2-C6 alkynyl, or halogen;R6is selected from H, D, halogen, or optionally substituted C1-C6 alkyl;R7is selected from H, D, or halogen;R8is selected from H, D, or halogen;R9and R10are independently optionally substituted C1-C6 alkyl; or R9and R10join to form optionally substituted phosphorus-containing 3- to 8-membered ring; and R11, R12, R13, and R14are independently selected from H, D, halogen, -CN, -NH2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, or - NH(optionally substituted C1-C3 alkyl).

[0092] Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein U-V is selected from =N- NR16-.

[0093] Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein U-V is selected from =CH- NR16-.

[0094] Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein U-V is selected from =N-O- , or =N-S-.

[0095] Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein U-V is selected from =CH- O-, or =CH-S-.

[0096] Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein ring A is* W-X selected from, wherein the * denotes point of attachment to phosphorous.

[0097] Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein W is N.

[0098] Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein X is N.

[0099] Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein Y is N.

[0100] Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein Z is N.

[0101] Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein W is C- R11.

[0102] Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein X is C- R12.

[0103] Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein Y is C- R13.

[0104] Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein Z is C- R14.

[0105] Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein each R11, R12, R13, and R14is independently selected from H, D, or halogen.

[0106] Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R9and R10are each independently methyl, ethyl, n-propyl, iso-propyl, n-butyl, or iso-butyl. Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R9and R10are each methyl. Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R9and R10are each ethyl. Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R9and R10join to form an optionally substituted phosphorus-containing 3- to 8-membered heterocyclyl. Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R9and R10join to form an optionally substituted phosphorus-containing 4- to 6-membered heterocyclyl. Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R9and R10join to form optionally substituted phosphorus-containing 4-membered heterocyclyl.Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R9and R10join to form an optionally substituted phosphorus-containing 5-membered heterocyclyl. Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R9and R10join to form optionally substituted phosphorus-containing 6-membered heterocyclyl. Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R9and R10taken together with the phosphorus atom to which they are attached join to form a ring selected from:provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R9and R10taken together with thephosphorus atom to which they are attached to join to form a ring selected from:

[0107] Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R6is H or D. Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R6is halogen.

[0108] Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R7is H or D. Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R7is halogen.

[0109] Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein ring A is an optionally substituted heteroarylene.

[0110] Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R8is H or D. Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R8is F. Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R8is Cl. [OHl] Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R5is F. Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R5is Cl. Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R5is optionally substituted C2-C6 alkynyl. Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R5is -C=CH or -C=CCH3. Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R5is -©(optionally substituted C1-C6 alkyl). Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R5is -OCHF2.

[0112] Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R2, R3, and R4are H or D.

[0113] Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R2is methyl, and R5is Cl or F.

[0114] Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R4is Cl or F.

[0115] Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R4is Cl or F, and R5is Cl or F.

[0116] Another embodiment provides the compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R2and R3are H or D.

[0117] One embodiment provides a TNFa inhibitory compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, having a structure presented in Table 1.Table 1

[0118] Another embodiment provides a TNFa inhibitory compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, having a structure presented in Table 2.Table 2Preparation of Compounds

[0119] The compounds used in the synthetic chemistry reactions described herein are made according 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 Company (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).

[0120] 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, "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.

[0121] Specific and analogous reactants are optionally identified through the indices of known chemicals 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 databases (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 and selection 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

[0122] In certain embodiments, the TNFa inhibitory compound described herein is administered as a pure chemical. In other embodiments, the TNFa 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)).

[0123] Provided herein is a pharmaceutical composition comprising at least one TNFa inhibitory compound as described herein, or pharmaceutically acceptable salt, solvate, deuteroisotope, 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.

[0124] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof.

[0125] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, and a pharmaceutically acceptable carrier.

[0126] In certain embodiments, the TNFa inhibitory compound as described by Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide 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.

[0127] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 1 or Table 2, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof.

[0128] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Table 1 or Table 2, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, and a pharmaceutically acceptable carrier.

[0129] In certain embodiments, the TNFa inhibitory compound as described by Table 1 or Table 2, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide 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.

[0130] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard 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)).

[0131] In some embodiments, the TNFa inhibitory compound as described by Formula (I), (la), (II), or (III), or Table 1 or Table 2, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide 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 nonaqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like.

[0132] The dose of the composition comprising at least one TNFa inhibitory compound as described 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.

[0133] Pharmaceutical compositions are administered in a manner appropriate to the disease to be 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 are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0134] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.Methods of Treatment

[0135] One embodiment provides a compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, for use in a method of treatment of the human or animal body.

[0136] One embodiment provides a compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, for use in a method of treatment of inflammatory or autoimmune disease or disorder. Another embodiment provides a compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, for use in a method of treatment of inflammatory disease or disorder. Yet another embodiment provides a compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, for use in a method of treatment of autoimmune disease or disorder.

[0137] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N- oxide thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of inflammatory or autoimmune disease or disorder.

[0138] One embodiment provides a use of a compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, in the manufacture of a medicament for the treatment of inflammatory or autoimmune disease or disorder.

[0139] 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 compound of Formula (I), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, 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), (la), (II), or (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide 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.

[0140] One embodiment provides a compound of Table 1 or Table 2, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, for use in a method of treatment of the human or animal body.

[0141] One embodiment provides a compound of Table 1 or Table 2, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, for use in a method of treatment of inflammatory or autoimmune disease or disorder.

[0142] One embodiment provides a pharmaceutical composition comprising a compound of Table 1 or Table 2, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide 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 Table 1 or Table 2, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide 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 autoimmune disease or disorder in a patient in need thereof, comprising administering to the patient a compound of Table 1 or Table 2, or pharmaceutically acceptable salt, solvate, deuteroisotope, 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, deuteroisotope, or N-oxide thereof, and a pharmaceutically acceptable excipient.

[0145] In some embodiments the inflammatory and autoimmune disease or disorder is selected from, 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 obstructivepulmonary 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.

[0146] Provided herein is the method wherein the pharmaceutical composition is administered orally. Provided herein is the method wherein the pharmaceutical composition is administered by injection.

[0147] One embodiment provides a method of inhibiting TNFa activity comprising contacting the TNFa protein with a compound of Formula (I), (la), (II), or (III), or Table 1 or Table 2. Another embodiment provides the method of inhibiting TNFa activity, wherein the TNFa protein is contacted in an in vivo setting. Another embodiment provides the method of inhibiting TNFa activity, wherein the TNFa protein is contacted in an in vitro setting.

[0148] Other embodiments and uses will be apparent to one skilled in the art considering the present disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way.EXAMPLESI. Chemical Synthesis

[0149] In some embodiments, the TNFa inhibitory compounds disclosed herein are synthesized 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 acetonitrile°C degrees Celsius5H chemical shift in parts per million downfield from tetramethylsilaneDCM di chloromethane (CH2Q2)DIAD diisopropyl azodicarboxylateDIEA diisopropylethylamineDMF dimethylformamideDMSO dimethylsulfoxideEA ethyl acetateEtOAc ethyl acetateESI electrospray ionizationEt ethylg gram(s) h hour(s)HPLC high performance liquid chromatographyHz hertzJ coupling constant (in NMR spectrometry)LCMS liquid chromatography mass spectrometry n micro m multiplet (spectral); meter(s); milliM molarM+parent molecular ionMe methylMsCl methanesulfonyl chlorideMHz megahertz min minute(s) mol mole(s); molecular (as in mol wt) mL milliliterMS 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 etherRT room temperature s singlet (spectral) t triplet (spectral)SFC Supercritical fluid chromatographyT temperatureTFA trifluoroacetic acidTHF tetrahydrofuranTPP Triphenylphosphine

[0150] Example 1 : (4-((8R,15R)-7-(difluoromethoxy)-8H,15H-8,15- methanobenzo[f]benzo[4, 5]imidazo[ 1 ,2-a]imidazo[ 1 ,2-d] [ 1 ,4]diazocin- 11 -yl)-2- fhrorophenyl)dimethylphosphine oxidePreparation 1 A: (7R,14R)-l l-chloro-l-(difluoromethoxy)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocine-5(14H)-thioneTo a stirred mixture of (7R,14R)-1 l-chloro-l-(difluoromethoxy)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one (500 mg, 1.331 mmol) in Toluene (10 mL) was added Lawesson's reagent (700 mg, 1.730 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 4 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CthCb / MeOH (20: 1) to afford (7R,14R)-l l-chloro-l- (difhioromethoxy)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocine- 5(14H)-thione (300 mg, 57%) as a yellow solid. MS ESI calculated for C18H12CIF2N3OS [M + H]+, 392.04 found 392.10. *HNMR (400 MHz, Chloroforms / ) 5 9.96 (s, 1H), 9.17 - 9.08 (m, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.51 (s, 1H), 7.43 - 7.35 (m, 2H), 7.25 - 7.23 (m, 1H), 6.84 (t, J = 72.5 Hz, 1H), 6.39 (d, J = 6.6 Hz, 1H), 5.27 - 5.18 (m, 1H), 3.54 - 3.37 (m, 1H), 2.94 (d, J = 13.3 Hz, 1H).Preparation IB: (7R,14R)-1 l-chloro-l-(difhioromethoxy)-5-(methylthio)-7,14-dihydro-7,14- methanobenzo[f]benzo[4, 5]imidazo[ 1 ,2-a] [ 1 , 4] di azocineTo a stirred solution of (7R,14R)-1 l-chloro-l-(difluoromethoxy)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocine-5(14H)-thione (300 mg, 0.766 mmol) in DCM (5 mL) was added Trimethyloxonium tetrafluoroborate (218 mg, 1.149 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with C LCh / MeOH (20: 1) to afford (7R,14R)-l l-chloro-l- (difluoromethoxy)-5-(methylthio)-7,14-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2- a][l,4]diazocine (230 mg, 74%) as a light yellow solid. MS ESI calculated for C19H14CIF2N3OS [M + H]+, 406.05 found 406.10. 'H NMR (400 MHz, Chloroforms / ) 5 8.24 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.44 - 7.36 (m, 2H), 7.32 (d, J = 8.2 Hz, 1H), 7.18 - 7.13 (m, 1H), 6.82(t, J = 72.6 Hz, 1H), 6.19 (d, J = 7.1 Hz, 1H), 5.85 (d, J = 5.1 Hz, 1H), 3.37 - 3.28 (m, 1H), 2.69 (d, J = 13.1 Hz, 1H), 2.35 (s, 3H).Preparation 1C: (7R,14R)-11 -chi oro-N-(2,2-di ethoxy ethyl)- l-(difluorom ethoxy)-7,l 4-dihydro- 7, 14-methanobenzo[f]benzo[4, 5]imidazo[ 1 ,2-a] [ 1 ,4]diazocin-5-amineA solution of ((7R,14R)-1 l-chloro-l-(difluoromethoxy)-5-(methylthio)-7,14-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocine (230 mg, 0.548 mmol) and 2,2- di ethoxy ethan-1 -amine (365 mg, 2.740 mmol) in 1-butanol (5 mL) was stirred at 100 °C for 16 h. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with C LCh / MeOH (10: 1) to afford (7R,14R)-l l-chloro-N-(2,2- di ethoxy ethyl)- l-(difluoromethoxy)-7,14-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l, 2- a][l,4]diazocin-5-amine (180 mg, 67%) as a white solid. MS ESI calculated for C24H25CIF2N4O3 [M + H]+, 491.16 found 491.15.Preparation ID: (8R,15R)-1 l-chloro-7-(difhioromethoxy)-8H,15H-8,15- methanobenzo[f]benzo[4, 5]imidazo[ 1 ,2-a]imidazo[ 1 ,2-d] [ 1 ,4]diazocine To a stirred solution of (7R,14R)-l l-chloro-N-(2,2-diethoxyethyl)-l-(difluoromethoxy)-7,14- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5-amine (150 mg, 0.306 mmol) in methanol (3 mL) was added cone. HC1 (1 mL) at room temperature. The resulting mixture was stirred at 80 °C for 1 h. 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 20 min; detector, 254 nm to afford (8R,15R)-l l-chloro-7- (difluoromethoxy)-8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2-a]imidazo[l,2- d][l,4]diazocine (90 mg, 74%) as a white solid. MS ESI calculated for C20H13CIF2N4O [M + H]+, 399.07 found 399.05. 'HNMR (400 MHz, Methanol-^) 8 8.48 - 8.34 (m, 1H), 7.59 (d, J = 1.4 Hz, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.47 - 7.41 (m, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.26 (s, 1H), 7.23 - 7.18 (m, 1H), 7.13 (d, J = 1.4 Hz, 1H), 6.57 - 6.52 (m, 1H), 6.02 (d, J = 6.4 Hz, 1H), 3.74 - 3.62 (m, 1H), 2.94 (d, J = 13.9 Hz, 1H).Example 1 : (4-((8R,15R)-7-(difluoromethoxy)-8H,15H-8,15- methanobenzo[f]benzo[4, 5]imidazo[ 1 ,2-a]imidazo[ 1 ,2-d] [ 1 ,4]diazocin- 11 -yl)-2- fluorophenyl)dimethylphosphine oxideTo a stirred solution of (8R,15R)-l l-chloro-7-(difluoromethoxy)-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a]imidazo[l,2-d][l,4]diazocine (30 mg, 0.075 mmol) and 2-[4-(dimethylphosphoryl)-3-fluorophenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (34 mg, 0.112 mmol) in 1,4-dioxane (1 mL) and H2O (0.2 mL) were added SPhos Pd G3 (6 mg, 0.007mmol), SPhos (6 mg, 0.015 mmol) and K3PO4 (48 mg, 0.225 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 4 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with C^CL / MeOH (20: 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 50% gradient in 30 min; detector, 254 nm to afford (4-((8R,15R)-7-(difluoromethoxy)-8H,15H-8,15- methanobenzo[f]benzo[4, 5]imidazo[ 1 ,2-a]imidazo[ 1 ,2-d] [ 1 ,4]diazocin- 11 -yl)-2- fluorophenyl)dimethylphosphine oxide (11 mg, 27%). MS ESI calculated for C28H22F3N4O2P [M + H]+, 535.14 found 535.15. *H NMR (400 MHz, DMSO-t / 6) 8 8.55 - 8.47 (m, 1H), 7.93 - 7.80 (m, 1H), 7.76 (d, J = 2.3 Hz, 2H), 7.72 (d, J = 5.8 Hz, 1H), 7.69 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.62 - 7.53 (m, 2H), 7.45 (t, J = 8.2 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.12 (d, J = 1.1 Hz, 1H), 6.50 (d, J = 7.4 Hz, 1H), 6.16 (d, J = 6.2 Hz, 1H), 3.76 - 3.64 (m, 1H), 2.91 (d, J = 13.8 Hz, 1H), 1.77 (s, 3H), 1.74 (s, 3H).19F NMR (377 MHz, DMSO-de) 8 -81.65, -82.10, -82.15, -82.60, -105.63, -105.64.31P NMR (162 MHz, DMSO-t / 6) 6 28.53.

[0151] Example 2: (4-((8R,15R)-7-(difluoromethoxy)-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[4,3-d][l,4]diazocin-l l-yl)-2- fluorophenyl)dimethylphosphine oxidePreparation 2A: (8R,15R)-1 l-chloro-7-(difluoromethoxy)-8H,15H-8,15- methanobenzo[f]benzo[4, 5]imidazo[ 1 ,2-a] [ 1 ,2,4]triazolo[4,3 -d] [ 1 ,4]diazocine A solution of (7R,14R)-1 l-chloro-l-(difluoromethoxy)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocine-5(14H)-thione (600 mg, 1.531 mmol) and Hydrazine monohydrate (958 mg, 15.310 mmol, 80%) in THF (8 mL) and methanol (2 mL) was stirred at room temperature for 4 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DMF (5 mL) followed by the addition of HOAc (5 mL) and trimethoxymethane (1.63 g, 15.310 mmol) at room temperature. The resulting mixture was stirred at room temperature for additional 16 h. The mixture was basified to pH 8 with saturated NaHCCL (aq.), the mixture was diluted with DCM (50 mL). The resulting mixture was washed with 3 x 20 mL of water, the combinedorganic 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 CH2CI2 / MeOH (20: 1) to afford (8R,15R)-l l-chloro-7-(difhioromethoxy)-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[4,3-d][l,4]diazocine (590 mg, 96%) as a light yellow solid. MS ESI calculated for C19H12CIF2N5O [M + H]+, 400.07 found 400.15.JH NMR (400 MHz, Chloroforms / ) 5 8.85 - 8.74 (m, 1H), 8.54 (s, 1H), 7.63 - 7.55 (m, 1H), 7.51 - 7.42 (m, 2H), 7.34 - 7.29 (m, 1H), 7.24 - 7.18 (m, 1H), 6.88 (t, J= 72.6 Hz, 1H), 6.45 (d, J= 7.5 Hz, 1H), 5.89 (d, J= 6.0 Hz, 1H), 3.71 - 3.53 (m, 1H), 2.95 (d, J= 13.8 Hz, 1H).Example 2: (4-((8R,15R)-7-(difhioromethoxy)-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[4,3-d][l,4]diazocin-l l-yl)-2- fhiorophenyl)dimethylphosphine oxideTo a stirred solution of (8R,15R)-l l-chloro-7-(difhioromethoxy)-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[4,3-d][l,4]diazocine (50 mg, 0.125 mmol) and (4-(dimethylphosphoryl)-3-fluorophenyl)boronic acid (41 mg, 0.188 mmol), Sphos (10 mg, 0.025 mmol), Sphos Pd G3 (10 mg, 0.013 mmol) in 1,4-dioxane (2 mL) and H2O (0.8 mL) was added K3PO4 (80 mg, 0.375 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for additional 1 h. The mixture was allowed to cool down to room temperature. The residue was purified by silica gel column chromatography, eluted with C^Cb / MeOH (6 / 1) to afford (4-((8R,15R)-7- (difluoromethoxy)-8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[4,3- d][l,4]diazocin-l l-yl)-2-fhiorophenyl)dimethylphosphine oxide as a yellow solid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 40% to 50% gradient in 10 min; detector, 254 nm. This resulted in (4-((8R,15R)-7-(difhioromethoxy)-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[4,3-d][l,4]diazocin-l l-yl)-2- fhiorophenyl)dimethylphosphine oxide (51 mg, 77%). MS ESI calculated for C27H21F3N5O2P [M + H]+, 536.14 found 536.15.XH NMR (400 MHz, DMSO-t / 6) 6 9.07 (s, 1H), 8.60 - 8.53 (m, 1H), 7.95 - 7.69 (m, 4H), 7.67 - 7.52 (m, 4H), 7.44 (d, J = 8.2 Hz, 1H), 6.52 (d, J = 7.4 Hz, 1H), 6.34 (d, J = 6.0 Hz, 1H), 3.78 - 3.63 (m, 1H), 2.99 (d, J = 14.0 Hz, 1H), 1.76 (s, 3H), 1.73 (s, 3H).19F NMR (377 MHZ, DMSO-t / 6) 6 -81.92, -82.37, -82.41, -82.86, -105.64, -105.65.31P NMR (162 MHz, DMSO-t / 6) 6 28.33.

[0152] Example 3: (2-fluoro-4-((8R,15R)-7-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4, 5]imidazo[ 1 ,2-a]tetrazolo[ 1 ,5-d] [ 1 ,4]diazocin- 11- yl)phenyl)dimethylphosphine oxidePreparation 3A: (8R,15R)-l l-chloro-7-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a]tetrazolo[l,5-d][l,4]diazocine To a stirred solution of (7R,14R)-1 l-chloro-l-fluoro-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one (250 mg, 0.763 mmol) in 4- methylpyridine (5 mL) was added DPPA (420 mg, 1.526 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 140 °C for 24 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The mixture was neutralized to pH 7 with IN HC1 (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. The residue was purified by silica gel column chromatography, eluted with C^CL / MeOH (12: 1) to afford (8R, 15R)- 11 -chi oro-7 -fluoro-8H, 15H-8, 15-methanobenzo[f]benzo[4, 5]imidazo[ 1 ,2- a]tetrazolo[l,5-d][l,4]diazocine (110 mg, 41%) as a yellow solid. MS ESI calculated for C17H10CIFN6 [M + H]+, 353.06 found 353.10. 'H NMR (400 MHz, Chloroforms / ) 5 8.62 (d, J = 7.9 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.60 - 7.51 (m, 1H), 7.50 - 7.40 (m, 2H), 7.34 (t, J = 7.7 Hz, 1H), 6.68 - 6.49 (m, 1H), 6.47 - 6.27 (m, 1H), 3.87 - 3.63 (m, 1H), 2.97 (d, J = 10.9 Hz, 1H).19F NMR (377 MHz, Chloroforms / ) 5 -116.87.Example 3: (2-fluoro-4-((8R,15R)-7-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4, 5]imidazo[ 1 ,2-a]tetrazolo[ 1 ,5-d] [ 1 ,4]diazocin- 11- yl)phenyl)dimethylphosphine oxideTo a stirred solution of (8R,15R)-l l-chloro-7-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a]tetrazolo[l,5-d][l,4]diazocine (40 mg, 0.113 mmol) and 4-(dimethylphosphoryl)-3-fluorophenylboronic acid (37 mg, 0.170 mmol) in 1,4-dioxane (0.8 mL) and H2O (0.2 mL) were added K3PO4 (72 mg, 0.339 mmol), SPhos (10 mg, 0.023 mmol) and SPhos Pd G3 (18 mg, 0.023 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with C^CL / MeOH (12:1) followed by Prep-HPLC with the following conditions (Column: YMC-Actus Triart Cl 8 ExRS,30*150 mm, 5pm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 22% B to 40% B in 15 min; Wave Length: 254 nm; RTl(min): 10.52 min) to afford (2-fluoro-4-((8R,15R)-7-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4, 5]imidazo[ 1 ,2-a]tetrazolo[ 1 ,5-d] [ 1 ,4]diazocin- 11- yl)phenyl)dimethylphosphine oxide (41 mg, 73%). MS ESI calculated for C25H19F2N6OP [M + H]+, 489.13 found 489.15. 'HNMR (400 MHz, Chloroform-^ 5 8.68 - 8.61 (m, 1H), 8.10 - 7.99 (m, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.66 - 7.61 (m, 1H), 7.59 - 7.47 (m, 3H), 7.47 - 7.38 (m, 1H), 7.36 - 7.28 (m, 1H), 6.62 (d, J = 6.0 Hz, 1H), 6.47 (d, J = 7.3 Hz, 1H), 3.85 - 3.73 (m, 1H), 3.00 (d, J = 13.9 Hz, 1H), 1.86 (s, 3H), 1.83 (s, 3H).19F NMR (377 MHz, Chloroforms / ) 5 - 105.58, -105.59, -117.07.31P NMR (162 MHz, Chloroforms / ) 5 30.51, 30.48.

