TNF-α activity regulator

Abstract

Provided herein are inhibitors of TNFα, pharmaceutical compositions containing the inhibitory compounds, and methods of using the TNFα inhibitory compounds for the treatment of diseases or disorders. One embodiment provides a pharmaceutical composition containing a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, and at least one pharmaceutically acceptable excipient. 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), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof. Another embodiment provides a method wherein the disease or disorder is rheumatoid arthritis.

Description

[Background technology]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 518,062, filed August 7, 2023, and U.S. Provisional Patent Application No. 63 / 384,919, filed November 23, 2022, both of which are incorporated herein by reference in their entireties.

[0002] Tumor necrosis factor alpha (TNFα) is a proinflammatory cytokine that is involved in a wide range of intracellular signaling events. Aberrant TNFα signaling leads to inflammatory conditions and is thought to be a key component of inflammatory diseases such as rheumatoid arthritis. Summary of the Invention

[0003] Provided herein are inhibitors of TNFα, pharmaceutical compositions containing the inhibitory compounds, and methods of using the inhibitory compounds for the treatment of inflammatory or autoimmune diseases or disorders.

[0004] One embodiment provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or N-oxide thereof: [ka] During the ceremony, In ring A, * indicates the attachment point to L. [ka] or an optionally substituted heteroarylene selected from pyrazolene, imidazoline, oxazolene or thiazolene; V is N or CR 11 and W is N or CR 5 and X is N or CR 6and Y is N or CR 7 and Z is N or CR 8 and L is a bond, -NH-, -(CH2)n-, -C(R 12 )(R 13 )-, -O(CH2)n-*, or -NH(CH2)n-*, where * represents the point of attachment to the phosphorus; n is 1, 2, or 3; R 1 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl; R 2 is hydrogen or optionally substituted C1-C3 alkyl; R 3 is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl; R 4 is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl, or R 3 and R 4 join to form an optionally substituted phosphorus-containing 3- to 8-membered ring; R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, halogen, —CN, —NH, optionally substituted C-C alkyl, optionally substituted C-C alkoxy, or —NH(optionally substituted C-C alkyl); R 9 is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; R 10 is selected from hydrogen or halogen; R 11 is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; and R 12 and R 13 are independently selected from hydrogen, —OH, F, and CH 3 .

[0005] One embodiment provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate or N-oxide thereof, and at least one pharmaceutically acceptable excipient.

[0006] 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), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof. Another embodiment provides a method wherein the disease or disorder is rheumatoid arthritis.

[0007] Incorporation by Reference All publications, patents, and patent applications mentioned herein are hereby incorporated by reference for the specific purposes identified herein. DETAILED DESCRIPTION OF THE INVENTION

[0008] As used in this specification and the appended claims, singular forms such as "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "an agent" includes a plurality of such agents, and a reference to "the cell" includes reference to one or more cells (or cells) and equivalents thereof known to those of skill in the art. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formula, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. When referring to a numerical value or numerical range, the term "about" means that the referenced numerical value or numerical range is an approximation within experimental variability (or statistical experimental error), and thus, in some instances, the numerical value or numerical range will vary between 1% and 15% of the stated numerical value or numerical range. The term "comprising" (and related terms, e.g., "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other particular embodiments, such as, for example, any composition of matter, composition of matter, method, or process described herein, "consists of" or "consists essentially of" the described features.

[0009] definition As used in this specification and the appended claims, unless specified to the contrary, the following terms have the meanings indicated below.

[0010] "Amino" refers to the -NH2 radical.

[0011] "Cyano" refers to the -CN radical.

[0012] "Nitro" refers to the -NO2 radical.

[0013] "Oxa" refers to the -O radical.

[0014] "Oxo" refers to the =O radical.

[0015] "Thioxo" refers to the =S radical.

[0016] "Imino" refers to the =NH radical.

[0017] "Oximo" refers to the =N-OH radical.

[0018] "Hydrazino" refers to the =N-NH2 radical.

[0019] "Alkyl" refers to a straight or branched hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, having from 1 to 15 carbon atoms (e.g., C1-C 15 In certain embodiments, alkyl contains 1 to 13 carbon atoms (e.g., C-C 13 In certain embodiments, alkyl contains 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, alkyl contains 1 to 5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, alkyl contains 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, alkyl contains 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, alkyl contains 1 to 2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, alkyl contains 1 carbon atom (e.g., C1 alkyl). In other embodiments, alkyl contains 5 to 15 carbon atoms (e.g., C5-C 15In other embodiments, an alkyl group contains 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, an alkyl group contains 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl group contains 3 to 5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, an alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). An alkyl is attached to the remainder of the molecule by a single bond. Unless stated otherwise expressly in the specification, an alkyl group is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t R a (wherein t is 1 or 2) and -S(O) t N(R a )2 (wherein t is 1 or 2), and each R aare 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, the optionally substituted alkyl is haloalkyl. In other embodiments, the optionally substituted alkyl is fluoroalkyl. In other embodiments, the optionally substituted alkyl is a -CF3 group.

[0020] "Alkoxy" refers to a radical attached through an oxygen atom of the formula --O-alkyl, where alkyl is an alkyl chain as defined above.

[0021] "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 2 to 12 carbon atoms. In certain embodiments, alkenyl contains 2 to 8 carbon atoms. In other embodiments, alkenyl contains 2 to 4 carbon atoms. Alkenyls are attached to the remainder of the molecule by a single bond and include, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless expressly stated otherwise in the specification, alkenyl groups are optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, and the like. a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t R a (wherein t is 1 or 2) and -S(O) t N(R a )2 (wherein t is 1 or 2), and each R aare 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).

[0022] "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, and having 2 to 12 carbon atoms. In certain embodiments, alkynyl contains 2 to 8 carbon atoms. In other embodiments, alkynyl contains 2 to 6 carbon atoms. In other embodiments, alkynyl contains 2 to 4 carbon atoms. Alkynyl is attached to the remainder of the molecule by a single bond and includes, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise expressly in the specification, alkynyl groups are optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, and the like. a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(Ra )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t R a (wherein t is 1 or 2) and -S(O) t N(R a )2 (wherein t is 1 or 2), and each R a are 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).

[0023] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain connecting the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and having 1 to 12 carbon atoms, such as methylene, ethylene, propylene, or n-butylene. 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 atom in the alkylene chain or through any two carbon atoms in the chain. In certain embodiments, an alkylene contains 1 to 8 carbon atoms (e.g., a C1-C8 alkylene). In other embodiments, an alkylene contains 1 to 5 carbon atoms (e.g., a C1-C5 alkylene). In other embodiments, an alkylene contains 1 to 4 carbon atoms (e.g., a C1-C4 alkylene). In other embodiments, an alkylene contains 1 to 3 carbon atoms (e.g., a C1-C3 alkylene). In other embodiments, an alkylene contains 1 to 2 carbon atoms (e.g., a C1-C2 alkylene). In other embodiments, an alkylene contains 1 carbon atom (e.g., a C1 alkylene). In other embodiments, an alkylene contains 5 to 8 carbon atoms (e.g., a C5-C8 alkylene). In other embodiments, an alkylene contains 2 to 5 carbon atoms (e.g., a C2-C5 alkylene). In other embodiments, an alkylene contains 3 to 5 carbon atoms (e.g., a C3-C5 alkylene). Unless stated otherwise clearly in the specification, an alkylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR. a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(Ra )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t R a (wherein t is 1 or 2) and -S(O) t N(R a )2 (wherein t is 1 or 2), and each R a are 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).

[0024] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain, composed solely of carbon and hydrogen, containing at least one carbon-carbon double bond and having 2 to 12 carbon atoms, that connects the rest of the molecule to a radical group. 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, the alkenylene contains 2 to 8 carbon atoms (e.g., C2-C8 alkenylene). In other embodiments, the alkenylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, the alkenylene contains 2 to 4 carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, the alkenylene contains 2 to 3 carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, the alkenylene contains 2 carbon atoms (e.g., C2 alkenylene). In other embodiments, an alkenylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkenylene). In other embodiments, an alkenylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkenylene). Unless stated otherwise clearly in the specification, an alkenylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t R a (wherein t is 1 or 2) and -S(O)t N(R a )2 (wherein t is 1 or 2), and each R a are independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0025] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain, composed solely of carbon and hydrogen, containing at least one carbon-carbon triple bond and having 2 to 12 carbon atoms, that connects the rest of the molecule to a radical group. 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, the alkynylene contains 2 to 8 carbon atoms (e.g., C2-C8 alkynylene). In other embodiments, the alkynylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkynylene). In other embodiments, the alkynylene contains 2 to 4 carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, the alkynylene contains 2 to 3 carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, the alkynylene contains 2 carbon atoms (e.g., C2 alkynylene). In other embodiments, an alkynylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, an alkynylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkynylene). Unless stated otherwise clearly in the specification, an alkynylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t R a (wherein t is 1 or 2) and -S(O)t N(R a )2 (wherein t is 1 or 2), and each R a are 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] "Aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. An aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and 5 to 18 carbon atoms, and at least one ring within the ring system is fully unsaturated, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel theory. Ring systems from which aryl groups can be derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless specifically stated otherwise herein, the term "aryl" or the prefix "ar-" (e.g., "aralkyl") is intended to include aryl radicals optionally substituted with one or more substituents, including optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, cyano, nitro, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (wherein t is 1 or 2), -R b -S(O) t Ra (wherein t is 1 or 2), -R b -S(O) t OR a (wherein t is 1 or 2) and -R b -S(O) t N(R a )2, where t is 1 or 2, a are 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); and each R b are independently a direct bond or a linear or branched alkylene or alkenylene chain; R c is a linear or branched alkylene or alkenylene chain, and R a , R b , or R c Each substituent is unsubstituted unless otherwise indicated.

[0027] "Aralkyl" means a group of the formula -R c -aryl radical, where R cis an alkylene chain as defined above, e.g., methylene, ethylene, etc. 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.

[0028] "Aralkenyl" means a group of the formula -R d -aryl radical, where R d is an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as defined above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0029] "Aralkynyl" means a group of the formula -R e -aryl radical, where R e is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as defined above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0030] "Aralkoxy" means a group of the formula -OR c -refers to a radical attached through an oxygen atom of an aryl, where R c is an alkylene chain as defined above, e.g., methylene, ethylene, etc. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0031] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, including fused or bridged ring systems having 3 to 15 carbon atoms. In certain embodiments, a carbocyclyl contains 3 to 10 carbon atoms. In other embodiments, a carbocyclyl contains 5 to 7 carbon atoms. A carbocyclyl is attached to the rest of the molecule by a single bond. A carbocyclyl may be saturated (i.e., containing only single C-C bonds) or unsaturated (i.e., containing one or more double or triple bonds). A fully saturated carbocyclyl radical is also referred to as a "cycloalkyl." Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as a "cycloalkenyl." Examples of monocyclic cycloalkenyl radicals include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless specifically stated otherwise in this specification, the term "carbocyclyl" is intended to include carbocyclyl radicals optionally substituted with one or more substituents, including optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, oxo, thioxo, cyano, nitro, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -Rb -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (wherein t is 1 or 2), -R b -S(O) t R a (wherein t is 1 or 2), -R b -S(O) t OR a (wherein t is 1 or 2) and -R b -S(O) t N(R a )2, where t is 1 or 2, a are 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); and each R bare independently a direct bond or a linear or branched alkylene or alkenylene chain; R c is a linear or branched alkylene or alkenylene chain, and R a , R b , or R c Each substituent is unsubstituted unless otherwise indicated.

[0032] "Carbocyclylalkyl" means a group of the formula -R c -carbocyclyl radical, where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0033] "Carbocyclylalkynyl" means a group of the formula -R c -carbocyclyl radical, where R c is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0034] "Carbocyclylalkoxy" means a group of the formula -OR c - refers to a radical attached through the oxygen atom of a carbocyclyl, where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0035] "Halo" or "halogen" refers to a bromo, chloro, fluoro, or iodo substituent.

[0036] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0037] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless specifically stated otherwise in the specification, a 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. If present, one or more nitrogen atoms are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in this specification, the term "heterocyclyl" is intended to include heterocyclyl radicals as defined above optionally substituted by one or more substituents, including optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b-C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (wherein t is 1 or 2), -R b -S(O) t R a (wherein t is 1 or 2), -R b -S(O) t OR a (wherein t is 1 or 2) and -R b -S(O) t N(R a )2, where t is 1 or 2, aare 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); and each R b are independently a direct bond or a linear or branched alkylene or alkenylene chain; R c is a linear or branched alkylene or alkenylene chain, and R a , R b , or R c Each substituent is unsubstituted unless otherwise indicated.

[0038] "N-heterocyclyl" or "N-linked heterocyclyl" refers to a heterocyclyl radical, as defined above, containing at least one nitrogen, where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. The N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, and imidazolidinyl.

[0039] "C-heterocyclyl" or "C-linked heterocyclyl" refers to a heterocyclyl radical, as defined above, containing at least one heteroatom, where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. The 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.

[0040] "Heterocyclylalkyl" means a group of the formula -R c -heterocyclyl radical, where R c is 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 heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl portion of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0041] "Heterocyclylalkoxy" means a heterocyclyl group of the formula -OR c - refers to a radical attached through the oxygen atom of a heterocyclyl, where R c is 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 portion of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0042] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical containing 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings within the ring system is fully unsaturated. That is, it contains a cyclic, delocalized (4n+2) π-electron system according to Hückel theory. Heteroaryl includes fused or bridged ring systems. Heteroatoms in a heteroaryl radical are optionally oxidized. If present, one or more nitrogen atoms are optionally quaternized. A heteroaryl is attached to the remainder of the molecule through any atom of the ring. Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imino dazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridaz ...10-Hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxazolyl Xoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl 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-cyclo[4,5]thieno[2,3-d]pyrimidinyl, 5, ... Hepta[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 intended to include a heteroaryl radical, as defined above, optionally substituted by one or more substituents, including optionally substituted alkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, optionally substituted fluoroalkyl, optionally substituted haloalkenyl, optionally substituted haloalkynyl, oxo, thioxo, cyano, nitro, -R, b -OR a , -R b-OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a ,,-R b -N(R a )S(O) t R a (wherein t is 1 or 2), -R b -S(O) t R a (wherein t is 1 or 2), -R b -S(O) t OR a (wherein t is 1 or 2) and -R b -S(O) t N(R a )2, where t is 1 or 2, aare 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); and each R b are independently a direct bond or a linear or branched alkylene or alkenylene chain; R c is a linear or branched alkylene or alkenylene chain, and R a , R b , or R c Each substituent is unsubstituted unless otherwise indicated.

[0043] "N-heteroaryl" refers to a heteroaryl radical, as defined above, containing at least one nitrogen, where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. The N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0044] "C-heteroaryl" refers to a heteroaryl radical as defined above, where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. The C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0045] "Heteroarylalkyl" means a group of the formula -R c -heteroaryl radical, where R c is 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 portion of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0046] "Heteroarylalkoxy" means a heteroaryl group of the formula -OR c - refers to a radical attached through an oxygen atom of a heteroaryl, where R c is 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 portion of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0047] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers, thus giving rise to enantiomers, diastereomers, and other stereoisomeric forms, which are defined in terms of absolute stereochemistry as (R)- or (S)-. Unless otherwise specified, all stereoisomeric forms of the compounds disclosed herein are intended to be contemplated by the present disclosure. When a compound described herein contains an alkene double bond, and unless otherwise specified, the present disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers, including their racemic and optically pure forms, and all tautomers, are intended to be included. The term "geometric isomer" refers to E or Z geometric isomers (e.g., cis or trans) of the 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.

[0048] As used herein, a "carboxylic acid bioisostere" refers to a functional group or moiety that exhibits similar physical, biological, and / or chemical properties to a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to: [ka] [ka] Examples include:

[0049] "Tautomer" refers to a molecule in which a proton transfer from one atom of the molecule to another atom of the same molecule is possible. In certain embodiments, the compounds presented herein exist as tautomers. In situations where tautomerization is possible, a chemical equilibrium of tautomers exists. The exact ratio of tautomers depends on several factors, including physical conditions, temperature, solvent, and pH. Some examples of tautomer equilibrium include the following: [ka]

[0050] In some embodiments, the compounds disclosed herein are used in various isotopically enriched forms, e.g., 2 H, 3 H, 11 C. 13 C and / or 14 The compound is used enriched in C content. In one particular embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures 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 metabolic stability and / or efficacy, thereby extending the duration of action of the drug.

[0051] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of a hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-enriched carbon, are within the scope of this disclosure.

[0052] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 It may be labeled with an isotope such as C. 2 H, 11 C. 13 C. 14 C. 15 C. 12 N, 13 N, 15 N, 16 N, 16 O. 17 O.14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 125 Isotopic substitutions with I are all contemplated. In some embodiments, 18 Isotopic substitution with F 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.

[0053] In certain embodiments, the compounds disclosed herein comprise: 1 Some or all of the H atoms 2 The compound is substituted with a H atom. Methods for synthesizing deuterium-containing compounds are known in the art, and non-limiting examples include the following synthetic methods.

[0054] Deuterium-substituted compounds are synthesized using a variety of methods, for example 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.

[0055] Deuterated starting materials are readily available and amenable to the synthetic methods described herein to synthesize deuterated compounds. Many deuterated reagents and building blocks are commercially available from chemical vendors such as, for example, Aldrich Chemical Co.

[0056] Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-d3 (CD3I), are readily available and can be used to transfer a deuterium-substituted carbon atom to a reaction substrate under nucleophilic substitution reaction conditions. The use of CD3I is illustrated in the following reaction scheme for illustrative purposes. [ka]

[0057] For example, a deuterium-transfer reagent, such as lithium aluminum deuteride (LiAlD4), is used to transfer deuterium to the reaction substrate under reducing conditions. The use of LiAlD4 is illustrated in the following reaction scheme for illustrative purposes. [ka]

[0058] For illustrative purposes, deuterium gas and a palladium catalyst are used to reduce the unsaturated carbon-carbon bond and effect reductive displacement of the aryl carbon-halogen bond, as depicted in the reaction scheme below. [ka]

[0059] 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 compounds disclosed herein are fully substituted with deuterium atoms and are not exchangeable. 1 In one embodiment, the level of deuterium incorporation is determined by a synthetic method in which deuterated synthetic building blocks are used as starting materials.

[0060] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. A pharmaceutically acceptable salt of any one of the TNFα inhibitory compounds described herein is intended to encompass any pharmaceutically suitable salt form. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0061] "Pharmaceutically acceptable acid addition salts" refer to salts that retain the biological effectiveness and properties of the free base and are not biologically or otherwise undesirable, such as those formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphoric acid, etc. Also included are salts formed with organic acids, such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic sulfonic acids, and aromatic sulfonic acids, including, 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, etc. Thus, exemplary salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as, for example, arginate, gluconate, and galacturonate (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt according to methods and techniques known to those skilled in the art.

[0062] A "pharmaceutically acceptable base addition salt" refers to a salt that retains the biological effectiveness and properties of the free acid and is not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as, for example, alkali metals, 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, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

[0063] "Pharmaceutically acceptable solvate" refers to a composition of matter that is in a solvent-added form. In some embodiments, the solvate contains a stoichiometric or non-stoichiometric amount of solvent and is formed during the preparation process using a pharmaceutically acceptable solvent, such as water, ethanol, etc. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein exist in either unsolvated or solvated form.

[0064] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any species of the following classes of mammals: humans, non-human primates such as chimpanzees, and other ape and monkey species; farm animals such as cows, horses, sheep, goats, pigs, and the like; domestic animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. In one embodiment, the mammal is a human.

[0065] As used herein, "treatment" or "treating" or "alleviating" or "ameliorating" are used interchangeably. These terms refer to a method for obtaining a beneficial or desired result, including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. "Therapeutic benefit" refers to the eradication or amelioration of the underlying disease being treated. Therapeutic benefit may also be achieved by the eradication or amelioration of one or more physiological symptoms associated with the underlying disease, where improvement is observed in the patient even if the patient still suffers from the underlying disease. For prophylactic benefit, in some embodiments, the composition is administered to a patient at risk of developing a particular disease or to a patient who has not been diagnosed with the disease but who reports one or more physiological symptoms of the disease.

[0066] Tumor necrosis factor alpha (TNFα) protein and function Tumor necrosis factor alpha (TNFα) protein is a member of the TNF superfamily, which includes various transmembrane proteins with homologous TNF domain-forming trimers. The TNF superfamily includes 19 members, including, but not limited to, tumor necrosis factor alpha (also known as tumor necrosis factor or TNF), lymphotoxin alpha (TNFβ), lymphotoxin beta (TNFγ), OX40 ligand, CD40 ligand, Fas ligand, CD27 ligand, CD30 ligand, CD137 ligand, CD137 ligand, and TNF-related apoptosis-inducing ligand. TNFα protein is a cytokine and an adipokine (a cytokine secreted by adipose tissue).

[0067] TNFα is a transmembrane protein, and proteolytic cleavage releases soluble TNFα (sTNFα). sTNFα can transmit signals by binding to two receptors, TNFR1 and TNFR2. TNFα is a regulator of immune responses, mediating cell signaling and signaling pathways that induce cell survival or cell death. TNF signaling has two receptors, TNFR1 and TNFR2. sTNFα-TNFR1 signaling promotes immune cell activation and induces acute and chronic inflammation. Membrane TNFα-TNFR2 signaling promotes inflammation resolution, immune cell regulatory function, and cell survival.

[0068] Although the extracellular regions of TNFR1 and TNFR2 both contain four homologous cysteine-rich domains, their intracellular regions are structurally distinct. TNFR1 contains a protein-binding region called the death domain, which allows for homotypic and heterotypic interactions with other death domain-containing proteins. In contrast, TNFR2 contains TNF receptor-associated factors (TRAFs), which allow for interaction with the TRAF family of signaling adaptors. The profiles of the two TNF receptors are quite distinct, and these differences affect cellular activity and physiological function. TNFR1 can activate NF-κB and MAPK signaling and cell death, making it important for regulating 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 often mediates local homeostatic effects, such as tissue regeneration and cell survival (D. Fresegna et al., Cells, 2020, 9, 2290).

[0069] Binding of TNFα to TNFR1 activates NF-κB, which can mediate the transcription of various proteins involved in cell survival and proliferation, anti-apoptotic factors, and inflammatory responses. Furthermore, the MAPK pathway can also be activated by the binding of TNFα to TNFR1. The MAPK pathway is involved in cell differentiation and proliferation. Binding of TNFα to TNFR1 induces receptor trimerization, resulting in the assembly of a TNFR1-associated signaling complex. This complex recruits receptor interacting protein 1 (RIP1) and the TNF receptor-associated death domain (TRADD) to TNFR1 via the receptor death domain. TRADD then recruits the adaptor proteins TRAF2 and TRAF5, which can engage the E3 ligase cellular inhibitor of apoptosis (c-IAP1, c-IAP2). c-IAP1 / 2 are critical for signaling of the TNFR1 complex, ultimately resulting in the recruitment of the signaling kinase complexes IKKα and IKKβ, inhibitors of kappa B kinase 1 and 2, and transforming growth factor beta-activated kinase 1 (TAK1), which activates NF-κB and MAPK signaling. Activation of these signaling pathways leads to gene activation and expression of pro-inflammatory cytokines and pro-survival proteins.

[0070] TNF signaling is regulated by post-translational ubiquitination, which is essential for biological processes. Post-translational modification of the TNFR1-associated signaling complex results in a shift from inflammatory gene signaling to cell death. This switch is dependent on the ubiquitination state of RIP1, which forms as part of the TNFR1-associated signaling complex following TNFα binding.

[0071] TNF has long been known to be a key regulator of inflammatory responses and has recently been implicated in brain function (D. Fresegna et al., Cells, 2020, 9, 2290). As a regulator of inflammatory responses, TNF can regulate many aspects of T cell function, including but not limited to proliferation, survival, priming, and apoptotic fate. TNF is also known to play a role in the outcome of lymphocyte responses through its ability to promote cell death via TNFR1 in both CD4 and CD8P T cells. Characteristic inflammatory conditions can also result in T cell apoptosis, which is promoted or supported by TNFR2.

[0072] In the normal adult brain, TNF is expressed at low levels, and its expression may be influenced by the presence or absence of cytokines that can cross the blood-brain barrier. TNFRs in the brain are expressed by glial and neuronal cells and have regulatory functions, including but not limited to, homeostatic synaptic plasticity, astrocyte-mediated synaptic transmission, and neurogenesis. These functions are useful in regulating learning and memory, among other roles.

[0073] TNF is recognized as a physiological gliotransmitter for communication between neurons and glial cells, which subsequently influences synaptic regulation. Glial TNF is important for maintaining normal surface expression of AMPA receptors and for homeostatic synaptic scaling, which can modulate the strength of all synapses on neurons.

[0074] Prior art small molecule inhibitors Diseases treated with biologic TNFα inhibitors include, but are not limited to, rheumatoid arthritis, inflammatory bowel disease, psoriatic arthritis, psoriasis, and ankylosing spondylitis. Patients with neuroinflammatory and neurodegenerative conditions, including, but not limited to, Alzheimer's disease, Parkinson's disease, multiple sclerosis, treatment-resistant depression, and tinnitus, may benefit from treatment with oral CNS sTNFα inhibitors. These inhibitors disrupt sTNFα signaling and suppress mTNFα signaling. Previous reports have also suggested targeting TNFR2 for the treatment of Alzheimer's disease (N. Orti-Casan et al., Front Neurosci. 2019;13:49).