[0153] Example 4: (4-((8R,15R)-7-(difhioromethoxy)-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-2- fhiorophenyl)dimethylphosphine oxidePreparation 4A: (7R,14R)-6-amino-l l-chloro-l-(difluoromethoxy)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-oneTo a stirred solution of (7R,14R)-1 l-chloro-l-(difluoromethoxy)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one (1.00 g, 2.661 mmol) in DMF (10 mL) was added LBuONa (1.10 g, 11.442 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 5 min. To the above mixture was added (aminooxy)sulfonic acid (602 mg, 5.322 mmol) at 0 °C. 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 C^CL / MeOH (10: 1) to afford (7R,14R)-6-amino-l 1- chloro-l-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one (620 mg, 60%) as a yellow solid. MS ESI calculated for C18H13CIF2N4O2 [M + H]+, 391.07 found 391.10. *H NMR (400 MHz, Chloroform^ / ) 5 8.45 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 8.7 Hz, 1H), 7.50 - 7.43 (m, 2H), 7.38 (d, J = 8.2 Hz, 1H), 7.26 - 7.22 (m, 1H), 6.84 (t, J = 72.5 Hz, 1H), 6.25 (d, J = 7.3 Hz, 1H), 5.48 (d, J = 7.2 Hz, 1H), 3.53 - 3.42 (m, 3H), 2.86 (d, J = 13.7 Hz, 1H).19F NMR (377 MHz, Chloroform^ / ) 5 -80.21, -80.66, - 81.13, -81.57.Preparation 4B: (8R,15R)-l l-chloro-7-(difluoromethoxy)-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocineTo a stirred mixture of (7R,14R)-6-amino-l l-chloro-l-(difluoromethoxy)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one (550 mg, 1.407 mmol) and diisopropylamine (1.10 g, 11.256 mmol) in 1,4-di oxane (6 mL) was added formimidamide acetate (1.20 g, 11.256 mmol) at room temperature. The resulting mixture was stirred at 90 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with C^Ch / MeOH (10: 1) to afford (8R, 15R)- 11 -chi oro-7 -(difluoromethoxy)-8H, 15H-8, 15-methanobenzo[f]benzo[4,5]imidazo[ 1,2- a][l,2,4]triazolo[l,5-d][l,4]diazocine (200 mg, 36%) as a white solid. MS ESI calculated for C19H12CIF2N5O [M + H]+, 400.07 found 399.95.XH NMR (400 MHz, Chloroforms / ) 5 8.61 (d, J = 8.2 Hz, 1H), 7.94 (s, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.49 (t, J = 8.2 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.36 - 7.31 (m, 1H), 7.22 - 7.17 (m, 1H), 6.88 (t, J = 72.5 Hz, 1H), 6.44 (d, J = 7.5 Hz, 1H), 6.17 (d, J = 6.3 Hz, 1H), 3.68 - 3.57 (m, 1H), 2.96 (d, J = 13.8 Hz, 1H).19F NMR (377 MHz, Chloroforms / ) 5 -80.35, -80.79, -81.14, -81.58.Example 4: (4-((8R,15R)-7-(difluoromethoxy)-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-2- fluorophenyl)dimethylphosphine oxideTo a stirred solution of (8R,15R)-l l-chloro-7-(difluoromethoxy)-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (40 mg, 0.100 mmol) and 4-(dimethylphosphoryl)-3-fluorophenylboronic acid (32 mg, 0.150 mmol) in 1,4- dioxane (1 mL) and H2O (0.2 mL) were added SPhos (8 mg, 0.020 mmol), SPhos Pd G3 (8 mg, 0.010 mmol), K3PO4 (64 mg, 0.300 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h. The resulting mixture was evaporated in vacuum. The residue was purified by silica gel column chromatography, eluted with CH2C12 / 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), 40% to 50% gradient in 10 min; detector, 254 nm. This resulted in (4-((8R,15R)-7- (difluoromethoxy)-8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-2-fluorophenyl)dimethylphosphine oxide (34 mg, 64%). MS ESI calculated for C27H21F3N5O2P [M + H]+, 536.14 found 536.20. 'H NMR (400 MHz, DMSO-t / 6) 5 8.51 - 8.43 (m, 1H), 8.13 (s, 1H), 7.96 - 7.75 (m, 3H), 7.72 (d, J = 8.5 Hz, 1H), 7.68 - 7.63 (m, 1H), 7.63 - 7.54 (m, 3H), 7.49 (d, J = 8.2 Hz, 1H), 6.56 (d, J = 7.4 Hz, 1H), 6.34 (d, J = 6.2 Hz, 1H), 3.79 - 3.65 (m, 1H), 3.05 (d, J = 14.0 Hz, 1H), 1.76 (s, 3H), 1.73 (s, 3H).19F NMR (377 MHz, DMSO-t / e) 8 -81.91, -82.36, -82.48, -82.93, -105.64, -105.65.31P NMR (162 MHz, DMSO- e) 6 28.33.

[0154] Example 5: (2-fluoro-4-((8R,15R)-7-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[4,3-d][l,4]diazocin-l l- yl)phenyl)dimethylphosphine oxidePreparation 5A: (7R,14R)-l l-chloro-l-fluoro-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocine-5(14H)-thione To a stirred solution of (7R,14R)-1 l-chloro-l-fluoro-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one (500 mg, 1.526 mmol) in Toluene (40 mL) was added Lawesson’s reagent (802 mg, 1.984 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CthCb / MeOH (50: 1) to afford (7R,14R)-l l-chloro-l-fluoro-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocine-5(14H)-thione (400 mg, 76%) as a yellow solid. MS ESI calculated for C17H11CIFN3S [M + H]+, 344.03 found 344.05. 'HNMR (400 MHz, Chloroform-^ 5 10.05 (s, 1H), 9.13 - 8.99 (m, 1H), 7.80 - 7.69 (m, 1H), 7.48 - 7.43 (m, 1H), 7.41 - 7.34 (m, 2H), 7.25 - 7.18 (m, 1H), 6.23 (d, J = 6.7 Hz, 1H), 5.24 - 5.10 (m, 1H), 3.52 - 3.38 (m, 1H), 2.95 (d, J = 13.2 Hz, 1H).Preparation 5B: (8R,15R)-1 l-chloro-7-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4, 5]imidazo[ 1 ,2-a] [ 1 ,2,4]triazolo[4,3 -d] [ 1 ,4]diazocine To a stirred solution of (7R,14R)-1 l-chloro-l-fluoro-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocine-5(14H)-thione (500 mg, 1.454 mmol) in THF (3 mL) and methanol (3 mL) was added Hydrazine monohydrate (728 mg, 14.540 mmol) at room temperature. The resulting mixture was stirred at room temperature for 4 h. The resulting mixture was concentrated under reduced pressure. The above residue in DMF (3 mL) and HOAc (9 mL) was treated with trimethoxymethane (1.54 g, 14.540 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 40% to 50% gradient in 10 min; detector, 254 nm. This resulted in (8R,15R)-1 l-chloro-7-fhioro-8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2- a][l,2,4]triazolo[4,3-d][l,4]diazocine (400 mg, 78%) as a yellow solid. MS ESI calculated for CisHiiCIFNs [M + H]+, 352.07 found 352.15. 'HNMR (400 MHz, Chloroforms / ) 5 8.74 - 8.67 (m, 1H), 8.53 (s, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.50 - 7.39 (m, 2H), 7.35 - 7.27 (m, 1H), 7.25 - 7.19 (m, 1H), 6.33 (d, J = 7.4 Hz, 1H), 5.91 (d, J = 6.1 Hz, 1H), 3.71 - 3.60 (m, 1H), 2.97 (d, J = 13.7 Hz, 1H).19F NMR (377 MHz, Chloroforms / ) 5 -117.97.Example 5: (2-fluoro-4-((8R,15R)-7-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[4,3-d][l,4]diazocin-l l- yl)phenyl)dimethylphosphine oxideTo a stirred solution of (8R,15R)-l l-chloro-7-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[4,3-d][l,4]diazocine (50 mg, 0.142 mmol) and (4-(dimethylphosphoryl)-3-fluorophenyl)boronic acid (64 mg, 0.213 mmol) in 1,4- dioxane (1 mL) and H2O (0.2 mL) were added SPhos (12 mg, 0.028 mmol), SPhos Pd G3 (11 mg, 0.014 mmol) and K3PO4 (91 mg, 0.426 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 C for 2 h. The resulting mixture was evaporated in vacuum. The residue was purified by silica gel column chromatography, eluted with CH2C12 / 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 10 min; detector, 254 nm. This resulted in (2-fhioro-4-((8R,15R)-7- fhioro-8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[4,3- d][l,4]diazocin-l l-yl)phenyl)dimethylphosphine oxide (55 mg, 80%). MS ESI calculated for C26H20F2N5OP [M + H]+, 488.14 found 488.25.XH NMR (400 MHz, DMSOs / 6) 8 9.08 (s, 1H), 8.53 - 8.46 (m, 1H), 7.92 - 7.80 (m, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.69 - 7.55 (m, 4H), 7.55 -7.45 (m, 2H), 6.49 (d, J = 7.2 Hz, 1H), 6.36 (d, J = 6.0 Hz, 1H), 3.77 - 3.66 (m, 1H), 3.04 (d, J = 14.0 Hz, 1H), 1.76 (s, 3H), 1.73 (s, 3H).19F NMR (377 MHz, DMSOs / 6) 8 -105.43, -105.44, - 117.00.31P NMR (162 MHz, DMSOs / 6) 6 28.31.

[0155] Example 6: (5-((8R,15R)-7-(difhroromethoxy)-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)pyridin-2- yl)dimethylphosphine oxidePreparation 6A: (8R,15R)-7-(difluoromethoxy)-l l-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-8H, 15H-8, 15-methanobenzo[f]benzo[4,5]imidazo[ 1 ,2-a] [ 1 , 2, 4]tri azolof 1 , 5 -d] [ 1 ,4]diazocine To a stirred solution of (8R,15R)-l l-chloro-7-(difluoromethoxy)-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (200 mg, 0.500 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (191 mg, 0.750 mmol) in 1,4-dioxane (4 mL) were added SPhos Pd G3 (39 mg, 0.050 mmol), SPhos (41 mg, 0.100 mmol) and KO Ac (147 mg, 1.500 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 4 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA / PE, 1 :2) to afford (8R,15R)-7-(difluoromethoxy)-l l-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2- a][l,2,4]triazolo[l,5-d][l,4]diazocine (170 mg, 69%) as a light yellow solid. MS ESI calculated for C25H24BF2N5O3 [M + H]+, 492.19, found 492.15. 'HNMR (400 MHz, Chloroforms / ) 5 8.62 - 8.54 (m, 1H), 7.98 - 7.90 (m, 2H), 7.74 - 7.63 (m, 2H), 7.46 (t, J = 8.2 Hz, 1H), 7.35 - 7.30 (m, 1H), 7.14 - 6.71 (m, 1H), 6.52 (d, J = 7.5 Hz, 1H), 6.24 (d, J = 6.2 Hz, 1H), 3.69 - 3.59 (m, 1H), 2.96 (d, J = 13.7 Hz, 1H), 1.34 (s, 12H).Example 6: (5-((8R,15R)-7-(difhioromethoxy)-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)pyridin-2- yl)dimethylphosphine oxideTo a stirred solution of (8R,15R)-7-(difhiorom ethoxy)- 1 l-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-8H, 15H-8, 15-methanobenzo[f]benzo[4, 5]imidazo[ 1 ,2-a] [ 1 , 2, 4]tri azolof 1,5- d][l,4]diazocine (40 mg, 0.081 mmol) and 5-bromo-2-(dimethylphosphoryl)pyridine (29 mg, 0.121 mmol) in 1,4-dioxane (2 mL) were added Pd(dppf)C12-CH2C12 (7 mg, 0.008 mmol) and K2CO3 (23 mg, 0.162 mmol) at room temperature. The resulting mixture was stirred at 80 °Cfor h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with C HCh / 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), 10% to 50% gradient in 30 min; detector, 254 nm to afford (5-((8R,15R)-7-(difluoromethoxy)- 8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l, 2, 4]tri azolof l,5-d][l,4]diazocin-l 1- yl)pyridin-2-yl)dimethylphosphine oxide (22 mg, 53%). MS ESI calculated for C26H21F2N6O2P [M + H]+, 519.14 found 519.15.XH NMR (400 MHz, DMSO-t / 6) 6 9.02 (d, J= 2.2 Hz, 1H), 8.50 - 8.41 (m, 1H), 8.24 - 8.17 (m, 1H), 8.13 (s, 1H), 8.07 - 8.00 (m, 1H), 7.95 - 7.46 (m, 6H), 6.57 (d, .7= 7.4 Hz, 1H), 6.35 (d, J= 6.1 Hz, 1H), 3.81 - 3.66 (m, 1H), 3.05 (d, J= 14.0 Hz, 1H), 1.73 (s, 3H), 1.69 (s, 3H).19F NMR (377 MHz, DMSO-t / 6) 6 -81.68, -82.13, -82.49, -82.94.31P NMR (162 MHz, DMSO-t / 6) 6 33.94.

[0156] Example 7: (5-((8R,15R)-7-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)pyridin-2- yl)dimethylphosphine oxidePreparation 7A: (8R,15R)-7-fluoro-l l-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-8H,15H-8, 15-methanobenzo[f]benzo[4, 5]imidazo[ 1 ,2-a] [ 1 , 2, 4]tri azolof 1 ,5-d] [ 1 ,4]diazocine To a stirred solution of (8R,15R)-l l-chloro-7-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (350 mg, 0.995 mmol) and bis(pinacolato)diboron (505 mg, 1.990 mmol) in 1,4-dioxane (5 mL) was added KO Ac (293 mg, 2.985 mmol) SPhos (41 mg, 0.100 mmol) and SPhos Pd G3 (78 mg, 0.100 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 vacuum. The residue was purified by silica gel column chromatography, eluted with C ECh / MeOH (15:1) to afford (8R,15R)-7-fhioro-l l-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-8H,15H- 8, 15-methanobenzo[f]benzo[4, 5]imidazo[ 1 ,2-a] [ 1 , 2, 4]tri azolof 1 ,5-d] [ 1 ,4]diazocine (380 mg, 86%) as a white solid. MS ESI calculated for C24H23BFN5O2 [M + H]+, 444.19 found 444.10.JH NMR (400 MHz, Chloroforms / ) 5 8.49 (d, J = 8.0 Hz, 1H), 7.94 (s, 1H), 7.90 (s, 1H), 7.76 - 7.62 (m, 2H), 7.51 - 7.39 (m, 1H), 7.37 - 7.30 (m, 1H), 6.39 (d, J = 7.3 Hz, 1H), 6.25 (d, J = 6.2Hz, 1H), 3.71 - 3.57 (m, 1H), 2.98 (d, J = 13.7 Hz, 1H), 1.35 (s, 12H).19F NMR (377 MHz, Chloroform-t / ) 5 -117.31.Example 7 : (5-((8R, 15R)-7-fluoro-8H, 15H-8, 15-methanobenzo[f]benzo[4,5]imidazo[l ,2- a] [ 1 , 2, 4]tri azolof 1 ,5-d] [ 1 ,4]diazocin- 11 -yl)pyridin-2-yl)dimethylphosphine oxideTo a stirred solution of (8R,15R)-7-fluoro-l l-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (30 mg, 0.068 mmol) and 5-bromo-2-(dimethylphosphoryl)pyridine (21 mg, 0.088 mmol) in 1,4- dioxane (1 mL) and H2O (0.1 mL) were added Pd(dppf)C12 (6 mg, 0.007 mmol) and K2CO3 (28 mg, 0.204 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 CH2C12 / MeOH (10:1) followed by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in water (0.1% FA), 20% to 40% gradient in 20 min; detector, 254 nm to afford (5-((8R,15R)-7-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)pyridin-2- yl)dimethylphosphine oxide (10 mg, 31%). MS ESI calculated for C25H20FN6OP [M + H]+, 471.14 found 471.15.XH NMR (400 MHz, DMSO-t / 6) 6 9.02 (d, J = 2.2 Hz, 1H), 8.44 - 8.35 (m, 1H), 8.24 - 8.18 (m, 1H), 8.14 (s, 1H), 8.08 - 8.01 (m, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.69 (d, J = 1.7 Hz, 1H), 7.63 - 7.58 (m, 1H), 7.58 - 7.51 (m, 2H), 6.53 (d, J = 7.2 Hz, 1H), 6.38 (d, J = 6.2 Hz, 1H), 3.84 - 3.58 (m, 1H), 3.10 (d, J = 14.0 Hz, 1H), 1.72 (s, 3H),1.69 (s, 3H).19F NMR (377 MHz, DMSO-t / e) 6 -117.04.31P NMR (162 MHz, DMSO-t / 6) 6 34.04.

[0157] Example 8: (5-((8R,15R)-7-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)pyrimidin-2- yl)dimethylphosphine oxideTo a stirred solution of (8R,15R)-7-fluoro-l l-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (40 mg, 0.090 mmol) and 5-bromo-2-(dimethylphosphoryl)pyrimidine (28 mg, 0.117 mmol) in 1,4- dioxane (1 mL) and H2O (0.1 mL) were added Pd(dppf)C12 (7 mg, 0.009 mmol) and K2CO3 (37 mg, 0.270 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CfhCh / MeOH (10: 1) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in water (0.1% FA), 20% to 40% gradient in 20 min; detector, 254 nm to afford (5-((8R, 15R)-7-fluoro-8H, 15H-8, 15-methanobenzo[f]benzo[4,5]imidazo[l ,2- a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)pyrimidin-2-yl)dimethylphosphine oxide (16 mg, 38%). MS ESI calculated for C24H19FN7OP [M + H]+, 472.14 found 472.15. 'HNMR (400 MHz, DMSO-t / e) 89.26 (s, 2H), 8.45 - 8.34 (m, 1H), 8.14 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 1.7 Hz, 1H), 7.69 - 7.63 (m, 1H), 7.57 - 7.50 (m, 2H), 6.53 (d, J = 7.2 Hz, 1H), 6.39 (d, J = 6.2 Hz, 1H), 3.83 - 3.65 (m, 1H), 3.10 (d, J = 14.0 Hz, 1H), 1.83 (s, 3H), 1.80 (s, 3H).19F NMR (377 MHz, DMSO-t / 6) 6 -116.71.31P NMR (162 MHz, DMSO-t / 6) 6 33.87.

[0158] Example 9: (2-fluoro-4-((8R,15R)-7-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l- yl)phenyl)dimethylphosphine oxidePreparation 9A: (7R,14R)-6-amino-l l-chloro-l-fluoro-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one To a stirred solution of (7R,14R)-1 l-chloro-l-fluoro-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one (600 mg, 1.831 mmol) in THF (10 mL) was added KHMDS (1 M in THF) (2.38 mL, 2.380 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 30 min under nitrogen atmosphere. To the above mixture was added (aminooxy)diphenylphosphine oxide (853 mg, 3.662 mmol) at -78 °C. The resulting mixture was stirred at room temperature for additional overnight. The reaction was quenched with sat. NH4CI (aq.) at room temperature. The resultingmixture was extracted with EtOAc (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 CFLCb / MeOH (30 / 1) to afford (7R,14R)-6-amino-l l-chloro-l- fhioro-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one (450 mg, 63%) as a yellow solid. MS ESI calculated for C17H12CIFN4O [M + H]+, 343.07 found 342.90. 'H NMR (400 MHz, Chloroform^ / ) 5 8.38 - 8.34 (m, 1H), 7.63 (d, J= 8.7 Hz, 1H), 7.47 - 7.30 (m, 3H), 7.23 - 7.17 (m, 1H), 6.10 (d, J= 7.1 Hz, 1H), 5.42 (d, J= 7.2 Hz, 1H), 4.40 (s, 2H), 3.49 - 3.40 (m, 1H), 2.85 (d, J= 13.6 Hz, 1H).19F NMR (377 MHz, Chloroform^ / ) 5 - 117.99.Preparation 9B: (8R,15R)-l l-chloro-7-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine To a stirred solution of (7R,14R)-6-amino-l 1 -chi oro-1 -fhioro-6,7-dihydro-7, 14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one (300 mg, 0.875 mmol) and formamidine acetate (729 mg, 7.000 mmol) in 1,4-di oxane (6 mL) was added diisopropylamine (709 mg, 7.000 mmol) at room temperature. The resulting mixture was stirred at 100 °C for overnight. The resulting mixture was concentrated under vacuum and purified by silica gel column chromatography, eluted with C LCh / MeOH (20 / 1) to afford (8R,15R)-l l-chloro-7- fhioro-8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l, 2, 4]tri azolof 1,5- d][l,4]diazocine (250 mg, 81%) as a light yellow solid. MS ESI calculated for CisHnQFNs [M + H]+, 352.07 found 351.95. 'HNMR (400 MHz, Chloroforms / ) 5 8.53 - 8.47 (m, 1H), 7.94 (s, 1H), 7.65 - 7.58 (m, 1H), 7.49 - 7.40 (m, 2H), 7.35 - 7.28 (m, 1H), 7.23 - 7.18 (m, 1H), 6.32 (d, J = 7.3 Hz, 1H), 6.19 (d, J = 6.2 Hz, 1H), 3.67 - 3.58 (m, 1H), 2.98 (d, J = 13.8 Hz, 1H).19F NMR (377 MHz, Chloroforms / ) 5 -117.99.Example 9: (2-fluoro-4-((8R,15R)-7-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l- yl)phenyl)dimethylphosphine oxideTo a stirred solution of (8R,15R)-l l-chloro-7-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (50 mg, 0.142 mmol) and (2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)dimethylphosphine oxide (51 mg, 0.170 mmol) in 1,4-di oxane (0.4 mL) and H2O (0.1 mL) were added K3PO4 (91 mg, 0.426 mmol), SPhos (6 mg, 0.014 mmol) and SPhos Pd G3 (11 mg, 0.014 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 1 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with C^CL / MeOH (10 / 1) followed byreversed-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; detector, 254 nm to afford (2-fluoro-4-((8R,15R)-7-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l- yl)phenyl)dimethylphosphine oxide (22 mg, 32%). MS ESI calculated for C26H20F2N5OP [M + H]+, 488.14 found 488.15. 'HNMR (400 MHz, Chloroform-; / ) 5 8.53 (d, J= 8.1 Hz, 1H), 8.09 - 7.99 (m, 1H), 7.97 (s, 1H), 7.83 (d, J= 8.5 Hz, 1H), 7.65 (s, 1H), 7.56 - 7.41 (m, 3H), 7.35 - 7.28 (m, 2H), 6.45 (d, J= 7.0 Hz, 1H), 6.35 (d, J= 5.9 Hz, 1H), 3.79 - 3.67 (m, 1H), 3.04 (d, J= 13.6 Hz, 1H), 1.86 (s, 3H), 1.83 (s, 3H).19F NMR (377 MHz, Chloroform-; / ) 5 -105.60, -105.61, -118.00.31P NMR (162 MHz, Chloroform-; / ) 5 30.36, 30.34.

[0159] Example 10: (4-((8R,15R)-7-chloro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[4,3-d][l,4]diazocin-l l-yl)-2- fluorophenyl)dimethylphosphine oxidePreparation 10A: (7R,14R)-l-chloro-l l-methoxy-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocine-5(14H)-thione A solution of (7R,14R)-1 -chi oro-1 l-methoxy-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one (1.5 g, 4.415 mmol) and Lawesson’s reagent (2.32 g, 5.740 mmol) in toluene (30 mL) was stirred at 100 °C for 4 h under nitrogen atmosphere. The reaction was diluted with water at room temperature and extracted with EtOAc (3 x 30 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 DCM / MeOH (10: 1) to afford (7R,14R)-1- chl oro-1 l-methoxy-6, 7-dihydro-7, 14-methanobenzo[f]b enzo[4,5]imidazo[l,2-a][l,4]diazocine- 5(14H)-thione (1.20 g, 76%) as a yellow solid. MS ESI calculated for C18H14CIN3OS [M + H]+, 356.05 found 355.90.XH NMR (400 MHz, Chloroform-; / ) 5 10.12 (d, J = 6.4 Hz, 1H), 9.33 - 9.16 (m, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.66 - 7.61 (m, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.15 (d, J =2.4 Hz, 1H), 6.94 - 6.85 (m, 1H), 6.52 (d, J = 7.2 Hz, 1H), 5.07 (t, J = 6.0 Hz, 1H), 3.84 (s, 3H),3.52 - 3.34 (m, 1H), 2.91 (d, J = 13.2 Hz, 1H).Preparation 10B: (8R,15R)-7-chloro-l l-methoxy-8H,15H-8,15- methanobenzo[f]benzo[4, 5]imidazo[ 1 ,2-a] [ 1 ,2,4]triazolo[4,3 -d] [ 1 ,4]diazocine To a stirred solution of (7R,14R)-1 -chi oro-1 l-methoxy-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocine-5(14H)-thione (1.00 g, 2.810 mmol) in methanol (4 mL) and THF (6 mL) was added Hydrazine monohydrate (1.76 g, 28.100 mmol, 80%) at room temperature. The resulting mixture was stirred at 50 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DMF (5 mL) and HOAc (5 mL). To the above mixture was added trimethoxymethane (2.98 g, 28.100 mmol) dropwise at room temperature. The resulting mixture was stirred at 30 °C for additional 4 h. 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 50% gradient in 10 min; detector, 254 nm to afford (8R,15R)-7-chloro-l 1-methoxy- 8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[4,3-d][l,4]diazocine (450 mg, 44%) as a light yellow solid. MS ESI calculated for C19H14CIN5O [M + H]+, 364.09 found 363.95. *H NMR (400 MHz, Chloroform^ / ) 5 8.93 - 8.83 (m, 1H), 8.62 (s, 1H), 7.61 -7.52 (m, 2H), 7.39 (t, J = 8.0 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H), 6.92 - 6.84 (m, 1H), 6.61 (d, J = 7.6 Hz, 1H), 5.97 (d, J = 6.0 Hz, 1H), 3.83 (s, 3H), 3.66 - 3.61 (m, 1H), 2.95 (d, J = 13.6 Hz, 1H).Preparation 10C : (8R, 15R)-7-chloro-8H, 15H-8, 15-methanobenzo[f]benzo[4,5]imidazo[l ,2- a][l,2,4]triazolo[4,3-d][l,4]diazocin-l l-olTo a stirred solution of (8R,15R)-7-chloro-l l-methoxy-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[4,3-d][l,4]diazocine (450 mg, 1.237 mmol) in DCM (5 mL) was added BBr? (6.18 mL, 6.185 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 h under nitrogen atmosphere. The resulting mixture was quenched with MeOH at room temperature and concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 10% to 30% gradient in 20 min; detector, 254 nm to afford (8R,15R)-7- chloro-8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[4,3- d][l,4]diazocin-l l-ol (220 mg, 50%) as a brown solid. MS ESI calculated for CisHnCINsO [M + H]+, 350.07, found 315.95.XH NMR (400 MHz, DMSO-t / 6) 6 9.47 (s, 1H), 9.02 (s, 1H), 8.75 - 8.68 (m, 1H), 7.79 - 7.69 (m, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 6.95 (d, J =2.4 Hz, 1H), 6.70 - 6.62 (m, 1H), 6.53 (d, J = 7.6 Hz, 1H), 6.21 (d, J = 6.0 Hz, 1H), 3.72 - 3.61 (m, 1H), 2.97 (d, J = 14.0 Hz, 1H).Preparation 10D: (8R,15R)-7-chloro-8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2- a][l,2,4]triazolo[4,3-d][l,4]diazocin-l l-yl trifluoromethanesulfonateTo a stirred solution of (8R,15R)-7-chloro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[4,3-d][l,4]diazocin-l l-ol (220 mg, 0.629 mmol), l,l,l-trifluoro-N-phenyl-N-(trifluoromethane)sulfonylmethanesulfonamide (359 mg, 1.006 mmol) in DCM (6 mL) were added EtsN (127 mg, 1.258 mmol) and DMAP (7 mg, 0.063 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10: 1) to afford (8R, 15R)-7-chloro-8H, 15H-8, 15-methanobenzo[f]benzo[4,5]imidazo[l ,2- a][l,2,4]triazolo[4,3-d][l,4]diazocin-l l-yl trifluoromethanesulfonate (260 mg, 85%) as a yellow solid. MS ESI calculated for C19H11CIF3N5O3S [M + H]+, 482.02 found 481.90. 'HNMR (400 MHz, Chloroform-t / ) 5 9.00 - 8.81 (m, 1H), 8.61 (s, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.67 - 7.59 (m, 2H), 7.42 (t, J = 8.0 Hz, 1H), 7.20 - 7.13 (m, 1H), 6.69 (d, J = 7.6 Hz, 1H), 6.01 (d, J = 6.0 Hz, 1H), 3.77 - 3.66 (m, 1H), 3.02 (d, J = 14.0 Hz, 1H).Example 10: (4-((8R,15R)-7-chloro-8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2- a][l,2,4]triazolo[4,3-d][l,4]diazocin-l l-yl)-2-fluorophenyl)dimethylphosphine oxide To a stirred solution of (8R,15R)-7-chloro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[4,3-d][l,4]diazocin-l l-yl trifluoromethanesulfonate (70 mg, 0.145 mmol) and 2-[4-(dimethylphosphoryl)-3- fluorophenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (56 mg, 0.189 mmol) in 1,4-dioxane (2 mL) and H2O (0.4 mL) were added K2CO3 (40 mg, 0.291 mmol) and Pd(PPh3)4 (16 mg, 0.014 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 4 h under nitrogen atmosphere. The reaction was diluted with water at room temperature. 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. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (0.1% FA), 40% to 50% gradient in 20 min; detector, 254 nm to afford (4-((8R,15R)-7-chloro-8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2- a][l,2,4]triazolo[4,3-d][l,4]diazocin-l l-yl)-2-fluorophenyl)dimethylphosphine oxide (25 mg, 34%). MS ESI calculated for C26H20CIFN5OP [M + H]+, 504.11 found 504.20.1H NMR (400 MHz, Chloroform-t / ) 5 8.98 - 8.91 (m, 1H), 8.72 (s, 1H), 8.11 - 7.99 (m, 1H), 7.90 (d, J = 1.7 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.67 - 7.60 (m, 1H), 7.58 - 7.50 (m, 2H), 7.44 (t, J = 8.1 Hz,1H), 7.36 - 7.27 (m, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.14 (d, J = 6.0 Hz, 1H), 3.82 - 3.70 (m, 1H), 3.05 (d, J = 13.9 Hz, 1H), 1.86 (s, 3H), 1.83 (s, 3H).19F NMR (377 MHz, Chloroforms / ) 5 - 105.42, -105.43.31P NMR (162 MHz, Chloroforms / ) 5 30.35, 30.33.

[0160] Example 11 : (5-((8R,15R)-7-(difhroromethoxy)-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)pyrimidin-2- yl)dimethylphosphine oxideTo a stirred solution of (8R,15R)-7-(difluorom ethoxy)- 1 l-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-8H, 15H-8, 15-methanobenzo[f]benzo[4, 5]imidazo[ 1 ,2-a] [ 1 , 2, 4]tri azolof 1,5- d][l,4]diazocine (40 mg, 0.081 mmol) and 5-bromo-2-(dimethylphosphoryl)pyrimidine (25 mg, 0.105 mmol) in 1,4-dioxane (1 mL) and H2O (0.2 mL) was added Pd(dppf)C12 (7 mg, 0.008 mmol), K2CO3 (34 mg, 0.243 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 16 h under nitrogen atmosphere and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CTfcCh / 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), 40% to 50% gradient in 10 min; detector, 254 nm. This resulted in (5-((8R,15R)-7- (difhioromethoxy)-8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5- d][l,4]diazocin-l l-yl)pyrimidin-2-yl)dimethylphosphine oxide (20 mg, 47%). MS ESI calculated for C25H20F2N7O2P [M + H]+, 520.14 found 520.20. 'H NMR (400 MHz, DMSO-t / 6) 5 9.24 (s, 2H), 8.50 - 8.43 (m, 1H), 8.13 (s, 1H), 7.97 - 7.67 (m, 4H), 7.63 - 7.57 (m, 1H), 7.49 (d, J = 8.2 Hz, 1H), 6.58 (d, J = 7.4 Hz, 1H), 6.36 (d, J = 6.2 Hz, 1H), 3.78 - 3.68 (m, 1H), 3.06 (d, J = 14.0 Hz, 1H), 1.83 (s, 3H), 1.80 (s, 3H).19F NMR (377 MHz, DMSO-tZ6) 5 -81.44, - 81.89, -82.73, -83.19.31P NMR (162 MHz, DMSO-t / 6) 6 33.89.

[0161] Example 12: (4-((8R,15R)-7-chloro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-2- fhrorophenyl)dimethylphosphine oxidePreparation 12A: (7R,14R)-6-amino-l-chloro-l l-methoxy-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-oneA solution of (7R,14R)-1 -chi oro-1 l-methoxy-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one (500 mg, 1.472 mmol) in DMF (8 mL) was added Z-BuONa (566 mg, 5.888 mmol) in DMF (4 mL) drop wise over 2 min at 0 °C. Followed by the addition of aminooxysulfonic acid (333 mg, 2.944 mmol) at 0 °C. The resulting mixture was stirred at room temperature for additional 30 min. The reaction was quenched by the addition of sat. ISfeSCL (aq.) (10 mL) at 0 °C. The resulting mixture was extracted with CH2CI2 (3 x 40 mL). The combined organic layers were washed with brine (5 x 10 mL), dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CFLCh / MeOH (10:1) to afford (7R,14R)-6-amino-l -chi oro-1 l-methoxy-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one (320 mg, 61%) as a brown solid. MS ESI calculated for CisHisC Ch [M + H]+, 355.09 found 354.95. 'H NMR (400 MHz, Chloroforms / ) 5 8.56 - 8.42 (m, 1H), 7.72 - 7.52 (m, 2H), 7.37 (t, J = 8.2 Hz, 1H), 7.09 (d, J = 2.6 Hz, 1H), 6.94 - 6.82 (m, 1H), 6.37 (d, J = 7.4 Hz, 1H), 5.34 (d, J = 7.2 Hz, 1H), 3.83 (s, 3H), 3.49 - 3.37 (m, 1H), 2.82 (d, J = 13.6 Hz, 1H).Preparation 12B: (8R,15R)-7-chloro-l l-methoxy-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine To a stirred solution of (7R,14R)-6-amino-l -chloro- 11 -m ethoxy-6, 7-dihydro-7, 14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one (260 mg, 0.733 mmol) and diisopropylamine (593 mg, 5.864 mmol) in 1,4-dioxane (10 mL) was added formamidine acetate (610 mg, 5.864 mmol) at room temperature. The resulting mixture was stirred at 90 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentratedunder reduced pressure and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford (8R,15R)-7-chloro-l l-methoxy-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (180 mg, 68%) as a brown solid. MS ESI calculated for C19H14CIN5O [M + H]+, 364.09 found 364.05. 'HNMR (400 MHz, Chloroform-t / ) 5 8.75 - 8.68 (m, 1H), 7.92 (s, 1H), 7.63 - 7.54 (m, 2H), 7.40 (t, J =8.1 Hz, 1H), 7.13 (d, J = 2.5 Hz, 1H), 6.89 - 6.82 (m, 1H), 6.61 (d, J = 7.6 Hz, 1H), 6.13 (d, J =6.2 Hz, 1H), 3.83 (s, 3H), 3.67 - 3.56 (m, 1H), 2.96 (d, J = 13.7 Hz, 1H).Preparation 12C : (8R, 15R)-7-chloro-8H, 15H-8, 15-methanobenzo[f]benzo[4,5]imidazo[l ,2- a] [ 1 , 2, 4]tri azolof 1 ,5-d] [ 1 ,4]diazocin- 11 -olTo a solution of (8R,15R)-7-chloro-l l-methoxy-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (180 mg, 0.495 mmol) in DCM (4 mL) was added BBr? (1.48 mL, 1.485 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for additional 3 h. The resulting mixture was concentrated under reduced pressure. The reaction was quenched with MeOH (2 mL) at 0 °C. 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 (0.1% FA), 20% to 50% gradient in 30 min; detector, 254 nm to afford (8R, 15R)-7-chloro-8H, 15H-8, 15-methanobenzo[f]benzo[4,5]imidazo[ 1 ,2- a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-ol (120 mg, 69%) as an off-white solid. MS ESI calculated for CI8HI2C1N5O [M + H]+, 350.07 found 350.10.Preparation 12D: (8R,15R)-7-chloro-8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2- a] [ 1 , 2, 4]tri azolof 1 ,5-d] [ 1 ,4]diazocin- 11 -yl trifluoromethanesulfonateTo a stirred solution of (8R,15R)-7-chloro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-ol (140 mg, 0.40 mmol) and l,l,l-trifluoro-N-phenyl-N-(trifluoromethane)sulfonylmethanesulfonamide (229 mg, 0.64 mmol) in DCM (3 mL) were added DMAP (5 mg, 0.04 mmol) and TEA (81 mg, 0.80 mmol) 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 silica gel column chromatography, eluted with CH2Cl2 / MeOH (10: 1) to afford (8R, 15R)-7-chloro-8H, 15H-8, 15-methanobenzo[f]benzo[4,5]imidazo[ 1 ,2- a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl trifluoromethanesulfonate (100 mg, 52%) as an off- white solid. MS ESI calculated for C19H11CIF3N5O3S [M + H]+, 482.02 found 482.10. 'HNMR (400 MHz, DMSO-t / e) 8 8.62 (d, J = 8.2 Hz, 1H), 8.14 (s, 1H), 7.85 - 7.74 (m, 2H), 7.63 - 7.52 (m, 2H), 7.38 - 7.28 (m, 1H), 6.73 (d, J = 7.4 Hz, 1H), 6.37 (d, J = 6.2 Hz, 1H), 3.79 - 3.65 (m, 1H), 3.12 (d, J = 14.2 Hz, 1H).Example 12: (4-((8R,15R)-7-chloro-8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2- a] [ 1 , 2, 4]tri azolof 1 ,5-d] [ 1 ,4]diazocin- 11 -yl)-2-fluorophenyl)dimethylphosphine oxide To a stirred solution of (8R,15R)-7-chloro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl trifluoromethanesulfonate (60 mg, 0.125 mmol) and 2-[4-(dimethylphosphoryl)-3- fluorophenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (48 mg, 0.162 mmol) in 1,4-dioxane (2 mL) and H2O (0.4 mL) were added K2CO3 (34 mg, 0.249 mmol) and Pd(PPhs)4 (14 mg, 0.012 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 and purified by silica gel column chromatography, eluted with CEECh / MeOEl (10: 1) followed by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (0.1% FA), 35% to 55% gradient in 20 min; detector, 254 nm to afford (4-((8R, 15R)-7-chloro-8H, 15H-8, 15-methanobenzo[f]benzo[4,5]imidazo[ 1 ,2- a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-2-fhiorophenyl)dimethylphosphine oxide (10 mg, 17%). MS ESI calculated for C26H20CIFN5OP [M + H]+, 504.11 found 504.20. 'H NMR (400 MHz, Chloroform-t / ) 5 8.80 - 8.73 (m, 1H), 8.13 - 8.02 (m, 1H), 7.99 (s, 1H), 7.95 - 7.80 (m, 2H), 7.66 (d, J = 7.6 Hz, 1H), 7.60 - 7.50 (m, 2H), 7.46 (t, J = 8.0 Hz, 1H), 7.36 - 7.28 (m, 1H), 6.89 - 6.74 (m, 1H), 6.63 - 6.43 (m, 1H), 4.03 - 3.80 (m, 1H), 3.16 - 3.05 (m, 1H), 1.87 (s, 3H), 1.83 (s, 3H).19F NMR (377 MHz, Chloroforms / ) 5 -105.33.31P NMR (162 MHz, Chloroform- d) 5 30.67.