[0075] Because some patients respond poorly to approved anti-TNFα monotherapy, small molecules have been developed for the treatment of rheumatoid arthritis (JD Dietrich et al., J. Med. Chem. 2021, 64, 417-429). Anti-TNFα drugs have 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. Because long-term clinical response rates for rheumatoid arthritis are generally approximately 60-70%, small molecules have been developed as an alternative to anti-TNFα biologics.

[0076] Previous studies have suggested that TNFα inhibitors may also be effective in treating multiple sclerosis (D. Fresegna et al., Cells, 2020, 9, 2290). Evidence exists for the involvement of TNF in various pathological problems of multiple sclerosis, including immune dysregulation, demyelination, synaptic degeneration, and neuroinflammation. TNFα inhibitors have potential for the treatment of multiple sclerosis and other potentially chronic neurodegenerative diseases of the central nervous system.

[0077] More than 50 million Americans suffer from tinnitus, a condition characterized by the perception of sound in the absence of an external sound source. TNFα has been shown to be 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). Specific inhibitors of TNFα are thought to have therapeutic effects on tinnitus.

[0078] Recent reports also suggest that TNFα inhibitors, alone or in combination, can be used to treat inflammatory bowel disease (SFowler Braga and KJ Clark, US Pharm. 2021;46(5):34-37). TNFα is a mediator of the abnormal immune response in inflammatory bowel disease, destroying the intestinal mucosa and epithelial barrier. Anti-TNF agents can block the activation of TNF-mediated pro-inflammatory pathways, resulting in attenuation of immune-mediated inflammation.

[0079] In addition to demonstrating efficacy in collagen antibody-induced arthritis models, small molecule sTNFα inhibitors also have efficacy in pharmacological models of sTNFα / TNFR1 signaling. Currently, limited data are available regarding small molecule sTNFα inhibitors. Some TNFα inhibitors include, but are not limited to, XPro1595, etanercept, infliximab, adalimumab, certolizumab pegol, golimumab, and other inhibitors described in "TNF-α: The Shape of Small Molecules to Come?" (A. Domling and X. Li, Drug Discovery Today 2022 January;27(1):3-7) and "Small Molecules that Inhibit TNF Signaling by Stabilizing an Asymmetric Form of the Trimer" (J. O'Connell et al., Nature Communications 10,5795 (2019)). Additional small molecule inhibitors of TNFα include, but are not limited to, "Biologic-like In Vivo Efficacy with Small Molecule Inhibitors of TNFα Identified Using Scaffold Hopping and Structure-Based Drug Design Approaches" (H.Y. Xiao et al., al., J.Med.Chem.2020,15050-15071), “Development of Orally Efficacious Allosteric Inhibitors of TNFα via Fragment-Based Drug Design” (JD Dietrich et al., J.Med.Chem.2021,64,417-429), and “Small-Molecule Inhibition of TNF-α” (MM He et al., Science,310(2015),1022-1025).

[0080] For patients currently treated with biologic TNFα inhibitors that affect mTNFα, small molecule sTNFα inhibitors have the potential to be valuable therapies, allowing for fine-tuning of oral dosing requirements, avoiding anti-drug antibody responses, and improving short- and long-term responses (A. Domling and X. Li, Drug Discov Today 2022 Jan;27(1):3-7).

[0081] Novel compounds that inhibit TNFα In one embodiment, provided herein are TNFα inhibitory compounds.

[0082] One embodiment provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or N-oxide thereof: [ka] During the ceremony, In ring A, * indicates the attachment point to L. [ka] or an optionally substituted heteroarylene selected from pyrazolene, imidazoline, oxazolene or thiazolene; V is N or CR 11 and W is N or CR 5 and X is N or CR 6 and Y is N or CR 7 and Z is N or CR 8 and L is a bond, -NH-, -(CH2)n-, or -CR 12 R 13 -, -O(CH2)n-*, or -NH(CH2)n-*, where * represents the point of attachment to the phosphorus; n is 1, 2, or 3; R 1is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl; R 2 is hydrogen or optionally substituted C1-C3 alkyl; R 3 is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl; R 4 is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl, or R 3 and R 4 join to form an optionally substituted phosphorus-containing 3- to 8-membered ring; R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, halogen, —CN, —NH, optionally substituted C-C alkyl, optionally substituted C-C alkoxy, or —NH(optionally substituted C-C alkyl); R 9 is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; R 10 is selected from hydrogen or halogen; R 11 is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; and R 12 and R 13 are independently selected from hydrogen, —OH, F, and CH 3 .

[0083] One embodiment provides a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate or N-oxide thereof: [ka] During the ceremony, In ring A, * indicates the attachment point to L. [ka] or an optionally substituted heteroarylene selected from pyrazolene, imidazoline, oxazolene or thiazolene; V is N or CR 11 and W is N or CR 5 and X is N or CR 6 and Y is N or CR 7 and Z is N or CR 8 and L is a bond, —NH—, —(CH)—, —O(CH)—*, or —NH(CH)—*, where * represents the point of attachment to the phosphorus; n is 1, 2, or 3; R 1 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl; R 2 is hydrogen or optionally substituted C1-C3 alkyl; R 3 is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl; R 4 is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl, or R 3 and R 4 join to form an optionally substituted phosphorus-containing 3- to 8-membered ring; R 5 , R 6 , R 7 , and R 8are each independently selected from hydrogen, halogen, —CN, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, or —NH(optionally substituted C1-C3 alkyl); R 9 is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; R 10 is selected from hydrogen or halogen, and R 11 is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl.

[0084] Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein A is [ka] wherein * represents the point of attachment to L.

[0085] Another embodiment provides a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein W is N. Another embodiment provides a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein W is CR 5 is.

[0086] Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein X is N. Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein X is CR 6 is.

[0087] Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein Y is N. Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein Y is CR 7 is.

[0088] Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein Z is N. Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein Z is CR 8 is.

[0089] Another embodiment provides a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein W is CR 5 and X is CR 6 and Y is CR 7 and Z is CR 8 Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein W is CF, X is CH, Y is CH, and Z is CH.

[0090] Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen or halogen.

[0091] Another embodiment provides a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein W is N and X is CR 6 and Y is CR 7and Z is CR 8 is.

[0092] Another embodiment provides a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein W is CR 5 , X is N, and Y is CR 7 and Z is CR 8 is.

[0093] Another embodiment provides a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein W is CR 5 and X is CR 6 and Y is N and Z is CR 8 is.

[0094] Another embodiment provides a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein W is CR 5 and X is CR 6 and Y is CR 7 and Z is N.

[0095] Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 1 is hydrogen.

[0096] Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 1 is an optionally substituted C1-C6 alkyl.

[0097] Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 1 is CH3.

[0098] Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 1 is CD3.

[0099] Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 2 is an optionally substituted C1-C3 alkyl. Another embodiment provides a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein the optionally substituted C1-C3 alkyl is substituted with halogen. Another embodiment provides a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein the optionally substituted C1-C3 alkyl is -CHF2.

[0100] Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 3 or R 4 Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 3 and R 4 Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 3 or R 4 Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 3 and R 4 is optionally substituted C1-C3 alkoxy. Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 3or R 4 Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 3 and R 4 is optionally substituted C1-C3 alkoxy. Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 3 and R 4 is each independently an optionally substituted C1-C6 alkyl. Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 3 and R 4 is each independently methyl, ethyl, n-propyl, iso-propyl, n-butyl, or iso-butyl. Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 3 and R 4 and each is methyl. Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 3 and R 4 and each is ethyl. Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 3 is hydroxy and R 4 is methyl, ethyl, n-propyl, iso-propyl, n-butyl, or iso-butyl. Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 3 and R 4 and R are each methyl or ethyl. Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 3 is OH and R4 is methyl.

[0101] Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 3 and R 4 are linked to form an optionally substituted phosphorus-containing 3-8 membered heterocyclyl. Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 3 and R 4 are joined to form an optionally substituted phosphorus-containing 3-8 membered heterocyclyl, the heterocyclyl containing one or two additional heteroatoms, each independently selected from N, O and S. Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein R 3 and R 4 are linked to form an optionally substituted phosphorus-containing 4-6 membered heterocyclyl. Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 3 and R 4 are linked to form an optionally substituted phosphorus-containing 4-membered heterocyclyl. Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 3 and R 4 are linked to form an optionally substituted phosphorus-containing 5-membered heterocyclyl. Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 3 and R 4 are linked to form an optionally substituted phosphorus-containing 6-membered heterocyclyl.

[0102] Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 3 and R 4 are taken together with the phosphorus atom to which they are attached to cooperate to form a ring selected from: [ka]

[0103] Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 3 and R 4 are taken together with the phosphorus atom to which they are attached to cooperate to form a ring selected from: [ka]

[0104] Another embodiment provides a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein L is a bond. Another embodiment provides a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein L is -CH-. Another embodiment provides a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein L is -OCH-*. Another embodiment provides a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein L is -NHCH-*.

[0105] Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 9 Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R9 Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 10 is hydrogen.

[0106] Another embodiment provides a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein Ring A is an optionally substituted heteroarylene.

[0107] Another embodiment provides a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein the optionally substituted heteroarylene is an N-linked heteroarylene, and the N-linkage is the bond to the benzimidazole ring of Formula (I).

[0108] Another embodiment provides a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein the optionally substituted heteroarylene is a C-linked heteroarylene, and the C-link is the bond to the benzimidazole ring of Formula (I).

[0109] Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein V is N. Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein V is CR 11 Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein V is CR 11 and R 11 is hydrogen.

[0110] Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein W is CF, X is CH, Y is CH, Z is CH, and L is a bond. Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein L is a bond and R 3 and R 4 are each methyl or ethyl. Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein W is CF, X is CH, Y is CH, Z is CH, L is a bond, and R 3 and R 4 are each methyl.

[0111] Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 1 is CD3 and R 2 is C1-C3 alkyl substituted with halogen. Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 1 is CD3 and R 2 is -CHF2.

[0112] Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 9 is hydrogen and R 10 is hydrogen and V is CH. Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 9 is F and R 10 is hydrogen and V is CH. Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 9is hydrogen and R 10 is hydrogen and V is CF.

[0113] Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 1 is CD3 and R 2 is C1-C3 alkyl substituted with halogen, and R 9 is hydrogen and R 10 is hydrogen and V is CH. Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 1 is CD3 and R 2 is C1-C3 alkyl substituted with halogen, and R 9 is F and R 10 is hydrogen and V is CH. Another embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R 1 is CD3 and R 2 is C1-C3 alkyl substituted with halogen, and R 9 is hydrogen and R 10 is hydrogen and V is CF.

[0114] One embodiment provides a TNFα inhibitory compound having a structure as presented in Table 1, or a pharmaceutically acceptable salt, solvate, or N-oxide thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 [Table 1-23] [Table 1-24] [Table 1-25] [Table 1-26] [Table 1-27] [Table 1-28] [Table 1-29] [Table 1-30]

[0115] Another embodiment provides TNFα inhibitory compounds having the structure presented in Table 2, or a pharmaceutically acceptable salt, solvate, or N-oxide thereof. [Table 2-1] [Table 2-2]

[0116] Preparation of compounds The compounds used in the synthetic chemistry reactions described herein are made according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" include Acros Organics (Pittsburgh, PA), Aldrich Chemical Co. (Sigma Chemical, and Fluka).Milwaukee, Wisconsin), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research Ltd. (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet Inc. (Cornwall, UK), Chemservice Inc. (West Chester, Pennsylvania), Crescent Chemical Co. (Hauppauge, New York), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, New York), Fisher Scientific Co. (Pittsburgh, Pennsylvania), Fisons Chemicals Ltd. (Leicestershire, UK), Frontier Scientific (Logan, Utah), ICN Biomedicals, Inc. (Costa Mesa, California), Key Organics Ltd. (Cornwall, UK), Lancaster Synthesis Ltd. (Windham, New Hampshire), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, Utah), Pfaltz & They are obtained from standard commercial sources, including Bauer, Inc. (Waterbury, Connecticut), Polyorganix, Inc. (Houston, Texas), Pierce Chemical Co. (Rockford, Illinois), Riedel de Haen AG (Hannover, Germany), Spectrum Quality Products, Inc. (New Brunswick, New Jersey), TCI America, Inc. (Portland, Oregon), Trans World Chemicals, Inc. (Rockville, Maryland), and Wako Chemicals USA, Inc. (Richmond, Virginia).

[0117] Suitable reference books and treatises detailing the synthesis of reactants useful in preparing the compounds described herein or providing references to articles describing 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.G. Gilchrist, "Heterocyclic Chemistry," 2nd Ed., John Wiley & Sons, New York, 1992; and J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and papers that detail the synthesis of reactants useful in the preparation of the compounds described herein or provide references to articles describing 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, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC "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: 3-527-29, 645-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 are included.

[0118] Specific and similar reactants are optionally identified through the index of known chemicals compiled by the Chemical Abstract Service of the American Chemical Society, which is available in most public and university libraries as well as online databases (for more information, contact the American Chemical Society, Washington, DC). Known but not commercially available chemicals are optionally prepared by custom chemical synthesis companies, where many standard chemical supply companies (e.g., those listed above) offer custom synthesis services. A useful reference 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.

[0119] Pharmaceutical Composition In certain embodiments, the TNFα inhibitory compounds described herein are administered as pure chemicals. In other embodiments, the TNFα inhibitory compounds described herein are administered as pure chemicals according to the selected route of administration and the dosage regimen described in, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 2011). st The pharmaceutical composition is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier), selected in accordance with standard pharmaceutical practice as described in "Pharmaceuticals and Pharmaceuticals," Ed. Mack Pub. Co., Easton, PA (2005)."

[0120] Provided herein are pharmaceutical compositions comprising at least one TNFα inhibitory compound described herein, or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other ingredients of the composition and not deleterious to the recipient of the composition (e.g., a subject or patient).

[0121] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof.

[0122] One embodiment provides a method for preparing a pharmaceutical composition, comprising mixing a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, and a pharmaceutically acceptable carrier.

[0123] In certain embodiments, the TNFα inhibitory compounds described by Formula (I) or (Ia), or pharmaceutically acceptable salts, solvates, or N-oxides thereof, are substantially pure in that they contain 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 small organic molecules, such as, for example, unreacted intermediates or synthetic by-products produced in one or more of the steps of the synthetic process.

[0124] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt, solvate, or N-oxide thereof.

[0125] One embodiment provides a method for preparing a pharmaceutical composition, comprising mixing a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, and a pharmaceutically acceptable carrier.

[0126] In certain embodiments, the TNFα inhibitory compounds described by Table 1 or Table 2, or pharmaceutically acceptable salts, solvates, or N-oxides thereof, are substantially pure in that they contain 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 small organic molecules, such as, for example, unreacted intermediates or synthetic by-products produced in one or more of the steps of the synthetic method.

[0127] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose, or another suitable material that dissolves easily in the digestive tract. In some embodiments, suitable non-toxic solid carriers are used, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21 st See Ed. Mack Pub. Co., Easton, PA (2005).

[0128] In some embodiments, the TNFα inhibitory compound of Formula (I) or (Ia) or Table 1 or Table 2, or its pharmaceutically acceptable salt or solvate, is formulated for injection administration. In some examples, the injection formulation is an aqueous formulation. In some examples, the injection formulation is a non-aqueous formulation. In some examples, the injection formulation is an oil-based formulation, such as sesame oil.

[0129] Doses of compositions comprising at least one TNFα inhibitory compound described herein will vary depending on the condition of the subject or patient (e.g., human), including, in some embodiments, general health, age, and other factors.

[0130] Pharmaceutical compositions can be administered in a manner suitable for the disease to be treated (or prevented).Appropriate dosage, and appropriate administration period and administration frequency are determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration.In general, appropriate dosage and treatment regimen provide a sufficient amount of composition to bring about therapeutic and / or preventive benefits (for example, improved clinical outcomes, such as a high frequency of complete or partial remission, or an extension of disease-free survival and / or overall survival, or a reduction in the severity of symptoms).Optimal dosages are generally determined using experimental models and / or clinical trials.Optimal dosages depend on the patient's body mass, weight, or blood volume.

[0131] Oral doses typically range from about 1.0 mg to about 1000 mg, 1 to 4 times or more per day.

[0132] Treatment method One embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate or N-oxide thereof, for use in a method of treatment of the human or animal body.

[0133] One embodiment provides a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, for use in a method for treating an inflammatory or autoimmune disease or disorder. Another embodiment provides a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, for use in a method for treating an inflammatory disease or disorder. Yet another embodiment provides a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, for use in a method for treating an autoimmune disease or disorder.

[0134] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, and a pharmaceutically acceptable carrier for use in a method for the treatment of an inflammatory or autoimmune disease or disorder.

[0135] One embodiment provides the use of a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate or N-oxide thereof, in the manufacture of a medicament for the treatment of an inflammatory or autoimmune disease or disorder.

[0136] In some embodiments, methods are provided for treating an inflammatory or autoimmune disease or disorder in a patient in need thereof, the methods comprising administering to the patient a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof. Some embodiments provide methods for treating an inflammatory or autoimmune disease or disorder in a patient in need thereof, the methods comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, and a pharmaceutically acceptable excipient. One embodiment provides a method for treating an inflammatory disease or disorder. Another embodiment provides a method for treating an autoimmune disease or disorder.

[0137] One embodiment provides a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, for use in a method of treatment of the human or animal body.

[0138] One embodiment provides a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, for use in a method for the treatment of an inflammatory or autoimmune disease or disorder.

[0139] One embodiment provides a pharmaceutical composition comprising a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, and a pharmaceutically acceptable carrier for use in a method for treating an inflammatory or autoimmune disease or disorder.

[0140] One embodiment provides the use of a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, in the manufacture of a medicament for the treatment of an inflammatory or autoimmune disease or disorder.

[0141] In some embodiments, there is provided a method of treating an inflammatory or autoimmune disease or disorder in a patient in need thereof, the method comprising administering to the patient a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt, solvate or N-oxide thereof. In some embodiments, there is provided a method of treating an inflammatory or autoimmune disease or disorder in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition comprising a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, and a pharmaceutically acceptable excipient.

[0142] In some embodiments, the inflammatory and autoimmune disease or disorder is selected from, but is not limited to, rheumatoid arthritis, psoriatic arthritis, systemic onset juvenile idiopathic arthritis, multiple sclerosis, lupus nephritis, systemic lupus erythematosus, psoriasis, Crohn's disease, colitis, asthma, graft-versus-host disease, allograft rejection, chronic obstructive pulmonary disease, multiple sclerosis, Alzheimer's disease, Graves' disease, cutaneous lupus erythematosus, ankylosing spondylitis, cryopyrin-associated periodic syndromes (CAPS), gout and gouty arthritis, TNF receptor associated periodic syndrome (TRAPS), granulomatosis with polyangiitis, sarcoidosis, familial Mediterranean fever (FMF), neuropathic pain, adult-onset Still's disease.

[0143] Methods are provided herein wherein the pharmaceutical composition is administered orally.Methods are provided herein wherein the pharmaceutical composition is administered by injection.

[0144] One embodiment provides a method of inhibiting TNFα activity, the method comprising contacting a TNFα protein with a compound of Formula (I) or (Ia), or a compound of Table 1 or Table 2. Another embodiment provides a method of inhibiting TNFα activity, the TNFα protein being contacted in an in vivo setting. Another embodiment provides a method of inhibiting TNFα activity, the TNFα protein being contacted in an in vitro setting.

[0145] Other embodiments and uses will be apparent to those skilled in the art in view of this disclosure. The following examples are provided only as illustrations of various embodiments and are not to be construed as limiting the invention in any way. [Example]

[0146] I. Chemical synthesis In some embodiments, the TNFα inhibitory compounds disclosed herein are synthesized according to the following examples. As used below, and throughout the description of the present invention, the following abbreviations shall be understood to have the following meanings, unless otherwise indicated: ACN Acetonitrile °C (Celsius) δ H Chemical shifts in parts per million downfield from tetramethylsilane DCM dichloromethane (CH2Cl2) DIAD Diisopropyl azodicarboxylate DIEA Diisopropylethylamine DMF Dimethylformamide DMSO dimethyl sulfoxide EA Ethyl acetate EtOAc ethyl acetate ESI electrospray ionization Et Ethyl g grams h time HPLC High Performance Liquid Chromatography Hz Hertz J coupling constant (in NMR spectroscopy) LCMS Liquid Chromatography Mass Spectrometry μ Micro m multilet (spectral); meter; millimeter M mole M + Parent molecular ion Me methyl MsCl methanesulfonyl chloride MHz Megahertz min mol mole; molecule (in the case of molecular weight) mL milliliter MS mass spectrometry nm nanometer NMR nuclear magnetic resonance pH: Potential of hydrogen; a measure of the acidity or basicity of an aqueous solution PE Petroleum Ether RT room temperature s Singlet (spectrum) t triplet (spectrum) SFC Supercritical Fluid Chromatography T temperature TFA trifluoroacetic acid THF tetrahydrofuran TPP Triphenylphosphine

[0147] Example 1: (7R,14R)-1-(difluoromethoxy)-11-(2-(dimethylphosphoryl)pyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one [ka]

[0148] Synthesis scheme [ka]

[0149] Preparation 1A: 2-Bromo-6-(difluoromethoxy)benzaldehyde [ka]

[0150] To a stirred solution of 2-bromo-6-hydroxybenzaldehyde (90.00 g, 447.719 mmol) in 1,4-dioxane (900 mL) was added dropwise a solution of NaOH (107.44 g, 2686.314 mmol) in HO (900 mL) at room temperature. The mixture was heated at 65 °C, and chlorodifluoromethane (gas) was passed through the solution. The reaction mixture was allowed to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 100 mL). The filtrate was extracted with EtOAc (3 × 500 mL). The combined organic phase was dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (20:1) to give 2-bromo-6-(difluoromethoxy)benzaldehyde (80.00 g, 71%) as a yellow oil. 1 H NMR (300 MHz, chloroform-d) δ 10.35 (s, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.41 (t, J = 8.1 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 6.61 (t, J = 73.4 Hz, 1H).

[0151] Preparation 1B: (S)-N-{[2-bromo-6-(difluoromethoxy)phenyl]methylidene}-2-methylpropane-2-sulfinamide [ka]

[0152] To a stirred solution of 2-bromo-6-(difluoromethoxy)benzaldehyde (80.00 g, 318.691 mmol) and (S)-2-methylpropane-2-sulfinamide (38.63 g, 318.691 mmol) in CHCl (800 mL) was added CsCO (207.67 g, 637.382 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with water (1 L). The resulting mixture was extracted with EtOAc (3 × 500 mL). The combined organic phase was washed with brine (1 × 1 L) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give (S)—N-{[2-bromo-6-(difluoromethoxy)phenyl]methylidene}-2-methylpropane-2-sulfinamide (90.00 g, 80%) as a yellow oil. MS ESI C 12 H 14 Calculated value for BrF2NO2S [M+H] + 353.99 355.99, actual reading 353.80 355.75. 1 H NMR (300 MHz, chloroform-d) δ 8.84 (s, 1H), 7.59–7.57 (m, 1H), 7.35–7.31 (m, 1H), 7.26–7.24 (m, 1H), 6.57 (t, J = 73.8 Hz, 1H), 1.30 (s, 9H).

[0153] Preparation 1C: Ethyl (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-{[(S)-2-methylpropane-2-sulfinyl]amino}propanoate [ka]

[0154] To a stirred solution of Zn powder (36.92 g, 564.640 mmol) in THF (200 mL) was added anhydrous CuCl (5.59 g, 56.464 mmol) at room temperature. The resulting mixture was stirred at 70°C for 0.5 hours. The mixture was allowed to cool to room temperature. To the above mixture was added a solution of ethyl bromoacetate (23.57 g, 141.160 mmol) in THF (200 mL) dropwise at room temperature. The resulting mixture was stirred at 50°C for an additional 0.5 hours. The resulting mixture was filtered. To the above filtrate was added a solution of (S)-N-{[2-bromo-6-(difluoromethoxy)phenyl]methylidene}-2-methylpropane-2-sulfinamide (20.00 g, 56.464 mmol) in THF (20 mL) dropwise at 0°C. The resulting mixture was stirred for an additional 2 hours at room temperature. The reaction was quenched with saturated NH4Cl (aq) at room temperature. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (3 x 100 mL). The filtrate was extracted with EtOAc (3 x 200 mL). The combined organic phases were washed with brine (1 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 eluting with CHCl2 / MeOH (10:1) to give ethyl (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-{[(S)-2-methylpropane-2-sulfinyl]amino}propanoate (21.00 g, 84%) as a yellow oil. MS ESI C 16 H 22 Calculated value for BrF2NO4S [M+H] + 442.04 444.4,441.90 443.90. 1 H NMR (300 MHz, chloroform-d) δ 7.50–7.42 (m, 1H), 7.23–7.00 (m, 2H), 6.62 (t, J = 73.0 Hz, 1H), 5.68–5.55 (m, 1H), 4.18–4.03 (m, 2H), 3.36–2.92 (m, 2H), 1.22 (t, J = 7.0 Hz, 3H), 1.16 (s, 9H).