[0162] Example 13: (4-((8R,15R)-7-ethynyl-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-2- fhrorophenyl)dimethylphosphine oxidePreparation 13 A: (S,E)-N-(2-bromo-6-chlorobenzylidene)-2-methylpropane-2-sulfinamide To a stirred solution of 2-bromo-6-chlorobenzaldehyde (100.00 g, 455.664 mmol) and CS2CO3 (163.00 g, 501.230 mmol) in DCM (1 L) was added (S)-2-methylpropane-2-sulfinamide (66.27 g, 546.797 mmol) in portions at room temperature. The resulting mixture was stirred for 3 h at room temperature. The resulting mixture was diluted with water (I L) and extracted with CH2Q2 (3 x 500 mL). The combined organic layers were washed with brine (3 x 500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PEZEA (10: 1) to afford (S, E)-N-(2-bromo-6-chlorobenzylidene)-2-methylpropane-2-sulfinamide (121.00 g, 82%). MS ESI calculated for CnHi3BrClNOS [M + H]+, 321.96 323.96 found 322.00 323.95. 'H NMR (400 MHz, Chloroform-t / ) 5 8.85 (s, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.22 (t, J = 8.1 Hz, 1H), 1.33 (s, 9H).Preparation 13B: tert-butyl (R)-3-(2-bromo-6-chlorophenyl)-3-(((S)-tert-butylsulfinyl) amino) propanoateA mixture ofZn (164.54 g, 2516.661 mmol) and CuCI (53.39 g, 539.284 mmol) in THF (1 L) was stirred for 2 h at 60 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. To the above mixture was added tert-butyl 2-bromoacetate (175.32 g,898.808 mmol) dropwise over 5 min at 25 °C. The resulting mixture was stirred for additional 2 h at 60 °C. The mixture was allowed to cool down to room temperature again. To the above mixture was added (S, E)-N-(2-bromo-6-chlorobenzylidene)-2-methylpropane-2-sulfinamide (116.00 g, 359.523 mmol) in portions over 5 min at 10 °C. The resulting mixture was stirred for additional 3 h at room temperature. The resulting mixture was filtered, the filter cake was washed with MTBE (3 x 100 mL) followed by addition of MTBE (1500 mL) and saturated citric acid solution (500 mL). The aqueous layer was extracted with MTBE (3 x 500 mL) and the combined organic layers were washed with saturated NaHCCh solution (500 mL), dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. This resulted in tert-butyl (R)-3-(2-bromo-6-chlorophenyl)-3-(((S)-tert-butylsulfinyl) amino) propanoate (127.00 g, 81%). MS ESI calculated for CnIfeBrCINChS [M + H]+, 438.04 440.04 found 438.05 440.05. 'H NMR (300 MHz, Chloroform-tZ) 5 7.51 (d, J = 8.1 Hz, 1H), 7.32 (d, J = 9.0 Hz, 1H), 7.06 (t, J = 8.0 Hz, 1H), 5.85 - 5.65 (m, 1H), 4.57 - 4.33 (m, 1H), 3.31 - 3.12 (m, 1H), 3.11 - 2.87 (m, 1H), 1.38 (s, 9H), 1.11 (s, 9H).Preparation 13C: tert-butyl (R)-3-amino-3-(2-bromo-6-chlorophenyl)propanoateTo a stirred solution of tert-butyl (R)-3-(2-bromo-6-chlorophenyl)-3-(((S)-tert-butylsulfinyl) amino) propanoate (127.00 g, 289.419 mmol) in THF (500 mL) and H2O (100 mL) was added I2 (18.36 g, 72.533 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 50 °C. The reaction was quenched by the addition of sat. NaHCCh (aq.) (1 L) at 0 °C followed by extraction with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (3 x 2 L) and dried over anhydrous ISfeSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in ACN (200 mL) followed by the addition of solution (2S)-2-hydroxy-2-phenylacetic acid (44.03 g, 289.419 mmol) in ACN (200 mL) dropwise at room temperature. The resulting mixture was stirred for additional 15 min at room temperature. The precipitated solids were collected by filtration and washed with ACN (200 mL). The above solids in CH2CI2 (500 mL) and sat. NaHCCL (aq.) (1.5 L). The mixture was stirred for additional 15 min at room temperature. The resulting mixture was extracted with CH2Q2 (3 x 500 mL). The combined organic layers were washed with brine (3 x 500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl (R)-3-amino-3-(2-bromo-6-chlorophenyl)propanoate (84.00 g, 87%). MS ESI calculated for CoHnBrClNCh [M + H]+, 334.01 336.01 found 334.00 336.00.1H NMR (400 MHz, Chloroform-^ 5 7.55 - 7.46 (m, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.02 (t, J = 8.0 Hz, 1H), 5.25 - 5.17 (m, 1H), 3.09 - 2.96 (m, 1H), 2.90 - 2.73 (m, 1H), 2.25 (s, 2H), 1.41 (s, 9H).Preparation 13D: tert-butyl (R)-3-(2-bromo-6-chlorophenyl)-3-((5-methoxy-2- nitrophenyl)amino)propanoateTo a stirred solution of tert-butyl (R)-3-amino-3-(2-bromo-6-chlorophenyl)propanoate (42.00 g, 125.508 mmol) and 2-fluoro-4-methoxy-l -nitrobenzene (23.63 g, 138.059 mmol) in DMAc (500 mL) was added DIEA (24.33 g, 188.262 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 80 °C. The resulting mixture was diluted with water (500 mL) followed by extraction with EA (3 x 500 mL). The combined organic layers were concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PEZEA (10: 1) to afford tert-butyl (R)-3-(2-bromo-6-chlorophenyl)- 3-((5-methoxy-2-nitrophenyl)amino)propanoate (50.00 g, 82%). MS ESI calculated for C2oH22BrClN205[M + H]+, 485.04 487.04 found 485.00 487.00. 'HNMR (300 MHz, Chloroforms / ) 5 9.29 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 9.5 Hz, 1H), 7.52 (s, 1H), 7.34 (s, 1H), 7.09 (t, J = 8.0 Hz, 1H), 6.27 - 6.08 (m, 2H), 6.01 - 5.79 (m, 1H), 3.78 (s, 3H), 3.27 (t, J = 13.0 Hz, 1H), 2.91 - 2.74 (m, 1H), 1.42 (s, 9H).Preparation 13E: (R)-3-(2-bromo-6-chlorophenyl)-3-((5-methoxy-2-nitrophenyl)amino)propanal To tert-butyl (R)-3-(2-bromo-6-chlorophenyl)-3-((5-methoxy-2-nitrophenyl)amino)propanoate (50.00 g, 102.931 mmol) in DCM (1 L) was added DIB AL-H (113.2 mL, 113.224 mmol, 1 M in THF) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 3 h at -78 °C under nitrogen atmosphere. The reaction was quenched with HC1 (IN) at -78 °C followed by extraction with CH2Q2 (3 x 1 L). The combined organic layers were washed with brine (3 x 1 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Q2 / PE (1 : 1) to afford (R)-3-(2-bromo-6-chlorophenyl)-3-((5-methoxy-2- nitrophenyl)amino)propanal (38.01 g, 89%). MS ESI calculated for CieHuBrChS CU [M + H]+, 412.98 414.98 found 413.00 415.00. 'H NMR (300 MHz, Chloroforms / ) 5 9.86 (s, 1H), 9.25 (d, J = 8.3 Hz, 1H), 8.15 - 8.08 (m, 1H), 7.63 - 7.50 (m, 1H), 7.51 - 7.34 (m, 1H), 7.12 (t, J = 8.0 Hz, 1H), 6.28 - 6.21 (m, 2H), 6.13 - 6.00 (m, 1H), 3.82 (s, 3H), 3.74 - 3.55 (m, 1H), 3.06 (d, J = 17.5 Hz, 1H).Preparation 13F : (R)-N-((R,E)-3-(2-bromo-6-chlorophenyl)-3-((5-methoxy-2- nitrophenyl)amino)propylidene)-2-methylpropane-2-sulfinamideTo a stirred solution of (R)-3-(2-bromo-6-chlorophenyl)-3-((5-methoxy-2- nitrophenyl)amino)propanal (39.00 g, 94.283 mmol) and Ti(O / -Pr)4 (53.59 g, 188.566 mmol) in DCM (300 mL) was added (R)-2-methylpropane-2-sulfinamide (13.71 g, 113.140 mmol) in portions at room temperature. The resulting mixture was stirred for 3 h at room temperature. The resulting mixture was diluted with water (500 mL) followed by extraction with CH2Q2 (3 x 500mL). The combined organic layers were washed with brine (3 x 500 mL) and dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PEZEA (10: 1) to afford (R)-N-((R,E)-3-(2-bromo-6-chlorophenyl)-3-((5-methoxy-2-nitrophenyl)amino)propylidene)-2- methylpropane-2-sulfmamide (44.10 g, 90%). MS ESI calculated for C2oH23BrClN304S [M + H]+, 516.03 518.03 found 516.10 518.00. 'HNMR (400 MHz, Chloroforms / ) 5 9.35 - 9.19 (m, 1H), 8.19 - 8.13 (m, 1H), 8.08 (d, J = 9.5 Hz, 1H), 7.61 - 7.30 (m, 2H), 7.12 (t, J = 8.1 Hz, 1H), 6.27 - 6.17 (m, 1H), 6.12 - 6.05 (m, 1H), 5.97 - 5.82 (m, 1H), 3.77 (s, 3H), 3.71 - 3.58 (m, 1H), 3.19 - 3.04 (m, 1H), 1.17 (s, 9H).Preparation 13G: (R)-N-((R, E)-3-(2-bromo-6-chlorophenyl)-3-((5-m ethoxy -2- nitrophenyl)amino)propylidene)-2-methylpropane-2-sulfinamideTo a stirred solution of (R)-N-[(lE,3R)-3-(2-bromo-6-chlorophenyl)-3-[(5-methoxy-2- nitrophenyl)amino]propylidene]-2-methylpropane-2-sulfinamide (44.00 g, 85.133 mmol) and CsF (25.86 g, 170.266 mmol) in DCM (500 mL) was added TMSCN (16.89 g, 170.266 mmol) in portions at room temperature. The resulting mixture was stirred for 3 h at room temperature. The resulting mixture was diluted with water (500 mL) followed by extraction with CH2CI2 (3 x 200 mL). The combined organic layers were washed with brine (3 x 500 mL) and dried over anhydrous ISfeSCH After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PEZEA (10: 1) to afford (R)-N-((3R)-3-(2-bromo-6-chlorophenyl)-l-cyano-3-((5-methoxy-2-nitrophenyl)amino)propyl)- 2-methylpropane-2-sulfinamide (39.80 g, 86%). MS ESI calculated for C2iH24BrClN4O4S [M + H]+, 543.04 545.04 found 543.00 545.00. 'HNMR (400 MHz, Chloroforms / ) 5 9.36 - 9.16 (m, 1H), 8.20 - 8.08 (m, 1H), 7.63 - 7.32 (m, 2H), 7.17 - 7.06 (m, 1H), 6.32 - 6.12 (m, 2H), 5.87 - 5.70 (m, 1H), 4.76 - 4.43 (m, 1H), 3.84 - 3.73 (m, 3H), 3.14 - 2.91 (m, 1H), 2.50 - 2.34 (m, 1H), 1.26 - 1.17 (m, 9H).Preparation 13H: (lR,3R)-l-(2-bromo-6-chlorophenyl)-7-methoxy-2,3-dihydro-lH- benzofd] pyrrol o[ 1 ,2-a]imidazol-3 -amineTo a stirred solution of (R)-N-((R,E)-3-(2-bromo-6-chlorophenyl)-3-((5-methoxy-2- nitrophenyl)amino)propylidene)-2-methylpropane-2-sulfinamide (39.80 g, 73.181 mmol) and TiCh (451.44 g, 585.448 mmol, 20%) in EtOH (500 mL) at room temperature. The resulting mixture was stirred overnight at 80 °C. The resulting mixture was diluted with EtOAc (100 mL). The residue was basified to pH 7 with saturated NaHCCh (aq.). The resulting mixture was filtered and the filter cake was washed with EtOAc (3 x 100 mL). The filtrate was washed with 2 x 1 L of water. The organic layer was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with C^CL / MeOH (10: 1) to afford (lR,3R)-l-(2-bromo-6-chlorophenyl)-7-methoxy-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-3-amine (18.70 g, 65%). MS ESI calculated for CnHisBrC O [M + H]+, 392.01 394.01 found 391.85 393.85. 'H NMR (300 MHz, Chloroform^ / ) 5 7.72 - 7.62 (m, 2H), 7.59 - 7.44 (m, 1H), 7.20 (t, J = 8.0 Hz, 1H), 6.92 - 6.80 (m, 1H), 6.33 - 6.19 (m, 1H), 6.13 - 6.06 (m, 1H), 4.87 - 4.65 (m, 1H), 3.73 - 3.66 (m, 3H), 3.60 - 3.20 (m, 1H), 3.01 - 2.59 (m, 1H).Preparation 131: (7R,14R)-l-chloro-l l-methoxy-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one To a stirred mixture of (lR,3R)-l-(2-bromo-6-chlorophenyl)-7-methoxy-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazol-3 -amine (7.80 g, 19.864 mmol) and pyridine-2-carboxylic acid (1.22 g, 9.932 mmol), K2CO3 (13.73 g, 99.320 mmol) in 1,4-dioxane (150 mL) were added PCy3.HBF4 (1.11 g, 3.973 mmol) and Pd(OAc)2 (0.89 g, 3.973 mmol) at room temperature. The resulting mixture was stirred for 16 h at 100 °C under carbon monoxide atmosphere (10 atm.). The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with C ECh / MeOH (10: 1) to afford (7R,14R)-l-chloro-l l- methoxy-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one (2.10 g, 31%). MS ESI calculated for C18H14CIN3O2 [M + H]+, 340.08 found 340.05. *H NMR (400 MHz, Chloroform-t / ) 5 8.56 - 8.47 (m, 1H), 7.71 - 7.53 (m, 2H), 7.45 (d, J = 6.4 Hz, 1H), 7.36 (t, J = 8.1 Hz, 1H), 7.12 (d, J = 2.5 Hz, 1H), 6.93 - 6.84 (m, 1H), 6.45 (d, J = 7.3 Hz, 1H), 4.90 (t, J = 6.5 Hz, 1H), 3.83 (s, 3H), 3.49 - 3.34 (m, 1H), 2.84 (d, J = 13.3 Hz, 1H).Preparation 13J: (7R,14R)-6-amino-l-chloro-l l-methoxy-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-oneA solution of (7R,14R)-1 -chi oro-1 l-methoxy-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one (500 mg, 1.472 mmol) in DMF (8 mL) was stirred at 0 °C for 2 min. To the above mixture was added LBuONa (566 mg, 5.888 mmol) in DMF (4 mL) dropwise over 2 min at 0 °C. To the above mixture was added (aminooxy)sulfonic acid (333 mg, 2.944 mmol) at 0 °C. The resulting mixture was stirred at room temperature for additional 30 min. The reaction was quenched by the addition of sat. Na2SO3 (aq.) (10 mL) at 0 °C followed by extraction with CH2CI2 (3 x 40 mL). The combined organic layers were washed with brine (3 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with C^CL / MeOH (10: 1) to afford (7R,14R)-6- amino- 1 -chloro- 11 -methoxy-6,7-dihydro-7, 14-methanobenzo[f]benzo[4,5]imidazo[ 1 ,2- a][l,4]diazocin-5(14H)-one (320 mg, 61%). MS ESI calculated for C18H15CIN4O2 [M + H]+, 355.09 found 354.95. 'H NMR (400 MHz, Chloroforms / ) 5 8.56 - 8.42 (m, 1H), 7.72 - 7.52 (m,2H), 7.37 (t, J = 8.2 Hz, 1H), 7.09 (d, J = 2.6 Hz, 1H), 6.94 - 6.82 (m, 1H), 6.37 (d, J = 7.4 Hz, 1H), 5.34 (d, J = 7.2 Hz, 1H), 3.83 (s, 3H), 3.49 - 3.37 (m, 1H), 2.82 (d, J = 13.6 Hz, 1H). Preparation 13K: (8R,15R)-7-chloro-l l-methoxy-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocineTo a stirred solution of (7R,14R)-6-amino-l -chloro- 11 -m ethoxy-6, 7-dihydro-7, 14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one (260 mg, 0.733 mmol) and diisopropylamine (593 mg, 5.864 mmol) in 1,4-dioxane (10 mL) was added formimidamide acetate (610 mg, 5.864 mmol) at room temperature. The resulting mixture was stirred at 90 °C for 16 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 (8R,15R)-7-chloro-l l-methoxy-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (180 mg, 68%)MS ESI calculated for C19H14CIN5O [M + H]+, 364.09 found 364.05. 'HNMR (400 MHz, Chloroforms / ) 5 8.75 - 8.68 (m, 1H), 7.92 (s, 1H), 7.63 - 7.54 (m, 2H), 7.40 (t, J = 8.1 Hz, 1H), 7.13 (d, J = 2.5 Hz, 1H), 6.89 - 6.82 (m, 1H), 6.61 (d, J = 7.6 Hz, 1H), 6.13 (d, J = 6.2 Hz, 1H), 3.83 (s, 3H), 3.67 - 3.56 (m, 1H), 2.96 (d, J = 13.7 Hz, 1H).Preparation 13L: (8R,15R)-7-chloro-8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2- a] [ 1 , 2, 4]tri azolof 1 ,5-d] [ 1 ,4]diazocin- 11 -olA solution of (8R,15R)-7-chloro-l l-methoxy-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (180 mg, 0.495 mmol) in DCM (4 mL) was stirred at 0 °C for 5 min under nitrogen atmosphere. To the above mixture was added BB (1.48 mL, 1.485 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for additional 3 h. The reaction was quenched with MeOH (2 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in water (0.1% FA), 20% to 50% gradient in 30 min; detector, 254 nm to afford (8R, 15R)-7-chloro-8H, 15H-8, 15-methanobenzo[f]benzo[4,5]imidazo[ 1 ,2- a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-ol (120 mg, 69%). MS ESI calculated for CisHnCINsO [M + H]+, 350.07 found 350.10.Preparation 13M: (8R,15R)-7-chloro-8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2- a] [ 1 , 2, 4]tri azolof 1 ,5-d] [ 1 ,4]diazocin- 11 -yl trifluorom ethanesulfonateTo a stirred solution of (8R,15R)-7-chloro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-ol (140 mg, 0.40 mmol) and l,l,l-trifluoro-N-phenyl-N-(trifluoromethane)sulfonylmethanesulfonamide (229 mg, 0.64 mmol) in DCM (3 mL) were added DMAP (5 mg, 0.04 mmol) and TEA (81 mg,0.80 mmol) 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 silica gel column chromatography, eluted with C LCh / MeOH (10: 1) to afford (8R,15R)-7-chloro-8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l, 2, 4]tri azolof 1,5- d][l,4]diazocin-l l-yl trifluoromethanesulfonate (100 mg, 52%). MS ESI calculated for C19H11CIF3N5O3S [M + H]+, 482.02 found 482.10.1H NMR (400 MHz, DMSO-t / 6) 8 8.62 (d, J = 8.2 Hz, 1H), 8.14 (s, 1H), 7.85 - 7.74 (m, 2H), 7.63 - 7.52 (m, 2H), 7.38 - 7.28 (m, 1H), 6.73 (d, J = 7.4 Hz, 1H), 6.37 (d, J = 6.2 Hz, 1H), 3.79 - 3.65 (m, 1H), 3.12 (d, J = 14.2 Hz, 1H). Preparation 13N : (4-((8R, 15R)-7-chloro-8H, 15H-8, 15-methanobenzo[f]benzo[4, 5]imidazo[ 1,2- a] [ 1 , 2, 4]tri azolof 1 ,5-d] [ 1 ,4]diazocin- 11 -yl)-2-fluorophenyl)dimethylphosphine oxide To a stirred solution of (8R,15R)-7-chloro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl trifluoromethanesulfonate (60 mg, 0.125 mmol) and 2-[4-(dimethylphosphoryl)-3- fhiorophenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (48 mg, 0.162 mmol) in 1,4-dioxane (2 mL) and H2O (0.4 mL) were added K2CO3 (34 mg, 0.249 mmol) and Pd(PPh3)4 (14 mg, 0.012 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 C^Cb / MeOH (10: 1) followed by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (0.1% FA), 35% to 55% gradient in 20 min; detector, 254 nm to afford (4-((8R, 15R)-7-chloro-8H, 15H-8, 15-methanobenzo[f]benzo[4,5]imidazo[ 1 ,2- a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-2-fhiorophenyl)dimethylphosphine oxide (10 mg, 17%). MS ESI calculated for C26H20CIFN5OP [M + H]+, 504.11 found 504.20. 'H NMR (400 MHz, Chloroforms / ) 5 8.80 - 8.73 (m, 1H), 8.13 - 8.02 (m, 1H), 7.99 (s, 1H), 7.95 - 7.80 (m, 2H), 7.66 (d, J = 7.6 Hz, 1H), 7.60 - 7.50 (m, 2H), 7.46 (t, J = 8.0 Hz, 1H), 7.36 - 7.28 (m, 1H), 6.89 - 6.74 (m, 1H), 6.63 - 6.43 (m, 1H), 4.03 - 3.80 (m, 1H), 3.16 - 3.05 (m, 1H), 1.87 (s, 3H), 1.83 (s, 3H).19F NMR (377 MHz, Chloroforms / ) 5 -105.33.31P NMR (162 MHz, Chloroform- d) 5 30.67.Preparation 130: (2-fluoro-4-((8R, 15R)-7-((triisopropylsilyl)ethynyl)-8H, 15H-8, 15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l- yl)phenyl)dimethylphosphine oxideTo a stirred solution of (4-((8R,15R)-7-chloro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-2- fluorophenyl)dimethylphosphine oxide (90 mg, 0.179 mmol) and ethynyltriisopropylsilane (65 mg, 0.358 mmol) in CH3CN (5 mL) were added Sphos (15 mg, 0.036 mmol), Sphos Pd G3 (28mg, 0.036 mmol) and K2CO3 (123 mg, 0.895 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CJbCh / MeOH (10:1) to afford (2-fluoro-4-((8R,15R)-7-((triisopropylsilyl)ethynyl)- 8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l, 2, 4]tri azolof l,5-d][l,4]diazocin-l 1- yl)phenyl)dimethylphosphine oxide (80 mg, 68%). MS ESI calculated for CsvEUiFNsOPSi [M + H]+, 650.28 found 650.25. 'HNMR (400 MHz, Chloroforms / ) 5 8.75 - 8.67 (m, 1H), 8.02 - 7.92 (m, 2H), 7.85 - 7.81 (m, 1H), 7.76 (t, J = 8.0 Hz, 2H), 7.48 - 7.40 (m, 3H), 7.25 - 7.20 (m, 1H), 6.85 (d, J = 7.2 Hz, 1H), 6.21 (d, J = 6.0 Hz, 1H), 3.70 - 3.66 (m, 1H), 3.03 (d, J = 13.6 Hz, 1H), 1.84 (s, 3H), 1.81 (s, 3H), 1.27 - 1.16 (m, 3H), 1.14 - 1.08 (m, 18H).19F NMR (377 MHz, Chloroforms / ) 5 -105.82, -105.83.3 XP NMR (162 MHz, Chloroforms / ) 5 30.13.Example 13 : (4-((8R, 15R)-7-ethynyl-8H, 15H-8, 15-methanobenzo[f]benzo[4,5]imidazo[ 1 ,2- a] [ 1 , 2, 4]tri azolof 1 ,5-d] [ 1 ,4]diazocin- 11 -yl)-2-fluorophenyl)dimethylphosphine oxide A solution of (2-fluoro-4-((8R,15R)-7-((triisopropylsilyl)ethynyl)-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l- yl)phenyl)dimethylphosphine oxide (80 mg, 0.123 mmol) and TBAF (35 mg, 0.135 mmol) in THF (4 mL) was stirred at room temperature for 1 h. The reaction was diluted with water at room temperature followed by extraction with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol / L NH4HC03+0.05%NH3'H20), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 23% B to 38% B in 14 min; Wave Length: 254nm / 220nm; RTl(min): 10.55) to afford (4-((8R,15R)-7- ethynyl-8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l, 2, 4]tri azolof 1,5- d][l,4]diazocin-l l-yl)-2-fluorophenyl)dimethylphosphine oxide (32 mg, 52%). MS ESI calculated for C28H21FN5OP [M + H]+, 494.15 found 494.15.XH NMR (400 MHz, Methanols^) 5 8.83 - 8.73 (m, 1H), 8.11 - 7.92 (m, 3H), 7.82 - 7.72 (m, 2H), 7.57 - 7.51 (m, 1H), 7.50 - 7.42 (m, 2H), 7.35 - 7.29 (m, 1H), 6.75 (d, J = 7.2 Hz, 1H), 6.21 (d, J = 6.0 Hz, 1H), 3.77 (s, 1H), 3.72 - 3.61 (m, 1H), 3.02 (d, J = 13.6 Hz, 1H), 1.85 (s, 3H), 1.82 (s, 3H).19F NMR (377 MHz, Chloroforms / ) 5 -105.74, -105.73.31P NMR (162 MHz, Chloroforms / ) 5 30.42, 30.39.

[0163] Example 14: (4-((8R,15R)-7-(difluoromethoxy)-2-methyl-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-2- fluorophenyl)dimethylphosphine oxidePreparation 14A: (7R,14R)-6-amino-l l-chloro-l-(difluoromethoxy)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-oneTo a stirred solution of (7R,14R)-1 l-chloro-l-(difluoromethoxy)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one (1.00 g, 2.661 mmol) in DMF (10 mL) was added Z-BuONa (1.10 g, 11.442 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 5 min. To the above mixture was added (aminooxy)sulfonic acid (602 mg, 5.322 mmol) at 0 °C. 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 CthCb / MeOH (10: 1) to afford (7R,14R)-6-amino-l l- chloro-l-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2- a][l,4]diazocin-5(14H)-one (620 mg, 60%). MS ESI calculated for C18H13CIF2N4O2 [M + H]+, 391.07 found 391.10. *H NMR (400 MHz, Chloroforms / ) 5 8.45 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 8.7 Hz, 1H), 7.50 - 7.43 (m, 2H), 7.38 (d, J = 8.2 Hz, 1H), 7.26 - 7.22 (m, 1H), 6.84 (t, J = 72.5 Hz, 1H), 6.25 (d, J = 7.3 Hz, 1H), 5.48 (d, J = 7.2 Hz, 1H), 3.53 - 3.42 (m, 3H), 2.86 (d, J = 13.7 Hz, 1H).19F NMR (377 MHz, Chloroforms / ) 5 -80.21, -80.66, -81.13, -81.57.Preparation 14B: (8R,15R)-l l-chloro-7-(difhioromethoxy)-2-methyl-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocineA mixture of ethanimidamide hydrochloride (735 mg, 7.776 mmol) and KOAc (764 mg, 7.776 mmol) in 1,4-di oxane (5 mL) was stirred at room temperature for 5 min under nitrogen atmosphere followed by addition (7R,14R)-6-amino-l l-chloro-l- (difhioromethoxy)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin- 5(14H)-one (380 mg, 0.972 mmol) and Diisopropylamine (787 mg, 7.776 mmol). The resulting mixture was stirred at 100 °C overnight. The resulting mixture was concentrated under reducedpressure. The residue was purified by silica gel column chromatography, eluted with CfhCh / MeOH (10:1) to afford (8R,15R)-l l-chloro-7-(difluoromethoxy)-2-methyl- 8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l, 2, 4]tri azolof l,5-d][l,4]diazocine (320 mg, 80%). MS ESI calculated for C20H14CIF2N5O [M + H]+, 414.09 found 414.15. 'H NMR (400 MHz, Methanol-^) 8 8.48 - 8.42 (m, 1H), 7.58 - 7.45 (m, 4H), 7.31 - 7.09 (m, 2H), 6.57 (d, J = 7.5 Hz, 1H), 6.14 (d, J = 6.3 Hz, 1H), 3.76 - 3.67 (m, 1H), 2.99 (d, J = 14.0 Hz, 1H), 2.36 (s, 3H).Example 14: (4-((8R, 15R)-7-(difluoromethoxy)-2-methyl-8H, 15H-8, 15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-2- fhiorophenyl)dimethylphosphine oxideTo a stirred solution of (8R,15R)-l l-chloro-7-(difhioromethoxy)-2-methyl-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (30 mg, 0.072 mmol) and 2-[4-(dimethylphosphoryl)-3-fluorophenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (32 mg, 0.108 mmol) in 1,4-di oxane (1 mL) and H2O (0.2 mL) were added K3PO4 (46 mg, 0.216 mmol), Sphos (6 mg, 0.014 mmol) and Sphos Pd G3 (6 mg, 0.007 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 C ECh / MeOH (10: 1) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in water (0.1% FA), 30% to 50% gradient in 20 min; detector, 254 nm to afford (4-((8R, 15R)-7-(difluoromethoxy)-2-methyl-8H, 15H-8, 15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-2- fhiorophenyl)dimethylphosphine oxide (28 mg, 70%). MS ESI calculated for C28H23F3N5O2P [M + H]+, 550.15 found 550.20.XH NMR (400 MHz, DMSO-t / 6) 6 8.41 (d, J = 8.1 Hz, 1H), 7.96 - 7.50 (m, 8H), 7.49 - 7.42 (m, 1H), 6.53 (d, J = 7.4 Hz, 1H), 6.22 (d, J = 6.2 Hz, 1H), 3.75 - 3.64 (m, 1H), 3.00 (d, J = 13.9 Hz, 1H), 2.32 (s, 3H), 1.76 (s, 3H), 1.73 (s, 3H).19F NMR (377 MHz, DMSO-t / e) 6-81.89, -82.34, -82.46, -82.48, -105.69.31P NMR (162 MHz, DMSO-t / 6) 6 28.44.

[0164] Example 15: (5-((8R,15R)-7-(difluoromethoxy)-2-methyl-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)pyridin-2- yl)dimethylphosphine oxidePreparation 15A: (8R,15R)-7-(difluoromethoxy)-2-methyl-l l-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-8H, 15H-8, 15-methanobenzo[f]benzo[4, 5]imidazo[ 1 ,2-a] [ 1 , 2, 4]tri azolof 1,5- d][l,4]diazocineTo a stirred mixture of (8R,15R)-l l-chloro-7-(difhioromethoxy)-2-methyl-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (270 mg, 0.652 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (215 mg, 0.848 mmol) in 1,4-dioxane (5 mL) were added Sphos Pd G3 (51 mg, 0.065 mmol), Sphos (54 mg, 0.130 mmol) and KO Ac (192 mg, 1.956 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 CFhCb / MeOH (10: 1) to afford (8R,15R)-7-(difluoromethoxy)-2- methyl-l l-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (300 mg, 91%). MS ESI calculated for C26H26BF2N5O3 [M + H]+, 506.21 found 506.10. 'HNMR (400 MHz, DMSO-tfc) 8 8.47 - 8.35 (m, 1H), 7.86 (s, 1H), 7.63 - 7.42 (m, 5H), 6.49 (d, J = 7.5 Hz, 1H), 6.19 (d, J = 6.2 Hz, 1H), 3.74 - 3.63 (m, 1H), 2.96 (d, J = 14.0 Hz, 1H), 2.31 (s, 3H), 1.29 (s, 12H).Example 15 : (5-((8R, 15R)-7-(difluoromethoxy)-2-methyl-8H, 15H-8, 15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)pyridin-2- yl)dimethylphosphine oxideTo a stirred solution of (8R,15R)-7-(difhioromethoxy)-2-methyl-l l-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-8H, 15H-8, 15-methanobenzo[f]benzo[4, 5]imidazo[ 1 ,2-a] [ 1 , 2, 4]tri azolof 1,5- d][l,4]diazocine (50 mg, 0.099 mmol) and 5-bromo-2-(dimethylphosphoryl)pyridine (30 mg, 0.129 mmol) in 1,4-dioxane (1 mL) and H2O (0.1 mL) were added Pd(dppf)C12 (8 mg, 0.010 mmol) and K2CO3 (41 mg, 0.297 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 CH2C12 / MeOH (10:1) followed by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in water (0.1% FA), 30% to 40% gradient in 20 min; detector, 254 nm to afford (5-((8R,15R)-7-(difluoromethoxy)-2-methyl-8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l, 2, 4]tri azolof l,5-d][l,4]diazocin-l 1- yl)pyri din-2 -yl)dimethylphosphine oxide (20 mg, 38%). MS ESI calculated for C27H23F2N6O2P [M + H]+, 533.16 found 508.10.XH NMR (400 MHz, DMSO-t / 6) 6 9.02 (d, J = 2.2 Hz, 1H), 8.45 - 8.38 (m, 1H), 8.22 - 8.15 (m, 1H), 8.07 - 7.99 (m, 1H), 7.94 - 7.71 (m, 3H), 7.65 - 7.59 (m, 1H), 7.56 (t, J = 8.2 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 6.54 (d, J = 7.3 Hz, 1H), 6.23 (d, J = 6.2 Hz, 1H), 3.76 - 3.64 (m, 1H), 3.00 (d, J = 13.9 Hz, 1H), 2.32 (s, 3H), 1.73 (s, 3H), 1.69 (d, J = 1.0 Hz, 3H).19F NMR (377 MHz, DMSO-t / 6) 6 -81.61, -82.06, -82.43, -82.89.31P NMR (162 MHz, DMSO-t / e) 5 33.96.

[0165] Example 16: (5-((8R,15R)-7-(difluoromethoxy)-2-methyl-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)pyrimidin-2- yl)dimethylphosphine oxideTo a stirred solution of (8R,15R)-7-(difluoromethoxy)-2-methyl-l l-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-8H, 15H-8, 15-methanobenzo[f]benzo[4, 5]imidazo[ 1 ,2-a] [ 1 , 2, 4]tri azolof 1,5- d][l,4]diazocine (50 mg, 0.099 mmol) and 5-bromo-2-(dimethylphosphoryl)pyrimidine (30 mg, 0.129 mmol) in 1,4-dioxane (1 mL) and H2O (0.1 mL) were added Pd(dppf)C12 (8 mg, 0.010 mmol) and K2CO3 (27 mg, 0.198 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 CTfcCh / MeOH (10:1) followed by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in water (0.1% FA), 30% to 40% gradient in 20 min; detector, 254 nm to afford (5-((8R,15R)-7-(difluoromethoxy)-2-methyl- 8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l, 2, 4]tri azolof l,5-d][l,4]diazocin-l 1- yl)pyrimidin-2-yl)dimethylphosphine oxide (20 mg, 38%). MS ESI calculated for C26H22F2N7O2P [M + H]+, 534.15 found 534.40. *HNMR (400 MHz, DMSO-t / 6) 8 9.24 (s, 2H), 8.41 (d, J = 8.0 Hz, 1H), 7.97 - 7.65 (m, 4H), 7.60 - 7.52 (m, 1H), 7.46 (d, J = 8.2 Hz, 1H), 6.55 (d, J = 7.3 Hz, 1H), 6.25 (d, J = 6.2 Hz, 1H), 3.76 - 3.65 (m, 1H), 3.01 (d, J = 14.0 Hz, 1H), 2.32 (s, 3H), 1.83 (s, 3H), 1.80 (s, 3H).19F NMR (377 MHz, DMSO-t / 6) 6 -81.36, -81.81, -82.68, - 83.13.31P NMR (162 MHz, DMSO-t / 6) 6 33.95.

[0166] Example 17: (4-((8R,15R)-7-(difluoromethoxy)-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-2,3- difluorophenyl)dimethylphosphine oxideTo a stirred solution of (8R,15R)-l l-chloro-7-(difluoromethoxy)-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (1.00 g, 2.501 mmol) and 2-[4-(dimethylphosphoryl)-2,3-difluorophenyl]-4, 4,5, 5-tetramethyl- 1,3,2- dioxaborolane (949 mg, 3.001 mmol) in 1,4-di oxane (20 mL) and H2O (2 mL) were added Sphos (205 mg, 0.500 mmol), Sphos Pd G3 (390 mg, 0.500 mmol) and K3PO4 (2.12 g, 10.004 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 CEECh / MeOEl (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), 40% to 60% gradient in 20 min; detector, 254 nm to afford (4-((8R,15R)-7-(difluoromethoxy)- 8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l 1- yl)-2,3-difluorophenyl)dimethylphosphine oxide (1.10 g, 72%). MS ESI calculated for C27H20F4N5O2P [M + H]+, 554.13 found 554.15. *H NMR (400 MHz, DMSO-t / 6) 8 8.47 (d, J = 8.0 Hz, 1H), 8.13 (s, 1H), 7.85 - 7.71 (m, 2H), 7.67 - 7.42 (m, 6H), 6.55 (d, J = 7.4 Hz, 1H), 6.36 (d, J = 6.2 Hz, 1H), 3.80 - 3.68 (m, 1H), 3.05 (d, J = 14.0 Hz, 1H), 1.81 (s, 3H), 1.78 (s, 3H).19F NMR (377 MHz, DMSO-t / 6) 6 -81.83, -82.28, -82.43, -82.88, -131.57, -131.63, -144.34, -144.40.31P NMR (162 MHz, DMSO-t / 6) 6 28.62, 28.59.

[0167] Example 18: (4-((8R,15R)-7-(difluoromethoxy)-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-3- fhrorophenyl)dimethylphosphine oxideTo a stirred solution of (8R,15R)-l l-chloro-7-(difluoromethoxy)-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (4.00 g, 10.005 mmol) and 2-[4-(dimethylphosphoryl)-2-fluorophenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (4.47 g, 15.008 mmol) in 1,4-dioxane (30 mL)and H2O (3 mL) were added Sphos Pd G3 (1.56 g, 2.001 mmol), Sphos (822 mg, 2.001 mmol) and K3PO4 (8.50 g, 40.020 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 CTfcCh / MeOH (12: 1) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 35% to 55% gradient in 30 min; detector, 254 nm to afford (4-((8R,15R)-7-(difhioromethoxy)-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-3- fhiorophenyl)dimethylphosphine oxide (3.20 g, 60%). MS ESI calculated for C27H21F3N5O2P [M + H]+, 536.14 found 536.15. *H NMR (400 MHz, Chloroform-; / ) 5 8.64 - 8.58 (m, 1H), 7.95 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.72 (t, J = 1.8 Hz, 1H), 7.63 - 7.52 (m, 3H), 7.47 (t, J = 8.2 Hz, 1H), 7.45 - 7.39 (m, 1H), 7.33 - 7.27 (m, 1H), 6.87 (t, J = 72.0 Hz, 1H), 6.55 (d, J = 7.4 Hz, 1H), 6.24 (d, J = 6.1 Hz, 1H), 3.73 - 3.62 (m, 1H), 2.99 (d, J = 13.8 Hz, 1H), 1.81 (s, 3H), 1.78 (s, 3H).19F NMR (377 MHZ, Chloroform-^ 5 -80.23, -80.67, -81.25, -81.70, -116.64.31P NMR (162 MHz, Chloroform-; / ) 5 33.07, 33.04.

[0168] Example 19: (4-((8R,15R)-7-ethynyl-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-3- fhrorophenyl)dimethylphosphine oxidePreparation 19A: (4-((8R,15R)-7-chloro-8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2- a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-3-fluorophenyl)dimethylphosphine oxide To a stirred mixture of (8R,15R)-7-chloro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl trifluoromethanesulfonate (100 mg, 0.208 mmol) and 2-[4-(dimethylphosphoryl)-2- fluorophenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (92 mg, 0.312 mmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL) were added Pd(dppf)C12 (16 mg, 0.021 mmol) and K3PO4 (88 mg, 0.416 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 45 °C for 3 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 (12 : 1) to afford (4-((8R,15R)-7-chloro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-3- fhiorophenyl)dimethylphosphine oxide (70 mg, 66%). MS ESI calculated for C26H20CIFN5OP [M + H]+, 504.11 found 504.25. 'HNMR (400 MHz, DMSO-t / 6) 8 8.66 - 8.57 (m, 1H), 8.14 (s, 1H), 7.83 (d, J = 1.8 Hz, 1H), 7.81 - 7.62 (m, 5H), 7.54 (t, J = 8.1 Hz, 1H), 7.47 - 7.39 (m, 1H),6.73 (d, J = 7.5 Hz, 1H), 6.35 (d, J = 6.1 Hz, 1H), 3.79 - 3.68 (m, 1H), 3.11 (d, J = 14.1 Hz, 1H),1.73 (s, 3H), 1.69 (s, 3H).19F NMR (377 MHz, DMSO-de) 8 -117.87, -117.88.31P NMR (162 MHz, DMSO-t / e) 6 32.05, 32.02.Preparation 19B : (3-fluoro-4-((8R, 15R)-7-((triisopropylsilyl)ethynyl)-8H, 15H-8, 15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l- yl)phenyl)dimethylphosphine oxideTo a stirred mixture of (4-((8R,15R)-7-chloro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-3- fhiorophenyl)dimethylphosphine oxide (50 mg, 0.099 mmol) and ethynyltriisopropylsilane (54 mg, 0.297 mmol) in CH3CN (2 mL) were added Sphos (8 mg, 0.020 mmol), K2CO3 (68 mg,0.495 mmol) and Sphos Pd G3 (7 mg, 0.010 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. The residue was purified by silica gel column chromatography, eluted with CthCb / MeOH (15: 1) to afford (3-fluoro-4-((8R,15R)- 7-((triisopropylsilyl)ethynyl)-8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2- a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)phenyl)dimethylphosphine oxide (40 mg, 62%). MS ESI calculated for C37H4iFN5OPSi [M + H]+, 650.28 found 650.40.Example 19: (4-((8R, 15R)-7-ethynyl-8H, 15H-8, 15-methanobenzo[f]benzo[4,5]imidazo[ 1 ,2- a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-3-fhiorophenyl)dimethylphosphine oxide To a stirred mixture of (3-fluoro-4-((8R,15R)-7-((triisopropylsilyl)ethynyl)-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l- yl)phenyl)dimethylphosphine oxide (40 mg, 0.062 mmol) in DMF (2 mL) was added CsF (93 mg, 0.620 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The resulting mixture was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 35% to 50% gradient in 10 min; detector, 254 nm. This resulted in (4-((8R, 15R)-7-ethynyl-8H, 15H-8, 15-methanobenzo[f]benzo[4,5]imidazo[ 1 ,2- a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-3-fhiorophenyl)dimethylphosphine oxide (8 mg, 26%). MS ESI calculated for C28H21FN5OP [M + H]+, 494.15 found 494.30. 'H NMR (400 MHz, DMSO-t / e) 8 8.68 - 8.59 (m, 1H), 8.13 (s, 1H), 7.96 (s, 1H), 7.82 - 7.76 (m, 1H), 7.75 - 7.62 (m, 4H), 7.54 (t, J = 7.9 Hz, 1H), 7.46 - 7.39 (m, 1H), 6.69 (d, J = 7.3 Hz, 1H), 6.35 (d, J = 6.1 Hz, 1H), 5.05 (s, 1H), 3.82 - 3.71 (m, 1H), 3.09 (d, J = 14.0 Hz, 1H), 1.73 (s, 3H), 1.70 (s, 3H).19F NMR (377 MHz, DMSO-t / 6) 6 -117.75, -117.76.31P NMR (162 MHz, DMSO-t / 6) 6 32.03, 32.01.

[0169] Example 20: (4-((8R,15R)-7-(difluoromethoxy)-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l- yl)phenyl)dimethylphosphine oxideTo a stirred solution of (8R,15R)-7-(difhrorom ethoxy)- 1 l-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-8H, 15H-8, 15-methanobenzo[f]benzo[4, 5]imidazo[ 1 ,2-a] [ 1 , 2, 4]tri azolof 1,5-d][l,4]diazocine (50 mg, 0.102 mmol) and l-bromo-4-(dimethylphosphoryl)benzene (28 mg, 0.122 mmol) in 1,4-dioxane (1 mL) and H2O (0.2 mL) were added Pd(dppf)C12 CH2CI2 (8 mg, 0.010 mmol) and K2CO3 (42 mg, 0.306 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for3 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CEECh / MeOEl (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), 35% to 45% gradient in 10 min; detector, 254 nm. This resulted in (4-((8R,15R)-7-(difluoromethoxy)-8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5- d][l,4]diazocin-l l-yl)phenyl)dimethylphosphine oxide (39 mg, 74%). MS ESI calculated for C27H22F2N5O2P [M + H]+, 518.15 found 518.10. *HNMR (400 MHz, DMSO-t / 6) 8 8.56 - 8.42 (m, 1H), 8.13 (s, 1H), 7.95 - 7.69 (m, 7H), 7.62 - 7.54 (m, 2H), 7.51 - 7.45 (m, 1H), 6.56 (d, J = 7.4 Hz, 1H), 6.33 (d, J = 6.2 Hz, 1H), 3.83 - 3.66 (m, 1H), 3.04 (d, J = 14.0 Hz, 1H), 1.70 (s, 3H), 1.67 (s, 3H).19F NMR (377 MHz, DMSO-t / 6) 6 -82.30.31P NMR (162 MHz, DMSO-t / 6) 632.23.