[0155] Preparation 1D: Ethyl (3R)-3-amino-3-[2-bromo-6-(difluoromethoxy)phenyl]propanoate hydrochloride [ka]

[0156] To a stirred solution of ethyl (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-{[(S)-2-methylpropane-2-sulfinyl]amino}propanoate (24.00 g, 54.259 mmol) in EtO (50 mL) and EtOH (25 mL) was added a solution of 4 N HCl (gas) in 1,4-dioxane (70 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure. This gave ethyl (3R)-3-amino-3-[2-bromo-6-(difluoromethoxy)phenyl]propanoate hydrochloride (20.00 g, 98%) as a yellow oil. MS ESI C 12 H 14 Calculated value for BrF2NO3 [M+H] + 338.01 340.01, actual value 338.00 340.00.

[0157] Preparation 1E: Ethyl (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-[(5-chloro-2-nitrophenyl)amino]propanoate [ka]

[0158] To a stirred solution of ethyl (3R)-3-amino-3-[2-bromo-6-(difluoromethoxy)phenyl]propanoate hydrochloride (20.00 g, 53.389 mmol) and 4-chloro-2-fluoro-1-nitrobenzene (11.25 g, 64.067 mmol) in ACN (200 mL) was added potassium carbonate (22.30 g, 160.167 mmol) at room temperature. The mixture was stirred at 80 °C for 16 h. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (3 × 500 mL). The combined organic phase was washed with brine (1 × 500 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give ethyl (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-[(5-chloro-2-nitrophenyl)amino]propanoate (20.00 g, 76%) as a yellow oil. MS ESI C 18 H 16 Calculated value for BrClF2N2O5 [M+H] + 492.99 494.99, actual reading 492.95 494.85. 1 H NMR (400 MHz, chloroform-d) δ 8.92 (d, J = 8.8 Hz, 1H), 8.08 (d, J = 9.1 Hz, 1H), 7.48–7.43 (m, 1H), 7.23–7.11 (m, 2H), 7.11–7.04 (m, 1H), 6.65 (t, J = 73.0 Hz, 1H), 6.63–6.57 (m, 1H), 5.87–5.77 (m, 1H), 4.18–4.09 (m, 2H), 3.23–3.17 (m, 1H), 3.02–2.85 (m, 1H), 1.22 (t, J = 7.1 Hz, 3H).

[0159] Preparation 1F: (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-[(5-chloro-2-nitrophenyl)amino]propanal [ka]

[0160] To a stirred solution of ethyl (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-[(5-chloro-2-nitrophenyl)amino]propanoate (18.00 g, 36.460 mmol) in CHCl (200 mL) was added dropwise a solution of 1 N DIBAl-H (73 mL, 73.000 mmol) in THF under a nitrogen atmosphere at −78°C. The reaction was stirred at −78°C for 3 hours under a nitrogen atmosphere. The resulting mixture was quenched with saturated NHCl (aq) at −78°C and extracted with CHCl (3 × 500 mL). The combined organic phase was dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-[(5-chloro-2-nitrophenyl)amino]propanal (12.00 g, 73%) as a yellow oil. MS ESI C 16 H 12 Calculated value for BrClF2N2O4 [M+H] + 448.96 450.96, actual values ​​448.95 450.95. 1 H NMR (400 MHz, chloroform-d) δ 9.81 (s, 1H), 8.84 (d, J = 9.0 Hz, 1H), 8.08 (d, J = 9.1 Hz, 1H), 7.49–7.43 (m, 1H), 7.22–7.14 (m, 2H), 7.13–7.06 (m, 1H), 6.67 (t, J = 73.0 Hz, 1H), 6.65–6.60 (m, 1H), 5.97–5.88 (m, 1H), 3.56–3.41 (m, 1H), 3.22–2.93 (m, 1H).

[0161] Preparation 1G: (4R)-4-[2-bromo-6-(difluoromethoxy)phenyl]-4-[(5-chloro-2-nitrophenyl)amino]-2-[(trimethylsilyl)oxy]butanenitrile [ka]

[0162] To a stirred solution of (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-[(5-chloro-2-nitrophenyl)amino]propanal (12.00 g, 26.689 mmol) in CHCl (120 mL) was added ZnI (852 mg, 2.669 mmol) and TMSCN (5.30 g, 53.378 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with water (50 mL) and extracted with CHCl (3 × 50 mL). The combined organic phase was dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give (4R)-4-[2-bromo-6-(difluoromethoxy)phenyl]-4-[(5-chloro-2-nitrophenyl)amino]-2-[(trimethylsilyl)oxy]butanenitrile (13.00 g, 89%) as a yellow oil. The crude product was used directly in the next step without further purification. MS ESI C 20 H 21 Calculated value for BrClF2N3O4Si [M+H] + 548.01 550.01, actual value 548.05 550.00.

[0163] Preparation 1H: (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-11-chloro-2,7-diazatricyclo[6.4.0.0^{2,6}]dodeca-1(8),6,9,11-tetraen-5-ol [ka]

[0164] To a stirred solution of (4R)-4-[2-bromo-6-(difluoromethoxy)phenyl]-4-[(5-chloro-2-nitrophenyl)amino]-2-[(trimethylsilyl)oxy]butanenitrile (13.00 g, 23.686 mmol) in EtOH (100 mL) was added SnCl2.2H2O (26.96 g, 118.430 mmol) at room temperature. The mixture was stirred at 80 °C for 16 h. The reaction was quenched by adding water (50 mL) at room temperature and basified to pH 8 with 1 N KOH (aq). The mixture was filtered, and the filter cake was washed with EtOAc (3 × 50 mL) and extracted with EtOAc (3 × 100 mL). The combined organic phase was washed with brine (1 × 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 eluting with PE / EA (1:2) to give (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-11-chloro-2,7-diazatricyclo[6.4.0.0^{2,6}]dodeca-1(8),6,9,11-tetraen-5-ol (7.00 g, 69%) as a yellow solid. MS ESI C 17 H 12 Calculated value for BrClF2N2O2 [M+H] + 428.97 430.97, actual values ​​429.00 431.00.

[0165] Preparation 1I: (3R)-5-Azido-3-[2-bromo-6-(difluoromethoxy)phenyl]-11-chloro-2,7-diazatricyclo[6.4.0.0^{2,6}]dodeca-1(8),6,9,11-tetraene [ka]

[0166] To a stirred solution of (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-11-chloro-2,7-diazatricyclo[6.4.0.0^{2,6}]dodeca-1(8),6,9,11-tetraen-5-ol (22.00 g, 51.204 mmol) in THF (200 mL) was added DPPA (16.91 g, 61.445 mmol) and DBU (15.59 g, 102.408 mmol) at 0 °C. The mixture was stirred at room temperature for 16 h. The resulting mixture was extracted with EtOAc (3 × 500 mL). The combined organic phase was washed with brine (1 × 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 eluting with CHCl / MeOH (20:1) to give (3R)-5-azido-3-[2-bromo-6-(difluoromethoxy)phenyl]-11-chloro-2,7-diazatricyclo[6.4.0.0^{2,6}]dodeca-1(8),6,9,11-tetraene (15.00 g, 64%) as a green oil. MS ESI C 17 H 11 Calculated value for BrClF2N5O [M+H] + 453.98 455.98, actual values ​​454.05 456.05.

[0167] Preparation 1J: (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-11-chloro-2,7-diazatricyclo[6.4.0.0^{2,6}]dodeca-1(8),6,9,11-tetraen-5-amine [ka]

[0168] To a stirred solution of (3R)-5-azido-3-[2-bromo-6-(difluoromethoxy)phenyl]-11-chloro-2,7-diazatricyclo[6.4.0.0^{2,6}]dodeca-1(8),6,9,11-tetraene (15.00 g, 32.992 mmol) in THF (50 mL) and HO (5 mL) was added PPh (12.98 g, 49.488 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (12:1) to give (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-11-chloro-2,7-diazatricyclo[6.4.0.0^{2,6}]dodeca-1(8),6,9,11-tetraen-5-amine (10 g, 71%) as a yellow solid. MS ESI C 17 H 13 Calculated value for BrClF2N3O [M+H] + 427.99 429.99, actual value 428.00 430.00. 1 H NMR (400 MHz, chloroform-d) δ 7.70–7.58 (m, 2H), 7.35–7.28 (m, 1H), 7.23–7.00 (m, 2H), 6.90–6.46 (m, 1H), 6.17–6.06 (m, 1H), 5.98–5.58 (m, 1H), 4.77–4.57 (m, 1H), 3.60–3.40 (m, 1H), 2.82–2.55 (m, 1H).

[0169] Preparation 1K: (1R,11R)-5-chloro-18-(difluoromethoxy)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0170] To a solution of (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-11-chloro-2,7-diazatricyclo[6.4.0.0^{2,6}]dodeca-1(8),6,9,11-tetraen-5-amine (500 mg, 1.166 mmol) in 1,4-dioxane (10 mL) was added K2CO3 (806 mg, 5.830 mmol), Xantphos (34 mg, 0.058 mmol), and Pd(OAc)2 (13 mg, 0.058 mmol) in a pressure tank. The mixture was purged with nitrogen for 5 min and then pressurized to 1 atm with carbon monoxide at 100 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (10:1) to give (1R,11R)-5-chloro-18-(difluoromethoxy)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (200 mg, 46%) as a white solid. MS ESI C 18 H 12 Calculated value for ClF2N3O2 [M+H] + 376.06, actual value 375.95. 1 H NMR (400 MHz, chloroform-d) δ 8.44 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.52–7.35 (m, 4H), 7.24–7.19 (m, 1H), 6.85 (t, J = 72.6 Hz, 1H), 6.29 (d, J = 7.3 Hz, 1H), 4.94 (t, J = 6.6 Hz, 1H), 3.53–3.41 (m, 1H), 2.85 (d, J = 13.3 Hz, 1H).

[0171] Preparation 1L: (1R,11R)-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0172] To a stirred solution of (1R,11R)-5-chloro-18-(difluoromethoxy)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.133 mmol) and BPD (51 mg, 0.200 mmol) in 1,4-dioxane (2 mL), Pd2(dba)3 (12 mg, 0.013 mmol), and PCy3.HBF4 (5 mg, 0.013 mmol) were added under a nitrogen atmosphere at room temperature. The mixture was stirred at 140 °C for 16 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (10:1) to give (1R,11R)-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (22 mg, 35%) as a yellow solid. MS ESI C 24 H 24 Calculated value for BF2N3O4 [M+H] + 468.18, actual value 467.95.

[0173] Example 1: (7R,14R)-1-(difluoromethoxy)-11-(2-(dimethylphosphoryl)pyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one [ka]

[0174] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (22 mg, 0.047 mmol) and 5-bromo-2-(dimethylphosphoryl)pyrimidine (11 mg, 0.047 mmol) in 1,4-dioxane (2 mL) was added a solution of KPO (30 mg, 0.141 mmol) in HO (0.5 mL) at room temperature under a nitrogen atmosphere. To the above mixture, Pd(dppf)Cl2.CHCl2 (4 mg, 0.005 mmol) was added at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The solution was purified by preparative HPLC to give (1R,11R)-18-(difluoromethoxy)-5-[2-(dimethylphosphoryl)pyrimidin-5-yl]-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (15 mg, 64%) as a white solid. MS ESI C 24 H 20 Calculated value of F2N5O3P [M+H] + 496.13, actual value 496.20. 1 H NMR(400MHz,DMSO-d6)δ 9.24(s,2H),9.16(d,J=6.8Hz,1H),8.26~8.21(m,1H),7.89~7.66(m,4H),7.52~7.50(m,2H),6.39 ~6.38(m,1H),4.93~4.90(m,1H),3.53~3.46(m,1H),2.78~2.75(m,1H),1.83(s,3H),1.80(s,3H). 19 F NMR(377MHz,DMSO-d6)δ -81.53(d,J=169.3Hz)(1F),-82.84(d,J=169.3Hz)(1F). 31 P NMR (162MHz, DMSO-d6) δ 33.89.

[0175] Example 2: (7R,14R)-1-(difluoromethoxy)-11-(6-(dimethylphosphoryl)pyridin-3-yl)-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one [ka]

[0176] Preparation 2A: (1R,11R)-5-chloro-18-(difluoromethoxy)-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0177] To a stirred solution of (1R,11R)-5-chloro-18-(difluoromethoxy)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (120 mg, 0.319 mmol) in anhydrous THF (2 mL) was added dropwise a solution of 1 N KHMDS (0.4 mL, 0.40 mmol) in THF under a nitrogen atmosphere at −78 °C. The reaction was stirred for 1 h at −78 °C under a nitrogen atmosphere. To the above solution, CHI (68 mg, 0.479 mmol) was added dropwise over 2 min at −78 °C. The mixture was stirred at room temperature for 1 h. The reaction was then quenched by the addition of saturated NH4Cl(aq) (1 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl2 / MeOH (10:1) to give (1R,11R)-5-chloro-18-(difluoromethoxy)-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (85 mg, 68%) as a yellow solid. MS ESI C 19 H 14 Calculated value for ClF2N3O2 [M+H] + 390.07 392.07, actual values ​​390.25 392.25. 1 H NMR (300 MHz, chloroform-d) δ 8.50 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.48–7.42 (m, 2H), 7.38–7.32 (m, 1H), 7.25–7.22 (m, 1H), 6.84 (t, J = 72.6 Hz, 1H), 6.24–6.21 (m, 1H), 5.02–5.00 (m, 1H), 3.53 (s, 3H), 3.49–3.41 (m, 1H), 2.90–2.86 (m, 1H).

[0178] Preparation 2B: (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0179] To a stirred solution of (1R,11R)-5-chloro-18-(difluoromethoxy)-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (85 mg, 0.218 mmol), KOAc (64 mg, 0.654 mmol), and BPD (83 mg, 0.327 mmol) in 1,4-dioxane (3 mL) was added PCy3.HBF4 (8 mg, 0.022 mmol) and Pd2(dba)3 (20 mg, 0.022 mmol) under a nitrogen atmosphere at room temperature. The mixture was stirred at 140 °C under a nitrogen atmosphere for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (10:1) to give (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (65 mg, 62%) as a yellow oil. MS ESI C 25 H 26 Calculated value for BF2N3O4 [M+H] + 482.20, actual value 481.90.

[0180] Example 2: (7R,14R)-1-(difluoromethoxy)-11-(6-(dimethylphosphoryl)pyridin-3-yl)-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one [ka]

[0181] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (60 mg, 0.125 mmol) and 5-bromo-2-(dimethylphosphoryl)pyridine (29 mg, 0.125 mmol) in 1,4-dioxane (3 mL) was added a solution of K3PO4 (79 mg, 0.375 mmol) in HO (1 mL) at room temperature under a nitrogen atmosphere. To the above solution was added Pd(dppf)Cl.CHCl (10 mg, 0.013 mmol) under nitrogen atmosphere at room temperature, and the mixture was stirred at 100 °C for 16 h. The solution was purified by reverse-phase flash chromatography (C18 column, 120 g; mobile phase A: water (10 mmol / L, FA), mobile phase B: CH3CN; flow rate: 50 mL / min; gradient: 20% B to 40% B in 25 min; 254 / 220 nm). Fractions containing the desired product were collected at 33% B and concentrated under reduced pressure to give (1R,11R)-18-(difluoromethoxy)-5-[6-(dimethylphosphoryl)pyridin-3-yl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (40 mg, 63%) as an off-white solid. MS ESI C 26 H 23 Calculated value of F2N4O3P [M+H] + 509.15, actual value 509.00.1 H NMR (400 MHz, chloroform-d) δ 8.97–8.92 (m, 1H), 8.52–8.47 (m, 1H), 8.22–8.15 (m, 1H), 8.05–7.99 (m, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.76–7.72 (m, 1H), 7.54–7.47 (m, 1H), 7.46–7.41 (m, 1H), 7.34–7.76 (m, 1H). .29(m,1H),6.86(t,J=72.9Hz,1H),6.31(d,J=7.1Hz,1H),5.02(d,J=7.0Hz,1H), 3.54(s,3H),3.53~3.45(m,1H),2.91(d,J=13.6Hz,1H),1.84(s,3H),1.81(s,3H). 19 F NMR (377 MHz, chloroform-d) δ −80.73 (2F). 31 P NMR (162 MHz, chloroform-d) δ 36.56.

[0182] Example 3: (7R,14R)-1-(difluoromethoxy)-11-(6-(dimethylphosphoryl)pyridin-3-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one [ka]

[0183] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.107 mmol) and 5-bromo-2-(dimethylphosphoryl)pyridine (25 mg, 0.107 mmol) in 1,4-dioxane (2 mL) was added a solution of KPO (68 mg, 0.321 mmol) in HO (0.5 mL) under a nitrogen atmosphere at room temperature. The mixture was then cooled to room temperature and cooled to room temperature. 2·CH2Cl2 (9 mg, 0.011 mmol) was added, and the mixture was stirred at 100° C. for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (40 g C18 column; mobile phase A: water (10 mmol / L, FA), mobile phase B: CH3CN; flow rate: 25 mL / min; gradient: 20% B to 40% B in 30 min; 254 / 220 nm) to give (1R,11R)-18-(difluoromethoxy)-5-[6-(dimethylphosphoryl)pyridin-3-yl]-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (25 mg, 47%) as a white solid. MS ESI C 25 H 21 Calculated value of F2N4O3P [M+H] + 495.13, actual value 495.00. 1 H NMR (400 MHz, chloroform-d) δ 8.95 (d, J = 2.3 Hz, 1H), 8.48-8.42 (m, 1H), 8.24-8.16 (m, 1H), 8.05-7.99 (m, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 1.7 Hz, 1H), 7.57-7.49 (m, 2H), 7.46 (t, J = 8.1 Hz, 1H),7.41~7.35(m,1H),6.87(t,J=72.7Hz,1H),6.42(d,J=7.2Hz,1H),5.07(t,J= 6.6Hz,1H),3.57~3.47(m,1H),2.91(d,J=13.3Hz,1H),1.85(s,3H),1.82(s,3H). 19 F NMR (377 MHz, chloroform-d) δ −80.82 (1F), −80.83 (1F). 31 P NMR (162 MHz, chloroform-d) δ 36.48.

[0184] Example 4: (7R,14R)-1-(difluoromethoxy)-11-(6-(dimethylphosphoryl)-5-fluoropyridin-3-yl)-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one [ka]

[0185] Preparation 4A: 5-Bromo-2-(dimethylphosphoryl)-3-fluoropyridine [ka]

[0186] To a stirred solution of 2,5-dibromo-3-fluoropyridine (5.00 g, 19.617 mmol) and (methylphosphonoyl)methane (1.68 g, 21.579 mmol) in 1,4-dioxane (50 mL) was added Pd(dba) (898 mg, 0.981 mmol) and TEA (3.3 mL, 23.540 mmol) at room temperature. The resulting mixture was stirred overnight at 90 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (10:1) to give 5-bromo-2-(dimethylphosphoryl)-3-fluoropyridine (1.78 g, 36%) as a brown solid. MS ESI calculated for C7H8BrFNOP [M+H] + 251.95 253.95, actual value 251.95 253.95. 1 H NMR (300 MHz, chloroform-d) δ 8.65 (s, 1H), 7.76–7.69 (m, 1H), 1.90 (s, 3H), 1.87 (s, 3H).

[0187] Example 4: (7R,14R)-1-(difluoromethoxy)-11-(6-(dimethylphosphoryl)-5-fluoropyridin-3-yl)-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one [ka]

[0188] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.104 mmol) and 5-bromo-2-(dimethylphosphoryl)-3-fluoropyridine (26 mg, 0.104 mmol) in 1,4-dioxane (2 mL) was added a solution of K3PO4 (66 mg, 0.312 mmol) in HO (0.5 mL) under a nitrogen atmosphere at room temperature. 2· CH2Cl2 (8 mg, 0.010 mmol) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 hours. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (0% to 10%), followed by preparative HPLC (C18 column 120 g; mobile phase A: water (0.1% FA), mobile phase B: CH3CN; flow rate: 50 mL / min; gradient: 20% B to 40% B in 40 min; 254 / 220 nm) to give (1R,11R)-18-(difluoromethoxy)-5-[6-(dimethylphosphoryl)-5-fluoropyridin-3-yl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (16 mg, 29%) as a white solid. MS ESI C 26 H 22 Calculated value of F3N4O3P [M+H] + 527.14, actual value 527.20. 1H NMR(300MHz,chloroform-d)δ 8.81(s,1H),8.54~8.44(m,1H),7.88~7.78(m,1H),7.77~7.71(m,1H),7.70~7.60(m,1H),7.51~7.37(m,2H),7.36~7.26(m,1H),6.90( t,J=72.8Hz,1H),6.37~6.26(m,1H),5.07~4.95(m,1H),3.53(s,3H),3.54~3.45(m,1H),2.97~2.85(m,1H),1.96(s,3H),1.90(s,3H). 19 F NMR (282 MHz, chloroform-d) δ −80.81 (1F), −80.83 (1F), −117.00 (1F). 31 P NMR (122 MHz, chloroform-d) δ 35.14 (1P).

[0189] Example 5: (1R,11R)-18-(difluoromethoxy)-12-methyl-5-[6-(1-oxo-1lambda-5-phosphoran-1-yl)pyridin-3-yl]-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0190] Preparation 5A: 1 Lambda 5-phospholan-1-one [ka]

[0191] To a solution of 1,4-dibromobutane (19.62 g, 90.868 mmol) in THF (100 mL) was added activated magnesium powder (4.42 g, 181.736 mmol) in several portions. The mixture was stirred below 30 °C for 2 hours. To the above mixture, a solution of dimethyl phosphite (5.00 g, 45.434 mmol) in 50 mL of THF was added dropwise over 0.5 hours below 30 °C. The resulting mixture was stirred at room temperature for an additional 1 hour. The reaction was quenched at 20 °C by adding 20 g of K2CO3 in water (50 mL). The resulting mixture was filtered, and the filter cake was washed with EtOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. This gave 1-lambda 5-phosphoran-1-one (3.10 g, 51%) as a colorless oil. 31 P NMR (162 MHz, chloroform-d) δ 47.62 (1P).

[0192] Preparation 5B: 1-(5-bromopyridin-2-yl)-1 lambda 5-phospholan-1-one [ka]

[0193] A solution of Pd2(dba)3 (320 mg, 0.352 mmol), DIPEA (0.55 g, 4.226 mmol), and Xantphos (410 mg, 0.704 mmol) in 1,4-dioxane (6 mL) was stirred at room temperature under a nitrogen atmosphere for 15 minutes. To the above mixture was added 5-bromo-2-iodopyridine (1.00 g, 3.522 mmol) and 1-lambda 5-phosphoran-1-one (1.47 g, 14.088 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was further stirred at 80 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl2 / MeOH (20:1) to afford 1-(5-bromopyridin-2-yl)-1-lambda 5-phosphoran-1-one (218 mg, 23%) as a yellow solid. MS ESI C9H 11 Calculated value of BrNOP [M+H] +, 259.98 261.98, actual value 259.90 261.90. 1 H NMR (400 MHz, chloroform-d) δ 8.78 (s, 1H), 8.09–8.02 (m, 1H), 8.02–7.95 (m, 1H), 2.25–1.87 (m, 8H).

[0194] Example 5: (1R,11R)-18-(difluoromethoxy)-12-methyl-5-[6-(1-oxo-1lambda-5-phosphoran-1-yl)pyridin-3-yl]-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0195] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.104 mmol) and 1-(5-bromopyridin-2-yl)-1lambda-5-phospholan-1-one (27 mg, 0.104 mmol) in 1,4-dioxane (2 mL) was added a solution of KPO (66 mg, 0.312 mmol) in HO (0.5 mL) at room temperature. The above solution was added with Pd(dppf)Cl at room temperature under a nitrogen atmosphere. 2·CHCl (8 mg, 0.010 mmol) was added. The resulting mixture was stirred at 100° C. for an additional 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (0% to 10%), followed by preparative HPLC (C18 column 120 g; mobile phase A: water (0.1% FA), mobile phase B: CHCN; flow rate: 50 mL / min; gradient: 20% B to 40% B in 40 min; 254 / 220 nm) to give (1R,11R)-18-(difluoromethacrylate)-2-(2-methyl-2-propanol). (oxy)-12-methyl-5-[6-(1-oxo-1lambda-5-phosphoran-1-yl)pyridin-3-yl]-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (25 mg, 45%) was obtained as a white solid. MS ESI C 28 H 25 Calculated value of F2N4O3P [M+H] + 535.16, actual value 535.15. 1 H NMR (300 MHz, chloroform-d) δ 8.95 (s, 1H), 8.50 (d, J = 8.1 Hz, 1H), 8.25–8.20 (m, 1H), 8.03–7.98 (m, 1H), 7.86–7.71 (m, 2H), 7.52–7.27 (m, 3H), 7.11–6.62 (m, 1H), 6.32–6.29 (m, 1H), 5.02–4.99 (m, 1H), 3.56–3.46 (m, 4H), 2.94–2.88 (m, 1H), 2.24–1.95 (m, 8H). 19 F NMR (282 MHz, chloroform-d) δ −80.73 (2F). 31 P NMR (122 MHz, chloroform-d) δ 62.17 (1P).