[0170] Example 21 : (2,3-difluoro-4-((8R,15R)-7-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l- yl)phenyl)dimethylphosphine oxidePreparation 21 A: (S,E)-N-(2-bromo-6-fluorobenzylidene)-2-methylpropane-2-sulfmamide To a stirred solution of 2-bromo-6-fluorobenzaldehyde (100.00 g, 492.587 mmol) and CS2CO3 (176.00 g, 541.846 mmol) in DCM (1 L) was added (S)-2-methylpropane-2-sulfinamide (71.64 g, 591.104 mmol) in portions at room temperature. The resulting mixture was stirred for 3 h at room temperature. The resulting mixture was diluted with water (I L) and extracted with CH2Q2 (3 x 500 mL). The combined organic layers were washed with brine (3 x 500 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 PEZEA (10: 1) to afford (S,E)-N-(2-bromo-6-fluorobenzylidene)-2-methylpropane-2-sulfmamide (145.00 g, 96%). MS ESI calculated for CnHi3BrFNOS [M + H]+, 305.99 307.99 found 306.00 308.05. 'HNMR (300 MHz, Chloroform-t / ) 5 8.85 (s, 1H), 7.54 - 7.45 (m, 1H), 7.39 - 7.26 (m, 1H), 7.22 - 7.09 (m, 1H), 1.31 (s, 9H).19F NMR (282 MHz, Chloroform^ / ) 5 -109.16.Preparation 21B: tert-butyl (R)-3-(2-bromo-6-fluorobenzylidene)-3-(((S)-tert-butylsulfmyl) amino) propanoateA mixture of Zn powder (224.20 g, 3429.245 mmol) and CuCl (101.85 g, 1028.774 mmol) in THF (I L) was stirred for 2 h at 60 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. To the above mixture was added tert-butyl 2-bromoacetate (334.45 g, 1714.623 mmol) dropwise over 5 min at 25 °C. The resulting mixture was stirred for additional 2 h at 60 °C. The mixture was allowed to cool down to room temperature again. To the above mixture was added (S, E)-N-(2-bromo-6- fluorobenzylidene)-2-methylpropane-2- sulfinamide (210.00 g, 685.849 mmol) in portions over 5 min at 10 °C. The resulting mixture was stirred for additional 3 h at room temperature. The resulting mixture was filtered, the filter cake was washed with EtOAc (3 x 1000 mL). To the above filtrate were added EtOAc (1.5 L) and saturated citric acid solution (500 mL). The aqueous layer was extracted with EtOAc (3 x 500 mL) and the combined organic layers were washed with saturated NaHCO3solution (1.5 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with PE (IL). This resulted in tert-butyl (R)-3- (2-bromo-6-fluorobenzylidene)-3-(((S)-tert-butylsulfmyl) amino) propanoate (210.00 g, 73%). MS ESI calculated for Ci7H25BrFNO3S [M + H]+, 422.07 424.07, found 421.95 423.90. 'H NMR (400 MHz, Chloroform-^ 5 7.38 (d, J = 8.1 Hz, 1H), 7.19 - 7.09 (m, 1H), 7.08 - 6.98 (m, 1H), 5.49 - 5.39 (m, 1H), 4.20 (d, J = 7.5 Hz, 1H), 3.15 - 3.05 (m, 1H), 2.97 - 2.87 (m, 1H), 1.39 (s, 9H), 1.14 (s, 9H).19F NMR (377 MHz, Chloroform-^ 5 -110.59.Preparation 21C: (R)-l-(2-bromo-6-fluorophenyl)-3-(tert-butoxy)-3 -oxopropan- 1-aminium (S)- 2-hydroxy-2-phenylacetateTo a stirred solution of tert-butyl (R)-3-(2-bromo-6-fluorobenzylidene)-3-(((S)-tert- butyl sulfinyl) amino) propanoate (201.00 g, 475.909 mmol) in THF (1000 mL) and H2O (200 mL) was added I2 (30.20 g, 118.977 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 50 °C. The reaction was quenched by the addition of sat. NaHCCh (aq.) (1 L) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (3 x 2 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in MTBE (500 mL) followed by the addition of solution (2S)-2-hydroxy-2- phenylacetic acid (72.41 g, 475.909 mmol) in MTBE (200 mL) dropwise at room temperature. The resulting mixture was stirred for additional 16 h at room temperature. The precipitated solids were collected by filtration. This resulted in (R)-l -(2 -bromo-6-fluorophenyl)-3 -(tertbutoxy)^ -oxopropan- 1-aminium (S)-2-hydroxy-2 -phenylacetate (170.00 g, 76%). MS ESI calculated for Ci3Hi7BrFNO2 [M + H]+, 318.04 320.04 found 318.10 320.10. 'HNMR (400 MHz, Chloroforms / , free base) 5 7.35 (d, J = 7.9 Hz, 1H), 7.12 - 6.98 (m, 2H), 4.92 - 4.85 (m, 1H), 2.89 - 2.80 (m, 1H), 2.76 - 2.68 (m, 1H), 1.41 (s, 9H).19F NMR (377 MHz, Chloroforms / )5 -112.37.Preparation 21D: tert-butyl (R)-3-(2-bromo-6-fluorophenyl)-3-((5-chloro-2- nitrophenyl)amino)propanoateTo a stirred solution of (R)-l-(2-bromo-6-fluorophenyl)-3-(tert-butoxy)-3 -oxopropan- 1-aminium (S)-2-hydroxy-2-phenylacetate (174.00 g, 369.949 mmol) and 4-chloro-2-fluoro-l -nitrobenzene (68.19 g, 388.446 mmol) in DMAc (1 L) was added DIEA (143.44 g, 1109.847 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 80 °C. The resulting mixture was diluted with water (I L) followed by extraction with MTBE (2 x 1 L) and washed with 5% critic acid (2 x 1 L). The combined organic layers were washed with 5% NaHCCL (2 x 1 L). The combined organic layers were washed with 5% NaCl (2 x 1 L). The combined organic layers were concentrated under vacuum to afford tert-butyl (3R)-3-(2-bromo-6-fluorophenyl)-3-[(5-chloro-2-nitrophenyl)amino]propanoate (170.00 g, 97%). MS ESI calculated for Ci9Hi9BrClFN2O4 [M + H]+, 473.02 475.02 found 473.00 474.95.XH NMR (400 MHz, Chloroforms / ) 5 8.79 (d, J = 8.7 Hz, 1H), 8.09 (d, J = 9.1 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.21 - 7.13 (m, 1H), 7.09 - 7.04 (m, 1H), 7.03 (d, J = 2.0 Hz, 1H), 6.66 - 6.54 (m, 1H), 5.73 - 5.59 (m, 1H), 3.14 - 3.04 (m, 1H), 2.90 - 2.82 (m, 1H), 1.40 (s, 9H).19F NMR (377 MHz, Chloroforms / ) 5 -111.95.Preparation 2 IE: (R)-3-(2-bromo-6-fluorophenyl)-3-((5-chloro-2-nitrophenyl)amino)propanal To tert-butyl (R)-3-(2-bromo-6-fluorophenyl)-3-((5-chloro-2-nitrophenyl)amino)propanoate (86.50 g, 182.597 mmol) in DCM (1 L) was added Diisobutylaluminum hydride (1.0 M inDCM) (237.4 mL, 237.376 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at -78 °C under nitrogen atmosphere. The reaction was quenched with HC1 (IN) at -78 °C followed by extraction with CH2CI2 (3 x 1 L). The combined organic layers were washed with brine (3 x 1 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PEZEA (3: 1) to afford (R)-3-(2-bromo-6-fluorophenyl)-3-((5- chloro-2-nitrophenyl)amino)propanal (59.00 g, 80%). MS ESI calculated for C15H1 iBrOF^Ch [M + H]+, 400.96 402.96, found 400.80 402.75. 'H NMR (400 MHz, Chloroforms / ) 5 9.82 (s, 1H), 8.73 (d, J = 8.9 Hz, 1H), 8.09 (d, J = 9.1 Hz, 1H), 7.45 - 7.37 (m, 1H), 7.25 - 7.12 (m, 1H), 7.12 - 7.00 (m, 2H), 6.67 - 6.55 (m, 1H), 5.85 - 5.74 (m, 1H), 3.48 - 3.38 (m, 1H), 3.13 - 3.03 (m, 1H).19F NMR (377 MHz, Chloroforms / ) 5 -112.20.Preparation 21F: (R)-N-((R,E)-3-(2-bromo-6-fluorophenyl)-3-((5-chloro-2- nitrophenyl)amino)propylidene)-2-methylpropane-2-sulfinamideTo a stirred solution of (R)-3-(2-bromo-6-fluorophenyl)-3-((5-chloro-2- nitrophenyl)amino)propanal (116.00 g, 288.830 mmol) and Ti(O -Pr)4 (164.18 g, 577.660 mmol) in DCM (1.2 L) was added (R)-2-methylpropane-2-sulfinamide (42.01 g, 346.596 mmol) in portions at room temperature. The resulting mixture was stirred for 3 h at room temperature. The resulting mixture was diluted with water (I L) followed by extraction with CH2Q2 (3 x 1 L). The combined organic layers were washed with brine (3 x 1 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PEZEA (3: 1) to afford (R)-N-((R,E)- 3-(2-bromo-6-fluorophenyl)-3-((5-chloro-2-nitrophenyl)amino)propylidene)-2-methylpropane- 2-sulfinamide (117.00 g, 80%). MS ESI calculated for Ci^oBrClFNsChS [M + H]+, 504.01 506.01 found 503.85 505.75.XH NMR (400 MHz, Chloroforms / ) 5 8.75 (d, J = 8.8 Hz, 1H),8.14 - 7.98 (m, 2H), 7.46 - 7.37 (m, 1H), 7.24 - 7.13 (m, 1H), 7.12 - 7.03 (m, 1H), 6.98 (d, J = 2.1 Hz, 1H), 6.68 - 6.59 (m, 1H), 5.73 - 5.63 (m, 1H), 3.51 - 3.39 (m, 1H), 3.21 - 3.10 (m, 1H),1.14 (s, 9H).19F NMR (377 MHz, Chloroform-tZ) 5 -112.19.Preparation 21G: (R)-N-((3R)-3-(2-bromo-6-fluorophenyl)-3-((5-chloro-2-nitrophenyl)amino)- l-cyanopropyl)-2-methylpropane-2-sulfinamideTo a stirred solution of (R)-N-((R,E)-3-(2-bromo-6-fluorophenyl)-3-((5-chloro-2- nitrophenyl)amino)propylidene)-2-methylpropane-2-sulfinamide (116.00 g, 229.794 mmol) in DCM (1.2 L) were added CsF (69.81 g, 459.588 mmol) and TMSCN (45.59 g, 459.588 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was diluted with water (500 mL) followed by extraction with CH2CI2 (3 x 500 mL). The combined organic layers were washed with brine (3 x 500 mL) and dried overanhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with PE / DCM (10: 1, 500 mL) to afford (R)-N-((3R)-3-(2- bromo-6-fluorophenyl)-3-((5-chloro-2-nitrophenyl)amino)-l-cyanopropyl)-2-methylpropane-2- sulfinamide (116.00 g, 94%, ee>98%). MS ESI calculated for C2oH2iBrClFN403S [M + H]+, 531.02 533.02 found 530.85 532.80. *H NMR (400 MHz, Chloroform^ / ) 5 8.67 (d, J = 9.6 Hz, 1H), 8.12 (d, J = 9.1 Hz, 1H), 7.46 - 7.39 (m, 1H), 7.25 - 7.15 (m, 1H), 7.13 - 7.04 (m, 1H), 6.97 (d, J = 2.1 Hz, 1H), 6.71 - 6.64 (m, 1H), 5.56 - 5.45 (m, 1H), 4.42 - 4.32 (m, 1H), 4.05 (d, J = 9.9 Hz, 1H), 2.82 (t, J = 10.5 Hz, 1H), 2.47 - 2.36 (m, 1H), 1.26 (s, 9H).19F NMR (377 MHz, Chloroform-t / ) 5 -112.39.Preparation 21H: (lR,3R)-l-(2-bromo-6-fluorophenyl)-7-chloro-2,3-dihydro-lH- benzofd] pyrrol o[ 1 ,2-a]imidazol-3 -amineTo a stirred solution of (R)-N-((3R)-3-(2-bromo-6-fluorophenyl)-3-((5-chloro-2- nitrophenyl)amino)-l-cyanopropyl)-2-methylpropane-2-sulfinamide (55.00 g, 103.417 mmol) and TiCh (637.96 g, 827.336 mmol, 20%) in EtOH (500 mL) at room temperature. The resulting mixture was stirred for overnight at 80 °C. The resulting mixture was diluted with EtOAc (500 mL). The residue was basified to pH 7 with saturated NaHCCL (aq.). The resulting mixture was filtered and the filter cake was washed with EtOAc (3 x 500 mL). The filtrate was washed with 2 x 1 L of water. The organic layer was concentrated under vacuum. The residue was purified by trituration with PE / DCM (10: 1, 500 mL) to afford (lR,3R)-l-(2-bromo-6-chlorophenyl)-7- methoxy-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-3-amine (33.00 g, 83%). MS ESI calculated for Ci6Hi2BrClFN3[M + H]+, 379.99 381.99 found 379.85 381.80.XH NMR (400 MHz, Chloroforms / ) 5 7.68 - 7.60 (m, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.43 - 7.21 (m, 1H), 7.19 - 7.13 (m, 1H), 7.03 - 6.94 (m, 1H), 6.78 - 6.58 (m, 1H), 6.08 - 5.93 (m, 1H), 4.74 - 4.60 (m, 1H), 3.68 - 3.53 (m, 1H), 2.61 - 2.46 (m, 1H).19F NMR (377 MHz, Chloroforms / ) 5 -111.99. Preparation 211: (7R,14R)-l l-chloro-l-fluoro-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-oneTo a stirred mixture of (lR,3R)-l-(2-bromo-6-fluorophenyl)-7-chloro-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazol-3 -amine (70.00 g, 183.896 mmol) and K2CO3 (101.66 g, 735.584 mmol) in 1,4-dioxane (3500 mL) were added PCy3.HBF(13.54 g, 36.779 mmol) and Pd(OAc)2 (4.13 g, 18.390 mmol) at room temperature. The resulting mixture was stirred for 16 h at 140 °C under carbon monoxide atmosphere (10 atm.). The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2C12 / MeOH (10: 1) to afford (7R,14R)-l l-chloro-l-fluoro-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one (46.00 g, 76%). MS ESI calculated for C17H11CIFN3O [M + H]+, 328.06 found 327.95. 'H NMR (400 MHz, Chloroform-d) 5 8.38 - 8.31 (m, 1H), 7.66 (d, J = 8.7 Hz, 1H), 7.60 (d, J = 6.7 Hz, 1H), 7.46 - 7.33 (m, 3H), 7.26 - 7.18 (m, 1H), 6.19 (d, J = 7.0 Hz, 1H), 5.01 (t, J = 6.7 Hz, 1H), 3.53 - 3.42 (m, 1H), 2.88 (d, J = 13.2 Hz, 1H).19F NMR (377 MHz, Chloroform^ / ) 5 -117.82.Preparation 21 J: (7R,14R)-6-amino-l l-chloro-l-fluoro-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one To a stirred solution of (7R,14R)-1 l-chloro-l-fluoro-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one (1.25 g, 3.814 mmol) in DMF (30 mL) was added Z-BuONa (1.47 g, 15.256 mmol) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 30 min under argon atmosphere. To the above mixture was added (aminooxy)sulfonic acid (863 mg, 7.628 mmol) at 0 °C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with sat. Na2SOs (aq.) at room temperature followed by extraction with EtOAc (200 mL). The resulting mixture was washed with 3 x 100 mL of water and 100 mL brine for once. The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with C^CL / MeOH (30 / 1) to afford (7R,14R)-6-amino-l l-chloro-l-fhioro-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one (400 mg, 31%). MS ESI calculated for C17H12CIFN4O [M + H]+, 343.07 found 343.00. 'H NMR (400 MHz, Chloroform- d) 5 8.38 - 8.34 (m, 1H), 7.63 (d, J= 8.7 Hz, 1H), 7.46 - 7.31 (m, 3H), 7.23 - 7.18 (m, 1H), 6.10 (d, J= 7.1 Hz, 1H), 5.42 (d, J= 7.3 Hz, 1H), 4.25 (s, 2H), 3.49 - 3.36 (m, 1H), 2.85 (d, J = 13.6 Hz, 1H).19F NMR (377 MHz, Chloroform-tZ) 5 -118.01.Preparation 2 IK: (8R,15R)-l l-chloro-7-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine To a stirred solution of (7R,14R)-6-amino-l 1 -chi oro-1 -fluoro-6,7-dihydro-7, 14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one (100 mg, 0.292 mmol) and Formamidine acetate (243 mg, 2.336 mmol) in 1,4-dioxane (2 mL) was added Diisopropylamine (236 mg, 2.336 mmol) at room temperature. The resulting mixture was stirred at 100 °C overnight. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with C^CL / MeOH (20 / 1) to afford (8R,15R)-11- chloro-7-fluoro-8H, 15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l, 2, 4]tri azolof 1,5- d][l,4]diazocine (50 mg, 49%). MS ESI calculated for CisHnQFNs [M + H]+, 352.07 found 352.00.XH NMR (400 MHz, Chloroform^ / ) 5 8.53 - 8.47 (m, 1H), 7.93 (s, 1H), 7.62 (d, J= 8.7 Hz, 1H), 7.49 - 7.41 (m, 2H), 7.35 - 7.28 (m, 1H), 7.23 - 7.17 (m, 1H), 6.32 (d, J= 7.0 Hz, 1H), 6.19 (d, J= 5.6 Hz, 1H), 3.68 - 3.56 (m, 1H), 2.98 (d, J= 13.6 Hz, 1H).19F NMR (377 MHz, Chloroform-t / ) 5 -118.00.Example 21: (2,3-difluoro-4-((8R,15R)-7-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l- yl)phenyl)dimethylphosphine oxideTo a stirred solution of (8R,15R)-l l-chloro-7-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (50 mg, 0.142 mmol) and 2-[4-(dimethylphosphoryl)-2,3-difluorophenyl]-4, 4,5, 5-tetramethyl- 1,3,2- dioxaborolane (90 mg, 0.284 mmol) in 1,4-di oxane (2 mL) and H2O (0.2 mL) were added Sphos (12 mg, 0.028 mmol), Sphos Pd G3 (22 mg, 0.028 mmol) and K3PO4 (91 mg, 0.426 mmol) at room temperature. The resulting mixture was stirred at 80 °C for2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CEECh / MeOEl (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), 35% to 45% gradient in 10 min; detector, 254 nm. This resulted in (2,3-difhioro-4-((8R,15R)-7- fluoro-8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5- d][l,4]diazocin-l l-yl)phenyl)dimethylphosphine oxide (57 mg, 79%). MS ESI calculated for C26H19F3N5OP [M + H]+, 506.13 found 506.00. 'HNMR (400 MHz, DMSO-t / 6) 8 8.44 - 8.37 (m, 1H), 8.14 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.69 - 7.59 (m, 2H), 7.58 - 7.50 (m, 3H), 7.48 - 7.41 (m, 1H), 6.52 (d, J = 7.2 Hz, 1H), 6.38 (d, J = 6.2 Hz, 1H), 3.76 - 3.64 (m, 1H), 3.09 (d, J = 14.1 Hz, 1H), 1.80 (s, 3H), 1.77 (s, 3H).19F NMR (377 MHz, DMSO- e) 6 -117.39, -131.37, - 131.43, -144.18, -144.24.31P NMR (162 MHz, DMSO-t / 6) 6 28.53.

[0171] Example 22: (4-((8R,15R)-7-(difhroromethoxy)-12-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-2- fhrorophenyl)dimethylphosphine oxidePreparation 22A: (7R,14R)-6-amino-l l-chloro-l-(difluoromethoxy)-10-fluoro-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-oneTo a stirred solution of (7R,14R)-1 l-chloro-l-(difhioromethoxy)-10-fhioro-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one (1.00 g, 2.540 mmol) in DMF (30 mL) was added Z-BuONa (0.98 g, 10.160 mmol) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 15 min under nitrogen atmosphere. To the above mixture was added amino diphenylphosphinate (1.18 g, 5.080 mmol) in portions at 0 °C. The resulting mixture was stirred at room temperature for additional 16 h. The reaction was quenched by the addition of water (200 mL) at 0 °C followed by extraction with ethyl acetate (500 mL). The resulting mixture was washed with 3 x 100 mL of water. The organic layer was washed with brine (3 x 100 mL) and dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CLBCh / MeOH (15 / 1) to afford (7R,14R)-6-amino-l l-chloro-l- (difhioromethoxy)-10-fhioro-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2- a][l,4]diazocin-5(14H)-one (300 mg, 28%). MS ESI calculated for C18H12CIF3N4O2 [M + H]+, 409.06 found 408.90. *H NMR (400 MHz, Chloroforms / ) 5 8.48 - 8.40 (m, 1H), 7.51 - 7.41 (m, 3H), 7.40 - 7.34 (m, 1H), 6.84 (t, J= 72.5 Hz, 1H), 6.20 (d, J= 7.2 Hz, 1H), 5.39 (d, J= 7.2 Hz, 1H), 3.85 - 3.08 (m, 3H), 2.83 (d, J= 13.7 Hz, 1H).19F NMR (377 MHz, Chloroforms / ) 5 - 80.25, -80.69, -81.05, -81.50, -120.68.Preparation 22B: (8R,15R)-l l-chloro-7-(difhioromethoxy)-12-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocineTo a stirred solution of (7R,14R)-6-amino-l l-chloro-l-(difhioromethoxy)-10-fluoro-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one (300 mg, 0.734 mmol) and Formamidine acetate (611 mg, 5.872 mmol) in 1,4-dioxane (10 mL) was added Diisopropylamine (594 mg, 5.872 mmol) at room temperature. The resulting mixture was stirred at 90 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with C^CL / MeOH (15 / 1) to afford (8R, 15R)-11 -chi oro-7-(difluorom ethoxy)- 12-fluoro-8H, 15H-8, 15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (200 mg, 65%). MS ESI calculated for C19H11CIF3N5O [M + H]+, 418.06 found 418.15.XH NMR (400 MHz, Chloroforms / ) 5 8.73 - 8.54 (m, 1H), 7.94 (s, 1H), 7.53 - 7.43 (m, 3H), 7.35 - 7.32 (m, 1H), 6.88 (t, J= 72.5 Hz, 1H), 6.44 (d, J= 7.5 Hz, 1H), 6.17 (d, J= 6.3 Hz, 1H), 3.68 - 3.51 (m, 1H), 2.96 (d, J= 13.9 Hz, 1H).19F NMR (377 MHz, Chloroforms / ) 5 -80.47, -80.91, -81.06, -81.51, -120.30.Example 22: (4-((8R, 15R)-7-(difluoromethoxy)-12-fluoro-8H, 15H-8, 15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-2- fhrorophenyl)dimethylphosphine oxideTo a stirred solution of (8R,15R)-1 l-chloro-7-(difhroromethoxy)-12-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (60 mg, 0.144 mmol) and (2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)dimethylphosphine oxide (64 mg, 0.216 mmol) in 1,4-dioxane (0.8 mL) and H2O (0.2 mL) were added K3PO4 (122 mg, 0.576 mmol), Sphos Pd G3 (11 mg, 0.014 mmol) and Sphos (12 mg, 0.029 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. The residue was purified by silica gel column chromatography, eluted with CTbCh / 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; detector, 254 nm to afford (4-((8R,15R)-7-(difluoromethoxy)-12-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-2- fhiorophenyl)dimethylphosphine oxide (53 mg, 67%). MS ESI calculated for C27H20F4N5O2P [M + H]+, 554.13 found 554.10. *H NMR (400 MHz, Chloroform^ / ) 5 8.68 - 8.57 (m, 1H), 8.10 - 7.99 (m, 1H), 7.96 (s, 1H), 7.54 - 7.43 (m, 4H), 7.35 - 7.28 (m, 2H), 6.88 (t, J= 72.6 Hz, 1H), 6.52 (d, J= 13 Hz, 1H), 6.24 (d, J= 6.1 Hz, 1H), 3.76 - 3.57 (m, 1H), 3.00 (d, J= 13.8 Hz, 1H), 1.87 (s, 3H), 1.83 (s, 3H).19F NMR (377 MHz, Chloroform^ / ) 5 -80.54, -80.98, -81.24, - 81.69, -105.98, -105.99, -121.95.31P NMR (162 MHz, Chloroform-^ 5 30.53, 30.51.