[0196] Example 6: (1R,11R)-18-(difluoromethoxy)-12-methyl-5-[6-(4-oxo-1,4lambda-5-oxaphosphinan-4-yl)pyridin-3-yl]-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0197] Preparation 6A: 4-Hydroxy-1,4 lambda 5-oxaphosphinan-4-one [ka]

[0198] A mixture of ammonium hypophosphite (3.49 g, 43.119 mmol) and hexamethyldisilazane (13.92 g, 86.238 mmol) was stirred at 120° C. for 4 hours under a nitrogen atmosphere. To the above mixture, 1-bromo-2-(2-bromoethoxy)ethane (10.00 g, 43.119 mmol) was added dropwise over 10 minutes at 120° C. The resulting mixture was stirred at 120° C. for an additional 4 hours. The mixture was allowed to cool to room temperature, and EtOH (20 mL) was added. The resulting mixture was stirred at 100° C. for an additional 1 hour. The resulting mixture was allowed to cool to room temperature. The mixture was filtered, and the filter cake was washed with dichloromethane (2×10 mL). The filtrate was concentrated under reduced pressure to give crude 4-hydroxy-1,4 lambda-5-oxaphosphinan-4-one (7.40 g, 25%) as a yellow liquid. The crude product was used directly in the next step without further purification.

[0199] Preparation 6B: 4-Chloro-1,4 lambda 5-oxaphosphinan-4-one [ka]

[0200] To a stirred solution of 4-hydroxy-1,4 lambda-5-oxaphosphinan-4-one (5.80 g, 42.620 mmol) in DCM (60 mL) was added oxalyl chloride (9.20 g, 72.454 mmol) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in toluene (50 mL). The mixture was concentrated in vacuo to give crude 4-chloro-1,4 lambda-5-oxaphosphinan-4-one (6.00 g, 91%) as a yellow liquid. The crude product was used directly in the next step without further purification.

[0201] Preparation 6C: 1,4 Lambda 5-Oxaphosphinan-4-one [ka]

[0202] To a stirred solution of 4-chloro-1,4 lambda 5-oxaphosphinan-4-one (5.60 g, 36.239 mmol) in DCM (60 mL) was added 1N DIBAL-H (36.24 mL, 36.239 mmol) dropwise at −78° C. under a nitrogen atmosphere. The resulting mixture was stirred at −78° C. for 2 h. The reaction was quenched by adding CHOH (6 mL) at −78° C., and the reaction was then stirred at −78° C. for 5 min. The mixture was warmed to 0° C., and an aqueous solution of 10% acetic acid (50 mL) was added. The resulting mixture was extracted with DCM (5×100 mL). The combined organic phases were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give the crude product, 1,4 lambda 5-oxaphosphinan-4-one (2.50 g, 57%), as a yellow oil. MS ESI Calculated for C4H9O2P [M+H] + 121.03, actual value 121.25.

[0203] Preparation 6D: 4-(5-bromopyridin-2-yl)-1,4 lambda 5-oxaphosphinan-4-one [ka]

[0204] A solution of Pd2(dba)3 (258 mg, 0.282 mmol) and Xantphos (326 mg, 0.564 mmol) in 1,4-dioxane (10 mL) was stirred at room temperature under a nitrogen atmosphere for 10 minutes. To the above mixture was added a solution of 5-bromo-2-iodopyridine (800 mg, 2.818 mmol) and TEA (0.60 mL, 4.227 mmol) in 1,4-dioxane (10 mL) at room temperature. The resulting mixture was further stirred overnight at 80 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl2 / MeOH (20:1) to give 4-(5-bromopyridin-2-yl)-1,4 lambda 5-oxaphosphinan-4-one (260 mg, 33%) as a white solid. MS ESI C9H 11 Calculated value of BrNO2P [M+H] + 275.97 277.97, actual value 275.95 277.95. 1 H NMR (300 MHz, chloroform-d) δ 8.82 (s, 1H), 8.04–7.99 (m, 2H), 4.25–4.15 (m, 4H), 2.51–2.36 (m, 2H), 2.13–1.99 (m, 2H).

[0205] Example 6: (1R,11R)-18-(difluoromethoxy)-12-methyl-5-[6-(4-oxo-1,4lambda-5-oxaphosphinan-4-yl)pyridin-3-yl]-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0206] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.104 mmol) and 4-(5-bromopyridin-2-yl)-1,4 lambda 5-oxaphosphinan-4-one (29 mg, 0.104 mmol) in 1,4-dioxane (2 mL) was added a solution of KPO (66 mg, 0.312 mmol) in HO (0.5 mL) under a nitrogen atmosphere at room temperature. The above solution was added with Pd(dppf)Cl at room temperature under a nitrogen atmosphere. 2· CHCl (8 mg, 0.010 mmol) was added. The resulting mixture was stirred at 100° C. for an additional 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (0% to 10%), followed by preparative HPLC (Column: C18 column 120 g; Mobile phase A: water (0.1% FA), Mobile phase B: CHCN; Flow rate: 50 mL / min; Gradient: 20% B to 40% B in 40 min; 254 / 220 nm) to give (1R,11R)-18-((2-methyl-2-propanol)-2-yl)-2H-pyridin-1-yl) as a white solid. Difluoromethoxy)-12-methyl-5-[6-(4-oxo-1,4 lambda 5-oxaphosphinan-4-yl)pyridin-3-yl]-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (25 mg, 44%) was obtained. MS ESI C 28 H 25 Calculated value of F2N4O4P [M+H] + 551.16, actual value 551.05. 1H NMR(300MHz,chloroform-d)δ 8.99(s,1H),8.58~8.41(m,1H),8.20~8.15(m,1H),8.06~8.01(m,1H), 7.86~7.66(m,2H),7.60~7.40(m,2H),7.37~7.21(m,1H),6.86(t,J=73. 1Hz, 1H), 6.32~6.29(m, 1H), 5.02~4.96(m, 1H), 4.28~4.18(m, 4H), 3.54 ~3.44(m,4H),2.94~2.85(m,1H),2.61~2.51(m,2H),2.13~2.02(m,2H). 19 F NMR (282 MHz, chloroform-d) δ −80.71 (2F). 31 P NMR (122 MHz, chloroform-d) δ 25.96 (1P).

[0207] Example 7: (1R,11R)-18-(difluoromethoxy)-5-{6-[(dimethylphosphoryl)methoxy]pyridin-3-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0208] Preparation 7A: 5-Bromo-2-[(dimethylphosphoryl)methoxy]pyridine [ka]

[0209] To a solution of 5-bromopyridin-2-ol (2.30 g, 13.219 mmol) and chloro(dimethylphosphoryl)methane (1.05 g, 8.276 mmol) in DMF (12 mL) was added K2CO3 (5.48 g, 39.657 mmol) at room temperature. The mixture was stirred at 100 °C overnight. The resulting mixture was cooled to room temperature and purified by reverse-phase flash chromatography to give 5-bromo-2-[(dimethylphosphoryl)methoxy]pyridine (538 mg, 29%) as a yellow solid. MS ESI C8H 11 Calculated value of BrNO2P [M+H] + 263.97 265.97, actual values ​​264.00 266.00. 1 H NMR (300 MHz, chloroform-d) δ 8.20 (d, J = 2.5 Hz, 1H), 7.73–7.68 (m, 1H), 6.75 (d, J = 8.7 Hz, 1H), 4.65 (d, J = 5.9 Hz, 2H), 1.63 (s, 3H), 1.59 (s, 3H).

[0210] Example 7: (1R,11R)-18-(difluoromethoxy)-5-{6-[(dimethylphosphoryl)methoxy]pyridin-3-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0211] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.104 mmol) and 5-bromo-2-[(dimethylphosphoryl)methoxy]pyridine (27 mg, 0.104 mmol) in 1,4-dioxane (2 mL) was added a solution of K3PO4 (66 mg, 0.312 mmol) in HO (0.5 mL) under a nitrogen atmosphere at room temperature. The above solution was added with Pd(dppf)Cl at room temperature under a nitrogen atmosphere. 2· CH2Cl2 (8 mg, 0.010 mmol) was added. The resulting mixture was stirred at 100 °C for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (0% to 10%), followed by preparative HPLC (C18 column 120 g; mobile phase A: water (0.1% FA), mobile phase B: CH3CN; flow rate: 50 mL / min; gradient: 20% B to 40% B in 40 min; 254 / 220 nm) to give (1R,11R)-18-(difluoromethoxy)-5-{6-[(dimethylphosphoryl)methoxy]pyridin-3-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (20 mg, 36%) as a white solid. MS ESI C 27 H 25 Calculated value of F2N4O4P [M+H] + 539.16, actual value 539.20. 1H NMR(300MHz,chloroform-d)δ 8.54~8.45(m,1H),8.40~8.33(m,1H),7.93~7.71(m,2H),7.67~7.60( m,1H),7.49~7.35(m,2H),7.36~7.23(m,1H),6.94~6.88(m,1H),6.85( t,J=72.9Hz,1H),6.34~6.19(m,1H),4.97~4.94(m,1H),4.78~4.71(m ,2H),3.61~3.33(m,4H),2.93~2.84(m,1H),1.66(s,3H),1.61(s,3H). 19 F NMR (282 MHz, chloroform-d) δ −80.68 (1F), −80.71 (1F). 31 P NMR (122 MHz, chloroform-d) δ 41.71 (1P).

[0212] Example 8: (1R,11R)-18-(difluoromethoxy)-5-[2-(dimethylphosphoryl)pyrimidin-5-yl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0213] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.104 mmol) and 5-bromo-2-(dimethylphosphoryl)pyrimidine (24 mg, 0.104 mmol) in 1,4-dioxane (2 mL) was added a solution of KPO (66 mg, 0.312 mmol) in HO (0.5 mL) under a nitrogen atmosphere at room temperature. 2·CH2Cl2 (8 mg, 0.010 mmol) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 hours. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (0%-10%), followed by preparative HPLC (C18 column 120 g; mobile phase A: water (0.1% FA), mobile phase B: CH3CN; flow rate: 50 mL / min; gradient: 20B to 40B in 40 min; 254 / 220 nm) to give (1R,11R)-18-(difluoromethoxy)-5-[2-(dimethylphosphoryl)pyrimidin-5-yl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (20 mg, 38%) as a white solid. MS ESI C 25 H 22 Calculated value of F2N5O3P [M+H] + 510.14, actual value 510.15. 1 H NMR(300MHz,chloroform-d)δ 9.14~9.04(m,2H),8.55~8.44(m,1H),7.92~7.82(m,1H),7.78~7.71(m,1H),7.53~7.36(m,2H),7.35~7.25(m,1H),6. 87(t,J=72.7Hz,1H),6.38~6.27(m,1H),5.06~4.96(m,1H),3.63~3.42(m,4H),2.98~2.86(m,1H),1.98~1.85(m,6H). 19 F NMR (282 MHz, chloroform-d) δ −80.68 (1F), −80.76 (1F). 31 P NMR (162 MHz, chloroform-d) δ 34.60 (1P).

[0214] Example 9: (1R,11R)-18-(difluoromethoxy)-5-{2-[(dimethylphosphoryl)methoxy]pyrimidin-5-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0215] Preparation 9A: 5-Bromo-2-[(dimethylphosphoryl)methoxy]pyrimidine [ka]

[0216] To a stirred solution of 5-bromo-2-chloropyrimidine (3.50 g, 18.094 mmol) and (dimethylphosphoryl)methanol (2.35 g, 21.713 mmol) in DMF (40 mL) was added K2CO3 (7.50 g, 54.282 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h. The resulting mixture was diluted with water (250 mL) and extracted with CHCl2 (3 × 100 mL). The combined organic phase was washed with brine (5 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl2 / MeOH (10:1) to give 5-bromo-2-[(dimethylphosphoryl)methoxy]pyrimidine (3.90 g, 81%) as a white solid. MS ESI C7H 10 Calculated value for BrN2O2P [M+H] + 264.97 266.97, actual values ​​264.85 266.85. 1 H NMR (300MHz, MeOD) δ 8.70 (s, 2H), 4.78 (d, J = 5.5Hz, 2H), 1.69 (s, 3H), 1.65 (s, 3H).

[0217] Example 9: (1R,11R)-18-(difluoromethoxy)-5-{2-[(dimethylphosphoryl)methoxy]pyrimidin-5-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0218] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.104 mmol) and 4-(5-bromopyridin-2-yl)-1,4 lambda 5-oxaphosphinan-4-one (29 mg, 0.104 mmol) in 1,4-dioxane (2 mL) was added a solution of KPO (66 mg, 0.312 mmol) in HO (0.5 mL) under a nitrogen atmosphere at room temperature. The above solution was added with Pd(dppf)Cl at room temperature under a nitrogen atmosphere. 2·CH2Cl2 (8 mg, 0.010 mmol) was added. The resulting mixture was stirred at 100 °C for an additional 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (0% to 10%) followed by preparative HPLC using the following conditions: Column: C18 column 120g; Mobile phase A: water (0.1% FA), Mobile phase B: CH3CN; Flow rate: 50 mL / min; Gradient: 20% B to 40% B in 40 min; 254 / 220 nm to give (1R,11R)-18-(difluoromethoxy)-5-{2-[(dimethylphosphoryl)methoxy]pyrimidin-5-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (25 mg, 45%) as a white solid. MS ESI C 26 H 24 Calculated value of F2N5O4P [M+H] + 540.15, actual value 540.20. 1 H NMR(400MHz,chloroform-d)δ 8.75(s,2H),8.53~847(m,1H),7.85(d,J=8.5,1H),7.68~7.65(m,1H),7.48~7.40(m,2H),7.35~7.31(m,1H),6.88(t,J=72.8Hz,1H),6. 32(d,J=7.2Hz,1H),5.10(d,J=7.1Hz,1H),4.81(d,J=6.9Hz,2H),3.52~3.48(m,4H),2.92(d,J=13.6Hz,1H),1.74(s,3H),1.70(s,3H). 19 F NMR (377 MHz, chloroform-d) δ −80.73 (1F), −80.90 (1F). 31 P NMR (162 MHz, chloroform-d) δ 43.56 (1P).

[0219] Example 10: (1R,11R)-18-(difluoromethoxy)-5-{6-[(dimethylphosphoryl)methoxy]-5-fluoropyridin-3-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0220] Preparation 10A: 5-Bromo-2-[(dimethylphosphoryl)methoxy]-3-fluoropyridine [ka]

[0221] A mixture of (dimethylphosphoryl)methanol (56 mg, 0.516 mmol) and NaH (21 mg, 0.516 mmol, 60%) in THF (2 mL) was stirred at 0 °C for 30 min. To the above mixture, 5-bromo-2,3-difluoropyridine (100 mg, 0.516 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for an additional 3 h. The reaction was quenched with water and purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, CHCN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 min; detector, 254 nm) to give 5-bromo-2-[(dimethylphosphoryl)methoxy]-3-fluoropyridine (120 mg, 82%) as a white solid. MS ESI CH 10 Calculated value of BrFNO2P [M+H] + ,281.96, actual value 281.9. 1 H NMR (400 MHz, chloroform-d) δ 8.02 (d, J = 2.1 Hz, 1H), 7.57–7.52 (m, 1H), 4.70 (d, J = 6.2 Hz, 2H), 1.66 (s, 3H), 1.63 (s, 3H).

[0222] Example 10: (1R,11R)-18-(difluoromethoxy)-5-{6-[(dimethylphosphoryl)methoxy]-5-fluoropyridin-3-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0223] 5-Bromo-2-[(dimethylphosphoryl)methoxy]-3-fluoropyridine (32 mg, 0.114 mmol) and (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.^{3, To a solution of 8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.104 mmol) in dioxane (0.5 mL) and HO (0.1 mL) was added KPO (66 mg, 0.312 mmol) and Pd(dppf)Cl.CHCl (8 mg, 0.010 mmol). After stirring at 100 °C under a nitrogen atmosphere for 2 h, the mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH, 0% to 10%) followed by preparative HPLC (C18 silica gel; mobile phase, CH3CN in water (10 mmol / L NH4HCO3), 10% to 40% gradient in 30 min; detector, 254 nm) to give (1R,11R)-18-(difluoromethoxy)-5-{6-[(dimethylphosphoryl)methoxy]-5-fluoropyridin-3-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (19 mg, 32%) as a white solid. MS ESI C 27 H 24Calculated value of F3N4O4P [M+H] + ,557.15, actual value 557.00. 1 H NMR (400 MHz, chloroform-d) δ 8.50 (d, J = 8.2 Hz, 1H), 8.15 (d, J = 2.1 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.66-7.56 (m, 2H), 7.43 (t, J = 8.2 Hz, 1H), 7.41-7.36 (m, 1H), 7.35-7.29 (m, 1H), 6.86 (t, J = 72 .9Hz,1H),6.29(d,J=7.1Hz,1H),4.99(d,J=7.1Hz,1H),4.79(d,J=6.4Hz,2H),3 .53(s,3H),3.52~3.42(m,1H),2.90(d,J=13.5Hz,1H),1.69(s,3H),1.66(s,3H). 19 F NMR (377 MHz, chloroform-d) δ −80.76 (2F), −139.34 (1F). 31 P NMR (162 MHz, chloroform-d) δ 42.01 (1P).

[0224] Example 11: (1R,11R)-18-(difluoromethoxy)-5-{6-[(dimethylphosphoryl)methoxy]pyridin-3-yl}-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0225] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (60 mg, 0.128 mmol) and 5-bromo-2-(dimethylphosphoryl)pyridine (25 mg, 0.107 mmol) in 1,4-dioxane (2 mL) was added a solution of KPO (82 mg, 0.384 mmol) in HO (0.5 mL) at room temperature. The solution was cooled to room temperature under a nitrogen atmosphere and Pd(dppf)Cl 2· CH2Cl2 (10 mg, 0.013 mmol) was added. The resulting mixture was stirred at 100°C for 2 hours. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH, 0%-10%) followed by preparative HPLC (C18 column 120 g; mobile phase A: water (0.1% FA), mobile phase B: CH3CN; flow rate: 50 mL / min; gradient: 20B to 40B in 40 min; 254 / 220 nm) to give (1R,11R)-18-(difluoromethoxy)-5-{6-[(dimethylphosphoryl)methoxy]pyridin-3-yl}-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (35 mg, 52%) as a white solid. MS ESI C 26 H 23 Calculated value of F2N4O4P [M+H] + 525.14, actual value 525.20. 1H NMR(400MHz,chloroform-d)δ 8.47~8.40(m,1H),8.39~8.29(m,1H),7.87~7.65(m,3H),7.64~7.53(m,1H),7.50~7.29(m,3H),7.08~6.65(m,2H),6.37(d,J= 7.2Hz,1H), 4.99(t,J=6.6Hz,1H),4.75(d,J=6.0Hz,2H),3.55~3.40(m,1H),2.88(d,J=13.3Hz,1H),1.66(s,3H),1.63(s,3H). 19 F NMR (377 MHz, chloroform-d) δ −80.79 (2F). 31 P NMR (162 MHz, chloroform-d) δ 41.85 (1P).

[0226] Example 12: (1R,11R)-18-(difluoromethoxy)-5-{2-[(dimethylphosphoryl)methoxy]pyrimidin-5-yl}-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0227] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (60 mg, 0.128 mmol) and 5-bromo-2-[(dimethylphosphoryl)methoxy]pyrimidine (34 mg, 0.128 mmol) in 1,4-dioxane (2 mL) was added a solution of KPO (82 mg, 0.384 mmol) in HO (0.5 mL) at room temperature. To the above solution was added Pd(dppf)Cl.CHCl (10 mg, 0.013 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. for 2 hours. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH, 0%-10%) followed by preparative HPLC (C18 column 120 g; mobile phase A: water (0.1% FA), mobile phase B: CH3CN; flow rate: 50 mL / min; gradient: 20B to 40B in 40 min; 254 / 220 nm) to give (1R,11R)-18-(difluoromethoxy)-5-{2-[(dimethylphosphoryl)methoxy]pyrimidin-5-yl}-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (35 mg, 52%) as a white solid. MS ESI C 25 H 22 Calculated value of F2N5O4P [M+H] + 526.14, actual value 526.05. 1H NMR(400MHz,DMSO-d6)δ 9.15(d,J=6.9Hz,1H),8.90(s,2H),8.28~8.17(m,1H),7.88~7.65(m,3H),7.58~7.53(m,1H),7.52~7.45(m,2H),6.36(d,J=7 .1Hz,1H), 4.89(t,J=6.8Hz,1H),4.70(d,J=5.2Hz,2H),3.53~3.44(m,1H),2.75(d,J=13.3Hz,1H),1.56(s,3H),1.52(s,3H). 19 F NMR (377MHz, DMSO-d6) δ -81.89(1F), -82.58(1F). 31 P NMR (162MHz, DMSO-d6) δ 37.61 (1P).

[0228] Example 13: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)phenyl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0229] Preparation 13A: 1-Bromo-4-(dimethylphosphoryl)benzene [ka]

[0230] To a stirred solution of 4-bromoiodobenzene (20.00 g, 70.695 mmol) and (methylphosphonoyl)methane (5.52 g, 70.695 mmol) in 1,4-dioxane (200 mL), Xantphos (4.09 g, 7.069 mmol), TEA (8.58 g, 84.834 mmol), and Pd(dba) (3.24 g, 3.535 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 4 hours. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (CHCl / MeOH, 10:1) to give 1-bromo-4-(dimethylphosphoryl)benzene (14.10 g, 85%) as a yellow solid. MS ESI CH 10 Calculated value of BrOP [M+H] + , 232.97 234.97, actual values ​​233.00 235.00. 1 H NMR (300 MHz, chloroform-d) δ 7.69–7.48 (m, 4H), 1.74 (s, 3H), 1.70 (s, 3H).

[0231] Example 13: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)phenyl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0232] (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one(6 A mixture of Pd(dppf)Cl.CHCl (10 mg, 0.013 mmol), 1-bromo-4-(dimethylphosphoryl)benzene (34 mg, 0.150 mmol), KPO (79 mg, 0.375 mmol), and Pd(dppf)Cl.CHCl (10 mg, 0.013 mmol) in dioxane (1 mL) and HO (0.2 mL) was stirred at 100 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH, 0%-10%) followed by preparative HPLC (C18 column, 120 g; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: CH3CN; flow rate: 60 mL / min; gradient: 30% B to 60% B in 20 min; 254 / 220 nm) to give (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)phenyl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (23 mg, 36%) as a white solid. MS ESI C 27 H 24 Calculated value of F2N3O3P [M+H] + , 508.15, actual value 508.25. 1 H NMR(300MHz,chloroform-d)δ 8.56~8.48(m,1H),7.91~7.70(m,6H),7.59~7.53(m,1H),7.46(t,J=8.2Hz,1H),7.37~7.30(m,1H),6.87(t,J=72.8Hz,1H),6. 34(d,J=6.9Hz,1H),5.08(d,J=6.7Hz,1H),3.57(s,3H),3.56~3.43(m,1H),2.93(d,J=13.5Hz,1H),1.83(s,3H),1.79(s,3H). 19F NMR (282 MHz, chloroform-d) δ −80.70 (2F). 31 P NMR (121 MHz, chloroform-d) δ 34.00 (1P).

[0233] Example 14: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3-fluorophenyl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0234] Preparation 14A: 4-Bromo-1-(dimethylphosphoryl)-2-fluorobenzene [ka]

[0235] To a solution of 4-bromo-2-fluoro-1-iodobenzene (2.00 g, 6.647 mmol) and (methylphosphonoyl)methane (0.57 g, 7.312 mmol) in 1,4-dioxane (20 mL) was added TEA (0.81 g, 7.976 mmol), Xantphos (0.38 g, 0.665 mmol), and Pd(dba) (0.30 g, 0.332 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 70 °C for 16 h under a nitrogen atmosphere. The mixture was diluted with water (50 mL). The aqueous phase was extracted with CHCl (3 × 100 mL). The combined organic phase was washed with brine (3 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH, 20:1) to give 4-bromo-1-(dimethylphosphoryl)-2-fluorobenzene (1.24 g, 74%) as a yellow solid. MS ESI calculated for C8H9BrFOP [M+H] +, 250.96 252.96, actual values ​​250.90 252.90. 1 H NMR (400 MHz, chloroform-d) δ 7.90–7.81 (m, 1H), 7.52–7.47 (m, 1H), 7.35–7.30 (m, 1H), 1.81 (d, J = 1.2 Hz, 3H), 1.78 (d, J = 1.2 Hz, 3H).

[0236] Example 14: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3-fluorophenyl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0237] (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (60 mg, 0. A mixture of Pd(dppf)Cl.CHCl (10 mg, 0.013 mmol), 4-bromo-1-(dimethylphosphoryl)-2-fluorobenzene (37 mg, 0.150 mmol), KPO (79 mg, 0.375 mmol), and Pd(dppf)Cl.CHCl (10 mg, 0.013 mmol) in 1,4-dioxane (1 mL) and HO (0.2 mL) was stirred at 100 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH, 0%-10%) followed by preparative HPLC (C18 column, 120 g; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: CH3CN; flow rate: 60 mL / min; gradient: 30% B to 55% B in 20 min; 254 / 220 nm) to give (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3-fluorophenyl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (17 mg, 26%) as a white solid. MS ESI C 27 H 23 Calculated value of F3N3O3P [M+H] + , 526.14, actual value 526.30. 1 H NMR(300MHz,chloroform-d)δ 8.52(d,J=8.2Hz,1H),8.14~7.98(m,1H),7.89~7.76(m,2H),7.62~7.52(m,2H),7.47(t,J=8.2Hz,1H),7.41~7.31(m,2H) ,6.89(t,J=72.9Hz,1H),6.40~6.30(m,1H),5.20~5.03(m,1H),3.58(s,3H),3.56~3.41(m,1H),1.89(s,4H),1.84(s,3H).19 F NMR (282 MHz, chloroform-d) δ −80.79 (2F), −105.70 (1F). 31 P NMR (121 MHz, chloroform-d) δ 30.54 (1P).

[0238] Example 15: (7R,14R)-1-(difluoromethoxy)-11-(6-((dimethylphosphoryl)methoxy)pyridin-3-yl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one [ka]

[0239] Preparation 15A: (7R,14R)-11-chloro-1-(difluoromethoxy)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one [ka]

[0240] To a stirred solution of (1R,11R)-5-chloro-18-(difluoromethoxy)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (300 mg, 0.798 mmol) in anhydrous THF (6 mL) was added 1N KHMDS (0.96 mL, 0.958 mmol) dropwise under a nitrogen atmosphere at −78°C. The resulting solution was stirred at −78°C for 1 h under a nitrogen atmosphere. To the above solution, iodomethane-d3 (231 mg, 1.596 mmol) was added dropwise over 2 min at −78°C. The resulting mixture was slowly warmed to room temperature and stirred at room temperature for 3 h under a nitrogen atmosphere. The resulting solution was quenched by the addition of saturated NH4Cl(aq) (10 mL) and extracted with EtOAc (2 x 15 mL). The combined organic phase was washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl2 / MeOH, 10:1) to give (7R,14R)-11-chloro-1-(difluoromethoxy)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (290 mg, 92%) as a white solid. MS ESI C 19 H 11 Calculated value for D3ClF2N3O2 [M+H] + 393.09 395.09, actual values ​​393.05 395.05. 1 H NMR (400 MHz, chloroform-d) δ 8.49 (dd, J = 8.2, 1.3 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.46–7.41 (m, 2H), 7.35–7.32 (m, 1H), 7.21 (dd, J = 8.7, 2.0 Hz, 1H), 7.02–6.65 (m, 1H), 6.21–6.19 (m, 1H), 4.95–4.93 (m, 1H), 3.47–3.40 (m, 1H), 2.88–2.84 (m, 1H).

[0241] Preparation 15B: (7R,14R)-1-(difluoromethoxy)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one [ka]

[0242] To a stirred mixture of (1R,11R)-5-chloro-18-(difluoromethoxy)-12-(2H)methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (300 mg, 0.764 mmol), KOAc (225 mg, 2.292 mmol), and BPD (291 mg, 1.146 mmol) in 1,4-dioxane (5 mL), PCy3.HBF4 (28 mg, 0.076 mmol) and Pd2(dba)3 (70 mg, 0.076 mmol) were added under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 140° C. for 16 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (10:1) to give (7R,14R)-1-(difluoromethoxy)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (300 mg, 81%) as a yellow oil. MS ESI C 25 H 23 Calculated value for D3BF2N3O4 [M+H] + 485.22, actual value 485.20.

[0243] Example 15: (7R,14R)-1-(difluoromethoxy)-11-(6-((dimethylphosphoryl)methoxy)pyridin-3-yl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one [ka]

[0244] To a stirred solution of (7R,14R)-1-(difluoromethoxy)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (50 mg, 0.103 mmol) and 5-bromo-2-[(dimethylphosphoryl)methoxy]pyridine (27 mg, 0.103 mmol) in 1,4-dioxane (2 mL) was added a solution of K3PO4 (66 mg, 0.309 mmol) in HO (0.5 mL) under a nitrogen atmosphere at room temperature. 2· CH2Cl2 (8 mg, 0.010 mmol) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. for an additional 2 hours. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH, 0%-10%) followed by preparative HPLC (C18 column 120 g; mobile phase A: water (0.1% FA); mobile phase B: CH3CN; flow rate: 50 mL / min; gradient: 20B to 40B in 40 min; 254 / 220 nm) to give (7R,14R)-1-(difluoromethoxy)-11-(6-((dimethylphosphoryl)methoxy)pyridin-3-yl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (20 mg, 36%) as a white solid. MS ESI C 27 H 22 Calculated value of D3F2N4O4P [M+H] +542.18, actual value 542.25. 1 H NMR(400MHz,DMSO-d6)δ 8.41(d,J=2.5Hz,1H),8.29~8.24(m,1H),8.02~7.98(m,1H),7.82~7.63(m,3H),7.52~7.45(m,3H),7.04~7.02(m,1H),6.3 0~6.28(m,1H),5.23~5.21(m,1H),4.63(d,J=5.2Hz,2H),3.48~3.40(m,1H),2.83~2.80(m,1H),1.54(s,3H),1.51(s,3H). 19 F NMR(377MHz,DMSO-d6)δ -82.00(1F),-82.15(1F). 31 P NMR (162MHz, DMSO-d6) δ 39.72 (1P).

[0245] Example 16: (1R,11R)-18-(difluoromethoxy)-5-(6-{[(dimethylphosphoryl)methyl]amino}-5-fluoropyridin-3-yl)-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0246] Preparation 16A: 5-Bromo-N-[(dimethylphosphoryl)methyl]-3-fluoropyridin-2-amine [ka]

[0247] To a solution of 5-bromo-3-fluoropyridin-2-amine (500 mg, 2.618 mmol) in THF (10 mL) was added sodium hydride (120 mg, 3.011 mmol, 60% in oil) in several portions at room temperature. The mixture was stirred at room temperature for 30 min. Chloro(dimethylphosphoryl)methane (380 mg, 3.011 mmol) was then added, and the mixture was warmed to 50 °C and stirred for 3 h. The reaction mixture was quenched with water and extracted with DCM (3 × 25 mL). The combined organic phase was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CH3CN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 min; detector, UV 254 nm. This gave 5-bromo-N-[(dimethylphosphoryl)methyl]-3-fluoropyridin-2-amine (227 mg, 30%) as a white solid. MS ESI CH 11 Calculated value of BrFN2OP [M+H] + ,280.98, actual value 280.9. 1 H NMR (300 MHz, chloroform-d) δ 7.93 (d, J = 1.9 Hz, 1H), 7.37–7.31 (m, 1H), 5.56 (s, 1H), 4.04–3.88 (m, 2H), 1.69 (s, 3H), 1.65 (s, 3H).

[0248] Example 16: (1R,11R)-18-(difluoromethoxy)-5-(6-{[(dimethylphosphoryl)methyl]amino}-5-fluoropyridin-3-yl)-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0249] 5-Bromo-N-[(dimethylphosphoryl)methyl]-3-fluoropyridin-2-amine (32 mg, 0.114 mmol) and (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3 To a solution of icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.104 mmol) in 1,4-dioxane (0.5 mL) and HO (0.1 mL) was added KPO (66 mg, 0.312 mmol) and Pd(dppf)Cl.CHCl (8 mg, 0.010 mmol). After stirring at 80 °C under a nitrogen atmosphere for 2 h, the resulting mixture was concentrated under reduced pressure. The resulting mixture was filtered, and the filter cake was washed with CHOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 min; detector, UV 254 nm. This afforded (1R,11R)-18-(difluoromethoxy)-5-(6-{[(dimethylphosphoryl)methyl]amino}-5-fluoropyridin-3-yl)-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (30 mg, 52%) as a white solid. MS ESI C 27 H 25 Calculated value of F3N5O3P [M+H] + ,556.16, actual value 556.10. 1H NMR(300MHz,chloroform-d)δ 8.53~8.45(m,1H),8.16~8.09(m,1H),7.79~7.71(m,1H),7.61~7.56(m, 1H),7.49~7.29(m,4H),6.85(t,J=72.9Hz,1H),6.27(d,J=7.2Hz,1H),5. 36~5.26(m,1H),4.97(d,J=7.1Hz,1H),4.03(t,J=6.0Hz,2H),3.52(s,3 H),3.51~3.41(m,1H),2.88(d,J=13.6Hz,1H),1.61(s,3H),1.57(s,3H). 19 F NMR (282 MHz, chloroform-d) δ −80.68 (1F), −80.73 (1F), −140.77 (1F). 31 P NMR (122 MHz, chloroform-d) δ 42.22 (1P).

[0250] Example 17: (7R,14R)-1-(difluoromethoxy)-11-(6-(dimethylphosphoryl)pyridin-3-yl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one [ka]

[0251] To a stirred solution of (7R,14R)-1-(difluoromethoxy)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (50 mg, 0.103 mmol) and 5-bromo-2-(dimethylphosphoryl)pyridine (24 mg, 0.103 mmol) in 1,4-dioxane (2 mL) was added a solution of K3PO4 (66 mg, 0.309 mmol) in HO (0.5 mL) under a nitrogen atmosphere at room temperature. To the above solution was added Pd(dppf)Cl2.CHCl2 (8 mg, 0.010 mmol) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 100°C for 2 hours. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (0%-10%) followed by preparative HPLC using the following conditions: Column: C18 column 120g; Mobile phase A: water (0.1% FA), Mobile phase B: CH3CN; Flow rate: 50 mL / min; Gradient: 20B to 40B in 40 min; 254 / 220 nm to give (7R,14R)-1-(difluoromethoxy)-11-(6-(dimethylphosphoryl)pyridin-3-yl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (20 mg, 38%) as a white solid. MS ESI C 26 H 20 Calculated value of D3F2N4O3P [M+H] + 512.17, actual value 512.20. 1 H NMR(400MHz,DMSO-d6)δ 9.03(s,1H),8.30~8.24(m,1H),8.21~8.16(m,1H),8.05~8.01(m,1H),7.86~7.67(m,3H),7.62~7.60(m,1H),7.51~ 7.49(m,2H),6.33~6.30(m,1H),5.27~5.24(m,1H),3.58~3.50(m,1H),2.87~2.82(m,1H),1.73(s,3H),1.69(s,3H). 19F NMR (377MHz, DMSO-d6) δ -81.82(1F), -82.28(1F). 31 P NMR (162MHz, DMSO-d6) δ 34.01 (1P).

[0252] Example 18: (1R,11R)-18-(difluoromethoxy)-5-{4-[(dimethylphosphoryl)methoxy]-3-fluorophenyl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0253] Preparation 18A: 4-Bromo-1-[(dimethylphosphoryl)methoxy]-2-fluorobenzene [ka]

[0254] A solution of 4-bromo-2-fluorophenol (200 mg, 1.047 mmol) in CHCN (4 mL) was treated with KCO (434 mg, 3.141 mmol) and NaI (16 mg, 0.105 mmol) at room temperature for 10 minutes, followed by the dropwise addition of chloro(dimethylphosphoryl)methane (265 mg, 2.094 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 48 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (12 / 1) to give 4-bromo-1-[(dimethylphosphoryl)methoxy]-2-fluorobenzene (252 mg, 85%) as an off-white solid. MS ESI CH 11 Calculated value of BrFO2P [M+H] + , 280.97, actual value 280.80. 1H NMR (300 MHz, chloroform-d) δ 7.33–7.28 (m, 1H), 7.27–7.22 (m, 1H), 6.98–6.90 (m, 1H), 4.29 (d, J = 8.1 Hz, 2H), 1.72 (s, 3H), 1.68 (s, 3H).

[0255] Example 18: (1R,11R)-18-(difluoromethoxy)-5-{4-[(dimethylphosphoryl)methoxy]-3-fluorophenyl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0256] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3,5,7,9,14,16,18-heptaen-13-one (80 mg, 0.166 mmol) and 4-bromo-1-[(dimethylphosphoryl)methoxy]-2-fluorobenzene (70 mg, 0.249 mmol) in 1,4-dioxane (1 mL) and HO (0.2 mL) was added KCO (57 mg, 0.415 mmol) and Pd(dppf)Cl. 2·CHCl (14 mg, 0.017 mmol) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80°C under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (12 / 1), followed by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NHHCO), gradient 30% to 50% in 30 min; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-{4-[(dimethylphosphoryl)methoxy]-3-fluorophenyl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (48 mg, 52%) as a white solid. MS ESI C 28 H 25 Calculated value of F3N3O4P [M+H] + , 556.15, actual value 556.10. 1 H NMR(400MHz,chloroform-d)δ 8.52~8.48(m,1H),7.78(d,J=8.5Hz,1H),7.66(d,J=1.7Hz,1H),7.49~7.4 0(m,2H),7.38~7.29(m,3H),7.16~7.08(m,1H),6.86(t,J=72.9Hz,1H),6. 31(d,J=6.9Hz,1H),5.08(d,J=6.8Hz,1H),4.36(d,J=8.2Hz,2H),3.55(s, 3H), 3.53~3.43 (m, 1H), 2.91 (d, J=13.4Hz, 1H), 1.73 (s, 3H), 1.70 (s, 3H). 19 F NMR (377 MHz, chloroform-d) δ −80.75 (2F), −133.46 (1F). 31 P NMR (162 MHz, chloroform-d) δ 42.79 (1P).

[0257] Example 19: (1R,11R)-18-(difluoromethoxy)-5-[6-(dimethylphosphoryl)pyridin-3-yl]-12-ethyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0258] Preparation 19A: (1R,11R)-5-chloro-18-(difluoromethoxy)-12-ethyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0259] To a stirred solution of (1R,11R)-5-chloro-18-(difluoromethoxy)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (100 mg, 0.266 mmol) in THF (3 mL) was added KHMDS (0.3 mL, 0.319 mmol, 1 M THF solution) dropwise at −78°C under a nitrogen atmosphere. The resulting mixture was stirred at −78°C for 0.5 h under a nitrogen atmosphere. Ethyl iodide (62 mg, 0.399 mmol) was added dropwise to the above mixture at −78°C. The resulting mixture was further stirred at room temperature overnight. The reaction was quenched with 1 mL of saturated NH4Cl(aq) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl2 / MeOH (20 / 1) to give (1R,11R)-5-chloro-18-(difluoromethoxy)-12-ethyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (75 mg, 64%) as a white solid. MS ESI C 20 H 16 Calculated value for ClF2N3O2 [M+H] + , 404.09, actual value 403.95. 1 H NMR (400 MHz, chloroform-d) δ 8.52(d,J=8.3Hz,1H),7.63(d,J=8.7Hz,1H),7.49(d,J=2.0Hz,1H),7.43(t ,J=8.2Hz,1H),7.37~7.31(m,1H),7.24~7.20(m,1H),6.83(t,J=73.1Hz,1H ),6.22(d,J=7.1Hz,1H),5.02(d,J=7.1Hz,1H),4.13~4.05(m,1H),3.90~3. 80(m,1H),3.53~3.42(m,1H),2.82(d,J=13.5Hz,1H),1.44(t,J=7.1Hz,3H).

[0260] Preparation 19B: (1R,11R)-18-(difluoromethoxy)-12-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0261] To a stirred mixture of (1R,11R)-5-chloro-18-(difluoromethoxy)-12-ethyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (75 mg, 0.186 mmol), potassium acetate (54 mg, 0.558 mmol), and BPD (70.75 mg, 0.279 mmol) in 1,4-dioxane (1 mL) was added Pd2(dba)3 (17 mg, 0.019 mmol) and PCy3.HBF4 (7 mg, 0.019 mmol) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 140 °C for 16 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (10 / 1) to give (1R,11R)-18-(difluoromethoxy)-12-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (100 mg, 86%) as a yellow oil. MS ESI C 26 H 28 Calculated value for BF2N3O4 [M+H] + 496.21, actual value 496.05.

[0262] Example 19: (1R,11R)-18-(difluoromethoxy)-5-[6-(dimethylphosphoryl)pyridin-3-yl]-12-ethyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0263] (1R,11R)-18-(difluoromethoxy)-12-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaene-13- To a solution of 1,4-dioxane (100 mg, 0.202 mmol) and 5-bromo-2-(dimethylphosphoryl)pyridine (47 mg, 0.202 mmol) in 1,4-dioxane (2 mL) and HO (0.4 mL) was added KPO (128 mg, 0.606 mmol) and Pd(dppf)Cl.CHCl (16 mg, 0.020 mmol). After stirring at 100 °C under a nitrogen atmosphere for 2 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (10 / 1) followed by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, aqueous CHCN (0.1% FA), 15% to 40% gradient in 25 min; detector, 254 nm, to give (1R,11R)-18-(difluoromethoxy)-5-[6-(dimethylphosphoryl)pyridin-3-yl]-12-ethyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 47%) as a white solid. MS ESI C 27 H 25 Calculated value of F2N4O3P [M+H] +,523.16,Actual value 523.15. 1 H NMR (400 MHz, chloroform-d) δ 8.98-8.93 (m, 1H), 8.53 (d, J = 8.3 Hz, 1H), 8.23-8.16 (m, 1H), 8.05-7.99 (m, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 1.9 Hz, 1H), 7.55-7.48 (m, 1H), 7.43 (t, J = 8.2 Hz, 1H), 7.39-7.27 (m, 1H), 6.85 ( t,J=72.9Hz,1H),6.32(d,J=7.0Hz,1H),5.05(d,J=7.1Hz,1H),4.16~4.03(m,1H),3.92~3.81(m, 1H),3.56~3.46(m,1H),2.86(d,J=13.4Hz,1H),1.84(s,3H),1.81(s,3H),1.47(t,J=7.1Hz,3H). 19 F NMR (377 MHz, chloroform-d) δ −80.76 (1F), −80.77 (1F). 31 P NMR (162 MHz, chloroform-d) δ 36.52.

[0264] Example 20: (1R,11R)-18-(difluoromethoxy)-5-{6-[(dimethylphosphoryl)amino]pyridin-3-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0265] Preparation 20A: 5-Bromo-N-(dimethylphosphoryl)pyridin-2-amine [ka]

[0266] A mixture of dimethylphosphinoyl chloride (430 mg, 3.823 mmol), 5-bromopyridin-2-amine (860 mg, 4.970 mmol), and TEA (774 mg, 7.646 mmol) in 1,4-dioxane (10 mL) was stirred overnight at 80 °C under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (9 / 1) to give 5-bromo-N-(dimethylphosphoryl)pyridin-2-amine (220 mg, 23%) as a white solid. MS ESI CH 10 Calculated value of BrN2OP [M+H] + ,248.97, actual value 248.80. 1 H NMR (400 MHz, chloroform-d) δ 8.20 (s, 1H), 7.62–7.56 (m, 1H), 6.82–6.74 (m, 1H), 1.83 (s, 3H), 1.80 (s, 3H).

[0267] Example 20: (1R,11R)-18-(difluoromethoxy)-5-{6-[(dimethylphosphoryl)amino]pyridin-3-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0268] 5-Bromo-N-(dimethylphosphoryl)pyridin-2-amine (28 mg, 0.114 mmol) and (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0 To a solution of ^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.104 mmol) in 1,4-dioxane (1 mL) and HO (0.1 mL) was added KPO (66 mg, 0.312 mmol) and Pd(dppf)Cl.CHCl (8 mg, 0.010 mmol). After stirring at 100 °C for 2 h under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (0% to 10%), followed by preparative HPLC using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NHHCO), gradient 10% to 50% in 30 min; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-{6-[(dimethylphosphoryl)amino]pyridin-3-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 92%) as a white solid. MS ESI C 26 H 24 Calculated value of F2N5O3P [M+H] + ,524.16, actual value 524.10. 1H NMR (400 MHz, chloroform-d) δ 8.49(d,J=8.2Hz,1H),8.40(d,J=2.5Hz,1H),7.80~7.71(m,2H),7.60(s,1H) ),7.46~7.36(m,2H),7.30(d,J=8.1Hz,1H),6.86(d,J=73.0Hz,1H),6.85~6. 82(m,1H),6.27(d,J=7.2Hz,1H),5.78(s,1H),4.97(d,J=7.1Hz,1H),3.52( s, 3H), 3.51~3.40 (m, 1H), 2.88 (d, J=13.6Hz, 1H), 1.89 (s, 3H), 1.85 (s, 3H). 19 F NMR (376 MHz, chloroform-d) δ −80.62 (1F), −80.71 (1F). 31 P NMR (162 MHz, chloroform-d) δ 41.80 (1P).

[0269] Example 21: (1R,11R)-18-(difluoromethoxy)-5-{1-[(dimethylphosphoryl)methyl]pyrazol-4-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0270] Preparation 21A: 4-Bromo-1-[(dimethylphosphoryl)methyl]pyrazole [ka]

[0271] To a solution of 4-bromopyrazole (100 mg, 0.680 mmol) in THF (2 mL) was added sodium hydride (30 mg, 0.748 mmol, 60% relative to the original amount) at 0 °C. The mixture was stirred for 30 min. Then, chloro(dimethylphosphoryl)methane (86 mg, 0.680 mmol) was added to the above solution. The mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with water and extracted with DCM (3 × 10 mL). The combined organic phase was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CH3CN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 min; detector, UV 254 nm. This gave 4-bromo-1-[(dimethylphosphoryl)methyl]pyrazole (100 mg, 62%) as a white solid. MS ESI C6H 10 Calculated value of BrN2OP [M+H] + ,236.97 238.97,actual value 236.90 238.90. 1 H NMR (400 MHz, chloroform-d) δ 7.59 (s, 1H), 7.50 (s, 1H), 4.53 (d, J = 7.4 Hz, 2H), 1.56 (s, 3H), 1.53 (s, 3H).

[0272] Example 21: (1R,11R)-18-(difluoromethoxy)-5-{1-[(dimethylphosphoryl)methyl]pyrazol-4-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0273] 4-Bromo-1-[(dimethylphosphoryl)methyl]pyrazole (27 mg, 0.114 mmol) and (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0 To a solution of ^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.104 mmol) in 1,4-dioxane (1 mL) and HO (0.1 mL) was added KPO (66 mg, 0.312 mmol) and Pd(dppf)Cl.CHCl (8 mg, 0.010 mmol). After stirring at 100 °C under a nitrogen atmosphere for 2 h, the mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (0% to 10%), followed by preparative HPLC using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NH4HCO3), gradient 10% to 50% over 30 min; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-{1-[(dimethylphosphoryl)methyl]pyrazol-4-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (38 mg, 72%) as a white solid. MS ESI C 25 H 24 Calculated value of F2N5O3P [M+H] + ,512.16, actual value 512.05. 1H NMR(400MHz,chloroform-d)δ 8.51(d,J=8.2Hz,1H),7.83(s,2H),7.78(d,J=8.5Hz,1H),7.68(s,1H),7. 52~7.43(m,2H),7.33(d,J=8.2Hz,1H),6.94(t,J=72.8Hz,1H),6.36(d,J= 6.3Hz,1H),5.26(s,1H),4.61(d,J=7.3Hz,2H),3.62(s,3H),3.59~3.48(m ,1H),2.95(d,J=13.3Hz,1H),1.61(d,J=3.9Hz,3H),1.57(d,J=3.9Hz,3H). 19 F NMR (376 MHz, chloroform-d) δ −80.78 (1F), −80.97 (1F). 31 P NMR (162 MHz, chloroform-d) δ 40.53.

[0274] Example 22: (1R,11R)-18-(difluoromethoxy)-5-{6-[(dimethylphosphoryl)methyl]pyridin-3-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0275] Preparation 22A: 5-Bromo-2-(chloromethyl)pyridine [ka]

[0276] To a stirred solution of (5-bromopyridin-2-yl)methanol (5.00 g, 26.592 mmol) in DCM (50 mL) was added thionyl chloride (4.75 g, 39.888 mmol) dropwise under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 h. The reaction was quenched by adding saturated sodium bicarbonate (50 mL) at 0 °C. The resulting mixture was extracted with CHCl (3 × 100 mL). The combined organic phase was washed with brine (2 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This gave 5-bromo-2-(chloromethyl)pyridine (4.50 g, 81%) as a brown oil. 1 H NMR (300 MHz, chloroform-d) δ 8.66–8.60 (m, 1H), 7.88–7.80 (m, 1H), 7.42–7.36 (m, 1H), 4.63 (s, 2H).

[0277] Preparation 22B: 5-Bromo-2-[(dimethylphosphoryl)methyl]pyridine [ka]

[0278] A solution of (methylphosphonoyl)methane (756 mg, 9.687 mmol) in THF (5 mL) was treated with NaHMDS (4.9 mL, 9.687 mmol, 2N THF solution) under a nitrogen atmosphere at 0 °C for 0.5 h, followed by the dropwise addition of a solution of 5-bromo-2-(chloromethyl)pyridine (2.00 g, 9.687 mmol) in THF (20 mL) at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 h. The reaction was quenched by the addition of water (50 mL) at room temperature. The resulting mixture was extracted with CHCl (3 × 50 mL). The combined organic phase was washed with brine (3 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (10:1) to give 5-bromo-2-[(dimethylphosphoryl)methyl]pyridine (270 mg, 11%) as a tan oil. MS ESI CH 11 Calculated value of BrNOP [M+H] + , 247.98 249.98, actual value 247.90 249.90. 1 H NMR (400 MHz, chloroform-d) δ 8.60 (d, J = 2.5 Hz, 1H), 7.83–7.78 (m, 1H), 7.31–7.27 (m, 1H), 3.35 (d, J = 14.9 Hz, 2H), 1.54 (s, 3H), 1.51 (s, 3H).