[0172] Example 23: (5-((8R,15R)-7,12-difluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)pyridin-2- yl)dimethylphosphine oxideTo a stirred solution of (8R,15R)-l l-chloro-7,12-difluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (30 mg, 0.081 mmol) and dimethyl(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)phosphine oxide (45 mg, 0.162 mmol) in 1,4-dioxane (0.4 mL) and H2O (0.1 mL) were added K3PO4 (51 mg, 0.243 mmol), Sphos Pd G3 (7 mg, 0.008 mmol) and S-Phos (7 mg, 0.016 mmol) at roomtemperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CJbCh / MeOH (10 / 1) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 25% to 45% gradient in 20 min; detector, 254 nm to afford (5- ((8R,15R)-7,12-difluoro-8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2- a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)pyridin-2-yl)dimethylphosphine oxide (7 mg, 19%). MS ESI calculated for C25H19F2N6OP [M + H]+, 489.13, found 489.10. 'HNMR (400 MHz, DMSO-t / e) 8 8.89 (s, 1H), 8.46 - 8.33 (m, 1H), 8.20 - 8.00 (m, 3H), 7.68 (d, J= 11.3 Hz, 1H), 7.60 - 7.47 (m, 3H), 6.52 (d, J= 7.1 Hz, 1H), 6.39 (d, J= 6.2 Hz, 1H), 3.83 - 3.61 (m, 1H), 3.10 (d, J= 14.1 Hz, 1H), 1.74 (s, 3H), 1.70 (s, 3H).19F NMR (377 MHz, DMSO-t / 6) 6 -116.95, - 123.67.31P NMR (162 MHz, DMSO-t / 6) 6 34.15.

[0173] Example 24: (4-((8R,15R)-7-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l- yl)phenyl)dimethylphosphine oxideTo a stirred solution of (8R,15R)-l l-chloro-7-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (50 mg, 0.142 mmol) and 2-[4-(dimethylphosphoryl)phenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (48 mg, 0.170 mmol) in H2O (0.4 mL) and 1,4-dioxane (2 mL) were added S-Phos (12 mg, 0.028 mmol), Sphos Pd G3 (11 mg, 0.014 mmol), K3PO4 (91 mg, 0.426 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with C^Cb / MeOH (10 / 1) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (0.1% TFA), 30% to 40% gradient in 10 min; detector, 254 nm. to afford (4-((8R, 15R)-7-fluoro-8H, 15H-8, 15-methanobenzo[f]benzo[4,5]imidazo[l ,2- a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)phenyl)dimethylphosphine oxide (24 mg, 29%). MS ESI calculated for C26H21FN5OP [M + H]+, 470.15, found 470.15. 'H NMR (400 MHz,Chloroform-t / ) 5 8.53 (d, J = 8.1 Hz, 1H), 7.98 (s, 1H), 7.90 - 7.78 (m, 3H), 7.75 - 7.70 (m, 2H), 7.68 (s, 1H), 7.57 - 7.52 (m, 1H), 7.51 - 7.43 (m, 1H), 7.36 - 7.29 (m, 1H), 6.47 (d, J = 8.0 Hz, 2H), 3.76 (d, J = 10.4 Hz, 1H), 3.06 (d, J = 13.2 Hz, 1H), 1.89 (s, 3H), 1.85 (s, 3H).19F NMR (377 MHz, Chloroforme d -76.10, -117.86.31P NMR (162 MHz, Chloroforme 8 40.04.

[0174] Example 25: (4-((8R,15R)-7-(difhroromethoxy)-12-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l- yl)phenyl)dimethylphosphine oxideTo a stirred solution of ((8R,15R)-l l-chloro-7-(difhroromethoxy)-12-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (50 mg, 0.120 mmol) and 2-[4-(dimethylphosphoryl)phenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (50 mg, 0.180 mmol) in 1,4-dioxane (1 mL) and H2O (0.1 mL) were added Sphos Pd G3 (9 mg, 0.012 mmo), S-Phos (9 mg, 0.024 mmol) and K3PO4 (63 mg, 0.300 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 C^Ch / MeOH (10: 1) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 10% to 34% gradient in 10 min; detector, 254 nm to afford (4-((8R,15R)-7-(difhioromethoxy)-12-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l- yl)phenyl)dimethylphosphine oxide (47 mg, 73%). MS ESI calculated for C27H21F3N5O2P [M + H]+, 536.14, found 536.15. 'HNMR (400 MHz, Chloroform-^ 6 8.63 (d, J = 8.2 Hz, 1H), 7.97 (s, 1H), 7.86 - 7.78 (m, 2H), 7.67 - 7.62 (m, 2H), 7.55 - 7.46 (m, 3H), 7.31 (d, J = 8.2 Hz, 1H), 6.95 (t, J = 72.6 Hz, 1H), 6.53 (d, J = 7.1 Hz, 1H), 6.27 (d, J = 5.8 Hz, 1H), 3.77 - 3.66 (m, 1H), 3.00 (d, J = 13.6 Hz, 1H), 1.81 (s, 3H), 1.78 (s, 3H).19F NMR (377 MHz, Chloroforms / ) 6 - 80.60, -81.04, -81.12, -81.56, -121.78.31P NMR (162 MHz, Chloroforms / ) 6 34.22.

[0175] Example 26: (5-((8R,15R)-7-(difhroromethoxy)-12-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)pyridin-2- yl)dimethylphosphine oxideTo a stirred solution of (8R,15R)-l l-chloro-7-(difluoromethoxy)-12-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (50 mg, 0.120 mmol) and 2-(dimethylphosphoryl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (134 mg, 0.480 mmol) in 1,4-dioxane (1 mL) and H2O (0.1 mL) were added Sphos Pd G3 (9 mg, 0.012 mmol), S-Phos (9 mg, 0.024 mmol) and KsPO4 (63 mg, 0.300 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 CTfcCh / MeOH (10: 1) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 10% to 33% gradient in 10 min; detector, 254 nm to afford (5-((8R,15R)-7-(difhioromethoxy)-12-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)pyridin-2- yl)dimethylphosphine oxide (50 mg, 90%). MS ESI calculated for C26H20F3N6O2P [M + H]+, 537.13, found 537.20. 'HNMR (400 MHz, Chloroforms / ) 5 8.90 (s, 1H), 8.64 (d, J = 8.1 Hz, 1H), 8.28 (t, J = 6.7 Hz, 1H), 8.08 (d, J = 7.6 Hz, 1H), 7.97 (s, 1H), 7.63 - 7.44 (m, 3H), 7.32 (d, J = 8.2 Hz, 1H), 6.80 (t, J = 72.5 Hz, 1H), 6.53 (d, J = 6.1 Hz, 1H), 6.26 (d, J = 6.2 Hz,lH), 3.78 - 3.63 (m, 1H), 3.01 (d, J = 13.1 Hz, 1H), 1.92 (s, 3H), 1.89 (s, 3H).19F NMR (377 MHz, Chloroforms / ) 5 -80.56, -81.00, -81.22, -81.67, -122.15.31P NMR (162 MHz, Chloroforms / ) 5 36.21.

[0176] Example 27: (8R,15R)-l l-(4-(dimethylphosphoryl)-3-fluorophenyl)-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine-7-carbonitrileTo a stirred mixture of (4-((8R,15R)-7-chloro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-2- fluorophenyl)dimethylphosphine oxide (50 mg, 0.099 mmol) and Zn(CN)2 (17 mg, 0.149 mmol) in DMF (1 mL) were added Zinc (1 mg, 0.010 mmol), EPhos Pd G4 (9 mg, 0.010 mmol) and E- Phos (5 mg, 0.010 mmol) at room temperature. The resulting mixture was stirred at 110 °C for 1 h under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL) followed by extraction with EtOAc (5 x 5 mL). The combined organic layers were washed with brine (3 x 10 mL) and 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: X Bridge Shield RP18 OBD Column 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol / L NH4HCO3 + 0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 35% B in 17 min; Wave Length: 254 nm) to afford (8R,15R)-11- (4-(dimethylphosphoryl)-3-fluorophenyl)-8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2- a][l,2,4]triazolo[l,5-d][l,4]diazocine-7-carbonitrile (17 mg, 35%). MS ESI calculated for C27H20FN6OP [M + H]+, 495.14, found 495.10. 'HNMR (400 MHz, DMSO-t / 6) 8 8.90 (d, J= 8.2 Hz, 1H), 8.21 - 8.14 (m, 2H), 7.92 (d, J= 1.8 Hz, 1H), 7.91 - 7.80 (m, 1H), 7.79 - 7.68 (m, 2H), 7.68 - 7.52 (m, 3H), 6.49 (d, J= 1A Hz, 1H), 6.39 (d, J= 6.1 Hz, 1H), 3.86 - 3.75 (m, 1H), 3.16 (d, J= 14.2 Hz, 1H), 1.77 (s, 3H), 1.74 (s, 3H).19F NMR (377 MHz, CDCI3) 6 -105.43, - 105.44.31P NMR (162 MHz, DMSO-t / 6) 6 28.52, 28.50.

[0177] Example 28: (4-((8R,15R)-7,12-difluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-2,3- difluorophenyl)dimethylphosphine oxideTo a stirred solution of (8R,15R)-l l-chloro-7,12-difluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (50 mg, 0.135 mmol) and 2-[4-(dimethylphosphoryl)-2,3-difluorophenyl]-4, 4,5, 5-tetramethyl- 1,3,2- dioxaborolane (51 mg, 0.162 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) were added S-Phos (11 mg, 0.027 mmol), Sphos Pd G3 (10 mg, 0.014 mmol) and K2CO3 (56 mg, 0.405 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere.The reaction was quenched with water followed by extraction with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 20% to 35% gradient in 25 min; detector, 254 nm to afford (4- ((8R,15R)-7,12-difluoro-8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2- a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-2,3-difhiorophenyl)dimethylphosphine oxide (36 mg, 50%). MS ESI calculated for C26H18F4N5OP [M + H]+, 524.12, found 524.15. 'H NMR (400 MHz, Chloroform-t / ) 5 8.54 (d, J = 8.0 Hz, 1H), 7.97 (s, 1H), 7.85 - 7.76 (m, 1H), 7.55 (d, J = 10.0 Hz, 1H), 7.52 - 7.40 (m, 2H), 7.36 - 7.27 (m, 2H), 6.47 - 6.37 (m, 1H), 6.37 - 6.25 (m, 1H), 3.88 - 3.65 (m, 1H), 3.03 (d, J = 13.6 Hz, 1H), 1.89 (s, 3H), 1.86 (s, 3H).19F NMR (377 MHz, Chloroform-t / ) 5 -118.01, -118.89, -118.93, -130.96, -130.97, -131.02, -131.03, -138.77, - 138.79, -138.81, -138.83, -138.85, -138.88, -138.89.31P NMR (162 MHz, Chloroform^ / ) 5 29.99, 29.96, 29.93.

[0178] Example 29: (4-((8R,15R)-7,12-difluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-3- fhiorophenyl)dimethylphosphine oxideTo a stirred solution of (8R,15R)-l l-chloro-7,12-difluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (80 mg, 0.216 mmol) and 2-[4-(dimethylphosphoryl)-2-fluorophenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (193 mg, 0.648 mmol) in 1,4-dioxane (1 mL) and H2O (0.2 mL) were added Sphos Pd G3 (17 mg, 0.022 mmol), S-Phos (18 mg, 0.043 mmol) and K3PO4 (115 mg, 0.540 mmol) at room temperature. The resulting mixture 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 C^CL / MeOH (10 / 1) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in water (10 mmol / L NH4HCO3), 30% to 70% gradient in 20 min; detector, 254 nm. This resulted in (4-((8R, 15R)-7, 12-difluoro-8H, 15H-8, 15-methanobenzo[f]benzo[4,5]imidazo[l ,2- a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-3-fhiorophenyl)dimethylphosphine oxide (26 mg,24%). MS ESI calculated for C26H19F3N5OP [M + H]+, 506.13, found 506.05. 'HNMR (400 MHz, DMSO-t / e) 8 8.42 (d, J = 7.6 Hz, 1H), 8.15 (s, 1H), 7.79 - 7.69 (m, 2H), 7.68 - 7.59 (m, 2H), 7.59 - 7.47 (m, 2H), 7.41 (d, J = 6.3 Hz, 1H), 6.51 (d, J = 7.2 Hz, 1H), 6.39 (d, J = 6.2 Hz, 1H), 3.76 - 3.65 (m, 1H), 3.10 (d, J = 14.0 Hz, 1H), 1.75 (s, 3H), 1.72 (s, 3H).19F NMR (377 MHz, DMSO- e) 8 -114.51, -114.52, -114.55, -114.57, -117.24, -120.89, -120.94.31P NMR (162 MHz, DMSO-t / e) 8 32.32, 32.29.

[0179] Example 30: (4-((8R,15R)-7,12-difluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-2- fluorophenyl)dimethylphosphine oxideTo a stirred solution of (8R,15R)-l l-chloro-7,12-difluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (100 mg, 0.270 mmol) and (2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)dimethylphosphine oxide (97 mg, 0.324 mmol) in 1,4-dioxane (2 mL) and H2O (0.5 mL) were added K3PO4 (143 mg, 0.675 mmol), S-Phos (22 mg, 0.054 mmol) and Sphos Pd Gen.3 (21 mg, 0.027 mmol) at room temperature. The resulting mixture 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 C ECh / MeOH (10 / 1) followeded by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 30% to 40% gradient in 15 min; detector, 254 nm to afford (4- ((8R,15R)-7,12-difluoro-8H,15H-8,15-methanobenzo[f]benzo[4,5]imidazo[l,2- a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-2-fhiorophenyl)dimethylphosphine oxide (55 mg, 40%). MS ESI calculated for C26H19F3N5OP [M + H]+, 506.13, found 506.20. 'HNMR (400 MHz, Chloroform-t / ) 8 8.53 (d, J = 8.0 Hz, 1H), 8.19 - 8.02 (m, 1H), 7.96 (s, 1H), 7.57 - 7.40 (m, 4H), 7.34 - 7.27 (m, 2H), 6.39 (d, J = 6.8 Hz, 1H), 6.25 (d, J = 5.8 Hz, 1H), 3.79 - 3.57 (m, 1H), 3.02 (d, J = 13.4 Hz, 1H), 1.86 (s, 3H), 1.83 (s, 3H).19F NMR (377 MHz, Chloroform^ / ) 8 -105.89, -105.90, -118.10, -121.95.31P NMR (162 MHz, Chloroform-^ 8 30.43.

[0180] Example 31 : (4-((8R,15R)-7,12-difluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l- yl)phenyl)dimethylphosphine oxidePreparation 31 A: tert-butyl (3R)-3-(2-bromo-6-fluorophenyl)-3-[(5-chloro-4-fluoro-2- nitrophenyl)amino]propanoateTo a stirred solution of (lR)-l-(2-bromo-6-fluorophenyl)-3-(tert-butoxy)-3-oxopropan-l- aminium (S)-hydroxy(phenyl)acetate (72.80 g, 154.783 mmol) and l-chloro-2,5-difluoro-4- nitrobenzene (29.96 g, 154.783 mmol) in N,N-dimethylacetamide (360 mL) was added DIEA (30.01 g, 232.174 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h. The resulting mixture was diluted with water (500 mL) followed by extraction with EtOAc (3 x 300 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PEZEA (10 / 1) to afford tert-butyl (3R)-3-(2-bromo-6-fluorophenyl)-3-[(5-chloro-4-fluoro-2-nitrophenyl)amino]propanoate (72.80 g, 96%). MS ESI calculated for Ci9H18BrClF2N2O4 [M + H]+, 491.01 493.01, found 491.10 493.10. ‘H NMR (400 MHz, Chloroform^ / ) 5 8.62 (d, J= 8.8 Hz, 1H), 7.96 (d, J= 9.2 Hz, 1H), 7.45 - 7.37 (m, 1H), 7.22 - 7.13 (m, 1H), 7.13 - 7.01 (m, 2H), 5.68 - 5.55 (m, 1H), 3.12 - 3.04 (m, 1H), 2.89 - 2.81 (m, 1H), 1.40 (s, 9H).19F NMR (377 MHz, Chloroform^ / ) 5 -112.05, -129.30.Preparation 3 IB: (3R)-3-(2-bromo-6-fluorophenyl)-3-[(5-chloro-4-fluoro-2- nitrophenyl)amino]propanalTo a stirred solution of tert-butyl (3R)-3-(2-brorno-6-fluorophenyl)-3-[(5-chloro-4-fluoro-2- nitrophenyl)amino]propanoate (72.00 g, 146.428 mmol) in DCM (1 L) was added Diisobutylaluminum hydride(l M in DCM) (161 mL, 161.071 mmol) dropwise at -78 °C undernitrogen atmosphere. The resulting mixture was stirred at -78 °C for 2 h under nitrogen atmosphere. The reaction was quenched with HC1 (IM) at -78 °C followed by extraction with CH2Q2 (3 x 1 L). The combined organic layers were washed with brine (1 L) and dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PEZEA (7 / 1) to afford (3R)-3-(2-bromo-6-fluorophenyl)-3-[(5-chloro-4-fluoro-2-nitrophenyl)amino]propanal (56.80 g, 92%). MS ESI calculated for Ci5HioBrClF2N203 [M + H]+, 418.95 420.95, found 418.95 420.95. 'HNMR (400 MHz, Chloroforms / ) 5 9.82 (s, 1H), 8.56 (d, J= 9.0 Hz, 1H), 7.96 (d, J= 9.2 Hz, 1H), 7.46 - 7.35 (m, 1H), 7.23 - 7.14 (m, 2H), 7.12 - 7.04 (m, 1H), 5.82 - 5.73 (m, 1H), 3.51 - 3.39 (m, 1H), 3.14 - 3.02 (m, 1H).19F NMR (377 MHz, Chloroform^ / ) 5 -112.31, -128.79. Preparation 31C: (R)-N-[(3R)-3-(2-bromo-6-fluorophenyl)-3-[(5-chloro-4-fluoro-2- nitrophenyl)amino]propylidene]-2-methylpropane-2-sulfinamideTo a stirred solution of (3R)-3-(2-bromo-6-fluorophenyl)-3-[(5-chloro-4-fluoro-2- nitrophenyl)amino]propanal (56.80 g, 135.364 mmol) and (R)-2-methylpropane-2-sulfinamide (19.69 g, 162.437 mmol) in DCM (570 mL) was added Titanium tetraisopropanolate (76.95 g, 270.728 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with water at room temperature. The precipitate was filtered, the filter cake was washed with DCM (3 x 200 mL). The filtrate was extracted with CH2Q2 (3 x 300 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous ISfeSCH After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PEZEA (12 / 1) to afford (R)-N-[(3R)-3-(2-bromo-6-fluorophenyl)-3-[(5-chloro-4-fluoro-2- nitrophenyl)amino]propylidene]-2-methylpropane-2-sulfinamide (70.20 g, 99%) as yellow oil. MS ESI calculated for CisJMrC^NsChS [M + H]+, 522.00 524.00, found 522.00 524.00. Preparation 3 ID: (R)-N-[(3R)-3-(2-bromo-6-fluorophenyl)-3-[(5-chloro-4-fluoro-2- nitrophenyl)amino]-l-cyanopropyl]-2-methylpropane-2-sulfinamideTo a stirred solution of (R)-N-[(3R)-3-(2-bromo-6-fluorophenyl)-3-[(5-chloro-4-fluoro-2- nitrophenyl)amino]propylidene]-2-methylpropane-2-sulfinamide (70.00 g, 133.897 mmol) and CsF (40.68 g, 267.794 mmol) in DCM (700 mL) was added TMSCN (26.57 g, 267.794 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with water (500 mL) and extracted with CH2CI2 (3 x 300 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford (R)-N-[(3R)-3-(2- bromo-6-fluorophenyl)-3-[(5-chloro-4-fluoro-2-nitrophenyl)amino]-l-cyanopropyl]-2- methylpropane-2-sulfmamide (61.10 g, 83%). MS ESI calculated for C2oH2oBrClF2N403S [M +H]+, 549.01 551.01, found 549.10 551.10.Preparation 3 IE: (lR,3R)-l-(2-bromo-6-fluorophenyl)-7-chloro-6-fluoro-2,3-dihydro-lH- benzofd] pyrrol o[ 1 ,2-a]imidazol-3 -amineA solution of (R)-N-[(3R)-3-(2-bromo-6-fluorophenyl)-3-[(5-chloro-4-fluoro-2- nitrophenyl)amino]-l-cyanopropyl]-2-methylpropane-2-sulfinamide (10.00 g, 18.188 mmol) and Titanium(III) chloride, 15-20% in 2N Hydrochloric acid) (128.22 g, 145.504 mmol, 17.5%) in EtOH (100 mL) was stirred at 80 °C for 2 h. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with water (100 mL) and basified to pH 8 with saturated NaHCCE (aq.) followed by extraction with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (1 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CTLCh / MeOH (10 / 1) to afford (lR,3R)-l-(2-bromo-6- fhiorophenyl)-7-chloro-6-fluoro-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-3-amine (5.50 g, 76%). MS ESI calculated for Ci6HiiBrClF2N3[M + H]+, 397.98 399.98, found 397.90 399.90. Preparation 31 F : (7R, 14R)- 11 -chloro- 1 , 10-difhi oro-6, 7 -dihydro-7, 14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-oneTo a mixture of (lR,3R)-l-(2-bromo-6-fluorophenyl)-7-chloro-6-fluoro-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazol-3 -amine (5.50 g, 13.797 mmol), PCy3.HBF4 (1016 mg, 2.759 mmol) and K2CO3 (7.63 g, 55.188 mmol) in 1,4-dioxane (300 mL) was added Pd(OAc)2 (310 mg, 1.380 mmol) in a pressure tank. The mixture was purged with nitrogen for 5 min and then was pressurized to 10 atm with carbon monoxide at 120 °C for 16 h. The resulting mixture was cooled to room temperature and filtered to remove insoluble solids. The resulting solution was diluted with water (500 mL) and extracted with CH2CI2 (3 x 500 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with C LCh / MeOH (20: 1) to afford (7R,14R)-11 -chi oro-1, 10-difluoro- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one (2.70 g, 57%). MS ESI calculated for C17H10CIF2N3O [M + H]+, 346.05, found 346.10. 'HNMR (400 MHz, Chloroforms / ) 5 8.34 (d, J= 7.8 Hz, 1H), 7.65 (d, J= 6.7 Hz, 1H), 7.51 (d, J= 9.4 Hz, 1H), 7.47 - 7.34 (m, 3H), 6.17 (d, J= 7.1 Hz, 1H), 4.97 (t, J= 6.7 Hz, 1H), 3.53 - 3.40 (m, 1H), 2.87 (d, J= 13.3 Hz, 1H).19F NMR (377 MHz, Chloroforms / ) 5 -117.89, -120.67.Preparation 31G: (7R,14R)-6-amino-l l-chloro-l, 10-difluoro-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-oneTo a stirred solution of (7R,14R)-1 l-chloro-l,10-difhioro-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one (2.60 g, 7.520 mmol) inDMF (100 mL) was added -BuONa (1.45 g, 15.040 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 2 min. To the above mixture was added amino diphenylphosphinate (3.51 g, 15.040 mmol) at 0 °C. The resulting mixture was stirred at room temperature for additional 30 min. The reaction was quenched with sat. Na2SOs (aq.) at room temperature followed by extraction with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2C12 / MeOH (10 / 1) to afford (7R,14R)-6-amino-l l-chloro-l,10-difluoro-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one (1.65 g, 61%). MS ESI calculated for C17H11CIF2N4O [M + H]+, 361.06, found 361.20. 'H NMR (400 MHz, Chloroform-t / ) 5 8.39 - 8.33 (m, 1H), 8.01 (s, 1H), 7.50 - 7.32 (m, 4H), 6.10 (d, J= 7.1 Hz, 1H), 5.42 (d, J= 13 Hz, 1H), 5.21 - 4.98 (m, 2H), 3.53 - 3.40 (m, 1H).19F NMR (377 MHz, Chloroform-t / ) 5 -118.00, -120.70.Preparation 31H: (8R,15R)-l l-chloro-7,12-difluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine To a stirred solution of (7R,14R)-6-amino-l 1 -chi oro-1, 10-difhioro-6,7-dihydro-7, 14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one (1.65 g, 4.574 mmol) and Formamidineacetate (3.81 g, 36.592 mmol) in 1-butanol (20 mL) was added DBU (5.57 g, 36.592 mmol) at room temperature. The resulting mixture was stirred at 90 °C for 16 h under nitrogen atmosphere. The resulting mixture was diluted with water (500 mL) and extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with C LCh / MeOH (10 / 1) to afford (8R,15R)-l l-chloro-7,12-difluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (1.56 g, 92%). MS ESI calculated for C18H10CIF2N5 [M + H]+, 370.06, found 370.00.Example 31 : (4-((8R, 15R)-7, 12-difluoro-8H, 15H-8, 15-methanobenzo[f]benzo[4,5]imidazo[ 1 ,2- a] [ 1 , 2, 4]tri azolof 1 ,5-d] [ 1 ,4]diazocin- 11 -yl)phenyl)dimethylphosphine oxide To a stirred solution of (8R,15R)-l l-chloro-7,12-difluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (80 mg, 0.216 mmol) and 2-[4-(dimethylphosphoryl)phenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (182 mg, 0.648 mmol) in 1,4-dioxane (1 mL) and H2O (0.2 mL) were added Sphos Pd G3 (17 mg, 0.022 mmol), S-Phos (18 mg, 0.043 mmol) and K3PO4 (115 mg, 0.540 mmol) at room temperature. The resulting mixture 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 columnchromatography, eluted with C^Cb / MeOH (10 / 1) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in water (10 mmol / L NH4HCO3), 30% to 70% gradient in 20 min; detector, 254 nm. This resulted in (4-((8R, 15R)-7, 12-difluoro-8H, 15H-8, 15-methanobenzo[f]benzo[4,5]imidazo[l ,2- a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)phenyl)dimethylphosphine oxide (25 mg, 24%). MS ESI calculated for C26H20F2N5OP [M + H]+, 488.14, found 488.15. 'HNMR (400 MHz, DMSO- tZ6) 8 8.44 - 8.35 (m, 1H), 8.14 (s, 1H), 7.95 - 7.79 (m, 2H), 7.67 - 7.40 (m, 6H), 6.51 (d, J= 7.2 Hz, 1H), 6.38 (d, J= 6.2 Hz, 1H), 3.73 - 3.65 (m, 1H), 3.09 (d, J= 14.0 Hz, 1H), 1.72 (s, 3H), 1.68 (s, 3H).19F NMR (377 MHz, DMSOs / 6) 6 -117.24, -123.41.31P NMR (162 MHz, DMSO- tZ6) 6 32.27.