[0279] Example 22: (1R,11R)-18-(difluoromethoxy)-5-{6-[(dimethylphosphoryl)methyl]pyridin-3-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0280] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (51 mg, 0.107 mmol) and 5-bromo-2-[(dimethylphosphoryl)methyl]pyridine (22 mg, 0.089 mmol) in 1,4-dioxane (2 mL), a solution of KPO (56 mg, 0.267 mmol) in HO (0.5 mL) and Pd(dppf)Cl 2· CH2Cl2 (7 mg, 0.009 mmol) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (0%-10%) followed by preparative HPLC using the following conditions: Column: C18 column 120g; Mobile phase A: water (0.1% NH4HCO3), Mobile phase B: CH3CN; Flow rate: 60 mL / min; Gradient: 20B to 50B in 30 min; 254 / 220 nm to give (1R,11R)-18-(difluoromethoxy)-5-{6-[(dimethylphosphoryl)methyl]pyridin-3-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (29 mg, 63%) as a white solid. MS ESI C 27 H 25 Calculated value of F2N4O3P [M+H] + , 523.16, actual value 523.20. 1H NMR(400MHz,DMSO-d6)δ 8.77(d,J=2.4Hz,1H),8.30~8.23(m,1H),8.00~7.94(m,1H),7.87~7.66 (m,3H),7.58~7.53(m,1H),7.52~7.46(m,2H),7.45~7.40(m,1H),6.30(d ,J=7.1Hz,1H),5.25(d,J=7.1Hz,1H),3.57~3.47(m,1H),3.39(d,J=15. 3Hz, 2H), 3.36 (s, 3H), 2.83 (d, J=13.8Hz, 1H), 1.45 (s, 3H), 1.42 (s, 3H). 19 F NMR(377MHz,DMSO-d6)δ -81.53,-81.98,-82.38,-82.83. 31 P NMR (162 MHz, DMSO) δ 38.92.

[0281] Example 23: (1R,11R)-18-(difluoromethoxy)-5-(6-{[(dimethylphosphoryl)methyl]amino}pyridin-3-yl)-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0282] Preparation 23A: 5-Bromo-N-[(dimethylphosphoryl)methyl]pyridin-2-amine [ka]

[0283] To a solution of 5-bromopyridin-2-amine (250 mg, 1.445 mmol) in THF (5 mL) was added sodium hydride (60% in oil, 64 mg) at 0 °C. The mixture was stirred for 30 min. Chloro(dimethylphosphoryl)methane (183 mg, 1.445 mmol) was added, and the mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was quenched with water and extracted with DCM (3 × 25 mL). The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CH3CN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 min; detector, UV 254 nm. This gave 5-bromo-N-[(dimethylphosphoryl)methyl]pyridin-2-amine (50 mg, 13%) as a white solid. MS ESI C8H 12 Calculated value of BrN2OP [M+H] + ,262.99 264.99, actual values ​​263.00 265.00. 1 H NMR (400 MHz, chloroform-d) δ 8.08 (d, J = 2.4 Hz, 1H), 7.53–7.45 (m, 1H), 6.52 (d, J = 8.9 Hz, 1H), 5.57 (s, 1H), 3.88 (s, 2H), 1.57 (s, 3H), 1.54 (s, 3H).

[0284] Example 23: (1R,11R)-18-(difluoromethoxy)-5-(6-{[(dimethylphosphoryl)methyl]amino}pyridin-3-yl)-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0285] 5-Bromo-N-[(dimethylphosphoryl)methyl]pyridin-2-amine (30 mg, 0.114 mmol) and (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8} To a solution of .0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.104 mmol) in 1,4-dioxane (0.5 mL) and HO (0.1 mL) was added KPO (66 mg, 0.312 mmol) and Pd(dppf)Cl.CHCl (8 mg, 0.010 mmol). After stirring at 100 °C under a nitrogen atmosphere for 2 h, the resulting mixture was concentrated under reduced pressure. The resulting mixture was filtered. The filter cake was washed with MeOH (3 × 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 min; detector, UV 254 nm. This afforded (1R,11R)-18-(difluoromethoxy)-5-(6-{[(dimethylphosphoryl)methyl]amino}pyridin-3-yl)-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (22 mg, 39%) as a white solid. MS ESI C 27 H 26 Calculated value of F2N5O3P [M+H] + ,538.17, actual value 538.05. 1H NMR (400 MHz, chloroform-d) δ 8.52-8.46 (m, 1H), 8.29 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.72-7.67 (m, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.46-7.34 (m, 2H), 7.30 (d, J = 8.1 Hz, 1H), 7.05-6.61 (m, 2H) ),6.25(d,J=7.2Hz,1H),5.49(s,1H),4.96(d,J=7.1Hz,1H),3.95(t,J=5.7Hz,2H) ,3.52(s,3H),3.51~3.42(m,1H),2.87(d,J=13.5Hz,1H),1.61(s,3H),1.58(s,3H). 19 F NMR (377 MHz, chloroform-d) δ −80.09, −80.54, −80.71, −81.15. 31 P NMR (162 MHz, chloroform-d) δ 42.08.

[0286] Example 24: (7R,14R)-1-(difluoromethoxy)-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one [ka]

[0287] To an 8 mL vial was added (7R,14R)-1-(difluoromethoxy)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (70 mg, 0.145 mmol), 4-bromo-1-(dimethylphosphoryl)-2-fluorobenzene (36 mg, 0.145 mmol), K3PO4 (92 mg, 0.435 mmol), Pd(dppf)Cl2.CHCl2 (10 mg, 0.014 mmol), 1,4-dioxane (2 mL), and water (0.6 mL). The resulting mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (0% to 10%), followed by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, aqueous CHCN (10 mmol / L NH4HCO3), 35% to 60% gradient in 20 min; detector, 254 nm, to give (7R,14R)-1-(difluoromethoxy)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (28 mg, 35%) as a white solid. MS ESI C 27 H 20 Calculated value of D3F3N3O3P [M+H] + , 529.16, actual value 529.30. 1H NMR (400 MHz, chloroform-d) δ 8.52~8.47(m,1H),8.07~7.98(m,1H),7.79(d,J=8.5Hz,1H),7.74(d,J=1.8 Hz,1H),7.59~7.54(m,1H),7.52~7.46(m,1H),7.43(t,J=8.2Hz,1H),7.39~ 7.28(m,2H),6.87(t,J=72.9Hz,1H),6.30(d,J=7.2Hz,1H),4.98(d,J=7.1H z, 1H), 3.54~3.43 (m, 1H), 2.90 (d, J=13.6Hz, 1H), 1.86 (s, 3H), 1.82 (s, 3H). 19 F NMR (377 MHz, chloroform-d) δ −80.77, −105.83, −105.84. 31 P NMR (162 MHz, chloroform-d) δ 30.76.

[0288] Example 25: (1R,11R)-18-(difluoromethoxy)-5-{2-[(dimethylphosphoryl)methoxy]-1,3-thiazol-5-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0289] Preparation 25A: 5-Bromo-2-[(dimethylphosphoryl)methoxy]-1,3-thiazole [ka]

[0290] To a stirred solution of 5-bromo-2-chloro-1,3-thiazole (500 mg, 2.519 mmol) in DMF (5 mL) was added NaH (111 mg, 2.771 mmol, 60%) under a nitrogen atmosphere at 0° C. The resulting mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. To the above mixture was added (dimethylphosphoryl)methanol (272 mg, 2.519 mmol) at 0° C. The resulting mixture was further stirred overnight at room temperature. The resulting mixture was diluted with EtOAc (100 mL). The resulting mixture was washed with 3×30 mL of water. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (12 / 1) to give 5-bromo-2-[(dimethylphosphoryl)methoxy]-1,3-thiazole (135 mg, 20%) as a yellow solid. MS ESI Calculated for C6H9BrNO2PS [M+H] + , 269.93 271.93, actual values ​​269.95 271.95. 1 H NMR (400 MHz, chloroform-d) δ 7.07 (s, 1H), 4.74 (d, J = 5.8 Hz, 2H), 1.65 (s, 3H), 1.62 (s, 3H). 31 P NMR (162 MHz, chloroform-d) δ 40.02.

[0291] Example 25: (1R,11R)-18-(difluoromethoxy)-5-{2-[(dimethylphosphoryl)methoxy]-1,3-thiazol-5-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0292] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3,5,7,9,14,16,18-heptaen-13-one (50 mg, 0.104 mmol) and 5-bromo-2-[(dimethylphosphoryl)methoxy]-1,3-thiazole (42 mg, 0.156 mmol) in 1,4-dioxane (1 mL) and HO (0.2 mL) was added Pd(dppf)Cl. 2· CHCl (9 mg, 0.010 mmol) and KCO (36 mg, 0.260 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 16 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (15 / 1), followed by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NHHCO), gradient 25% to 40% in 30 min; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-{2-[(dimethylphosphoryl)methoxy]-1,3-thiazol-5-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (37 mg, 65%) as a white solid. MS ESI C 25 H 23 Calculated value of F2N4O4PS [M+H] + , 545.11, actual value 545.00. 1H NMR(400MHz,chloroform-d)δ 8.52~8.47(m,1H),7.70(d,J=8.5Hz,1H),7.56(d,J=1.7Hz,1H),7.43(t,J=8.3Hz,1H),7.38~7.27(m,3H),6.87(t,J=72.9Hz,1H),6.26(d,J =7.2Hz,1H),4.97(d,J=7.1Hz,1H),4.79(d,J=6.0Hz,2H),3.52(s,3H),3.50~3.41(m,1H),2.88(d,J=13.6Hz,1H),1.68(s,3H),1.65(s,3H). 19 F NMR (377 MHz, chloroform-d) δ −80.54. 31 P NMR (162 MHz, chloroform-d) δ 40.06.

[0293] Example 26: (1R,11R)-18-(difluoromethoxy)-5-{2-[(dimethylphosphoryl)amino]pyrimidin-5-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0294] Preparation 26A: 5-Bromo-N-(dimethylphosphoryl)pyrimidin-2-amine [ka]

[0295] A solution of 5-bromopyrimidin-2-amine (619 mg, 3.556 mmol) in DMF (7 mL) was treated with NaH (142 mg, 3.556 mmol, 60%) under a nitrogen atmosphere at 50° C. for 30 minutes, followed by the addition of dimethylphosphinoyl chloride (100 mg, 0.889 mmol) at 0° C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was quenched with water at room temperature. The aqueous phase was extracted with EtOAc (3×100 mL). The aqueous phase was concentrated under reduced pressure to give 5-bromo-N-(dimethylphosphoryl)pyrimidin-2-amine (80 mg, 9%) as a yellow solid. MS ESI calculated for CHBrNOP [M+H] + , 249.97 251.97, actual values ​​250.10, 252.10. 1 H NMR (400 MHz, chloroform-d) δ 8.50 (s, 2H), 1.86 (s, 3H), 1.82 (s, 3H).

[0296] Example 26: (1R,11R)-18-(difluoromethoxy)-5-{2-[(dimethylphosphoryl)amino]pyrimidin-5-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0297] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3,5,7,9,14,16,18-heptaen-13-one (50 mg, 0.104 mmol) and 5-bromo-N-(dimethylphosphoryl)pyrimidin-2-amine (26 mg, 0.104 mmol) in 1,4-dioxane (1 mL) and HO (0.2 mL) was added KPO (66 mg, 0.312 mmol) and Pd(dppf)Cl. 2· CHCl (9 mg, 0.010 mmol) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (15 / 1), followed by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NHHCO), gradient 25% to 40% in 30 minutes; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-{2-[(dimethylphosphoryl)amino]pyrimidin-5-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (10 mg, 18%) as a white solid. MS ESI C 25 H 23 Calculated value of F2N6O3P [M+H] + , 525.15, actual value 525.10. 1H NMR(400MHz,chloroform-d)δ 8.71(s,2H),8.51~8.47(m,1H),7.80(d,J=8.5Hz,1H),7.63(d,J=1.7H z,1H),7.47~7.36(m,2H),7.35~7.31(m,1H),7.21~6.80(m,1H),6.30( d,J=7.2Hz,1H),4.99(d,J=7.1Hz,1H),3.53(s,3H),3.52~3.43(m,1H),2.90(d,J=13.5Hz,1H),1.93(d,J=3.2Hz,3H),1.89(d,J=3.2Hz,3H). 19 F NMR (377 MHz, chloroform-d) δ −80.44, −80.88, −81.30, −81.75. 31 P NMR (162 MHz, chloroform-d) δ 41.11.

[0298] Example 27: (1R,11R)-5-[2-chloro-4-(dimethylphosphoryl)phenyl]-18-(difluoromethoxy)-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0299] Preparation 27A: 1-Bromo-2-chloro-4-(dimethylphosphoryl)benzene [ka]

[0300] A mixture of 1-bromo-2-chloro-4-iodobenzene (1.00 g, 3.151 mmol), (methylphosphonoyl)methane (270 mg, 3.466 mmol), Pd(dba) (144 mg, 0.158 mmol), Xantphos (182 mg, 0.315 mmol), and TEA (383 mg, 3.781 mmol) in 1,4-dioxane (10 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (12 / 1) to give 1-bromo-2-chloro-4-(dimethylphosphoryl)benzene (800 mg, 95%) as a yellow solid. MS ESI calculated for CHBrClOP [M+H] + , 266.93 268.92, actual values ​​267.00 269.00. 1 H NMR (400 MHz, chloroform-d) δ 7.92–7.71 (m, 2H), 7.52–7.41 (m, 1H), 1.76 (s, 3H), 1.73 (s, 3H). 31 P NMR (162 MHz, chloroform-d) δ 33.00.

[0301] Example 27: (1R,11R)-5-[2-chloro-4-(dimethylphosphoryl)phenyl]-18-(difluoromethoxy)-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0302] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3,5,7,9,14,16,18-heptaen-13-one (50 mg, 0.104 mmol) and 1-bromo-2-chloro-4-(dimethylphosphoryl)benzene (42 mg, 0.156 mmol) in 1,4-dioxane (1 mL) and HO (0.2 mL) was added KCO (36 mg, 0.260 mmol) and Pd(dppf)Cl. 2· CHCl (9 mg, 0.010 mmol) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (15 / 1), followed by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NHHCO), gradient 25% to 40% in 30 minutes; detector, 254 nm. This gave (1R,11R)-5-[2-chloro-4-(dimethylphosphoryl)phenyl]-18-(difluoromethoxy)-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (37 mg, 65%) as a white solid. MS ESI C 27 H 23 Calculated value of ClF2N3O3P [M+H] + , 542.11, actual value 542.00. 1H NMR(400MHz,chloroform-d)δ 8.52~8.48(m,1H),7.88~7.76(m,2H),7.72~7.63(m,1H),7.63~7.59(m, 1H),7.50~7.46(m,1H),7.42(t,J=8.2Hz,1H),7.36~7.27(m,2H),6.78(d ,J=72.3Hz,1H),6.28(d,J=7.2Hz,1H),5.01(d,J=7.1Hz,1H),3.54(s,3 H),3.51~3.42(m,1H),2.90(d,J=13.6Hz,1H),1.82(s,3H),1.78(s,3H). 19 F NMR (377 MHz, chloroform-d) δ −80.04, −80.48, −80.93, −81.37. 31 P NMR (162 MHz, chloroform-d) δ 33.04.

[0303] Example 28: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2-fluorophenyl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0304] Preparation 28A: 1-Bromo-4-(dimethylphosphoryl)-2-fluorobenzene [ka]

[0305] A mixture of 1-bromo-2-fluoro-4-iodobenzene (1.00 g, 3.323 mmol), (methylphosphonoyl)methane (285 mg, 3.655 mmol), Pd(dba) (152 mg, 0.166 mmol), Xantphos (192 mg, 0.332 mmol), and TEA (404 mg, 3.988 mmol) in 1,4-dioxane (10 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (12 / 1) to give 1-bromo-4-(dimethylphosphoryl)-2-fluorobenzene (820 mg, 98%) as a yellow solid. MS ESI calculated for CHBrFOP [M+H] + , 250.96 252.98, actual values ​​251.00 253.00. 1 H NMR (400 MHz, chloroform-d) δ 7.73–7.69 (m, 1H), 7.53–7.47 (m, 1H), 7.41–7.34 (m, 1H), 1.77 (s, 3H), 1.73 (s, 3H). 31 P NMR (162 MHz, chloroform-d) δ 33.08.

[0306] Example 28: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2-fluorophenyl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0307] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3,5,7,9,14,16,18-heptaen-13-one (50 mg, 0.104 mmol) and 1-bromo-4-(dimethylphosphoryl)-2-fluorobenzene (39 mg, 0.156 mmol) in 1,4-dioxane (1 mL) and HO (0.2 mL) was added KCO (36 mg, 0.260 mmol) and Pd(dppf)Cl. 2· CHCl (9 mg, 0.010 mmol) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (15 / 1), followed by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NHHCO), gradient 25% to 40% in 30 minutes; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2-fluorophenyl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (20 mg, 36%) as a white solid. MS ESI C 27 H 23 Calculated value of F3N3O3P [M+H] + , 526.14, actual value 526.15. 1H NMR (400 MHz, chloroform-d) δ 8.49 (d, J = 8.1 Hz, 1H), 7.85–7.78 (m, 1H), 7.75 (s, 1H), 7.62–7.51 (m, 3H), 7.47–7.40 (m, 2H), 7.34–7.29 (m, 1H), 6.81 (t, J = 72.8 Hz, 1H), 6.31 (d, J = 7.1 Hz, 1H), 5.04 (s, 1H), 3.54 (s, 3H), 3.53–3.44 (m, 1H), 2.90 (d, J = 13.5 Hz, 1H), 1.82 (s, 3H), 1.78 (s, 3H). 19 F NMR (377 MHz, chloroform-d) δ −79.94, −80.39, −81.12, −81.57, −116.60. 31 P NMR (162 MHz, chloroform-d) δ 33.07.

[0308] Example 29: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2-methylphenyl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0309] Preparation 29A: 1-Bromo-4-(dimethylphosphoryl)-2-methylbenzene [ka]

[0310] A solution of 1-bromo-4-iodo-2-methylbenzene (1.00 g, 3.368 mmol), (methylphosphonoyl)methane (289 mg, 3.705 mmol), Pd(dba) (154 mg, 0.168 mmol), Xantphos (195 mg, 0.337 mmol), and TEA (409 mg, 4.042 mmol) in 1,4-dioxane (10 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (15 / 1) to give 1-bromo-4-(dimethylphosphoryl)-2-methylbenzene (453 mg, 54%) as a yellow solid. MS ESI C9H 12 Calculated value of BrOP [M+H] + , 246.98 248.98, actual values ​​247.05 249.15. 1 H NMR (400 MHz, chloroform-d) δ 7.71–7.57 (m, 2H), 7.38–7.31 (m, 1H), 1.74 (s, 3H), 1.71 (s, 3H). 31 P NMR (162 MHz, chloroform-d) δ 33.90.

[0311] Example 29: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2-methylphenyl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0312] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.104 mmol) and 1-bromo-4-(dimethylphosphoryl)-2-methylbenzene (39 mg, 0.156 mmol) in 1,4-dioxane (1 mL) and HO (0.2 mL) was added KPO (66 mg, 0.312 mmol) and Pd(dppf)Cl. 2· CHCl (9 mg, 0.010 mmol) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100°C for 16 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (15 / 1), followed by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NHHCO), gradient 25% to 40% in 30 min; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2-methylphenyl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (12 mg, 21%) as a white solid. MS ESI C 28 H 26 Calculated value of F2N3O3P [M+H] + , 522.17, actual value 522.20. 1H NMR (400 MHz, chloroform-d) δ 8.54~8.47(m,1H),7.77(d,J=8.4Hz,1H),7.73~7.65(m,1H),7.60~7.51(m, 1H),7.47~7.38(m,2H),7.38~7.27(m,2H),7.24~7.17(m,1H),6.75(t,J=72 .8Hz,1H),6.25(d,J=7.1Hz,1H),5.00(d,J=7.0Hz,1H),3.54(s,3H),3.52~ 3.43(m,1H),2.89(d,J=13.6Hz,1H),2.30(s,3H),1.80(s,3H),1.77(s,3H). 19 F NMR (377 MHz, chloroform-d) δ −80.16, −80.61, −80.73, −81.17. 31 P NMR (162 MHz, chloroform-d) δ 34.08.

[0313] Example 30: (1R,11R)-18-(difluoromethoxy)-5-(6-{[(dimethylphosphoryl)methyl](methyl)amino}pyridin-3-yl)-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0314] Preparation 30A: 5-Bromo-N-[(dimethylphosphoryl)methyl]-N-methylpyridin-2-amine [ka]

[0315] To a solution of 5-bromopyridin-2-amine (250 mg, 1.445 mmol) in THF (5 mL) was added sodium hydride (60% in oil, 64 mg) at 0 °C. The mixture was stirred for 30 min. Chloro(dimethylphosphoryl)methane (183 mg, 1.445 mmol) was added, and the mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was quenched with water and extracted with DCM (3 × 25 mL). The combined organic phase was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CH3CN in water (10 mmol / L NH4HCO3), gradient 10% to 50% in 30 min; detector, UV 254 nm. This gave 5-bromo-N-[(dimethylphosphoryl)methyl]-N-methylpyridin-2-amine (50 mg, 12%) as a white solid. MS ESI CH 14 Calculated value of BrN2OP [M+H] + ,277.00, actual value 277.01. 1 H NMR (400 MHz, chloroform-d) δ 8.13–8.09 (m, 1H), 7.58–7.52 (m, 1H), 6.53–6.47 (m, 1H), 4.13 (d, J = 4.7 Hz, 2H), 3.19 (s, 3H), 1.51 (s, 3H), 1.48 (s, 3H). 31 P NMR (162 MHz, chloroform-d) δ 43.67.

[0316] Example 30: (1R,11R)-18-(difluoromethoxy)-5-(6-{[(dimethylphosphoryl)methyl](methyl)amino}pyridin-3-yl)-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0317] 5-Bromo-N-[(dimethylphosphoryl)methyl]-N-methylpyridin-2-amine (32 mg, 0.114 mmol) and (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3 To a solution of icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.104 mmol) in 1,4-dioxane (0.5 mL) and HO (0.1 mL) was added KPO (66 mg, 0.312 mmol) and Pd(dppf)Cl.CHCl (8 mg, 0.010 mmol). After stirring at 100 °C under a nitrogen atmosphere for 2 h, the resulting mixture was concentrated under reduced pressure. The resulting mixture was filtered. The filter cake was washed with MeOH (3 × 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 min; detector, UV 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-(6-{[(dimethylphosphoryl)methyl](methyl)amino}pyridin-3-yl)-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (21 mg, 36%) as a white solid. MS ESI C 28 H 28 Calculated value of F2N5O3P [M+H] + ,552.19, actual value 552.10. 1H NMR(400MHz,chloroform-d)δ 8.51~8.46(m,1H),8.36(d,J=2.4Hz,1H),7.80~7.72(m,2H),7.60(d,J=1 .7Hz,1H),7.46~7.36(m,2H),7.33~7.28(m,1H),7.07~6.62(m,2H),6.27( d,J=7.1Hz,1H),4.96(d,J=7.0Hz,1H),4.26(s,2H),3.52(s,3H),3.51~3. 41(m,1H),3.28(s,3H),2.88(d,J=13.5Hz,1H),1.57(s,3H),1.54(s,3H). 19 F NMR (376 MHz, chloroform-d) δ −80.11, −80.56, −80.74, −81.19. 31 P NMR (162 MHz, chloroform-d) δ 43.95.

[0318] Example 31: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2-fluorophenyl]-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0319] 1-Bromo-4-(dimethylphosphoryl)-2-fluorobenzene (30 mg, 0.118 mmol) and (1R,11R)-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14 To a solution of icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.107 mmol) in 1,4-dioxane (0.5 mL) and HO (0.1 mL) was added KPO (68 mg, 0.321 mmol) and Pd(dppf)Cl.CHCl (9 mg, 0.011 mmol). After stirring at 100 °C under a nitrogen atmosphere for 1 h, the resulting mixture was concentrated under reduced pressure. The resulting mixture was filtered. The filter cake was washed with MeOH (3 × 4 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NH4HCO3), 20% to 60% gradient in 30 min; detector, UV 254 nm. This afforded (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2-fluorophenyl]-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (16 mg, 29%) as a white solid. MS ESI C 26 H 21 Calculated value of F3N3O3P [M+H] + ,512.13, actual value 512.05. 1H NMR(400MHz,chloroform-d)δ 8.46~8.40(m,1H),7.82(d,J=8.5Hz,1H),7.72(d,J=1.8Hz,1H),7.64~7.51(m,3H),7.48~7.40(m,2H),7.38~7.33(m,1H),7.32~7.29(m,1H) ,6.82(t,J=73.3Hz,1H),6.39(d,J=7.2Hz,1H),5.00(t,J=6.6Hz,1H),3.55~3.45(m,1H),2.89(d,J=13.3Hz,1H),1.81(s,3H),1.78(s,3H). 19 F NMR (377 MHz, chloroform-d) δ −80.04, −80.49, −81.15, −81.59, −116.63. 31 P NMR (162 MHz, chloroform-d) δ 33.04.

[0320] Example 32: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2-methylphenyl]-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0321] 1-Bromo-4-(dimethylphosphoryl)-2-methylbenzene (29 mg, 0.118 mmol) and (1R,11R)-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14 To a solution of icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.107 mmol) in 1,4-dioxane (0.5 mL) and HO (0.1 mL) was added KPO (68 mg, 0.321 mmol) and Pd(dppf)Cl.CHCl (9 mg, 0.011 mmol). After stirring at 100 °C under a nitrogen atmosphere for 1 h, the resulting mixture was concentrated under reduced pressure. The resulting mixture was filtered. The filter cake was washed with MeOH (3 × 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CH3CN in water (10 mmol / L NH4HCO3), 20% to 60% gradient in 10 min; detector, UV 254 nm. This afforded (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2-methylphenyl]-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (39 mg, 70%) as a white solid. MS ESI C 27 H 24 Calculated value of F2N3O3P [M+H] + ,508.15, actual value 508.10. 1H NMR (400 MHz, chloroform-d) δ 8.49~8.42(m,1H),7.79(d,J=8.4Hz,1H),7.70(d,J=12.0Hz,1H),7.61~7.51 (m,1H),7.54~7.49(m,1H),7.49~7.41(m,2H),7.39~7.31(m,2H),7.23(d,J= 8.0Hz,1H),6.77(t,J=72.6Hz,1H),6.37(d,J=6.6Hz,1H),5.10(s,1H),3.56 ~3.48(m,1H),2.90(d,J=13.1Hz,1H),2.29(s,3H),1.81(s,3H),1.77(s,3H). 19 F NMR (377 MHz, chloroform-d) δ −80.32, −80.77, −80.80, −81.25. 31 P NMR (162 MHz, chloroform-d) δ 33.88.

[0322] Example 33: (1R,11R)-18-(difluoromethoxy)-5-{4-[(dimethylphosphoryl)methyl]phenyl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0323] Preparation 33A: 1-Bromo-4-[(dimethylphosphoryl)methyl]benzene [ka]

[0324] A solution of (methylphosphonoyl)methane (172 mg, 2.201 mmol) in THF (5 mL) was treated with NaHMDS (1 mL, 2.001 mmol, 1N THF solution) under a nitrogen atmosphere at 0 °C for 15 minutes, followed by the dropwise addition of a solution of 1-bromo-4-(bromomethyl)benzene (500 mg, 2.001 mmol) in THF (3 mL) at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with CHCl (3 × 100 mL). The combined organic phase was washed with brine (2 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (10:1) to give 1-bromo-4-[(dimethylphosphoryl)methyl]benzene (240 mg, 48%) as a white solid. MS ESI CH 12 Calculated value of BrOP [M+H] + , 246.98 248.98, actual values ​​247.05 249.05. 1 H NMR (400 MHz, chloroform-d) δ 7.51–7.42 (m, 2H), 7.18–7.09 (m, 2H), 3.12 (d, J = 14.9 Hz, 2H), 1.47 (s, 3H), 1.44 (s, 3H).

[0325] Example 33: (1R,11R)-18-(difluoromethoxy)-5-{4-[(dimethylphosphoryl)methyl]phenyl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0326] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (51 mg, 0.107 mmol) and 1-bromo-4-[(dimethylphosphoryl)methyl]benzene (22 mg, 0.089 mmol) in 1,4-dioxane (2 mL), was added a solution of KPO (57 mg, 0.267 mmol) in HO (0.5 mL) and Pd(dppf)Cl. 2· CH2Cl2 (7 mg, 0.009 mmol) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (0%-10%) followed by preparative HPLC using the following conditions: Column: C18 120g; Mobile phase A: water (0.1% NH4HCO3), Mobile phase B: CH3CN; Flow rate: 60 mL / min; Gradient: 30B to 50B in 30 min; 254 / 220 nm to give (1R,11R)-18-(difluoromethoxy)-5-{4-[(dimethylphosphoryl)methyl]phenyl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (28 mg, 59%) as a white solid. MS ESI C 28 H 26 Calculated value of F2N3O3P [M+H] + , 522.17, actual value 522.15. 1H NMR (400 MHz, chloroform-d) δ 8.53~8.46(m,1H),7.80~7.75(m,1H),7.69(d,J=1.7Hz,1H),7.57(d,J=7.8Hz,2 H),7.52~7.46(m,1H),7.42(t,J=8.2Hz,1H),7.37~7.28(m,3H),6.84(t,J=72.8 Hz,1H),6.29(d,J=7.1Hz,1H),5.00(d,J=7.0Hz,1H),3.54(s,3H),3.52~3.42(m ,1H),3.21(d,J=15.1Hz,2H),2.89(d,J=13.5Hz,1H),1.51(s,3H),1.48(s,3H). 19 F NMR (377 MHz, chloroform-d) δ −80.20, −80.64, −80.86, −81.30. 31 P NMR (162 MHz, chloroform-d) δ 40.86.

[0327] Example 34: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2,3-difluorophenyl]-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0328] Preparation 34A: 1-Bromo-4-(dimethylphosphoryl)-2,3-difluorobenzene [ka]

[0329] To a stirred mixture of 1-bromo-2,3-difluoro-4-iodobenzene (1.00 g, 3.136 mmol) and (methylphosphonoyl)methane (0.27 g, 3.450 mmol) in 1,4-dioxane (10 mL), KPO (0.80 g, 3.763 mmol), Xantphos (0.18 g, 0.314 mmol), and Pd(dba) (0.14 g, 0.157 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 16 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (15:1) to give 1-bromo-4-(dimethylphosphoryl)-2,3-difluorobenzene (650 mg, 77%) as a yellow solid. MS ESI Calculated for C8H8BrF2OP [M+H] + , 268.95 270.94, actual values ​​268.80 270.80. 1 H NMR (400 MHz, chloroform-d) δ 7.70–7.59 (m, 1H), 7.52 (m, J = 8.1, 5.5 Hz, 1H), 1.85 (s, 3H), 1.81 (s, 3H). 31 P NMR (162 MHz, chloroform-d) δ 30.19.

[0330] Example 34: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2,3-difluorophenyl]-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0331] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3,5,7,9,14,16,18-heptaen-13-one (50 mg, 0.107 mmol) and 1-bromo-4-(dimethylphosphoryl)-2,3-difluorobenzene (43 mg, 0.161 mmol) in 1,4-dioxane (1 mL) and HO (0.2 mL) was added KCO (37 mg, 0.268 mmol) and Pd(dppf)Cl. 2· CHCl (9 mg, 0.011 mmol) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (15 / 1), followed by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NHHCO), gradient 25% to 40% in 30 minutes; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2,3-difluorophenyl]-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (17 mg, 30%) as a white solid. MS ESI C 26 H 20 Calculated value of F4N3O3P [M+H] + , 530.12, actual value 529.95. 1H NMR (400 MHz, chloroform-d) δ 8.47–8.41 (m, 1H), 7.87–7.70 (m, 3H), 7.50–7.34 (m, 4H), 7.29 (d, J = 6.2 Hz, 1H), 6.84 (t, J = 72.6 Hz, 1H), 6.41 (d, J = 7.1 Hz, 1H), 5.06 (t, J = 6.4 Hz, 1H), 3.58–3.45 (m, 1H), 2.90 (d, J = 13.3 Hz, 1H), 1.89 (s, 3H), 1.86 (s, 3H). 19 F NMR (377 MHz, chloroform-d) δ −80.28, −80.73, −81.05, −81.49, −131.17, −131.18, −131.23, −131.24, −143.47, −143.49, −143.53, −143.55. 31 P NMR (162 MHz, chloroform-d) δ 29.81.

[0332] Example 35: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3,5-difluorophenyl]-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0333] Preparation 35A: 5-Bromo-2-(dimethylphosphoryl)-1,3-difluorobenzene [ka]

[0334] To a stirred mixture of (methylphosphonoyl)methane (0.27 g, 3.450 mmol) and 5-bromo-1,3-difluoro-2-iodobenzene (1.00 g, 3.136 mmol) in 1,4-dioxane (10 mL) was added KPO (0.80 g, 3.763 mmol), Xantphos (0.18 g, 0.314 mmol), and Pd(dba) (0.14 g, 0.157 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 16 h under a nitrogen atmosphere. The reaction was quenched with saturated NaHCO (aq) at room temperature. The aqueous phase was extracted with CHCl (3 × 50 mL). The combined organic phase was washed with brine (2 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (20 / 1) to give 5-bromo-2-(dimethylphosphoryl)-1,3-difluorobenzene (170 mg, 20%) as a tan solid. MS ESI calculated for C8H8BrF2OP [M+H] + , 268.95 270.94, actual values ​​268.80 270.80. 1 H NMR (400 MHz, chloroform-d) δ 7.23–7.14 (m, 2H), 1.93 (t, J = 1.8 Hz, 3H), 1.89 (t, J = 1.8 Hz, 3H). 31 P NMR (162 MHz, chloroform-d) δ 30.03.

[0335] Example 35: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3,5-difluorophenyl]-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0336] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3,5,7,9,14,16,18-heptaen-13-one (50 mg, 0.107 mmol) and 5-bromo-2-(dimethylphosphoryl)-1,3-difluorobenzene (43 mg, 0.161 mmol) in 1,4-dioxane (1 mL) and HO (0.2 mL) was added KCO (37 mg, 0.268 mmol) and Pd(dppf)Cl. 2· CHCl (9 mg, 0.011 mmol) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (15 / 1), followed by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NHHCO), gradient 25% to 40% in 30 minutes; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3,5-difluorophenyl]-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (17 mg, 30%) as a white solid. MS ESI C 26 H 20 Calculated value of F4N3O3P [M+H] + , 530.12, actual value 529.95. 1H NMR(400MHz,chloroform-d)δ 8.46~8.42(m,1H),7.83(d,J=8.5Hz,1H),7.69(d,J=1.8Hz,1H),7.49~7.43(m,2H),7.42~7.35(m,2H),7.22~7.15(m,2H),6.89(t, J=72.8Hz,1H),6.41(d,J=7.1Hz,1H),5.04(t,J=6.6Hz,1H),3.59~3.47(m,1H),2.90(d,J=13.4Hz,1H),1.98(s,3H),1.94(s,3H). 19 F NMR (377 MHz, chloroform-d) δ −80.45, −80.90, −81.03, −81.48, −101.77. 31 P NMR (162 MHz, chloroform-d) δ 30.76.

[0337] Example 36: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2,3-difluorophenyl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0338] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3,5,7,9,14,16,18-heptaen-13-one (50 mg, 0.104 mmol) and 1-bromo-4-(dimethylphosphoryl)-2,3-difluorobenzene (42 mg, 0.156 mmol) in 1,4-dioxane (1 mL) and HO (0.2 mL) was added KCO (36 mg, 0.260 mmol) and Pd(dppf)Cl. 2·CHCl (9 mg, 0.010 mmol) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (15 / 1), followed by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NHHCO), gradient 25% to 40% in 30 minutes; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2,3-difluorophenyl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (17 mg, 31%) as a white solid. MS ESI C 27 H 22 Calculated value of F4N3O3P [M+H] + , 544.13, actual value 544.00. 1 H NMR (400 MHz, chloroform-d) δ 8.53–8.47 (m, 1H), 7.86–7.71 (m, 3H), 7.50–7.36 (m, 3H), 7.34–7.29 (m, 1H), 6.82 (t, J = 72.8 Hz, 1H), 6.31 (d, J = 7.1 Hz, 1H), 5.03 (d, J = 7.0 Hz, 1H), 3.54 (s, 3H), 3.53–3.44 (m, 1H), 2.91 (d, J = 13.5 Hz, 1H), 1.89 (s, 3H), 1.85 (s, 3H). 19 F NMR (377 MHz, chloroform-d) δ −80.11, −80.56, −81.01, −81.45, −131.22, −131.23, −131.28, −131.29, −143.47, −143.48, −143.53, −143.54. 31 P NMR (162 MHz, chloroform-d) δ 29.83.

[0339] Example 37: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3,5-difluorophenyl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0340] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3,5,7,9,14,16,18-heptaen-13-one (50 mg, 0.104 mmol) and 5-bromo-2-(dimethylphosphoryl)-1,3-difluorobenzene (42 mg, 0.156 mmol) in 1,4-dioxane (1 mL) and HO (0.2 mL) was added KCO (36 mg, 0.260 mmol) and Pd(dppf)Cl. 2·CHCl (8 mg, 0.010 mmol) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (15 / 1), followed by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NHHCO), gradient 25% to 40% in 30 minutes; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3,5-difluorophenyl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (22 mg, 39%) as a white solid. MS ESI C 27 H 22 Calculated value of F4N3O3P [M+H] + , 544.13, actual value 544.05. 1 H NMR(400MHz,chloroform-d)δ 8.52~8.47(m,1H),7.82(d,J=8.5Hz,1H),7.73(d,J=1.7Hz,1H),7.52~7.41(m,2H),7.36~7.30(m,1H),7.24~7.16(m,2H),6.88(t,J=72. 9Hz,1H),6.32(d,J=7.1Hz,1H),5.06(d,J=7.0Hz,1H),3.55(s,3H),3.54~3.45(m,1H),2.92(d,J=13.6Hz,1H),1.98(s,3H),1.94(s,3H). 19 F NMR (377 MHz, chloroform-d) δ −80.38, −80.83, −80.91, −81.36, −101.70. 31 P NMR (162 MHz, chloroform-d) δ 30.80.

[0341] Example 38: (1R,11R)-18-(difluoromethoxy)-5-{4-[(dimethylphosphoryl)methoxy]phenyl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0342] Preparation 38A: 1-Bromo-4-[(dimethylphosphoryl)methoxy]benzene [ka]

[0343] A solution of 4-bromophenol (200 mg, 1.156 mmol) in MeCN (4 mL) was treated with KCO (367 mg, 3.468 mmol) and NaI (17 mg, 0.116 mmol) at room temperature for 10 minutes, followed by the dropwise addition of chloro(dimethylphosphoryl)methane (146 mg, 1.156 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 48 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (12:1) to give 1-bromo-4-[(dimethylphosphoryl)methoxy]benzene (190 mg, 62.48%) as an off-white solid. MS ESI CH 12 Calculated value of BrO2P [M+H] + , 262.98 264.98, actual values ​​262.80 264.80. 1 H NMR (400 MHz, chloroform-d) δ 7.46–7.38 (m, 2H), 6.87–6.78 (m, 2H), 4.21 (d, J = 8.3 Hz, 2H), 1.68 (s, 3H), 1.64 (s, 3H). 31 P NMR (162 MHz, chloroform-d) δ 42.12.

[0344] Example 38: (1R,11R)-18-(difluoromethoxy)-5-{4-[(dimethylphosphoryl)methoxy]phenyl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0345] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3,5,7,9,14,16,18-heptaen-13-one (50 mg, 0.104 mmol) and 1-bromo-4-[(dimethylphosphoryl)methoxy]benzene (41 mg, 0.156 mmol) in 1,4-dioxane (1 mL) and HO (0.2 mL) was added KCO (36 mg, 0.260 mmol) and Pd(dppf)Cl. 2· CHCl (9 mg, 0.010 mmol) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (15 / 1), followed by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NHHCO), gradient 25% to 40% in 30 minutes; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-{4-[(dimethylphosphoryl)methoxy]phenyl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (20 mg, 35%) as a white solid. MS ESI C 28H 26 Calculated value of F2N3O4P [M+H] + , 538.16, actual value 538.05. 1 H NMR (400 MHz, chloroform-d) δ 8.52~8.47(m,1H),7.77(d,J=8.5Hz,1H),7.66(d,J=1.7Hz,1H),7.59~7.52(m, 2H),7.48~7.39(m,2H),7.30(d,J=8.3Hz,1H),7.08~6.99(m,2H),6.74(t,J=72. 9Hz,1H),6.30(d,J=7.1Hz,1H),5.02(d,J=7.0Hz,1H),4.30(d,J=8.3Hz,2H),3. 54(s,3H),3.52~3.41(m,1H),2.89(d,J=13.5Hz,1H),1.70(s,3H),1.67(s,3H). 19 F NMR (377 MHz, chloroform-d) δ −80.14, −80.59, −80.67, −81.12. 31 P NMR (162 MHz, chloroform-d) δ 42.08.

[0346] Example 39: (1R,11R)-18-(difluoromethoxy)-5-{6-[2-(dimethylphosphoryl)ethoxy]pyridin-3-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0347] Preparation 39A: {[2-(dimethylphosphoryl)ethoxy]methyl}benzene [ka]

[0348] To a stirred solution of (methylphosphonoyl)methane (1.81 g, 23.246 mmol) in THF (20 mL) was added dropwise NaHMDS (11.62 mL, 23.246 mmol, 2N THF solution) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 15 minutes under a nitrogen atmosphere. A solution of [(2-bromoethoxy)methyl]benzene (5.00 g, 23.246 mmol) in THF (30 mL) was added dropwise to the above solution at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with CHCl (3 × 100 mL). The combined organic phase was washed with brine (1 × 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (7 / 1) to give {[2-(dimethylphosphoryl)ethoxy]methyl}benzene (3.44 g, 69%) as a colorless liquid. 1 H NMR (400 MHz, chloroform-d) δ 7.38–7.28 (m, 5H), 4.53 (s, 2H), 3.87–3.79 (m, 2H), 2.09 (t, J = 6.2 Hz, 2H), 1.55 (s, 3H), 1.52 (s, 3H).

[0349] Preparation 39B: 2-(dimethylphosphoryl)ethanol [ka]

[0350] To a solution of {[2-(dimethylphosphoryl)ethoxy]methyl}benzene (3.44 g, 16.209 mmol) in 30 mL of MeOH in a 100 mL round-bottom flask was added Pd / C (10%, 300 mg) under a nitrogen atmosphere. The mixture was hydrogenated under a hydrogen atmosphere using a hydrogen balloon at room temperature overnight, filtered through a bed of Celite, and concentrated under reduced pressure to give 2-(dimethylphosphoryl)ethanol (1.95 g, 98%) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ 4.76 (s, 1H), 4.09–4.01 (m, 2H), 2.05–1.99 (m, 2H), 1.59 (s, 3H), 1.56 (s, 3H).

[0351] Preparation 39C: 5-Bromo-2-[2-(dimethylphosphoryl)ethoxy]pyridine [ka]

[0352] To a stirred solution of 2-(dimethylphosphoryl)ethanol (300 mg, 2.457 mmol) in THF (3 mL) was added NaH (117 mg, 2.948 mmol, 60%) at 0 °C. The resulting mixture was stirred at room temperature for 15 minutes. To the above mixture, 5-bromo-2-fluoropyridine (432 mg, 2.457 mmol) was added dropwise at 0 °C. The resulting mixture was stirred for an additional 2 hours at room temperature. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic phase was washed with water (2 × 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 eluting with CH2Cl2 / MeOH (8 / 1) to give 5-bromo-2-[2-(dimethylphosphoryl)ethoxy]pyridine (187 mg, 27%) as a colorless oil. MS ESI CH 13 Calculated value of BrNO2P [M+H] + , 277.99 279.99, actual value 278.00 279.00. 1 H NMR (300 MHz, chloroform-d) δ 8.21 (d, J = 2.4 Hz, 1H), 7.70–7.66 (m, 1H), 6.67 (d, J = 8.8 Hz, 1H), 4.71–4.61 (m, 2H), 2.38–2.27 (m, 2H), 1.64 (s, 3H), 1.59 (s, 3H).

[0353] Example 39: (1R,11R)-18-(difluoromethoxy)-5-{6-[2-(dimethylphosphoryl)ethoxy]pyridin-3-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0354] 5-Bromo-2-[2-(dimethylphosphoryl)ethoxy]pyridine (31 mg, 0.114 mmol), (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19 A mixture of icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.104 mmol), Pd(dppf)Cl.CHCl (8 mg, 0.010 mmol), and KPO (66 mg, 0.312 mmol) in 1,4-dioxane (1 mL) and HO (0.2 mL) was stirred at 100 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (0% to 10%), followed by filtration under the following conditions: Column: C18 column 120 g; Mobile phase A: water (10 mmol / L) Purification by preparative HPLC using (NH4HCO3), mobile phase B: CH3CN; flow rate: 60 mL / min; gradient: 30% B to 70% B in 20 min; 254 / 220 nm gave (1R,11R)-18-(difluoromethoxy)-5-{6-[2-(dimethylphosphoryl)ethoxy]pyridin-3-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (24 mg, 42%) as a white solid. MS ESI C 28 H27 Calculated value of F2N4O4P [M+H] + , 553.17, actual value 553.20. 1 H NMR (400 MHz, chloroform-d) δ 8.50(d,J=8.2Hz,1H),8.36(d,J=2.2Hz,1H),7.83~7.76(m,2H),7.65~7.61(m ,1H),7.42(t,J=8.2Hz,2H),7.31(d,J=7.9Hz,1H),7.04~6.65(m,2H),6.29(d, J=7.1Hz,1H),5.00(d,J=7.0Hz,1H),4.77~4.67(m,2H),3.54(s,3H),3.51~3.4 4(m,1H),2.89(d,J=13.6Hz,1H),2.37~2.30(m,2H),1.63(s,3H),1.60(s,3H); 19 F NMR (377 MHz, chloroform-d) δ −80.18, −80.63, −80.74, −81.19. 31 P NMR (162 MHz, chloroform-d) δ 40.68.

[0355] Example 40: (1R,11R)-18-(difluoromethoxy)-5-{6-[3-(dimethylphosphoryl)propoxy]pyridin-3-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0356] Preparation 40A: {[3-(dimethylphosphoryl)propoxy]methyl}benzene [ka]

[0357] To a stirred solution of (methylphosphonoyl)methane (0.68 g, 8.729 mmol) in THF (30 mL) was added dropwise NaHMDS (4.36 mL, 8.729 mmol, 2N THF solution) at approximately 0°C under a nitrogen atmosphere. The mixture was stirred for less than 15 minutes. The above mixture was added dropwise to a solution of [(3-bromopropoxy)methyl]benzene (2.00 g, 8.729 mmol) in THF (30 mL) at room temperature over 2 minutes. The resulting mixture was stirred at room temperature for an additional 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (10 / 1) to give {[3-(dimethylphosphoryl)propoxy]methyl}benzene (1.20 g, 60%) as a colorless oil. MS ESI C 12 H 19 Calculated O2P value [M+H] + , 227.11, actual value 226.95. 1 H NMR (400 MHz, chloroform-d) δ 7.38–7.28 (m, 5H), 4.51 (s, 2H), 3.56 (t, J = 5.8 Hz, 2H), 1.98–1.79 (m, 4H), 1.50 (s, 3H), 1.47 (s, 3H).

[0358] Preparation 40B: 3-(dimethylphosphoryl)propan-1-ol [ka]

[0359] To a solution of {[3-(dimethylphosphoryl)propoxy]methyl}benzene (1.80 g, 7.956 mmol) in MeOH (20 mL) was added Pd / C (0.42 g, 0.398 mmol, 10%) under a nitrogen atmosphere. The mixture was hydrogenated under a hydrogen atmosphere using a hydrogen balloon at room temperature overnight, filtered through a bed of Celite, and concentrated under reduced pressure to give 3-(dimethylphosphoryl)propan-1-ol (1.00 g, 92%) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ 3.72 (t, J = 5.3 Hz, 2H), 1.96–1.83 (m, 4H), 1.55 (s, 3H), 1.52 (s, 3H).

[0360] Preparation 40C: 5-Bromo-2-[3-(dimethylphosphoryl)propoxy]pyridine [ka]

[0361] To a solution of 3-(dimethylphosphoryl)propan-1-ol (300 mg, 2.204 mmol) in DMF (10 mL) was added NaH (105 mg, 2.645 mmol, 60%) at 0 °C. The mixture was stirred for 15 min. 5-Bromo-2-fluoropyridine (388 mg, 2.204 mmol) was added, and the mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with water and purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 20 min; detector, UV 254 nm. This gave 5-bromo-2-[3-(dimethylphosphoryl)propoxy]pyridine (380 mg, 59%) as a colorless oil. MS ESI C 10 H 15 Calculated value of BrNO2P [M+H] + , 292.00 294.00, actual values ​​291.80 293.80. 1 H NMR (400 MHz, chloroform-d) δ 8.17 (d, J = 2.3 Hz, 1H), 7.66–7.63 (m, 1H), 6.65 (d, J = 8.8 Hz, 1H), 4.35 (t, J = 6.2 Hz, 2H), 2.15–2.05 (m, 2H), 1.92–1.85 (m, 2H), 1.54 (s, 3H), 1.51 (s, 3H).