[0181] Example 32: (3-fluoro-4-((8R,15R)-7-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l- yl)phenyl)dimethylphosphine oxideTo a stirred solution of (8R,15R)-l l-chloro-7-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (40 mg, 0.114 mmol) and 2-[4-(dimethylphosphoryl)-2-fluorophenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (50 mg, 0.171 mmol) in 1,4-dioxane (1.5 mL) and H2O (0.3 mL) were added S-Phos (9 mg, 0.023 mmol), Sphos Pd G3 (17 mg, 0.023 mmol) and K3PO4 (96 mg, 0.456 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CTfcCh / MeOH (10: 1) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 10% to 28% gradient in 10 min; detector, 254 nm to afford (3-fhioro-4-((8R,15R)-7-fhioro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l- yl)phenyl)dimethylphosphine oxide (30 mg, 98%). MS ESI calculated for C26H20F2N5OP [M + H]+, 488.14, found 488.15. 'HNMR (400 MHz, Chloroforms / ) 5 8.52 (d, J = 8.0 Hz, 1H), 7.96 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.60 - 7.52 (m, 3H), 7.48 - 7.42 (m, 2H), 7.30 (d,J = 9.1 Hz, 1H), 6.44 (d, J = 7.1 Hz, 1H), 6.34 (d, J = 6.1 Hz, 1H), 3.78 - 3.68 (m, 1H), 3.03 (d, J = 13.6 Hz, 1H), 1.81 (s, 3H), 1.78 (s, 3H).19F NMR (377 MHz, Chloroform-^ 5 -116.11, - 116.12, -117.91.31P NMR (162 MHz, Chloroform-tZ) 5 33.04, 33.01.

[0182] Example 33: (5-((8R,15R)-7-(difhioromethoxy)-12-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-3- fhioropyridin-2-yl)dimethylphosphine oxidePreparation 33A: (8R,15R)-7-(difluoromethoxy)-12-fluoro-l l-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-8H, 15H-8, 15-methanobenzo[f]benzo[4, 5]imidazo[ 1 ,2-a] [ 1 , 2, 4]tri azolof 1,5- d][l,4]diazocineTo a stirred solution of (8R,15R)-l l-chloro-7-(difhroromethoxy)-12-fluoro-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (200 mg, 0.479 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (182 mg, 0.718 mmol) in 1,4-dioxane (5 mL) were added KOAc (141 mg, 1.437 mmol), Sphos Pd G3 (37 mg, 0.048 mmol) and S-Phos (39 mg, 0.096 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CThCh / MeOH (10 / 1) to afford (8R,15R)-7-(difhroromethoxy)-12-fluoro-l l- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-8H,15H-8,15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocine (200 mg, 82%). MS ESI calculated for C25H23BF3N5O3 [M + H]+, 510.18, found 510.10.Example 33 : (5-((8R, 15R)-7-(difluoromethoxy)- 12-fluoro-8H, 15H-8, 15- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-3- fhioropyridin-2-yl)dimethylphosphine oxideTo a stirred solution of (8R,15R)-7-(difhiorom ethoxy)- 12-fluoro-l l-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-8H, 15H-8, 15-methanobenzo[f]benzo[4, 5]imidazo[ 1 ,2-a] [ 1 , 2, 4]tri azolof 1,5- d][l,4]diazocine (100 mg, 0.196 mmol) and (5-bromo-3-fhioropyridin-2-yl)dimethylphosphine oxide (59 mg, 0.235 mmol) in 1,4-dioxane (2 mL) and H2O (0.4 mL) were added K2CO3 (68 mg, 0.490 mmol) and Pd(dppf)C12-CH2C12 (16 mg, 0.020 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography,eluted with C ECh / MeOH (10 / 1) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 30% to 40% gradient in 15 min; detector, 254 nm to afford (5-((8R,15R)-7- (difhrorom ethoxy)- 12-fhroro-8H, 15H-8, 15 -methanobenzo[f]benzo[4,5]imidazo[ 1,2- a][l,2,4]triazolo[l,5-d][l,4]diazocin-l l-yl)-3-fhroropyri din-2 -yl)dimethylphosphine oxide (34 mg, 31%). MS ESI calculated for C26H19F4N6O2P [M + H]+, 555.12, found 555.15. 'H NMR (400 MHz, Chloroform-t / ) 5 8.71 (s, 1H), 8.68 - 8.58 (m, 1H), 7.97 (s, 1H), 7.74 - 7.63 (m, 1H), 7.60 - 7.47 (m, 3H), 7.32 (d, J = 8.2 Hz, 1H), 6.89 (t, J = 72.6 Hz, 1H), 6.53 (d, J = 7.2 Hz, 1H), 6.24 (d, J = 6.0 Hz, 1H), 3.80 - 3.58 (m, 1H), 3.01 (d, J = 13.4 Hz, 1H), 1.97 (s, 3H), 1.93 (s, 3H).19F NMR (377 MHZ, Chloroform-^ 5 -80.57, -81.04, -81.20, -81.65, -116.85, -116.88, - 122.24.31P NMR (162 MHz, Chloroforms / ) 5 35.06, 34.99.II. Biological EvaluationTNF-a Induced THP 1 dual Cellular Assay

[0183] Test articles were diluted in DMSO and serially diluted into 384 well assay plate (Corning 3765), at final concentrations ranging from 30 mM to 0.5 nM. THP1 dual cell reporter cells were added at a final density of 10,000 cell per well in assay media [DMEM (Gibco, cat# 21063-029), 10% fetal bovine serum (ExcelBio, cat# FND500), 1% Penicillin-Streptomycin (Solarbio, cat# P1400-100], TNF-a (R&D 210-TA-020 / CF) was then added to the assay plate at a final concentration of 100 pg / ml. This plate was then incubated for 24 hrs at 37 °C and 5 % CO2. Secreted alkaline phosphatase expression was then measured using QUANTI-Blue™ (Invivogen), according to manufacturer instructions and read on an Envision microplate reader at 620nm.

[0184] Inhibition data for test compound over a range of concentration was plotted as percentage inhibition of the test compound (100% = maximum inhibition). IC50 values were determined after correcting for background [(sample read-mean of low control ) / (mean of high control-mean of low control)] whereby the low control is DMSO without stimulation and high control is DMSO with stimulation. The IC50 is defined as the concentration of test compound which produces 50% inhibition and was quantified using the 4-parameter logistic equation to fit the data.

[0185] Representative data for exemplary compounds is presented in Table 3.Table 3a) Note: IC50 data are designated within the following ranges: b) A: < 0.1 pM c) B: > 0.1 pM to < 1.0 pM d) C: > 1.0 pM to < 10 pM e) D: > 10 pM to < 30 pMIII. Preparation of Pharmaceutical Dosage FormsExample 1: Oral capsule

[0186] The active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof. A capsule for oral administration is prepared by mixing 1-1000 mg of active ingredient with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration.Example 2: Solution for injection

[0187] The active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and is formulated as a solution in sesame oil at a concentration of 50 mg-eq / mL.

[0188] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

CLAIMSWe Claim:

1. A compound of Formula (I), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof:wherein,B is C-R15or N;R15is H, D, -OH, -NH2, or optionally substituted C1-C6 alkyl;* W-XH='HRing A is selected fromz Y, wherein the * denotes point of attachment to phosphorous, or an optionally substituted heteroarylene selected from pyrazolene, imidazoline, oxazolene, or thiazolene;W is N or C-R11;X is N or C-R12;Y is N or C-R13;Z is N or C-R14;R2is selected from H, D, Cl, F, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl;R3, and R4are selected from H, D, Cl, or F;R5is selected from H, -OH, -CN, -©(optionally substituted C1-C6 alkyl), -©(optionally substituted C3-C6 cycloalkyl), optionally substituted C2-C6 alkynyl, or halogen;R6is selected from H, D, halogen, or optionally substituted C1-C6 alkyl;R7is selected from H, D, or halogen;R8is selected from H, D, or halogen;R9and R10are independently optionally substituted C1-C6 alkyl; or R9and R10join to form optionally substituted phosphorus-containing 3- to 8-membered ring; andR11, R12, R13, and R14are independently selected from H, D, halogen, -CN, -NH2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, or - NH(optionally substituted C1-C3 alkyl).

2. A compound of Formula (la), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof:wherein,B is C-R15or N;R15is H, D, -OH, -NH2, or optionally substituted C1-C6 alkyl;* w-xH='HRing A is selected fromz Y, wherein the * denotes point of attachment to phosphorous, or an optionally substituted heteroarylene selected from pyrazolene, imidazoline, oxazolene, or thiazolene;W is N or C-R11;X is N or C-R12;Y is N or C-R13;Z is N or C-R14;R2is selected from H, D, Cl, F, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl;R3, and R4are selected from H, D, Cl, or F;R5is selected from H, -OH, -©(optionally substituted C1-C6 alkyl), -©(optionally substituted C3-C6 cycloalkyl), optionally substituted C2-C6 alkynyl, or halogen;R6is selected from H, D, halogen, or optionally substituted C1-C6 alkyl;R7is selected from H, D, or halogen;R8is selected from H, D, or halogen;R9and R10are independently optionally substituted C1-C6 alkyl; or R9and R10join to form optionally substituted phosphorus-containing 3- to 8-membered ring; andR11, R12, R13, and R14are independently selected from H, D, halogen, -CN, -NEh, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, or - NH(optionally substituted C1-C3 alkyl).

3. The compound of claim 1, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein B is C-R15.

4. The compound of claim 2, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R15is optionally substituted C1-C6 alkyl.

5. The compound of claim 3, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R15is optionally substituted Cl alkyl.

6. The compound of claim 3, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R15is H or D.

7. The compound of claim 1, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein B is N.

8. A compound of Formula (II), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof:wherein,Q-T is selected from -CO-N=, -O-CH=, -O-N=, -S-CH=, or -S-N=;* W-XH H 7— VRing A is selected from , wherein the * denotes point of attachment to phosphorous, or an optionally substituted heteroarylene selected from pyrazolene, imidazoline, oxazolene, or thiazolene;W is N or C-R11;X is N or C-R12;Y is N or C-R13;Z is N or C-R14;R2is selected from H, D, Cl, F, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl;R3, and R4are selected from H, D, Cl, or F;R5is selected from H, -OH, -©(optionally substituted C1-C6 alkyl), -©(optionally substituted C3-C6 cycloalkyl), optionally substituted C2-C6 alkynyl, or halogen; R6is selected from H, D, halogen, or optionally substituted C1-C6 alkyl;R7is selected from H, D, or halogen;R8is selected from H, D, or halogen;R9and R10are independently optionally substituted C1-C6 alkyl; or R9and R10join to form optionally substituted phosphorus-containing 3- to 8-membered ring; and R11, R12, R13, and R14are independently selected from H, D, halogen, -CN, -NH2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, or - NH(optionally substituted C1-C3 alkyl).

9. The compound of claim 8, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein Q-T is selected from -CO-N=.

10. The compound of claim 8, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein Q-T is selected from -O-CH=, or -S-CH=.

11. The compound of claim 8, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein Q-T is selected from -O-N=, or -S-N=.

12. A compound of Formula (III), or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof:wherein,U-V is selected from =N-NR16-, =N-O-, =N-S-, =CH-NR16-, =CH-O-, =CH-S-;R16is H or optionally substituted C1-C6 alkyl;W-XRing A is selected from, wherein the * denotes point of attachment to phosphorous, or an optionally substituted heteroarylene selected from pyrazolene, imidazoline, oxazolene, or thiazolene;W is N or C-R11;X is N or C-R12;Y is N or C-R13;Z is N or C-R14;R2is selected from H, D, Cl, F, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl;R3, and R4are selected from H, D, Cl, or F;R5is selected from H, -OH, -©(optionally substituted C1-C6 alkyl), -©(optionally substituted C3-C6 cycloalkyl), optionally substituted C2-C6 alkynyl, or halogen;R6is selected from H, D, halogen, or optionally substituted C1-C6 alkyl;R7is selected from H, D, or halogen;R8is selected from H, D, or halogen;R9and R10are independently optionally substituted C1-C6 alkyl; or R9and R10join to form optionally substituted phosphorus-containing 3- to 8-membered ring; and R11, R12, R13, and R14are independently selected from H, D, halogen, -CN, -NH2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, or - NH(optionally substituted C1-C3 alkyl).

13. The compound of claim 12, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein U-V is selected from =N-NR16-.

14. The compound of claim 12, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein U-V is selected from =CH-NR16-.

15. The compound of claim 12, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein U-V is selected from =N-O-, or =N-S-.

16. The compound of claim 12, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein U-V is selected from =CH-O-, or =CH-S-.

17. The compound of any one of the preceding claims, or pharmaceutically acceptable salt,* W-Xsolvate, deuteroisotope, or N-oxide thereof, wherein ring A is selected fromZ-Ywherein the * denotes point of attachment to phosphorous.

18. The compound of claim 17, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein W is N.

19. The compound of claim 17 or 18, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein X is N.

20. The compound of any one of claims 17-19, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein Y is N.

21. The compound of any one of claims 17-20, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein Z is N.

22. The compound of any one of claims 17, or 19-21, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein W is C-R11.

23. The compound of any one of claims 17, 18, or 20-22, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein X is C-R12.

24. The compound of any one of claims 17-19, or 21-23, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein Y is C-R13.

25. The compound of any one of claims 17-20, or 22-24, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein Z is C-R14.

26. The compound of any one of claims 1-25, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein each R11, R12, R13, and R14is independently selected from H, D, or halogen.

27. The compound of any one of the preceding claims, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R9and R10are each independently methyl, ethyl, n-propyl, iso-propyl, n-butyl, or iso-butyl.

28. The compound of claim 27, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, wherein R9and R10are each methyl.

29. The compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of claim 27, wherein R9and R10are each ethyl.

30. The compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of any one of claims 1-26, wherein R9and R10join to form an optionally substituted phosphorus-containing 3- to 8-membered heterocyclyl.

31. The compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of claim 30, wherein R9and R10join to form an optionally substituted phosphorus- containing 4- to 6-membered heterocyclyl.

32. The compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of claim 30, wherein R9and R10join to form optionally substituted phosphorus- containing 4-membered heterocyclyl.

33. The compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of claim 30, wherein R9and R10join to form an optionally substituted phosphorus- containing 5-membered heterocyclyl.

34. The compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of claim 30, wherein R9and R10join to form optionally substituted phosphorus- containing 6-membered heterocyclyl.

35. The compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of claim 30, wherein R9and R10taken together with the phosphorus atom to which they are attached join to form a ring selected from:

36. The compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of claim 30, wherein R9and R10taken together with the phosphorus atom to which they are attached to join to form a ring selected from:

37. The compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of any one of claims 1-36, wherein R6is H or D.

38. The compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of any one of claims 1-36, wherein R6is halogen.

39. The compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of any one of claims 1-38, wherein R7is H or D.

40. The compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of any one of claims 1-38, wherein R7is halogen.

41. The compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of any one of claims 1-12, wherein ring A is an optionally substituted heteroarylene.

42. The compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of any one of claims 1-41, wherein R8is H or D.

43. The compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of any one of claims 1-41, wherein R8is F.

44. The compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of any one of claims 1-41, wherein R8is Cl.

45. The compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of any one of claims 1-44, wherein R5is F.

46. The compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of any one of claims 1-44, wherein R5is Cl.

47. The compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of any one of claims 1-44, wherein R5is optionally substituted C2-C6 alkynyl.

48. The compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of any one of claims 1-44, wherein R5is -C=CH or -C=CCH3.

49. The compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of any one of claims 1-44, wherein R5is -©(optionally substituted C1-C6 alkyl).

50. The compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of any one of claims 1-44, wherein R5is -OCHF2.

51. The compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of any one of claims 1-50, wherein R2, R3, and R4are H or D.

52. The compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of any one of claims 45 or 46, wherein R2is methyl, and R5is Cl or F.

53. The compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of any one of claims 1-44, wherein R4is Cl or F.

54. The compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of any one of claims 1-44, wherein R4is Cl or F, and R5is Cl or F.

55. The compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of any one of claims 1-51, 53 or 54, wherein R2and R3are H or D.

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

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

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

59. A method of preparing a pharmaceutical composition comprising mixing the compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of any one of claims 1-57, and a pharmaceutically acceptable excipient or carrier.

60. A compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of any one of claims 1-57, or the pharmaceutical composition of claim 58, for use in a method of treatment of the human or animal body.

61. A compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of any one of claims 1-57 or the pharmaceutical composition of claim 58, for use in a method of treatment of inflammatory or autoimmune disease or disorder.

62. Use of a compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N- oxide thereof, of any one of claims 1-57 or the pharmaceutical composition of claim 58, in the manufacture of a medicament for the treatment of an inflammatory or autoimmune disease or disorder.

63. A pharmaceutical composition comprising the compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of any one of claims 1-57, for use in an inflammatory or autoimmune disease or disorder in a patient in need thereof.

64. A method of treating an inflammatory or autoimmune disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effectively amount of the compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of any one of claims 1-57, or the pharmaceutical composition of claim 58.

65. A method of inhibiting TNFa activity comprising contacting the TNFa protein with the compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of any one of claims 1-57, or the pharmaceutical composition of claim 58, wherein the TNFa protein is contacted in an in vitro setting.

66. A method of inhibiting TNFa activity comprising contacting the TNFa protein with the compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, ofany one of claims 1-57, or the pharmaceutical composition of claim 58, wherein the TNFa protein is contacted in an in vivo setting.

67. A method of treating or preventing a condition conducive to treatment or prevention by inhibition of TNFa in a patient comprising administering to the patient a therapeutically effective amount of the compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of any one of claims 1-57, or the pharmaceutical composition of claim 58.

68. A pharmaceutical composition comprising the compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of any one of claims 1-57, for use in treating or preventing a condition conducive to treatment or prevention by inhibition of TNFa in a patient.

69. The compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof, of any one of claims 1-57 or the pharmaceutical composition of claim 58, for use in treating or preventing a condition conducive to treatment or prevention by inhibition of TNFa in a patient.

70. Use of the compound, or pharmaceutically acceptable salt, solvate, deuteroisotope, or N- oxide thereof, of any one of claims 1-57, or the pharmaceutical composition of claim 58, in the preparation of a medicament for treating or preventing a condition conducive to treatment or prevention by inhibition of TNFa in a patient.

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