[0362] Example 40: (1R,11R)-18-(difluoromethoxy)-5-{6-[3-(dimethylphosphoryl)propoxy]pyridin-3-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0363] 5-Bromo-2-[3-(dimethylphosphoryl)propoxy]pyridine (33 mg, 0.114 mmol), (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.104 mmol), Pd(dppf)Cl 2· A mixture of CHCl (8 mg, 0.010 mmol) and KPO (66 mg, 0.312 mmol) in 1,4-dioxane (1 mL) and HO (0.2 mL) was stirred at 100°C under a nitrogen atmosphere for 2 hours. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (0% to 10%), followed by filtration under the following conditions: Column: C18 column 120 g; Mobile phase A: water (10 mmol / L) Purification by preparative HPLC using (NH4HCO3), mobile phase B: CH3CN; flow rate: 60 mL / min; gradient: 30% B to 70% B in 20 min; 254 / 220 nm gave (1R,11R)-18-(difluoromethoxy)-5-{6-[3-(dimethylphosphoryl)propoxy]pyridin-3-yl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (20 mg, 34%) as a white solid. MS ESI C29 H 29 Calculated value of F2N4O4P [M+H] + , 567.19, actual value 567.20. 1 H NMR (400 MHz, chloroform-d) δ 8.53–8.47 (m, 1H), 8.35 (d, J = 2.3 Hz, 1H), 7.81–7.78 (m, 2H), 7.66–7.62 (m, 1H), 7.45–7.41 (m, 2H), 7.31 (d, J = 7.9 Hz, 1H), 7.04–6.64 (m, 2H), 6.31 (d, J = 7.1 Hz, 1H), 5 .04(d,J=7.1Hz,1H),4.44(t,J=6.1Hz,2H),3.55(s,3H),3.53~3.45(m,1H),2.91( d,J=13.5Hz,1H),2.19~2.10(m,2H),1.96~1.90(m,2H),1.55(s,3H),1.52(s,3H); 19 F NMR (377 MHz, chloroform-d) δ −80.20, −80.64, −80.77, −81.21. 31 P NMR (162 MHz, chloroform-d) δ 42.25.

[0364] Example 41: (1R,11R)-5-[2-chloro-4-(dimethylphosphoryl)phenyl]-18-(difluoromethoxy)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0365] 1-Bromo-2-chloro-4-(dimethylphosphoryl)benzene (31 mg, 0.118 mmol) and (1R,11R)-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14 To a solution of icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.107 mmol) in 1,4-dioxane (0.5 mL) and HO (0.1 mL) was added KPO (68 mg, 0.321 mmol) and Pd(dppf)Cl.CHCl (9 mg, 0.011 mmol). After stirring at 100 °C under a nitrogen atmosphere for 1 h, the resulting mixture was concentrated under reduced pressure. The resulting mixture was filtered. The filter cake was washed with MeOH (3 × 4 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CH3CN in water (10 mmol / L NH4HCO3), 20% to 60% gradient in 30 min; detector, UV 254 nm. This afforded (1R,11R)-5-[2-chloro-4-(dimethylphosphoryl)phenyl]-18-(difluoromethoxy)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (23 mg, 41%) as a white solid. MS ESI C 26 H 21 Calculated value of ClF2N3O3P [M+H] + ,528.10, actual value 527.95. 1H NMR(400MHz,chloroform-d)δ 8.47~8.41(m,1H),7.89~7.78(m,2H),7.72~7.65(m,1H),7.61(d,J=1.6Hz,1H),7.51~7.41(m,2H),7.39~7.32(m,2H),6.79(t,J =72.6Hz,1H),6.39(d,J=7.2Hz,1H),5.07(t,J=6.6Hz,1H),3.57~3.44(m,1H),2.90(d,J=13.3Hz,1H),1.82(s,3H),1.79(s,3H). 19 F NMR (377 MHz, chloroform-d) δ −80.23, −80.68, −80.99, −81.43. 31 P NMR (162 MHz, chloroform-d) δ 33.28.

[0366] Example 42: (1R,11R)-18-(difluoromethoxy)-5-{2-[(dimethylphosphoryl)methoxy]-1,3-thiazol-5-yl}-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0367] Preparation 42A: 5-Bromo-2-[(dimethylphosphoryl)methoxy]-1,3-thiazole [ka]

[0368] To a stirred solution of (dimethylphosphoryl)methanol (272 mg, 2.519 mmol) in DMF (5 mL) was added NaH (111 mg, 2.771 mmol, 60%) under a nitrogen atmosphere at 0° C. The resulting mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. To the above mixture was added 5-bromo-2-chloro-1,3-thiazole (500 mg, 2.519 mmol) at 0° C. The resulting mixture was further stirred overnight at room temperature. The resulting mixture was quenched with water and extracted with EtOAc (3×50 mL). The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (12:1) to give 5-bromo-2-[(dimethylphosphoryl)methoxy]-1,3-thiazole (135 mg, 20%) as a yellow solid. MS ESI calculated for CHBrNOPS [M+H] + , 269.93 271.93, actual value 269.95 272.00. 1 H NMR (400 MHz, chloroform-d) δ 7.07 (s, 1H), 4.74 (d, J = 5.8 Hz, 2H), 1.65 (s, 3H), 1.62 (s, 3H).

[0369] Example 42: (1R,11R)-18-(difluoromethoxy)-5-{2-[(dimethylphosphoryl)methoxy]-1,3-thiazol-5-yl}-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0370] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.107 mmol) and 5-bromo-2-[(dimethylphosphoryl)methoxy]-1,3-thiazole (24 mg, 0.089 mmol) in 1,4-dioxane (2 mL) was added Pd(dppf)Cl. 2· A solution of CH2Cl2 (7 mg, 0.009 mmol) and K3PO4 (57 mg, 0.267 mmol) in HO (0.5 mL) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (0%-15%) followed by preparative HPLC using the following conditions: Column: C18 column 120g; Mobile phase A: water (0.1% NH4HCO3), Mobile phase B: CH3CN; Flow rate: 60 mL / min; Gradient: 30B to 50B in 30 min; 254 / 220 nm to give (1R,11R)-18-(difluoromethoxy)-5-{2-[(dimethylphosphoryl)methoxy]-1,3-thiazol-5-yl}-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (15 mg, 32%) as a white solid. MS ESI C 24 H 21 Calculated value of F2N4O4PS [M+H] + , 531.10, actual value 530.95. 1H NMR (400 MHz, chloroform-d) δ 8.47–8.40 (m, 1H), 7.75–7.67 (m, 1H), 7.60–7.51 (m, 1H), 7.49–7.41 (m, 1H), 7.37–7.24 (m, 3H), 6.88 (t, J = 72.8 Hz, 1H), 6.39–6.31 (m, 1H), 4.96 (t, J = 6.6 Hz, 1H), 4.85–4.76 (m, 2H), 3.54–3.43 (m, 1H), 2.92–2.83 (m, 1H), 1.69 (s, 3H), 1.65 (s, 3H). 19 F NMR (377 MHz, chloroform-d) δ −80.18, −80.62, −80.66, −81.11. 31 P NMR (162 MHz, chloroform-d) δ 40.00.

[0371] Example 43: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3-fluorophenyl]-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0372] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.106 mmol) and 4-bromo-1-(dimethylphosphoryl)-2-fluorobenzene (22 mg, 0.088 mmol) in 1,4-dioxane (2 mL) was added Pd(dppf)Cl. 2·A solution of CH2Cl2 (7 mg, 0.009 mmol) and K3PO4 (56 mg, 0.264 mmol) in HO (0.5 mL) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (0%-15%) followed by preparative HPLC using the following conditions: Column: C18 120g; Mobile phase A: water (0.1% NH4HCO3), Mobile phase B: CH3CN; Flow rate: 60 mL / min; Gradient: 30B to 50B in 30 min; 254 / 220 nm to give (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3-fluorophenyl]-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (10 mg, 21%) as a white solid. MS ESI C 26 H 21 Calculated value of F3N3O3P [M+H] + , 512.13, actual value 512.00. 1 H NMR(400MHz,chloroform-d)δ 8.44(d,J=8.0Hz,1H),8.06~8.02(m,1H),7.81(d,J=7.9Hz,1H),7.73(s,1H),7.56~7.50(m,2H),7.47~7.42(m,1H),7.41~7.30(m ,2H),7.06~6.69(m,1H),6.41(d,J=6.7Hz,1H),5.03(s,1H),3.51(t,J=7.0Hz,1H),3.01~2.81(m,1H),1.87(s,3H),1.83(s,3H). 19 F NMR (377 MHz, chloroform-d) δ −80.41, −80.86, −80.92, −81.36, −105.79. 31 P NMR (162 MHz, chloroform-d) δ 30.56.

[0373] Example 44: (1R,11R)-18-(difluoromethoxy)-5-{4-[(dimethylphosphoryl)methoxy]phenyl}-12-ethyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0374] (1R,11R)-18-(difluoromethoxy)-12-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one(5 To a stirred solution of (200 mg, 0.101 mmol) and 1-bromo-4-[(dimethylphosphoryl)methoxy]benzene (26 mg, 0.101 mmol) in 1,4-dioxane (2 mL) and HO (0.4 mL) was added KPO (64 mg, 0.303 mmol) and Pd(dppf)Cl.CHCl (8 mg, 0.010 mmol) at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (10:1) followed by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NHHCO), gradient 20% to 50% in 30 min; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-{4-[(dimethylphosphoryl)methoxy]phenyl}-12-ethyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (15 mg, 26%) as a white solid. MS ESI C 29 H28 Calculated value of F2N3O4P [M+H] + , 552.18, actual value 552.15. 1 H NMR(400MHz,DMSO-d6)δ 8.35~8.29(m,1H),7.85~7.63(m,3H),7.61~7.53(m,2H),7.53~7.41(m,3H),7.18~7.10(m,2H),6.28(d,J=7.1Hz,1H),5.28(d,J=7.2Hz,1 H),4.36(d,J=6.7Hz,2H),3.90~3.73(m,2H),3.57~3.45(m,1H),2.78(d,J=13.6Hz,1H),1.54(s,3H),1.51(s,3H),1.35(t,J=7.0Hz,3H). 19 F NMR(377MHz,DMSO-d6)δ -81.72,-82.64. 31 P NMR(162MHz,DMSO-d6)δ 38.42.

[0375] Example 45: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3-fluorophenyl]-12-ethyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0376] (1R,11R)-18-(difluoromethoxy)-12-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one(50 To a stirred solution of 4-bromo-1-(dimethylphosphoryl)-2-fluorobenzene (25 mg, 0.101 mmol) and 4-bromo-1-(dimethylphosphoryl)-2-fluorobenzene (25 mg, 0.101 mmol) in 1,4-dioxane (2 mL) and HO (0.4 mL) was added KPO (64 mg, 0.303 mmol) and Pd(dppf)Cl.CHCl (8 mg, 0.010 mmol) at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (10:1) followed by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NHHCO), gradient 20% to 50% in 30 min; detector, 254 nm. The resulting mixture was concentrated under reduced pressure. This gave (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3-fluorophenyl]-12-ethyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (26 mg, 47%) as a white solid. MS ESI C 28 H 25 Calculated value of F3N3O3P [M+H] + , 540.16, actual value 540.10. 1H NMR(400MHz,DMSO-d6)δ 8.35~8.28(m,1H),7.89~7.80(m,1H),7.83~7.76(m,1H),7.73(d,J=8.5Hz,1H),7.71~7.46(m,6H),6.31(d,J=7.0Hz,1H),5.30( d,J=7.2Hz,1H),3.89~3.76(m,2H),3.58~3.48(m,1H),2.80(d,J=13.7Hz,1H),1.76(s,3H),1.73(s,3H),1.35(t,J=7.0Hz,3H). 19 F NMR(377MHz,DMSO-d6)δ -81.77,-82.23,-82.38,-82.83,-105.69. 31 P NMR(162MHz,DMSO-d6)δ 28.34.

[0377] Example 46: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3,5-difluorophenyl]-12-ethyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0378] (1R,11R)-18-(difluoromethoxy)-12-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (50m To a stirred solution of 5-bromo-2-(dimethylphosphoryl)-1,3-difluorobenzene (27 mg, 0.101 mmol) and 5-bromo-2-(dimethylphosphoryl)-1,3-difluorobenzene (27 mg, 0.101 mmol) in 1,4-dioxane (2 mL) and HO (0.4 mL) was added KPO (64 mg, 0.303 mmol) and Pd(dppf)Cl.CHCl (8 mg, 0.010 mmol) at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (10:1) followed by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NHHCO), gradient 20% to 50% in 30 min; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3,5-difluorophenyl]-12-ethyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (19 mg, 34%) as a white solid. MS ESI C 28 H 24 Calculated value of F4N3O3P [M+H] + , 558.15, actual value 558.10. 1H NMR(400MHz,DMSO-d6)δ 8.36~8.27(m,1H),7.92~7.69(m,3H),7.66~7.61(m,1H),7.55~7.44(m,4H),6.31(d,J=7.0Hz,1H),5.31(d,J=7.3Hz) ,1H),3.90~3.75(m,2H),3.57~3.48(m,1H),2.80(d,J=13.8Hz,1H),1.88(s,3H),1.84(s,3H),1.35(t,J=7.0Hz,3H). 19 F NMR(377MHz,DMSO-d6)δ -81.82,-82.27,-82.49,-82.95,-102.26. 31 P NMR(162MHz,DMSO-d6)δ 29.10.

[0379] Example 47: (1R,11R)-12-Cyclopropyl-18-(difluoromethoxy)-5-[6-(dimethylphosphoryl)pyridin-3-yl]-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0380] Preparation 47A: (1R,11R)-5-chloro-12-cyclopropyl-18-(difluoromethoxy)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0381] To a solution of (1R,11R)-5-chloro-18-(difluoromethoxy)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (320 mg, 0.852 mmol) and cyclopropylboronic acid (146 mg, 1.704 mmol) in toluene (10 mL) was added Na2CO3 (135 mg, 1.278 mmol) and copper(I) acetate (157 mg, 1.278 mmol) at room temperature. The mixture was purged with nitrogen for 5 minutes and then pressurized to 1-2 atmospheres with oxygen gas at 80 °C for 2 days. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give (1R,11R)-5-chloro-12-cyclopropyl-18-(difluoromethoxy)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (210 mg, 59%) as a pale yellow solid. MS ESI C 21 H 16 Calculated value for ClF2N3O2 [M+H] + , 416.09, actual value 415.90. 1 H NMR (400 MHz, chloroform-d) δ 8.39~8.33(m,1H),7.66~7.57(m,1H),7.52~7.44(m,1H),7.40(t,J=8.2Hz ,1H),7.34~7.24(m,1H),7.23~7.15(m,1H),6.81(t,J=72.7Hz,1H),6.22~6 .12(m,1H),5.25~5.16(m,1H),3.49~3.36(m,1H),3.29~3.18(m,1H),2.82( d,J=13.5Hz,1H),1.53~1.41(m,1H),1.14~1.02(m,2H),0.76~0.60(m,1H).

[0382] Preparation 47B: (1R,11R)-12-Cyclopropyl-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0383] To a solution of (1R,11R)-5-chloro-12-cyclopropyl-18-(difluoromethoxy)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (210 mg, 0.505 mmol) and BPD (192 mg, 0.758 mmol) in 1,4-dioxane (8 mL) was added potassium acetate (149 mg, 1.515 mmol), PCy3.HBF4 (28 mg, 0.076 mmol), and Pd2(dba)3 (46 mg, 0.051 mmol). After stirring at 140 °C for 16 h under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE / EA (1:1) to give (1R,11R)-12-cyclopropyl-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (250 mg, 97%) as a pale yellow oil. MS ESI C 27 H 28 Calculated value for BF2N3O4 [M+H] + , 508.21, actual value 508.15.

[0384] Example 47: (1R,11R)-12-Cyclopropyl-18-(difluoromethoxy)-5-[6-(dimethylphosphoryl)pyridin-3-yl]-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0385] (1R,11R)-12-cyclopropyl-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one( A solution of Pd(dppf)Cl.CHCl (9 mg, 0.012 mmol) in 1,4-dioxane (2 mL) and HO (0.4 mL) was stirred at 100 °C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (0% to 10%), followed by filtration under the following conditions: Column: C18 column 120 g; Mobile phase A: water (10 mmol / L) NH4HCO3), mobile phase B: CH3CN; flow rate: 60 mL / min; gradient: 30% B to 55% B in 20 min; 254 / 220 nm to give (1R,11R)-12-cyclopropyl-18-(difluoromethoxy)-5-[6-(dimethylphosphoryl)pyridin-3-yl]-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (21 mg, 33%) as a white solid. MS ESI C 28 H 25Calculated value of F2N4O3P [M+H] + , 535.16, actual value 535.15. 1 H NMR (400 MHz, chloroform-d) δ 8.95 (d, J = 2.2 Hz, 1H), 8.40–8.34 (m, 1H), 8.24–8.16 (m, 1H), 8.06–8.00 (m, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 1.7 Hz, 1H), 7.53–7.47 (m, 1H), 7.41 (t, J = 8.2 Hz, 1H), 7.33–7.28 (m, 1H), 6.83 (t, J = 72. 9Hz,1H),6.28(d,J=7.0Hz,1H),5.27(d,J=7.2Hz,1H),3.56~3.44(m,1H),3.31~3.24(m,1H),2.88(d ,J=13.5Hz,1H),1.84(s,3H),1.81(s,3H),1.57~1.48(m,1H),1.16~1.08(m,2H),0.74~0.66(m,1H). 19 F NMR (376 MHz, chloroform-d) δ −80.28, −80.72, −80.81 −81.26. 31 P NMR (162 MHz, chloroform-d) δ 36.29.

[0386] Example 48: (1R,11R)-12-Cyclopropyl-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3-fluorophenyl]-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0387] (1R,11R)-12-cyclopropyl-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (60mg) A mixture of Pd(dppf)Cl.CHCl (9 mg, 0.012 mmol) in 1,4-dioxane (2 mL) and HO (0.4 mL) was stirred at 100 °C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (0% to 10%), followed by filtration under the following conditions: Column: C18 column 120 g; Mobile phase A: water (10 mmol / L) NH4HCO3), mobile phase B: CH3CN; flow rate: 60 mL / min; gradient: 30% B to 70% B in 20 min; 254 / 220 nm to give (1R,11R)-12-cyclopropyl-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3-fluorophenyl]-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (20 mg, 30%) as a white solid. MS ESI C 29 H 25 Calculated value of F3N3O3P [M+H] + , 552.16, actual value 552.20. 1H NMR (400 MHz, chloroform-d) δ 8.39–8.34 (m, 1H), 8.08–7.98 (m, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 1.8 Hz, 1H), 7.59–7.52 (m, 1H), 7.56–7.43 (m, 1H), 7.46–7.26 (m, 3H), 6.84 (t, J = 72.9 Hz, 1H), 6.27 (d, J = 7.0Hz,1H),5.26(d,J=7.4Hz,1H),3.53~3.42(m,1H),3.31~3.22(m,1H),2.91~2.83(m, 1H), 1.86 (s, 3H), 1.82 (s, 3H), 1.59~1.43 (m, 1H), 1.16~1.06 (m, 2H), 0.73~0.66 (m, 1H). 19 F NMR (376 MHz, chloroform-d) δ −80.25, −80.70, −80.87, −81.32, −105.83. 31 P NMR (162 MHz, chloroform-d) δ 30.34.

[0388] Example 49: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)phenyl]-12-ethyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0389] Preparation 49A: 1-Bromo-4-(dimethylphosphoryl)benzene [ka]

[0390] To a stirred solution of 4-bromoiodobenzene (20.00 g, 70.695 mmol) and (methylphosphonoyl)methane (5.52 g, 70.695 mmol) in 1,4-dioxane (500 mL), Xantphos (4.09 g, 7.069 mmol), EtN (8.58 g, 84.834 mmol), and Pd(dba) (3.24 g, 3.535 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 4 hours. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (10:1) to give 1-bromo-4-(dimethylphosphoryl)benzene (14.01 g, 85%) as a yellow solid. 1 H NMR (300 MHz, chloroform-d) δ 7.63–7.50 (m, 4H), 1.71 (s, 3H), 1.67 (s, 3H).

[0391] Example 49: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)phenyl]-12-ethyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0392] (1R,11R)-18-(Difluoromethoxy)-12-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-o To a stirred solution of phenylalanine (50 mg, 0.101 mmol) and 1-bromo-4-(dimethylphosphoryl)benzene (23 mg, 0.101 mmol) in 1,4-dioxane (2 mL) and HO (0.4 mL) was added KPO (64 mg, 0.303 mmol) and Pd(dppf)Cl.CHCl (8 mg, 0.010 mmol) at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (10:1) followed by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NHHCO), gradient 20% to 50% in 30 min; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)phenyl]-12-ethyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (27 mg, 51%) as a white solid. MS ESI C 28 H 26 Calculated value of F2N3O3P [M+H] + , 522.17, actual value 522.10. 1H NMR(400MHz,DMSO-d6)δ 8.36~8.29(m,1H),7.93~7.63(m,7H),7.59~7.53(m,1H),7.52~7.45(m,2H),6.31(d,J=7.0Hz,1H),5.30(d,J=7.2Hz) ,1H),3.93~3.75(m,2H),3.58~3.47(m,1H),2.80(d,J=13.7Hz,1H),1.71(s,3H),1.68(s,3H),1.36(t,J=7.0Hz,3H). 19 F NMR(377MHz,DMSO-d6)δ -81.68,-82.13,-82.19,-82.64. 31 P NMR (162MHz, DMSO-d6)δ 32.30.

[0393] Example 50: (1R,11R)-18-(difluoromethoxy)-5-{4-[(dimethylphosphoryl)amino]phenyl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0394] Preparation 50A: 4-Bromo-N-(dimethylphosphoryl)aniline [ka]

[0395] To a solution of 4-bromoaniline (150 mg, 0.872 mmol) in THF (4 mL) was added sodium hydride (60% in oil, 38 mg) at 0 °C. The mixture was stirred for 20 min. Dimethylphosphinoyl chloride (108 mg, 0.959 mmol) was added, and the mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with water and extracted with DCM (3 × 10 mL). The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic phase was washed with brine (2 × 5 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (9 / 1) to give 4-bromo-N-(dimethylphosphoryl)aniline (37 mg, 17%) as a yellow solid. MS ESI C8H 11 Calculated value of BrNOP [M+H] + ,247.98 249.98,actual value 248.00 250.00. 1 H NMR (400 MHz, chloroform-d) δ 7.37–7.32 (m, 2H), 6.97 (d, J = 8.7 Hz, 2H), 5.17 (s, 1H), 1.70 (s, 3H), 1.66 (s, 3H).

[0396] Example 50: (1R,11R)-18-(difluoromethoxy)-5-{4-[(dimethylphosphoryl)amino]phenyl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0397] 4-Bromo-N-(dimethylphosphoryl)aniline (28 mg, 0.114 mmol) and (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14 To a solution of icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.104 mmol) in 1,4-dioxane (0.5 mL) and HO (0.1 mL) was added KPO (66 mg, 0.312 mmol) and Pd(dppf)Cl.CHCl (8 mg, 0.010 mmol). After stirring at 100 °C for 2 h under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (9 / 1), followed by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NHHCO), gradient 20% to 50% in 30 min; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-{4-[(dimethylphosphoryl)amino]phenyl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (22 mg, 38%) as a white solid. MS ESI C 27 H 25 Calculated value of F2N4O3P [M+H] + ,523.16, actual value 523.10. 1H NMR(400MHz,chloroform-d)δ 8.50~8.43(m,1H),7.72(d,J=8.5Hz,1H),7.59(d,J=1.7Hz,1H),7.49~7.3 3(m,4H),7.32~7.25(m,1H),7.17~7.11(m,2H),6.82(t,J=72.9Hz,1H),6. 22(d,J=7.2Hz,1H),5.26(d,J=9.4Hz,1H),4.97(d,J=7.1Hz,1H),3.52(s, 3H), 3.50~3.42 (m, 1H), 2.86 (d, J=13.5Hz, 1H), 1.74 (s, 3H), 1.71 (s, 3H). 19 F NMR (377 MHz, chloroform-d) δ −80.10, −80.55, −80.74, 81.19. 31 P NMR (162 MHz, chloroform-d) δ 34.53.

[0398] Example 51: (1R,11R)-5-[4-(diethylphosphoryl)-3-fluorophenyl]-18-(difluoromethoxy)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0399] Preparation 51A: 4-Bromo-1-(diethylphosphoryl)-2-fluorobenzene [ka]

[0400] To a stirred mixture of 4-bromo-2-fluoro-1-iodobenzene (1.00 g, 3.323 mmol) and (ethylphosphonoyl)ethane (0.39 g, 3.655 mmol) in 1,4-dioxane (10 mL) was added TEA (0.40 g, 3.988 mmol), Xantphos (0.19 g, 0.332 mmol), and Pd(dba) (0.15 g, 0.166 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 16 h under a nitrogen atmosphere. The mixture was basified to pH 8 with saturated NaHCO (aq). The aqueous phase was extracted with CHCl (3 × 100 mL). The combined organic phase was washed with brine (3 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (20 / 1) to give 4-bromo-1-(diethylphosphoryl)-2-fluorobenzene (778 mg, 83%) as a yellow solid. MS ESI C 10 H 13 BrFOP calculated value [M+H] + , 278.99 280.99, actual value 278.95 280.95. 1 H NMR (400 MHz, chloroform-d) δ 7.90–7.81 (m, 1H), 7.52–7.47 (m, 1H), 7.33–7.28 (m, 1H), 2.15–1.86 (m, 4H), 1.18–1.06 (m, 6H). 31 P NMR (162 MHz, chloroform-d) δ 42.44.

[0401] Example 51: (1R,11R)-5-[4-(diethylphosphoryl)-3-fluorophenyl]-18-(difluoromethoxy)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0402] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3,5,7,9,14,16,18-heptaen-13-one (50 mg, 0.107 mmol) and 4-bromo-1-(diethylphosphoryl)-2-fluorobenzene (36 mg, 0.128 mmol) in 1,4-dioxane (1 mL) and HO (0.2 mL) was added KCO (37 mg, 0.268 mmol) and Pd(dppf)Cl. 2· CHCl (9 mg, 0.011 mmol) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80°C under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (15 / 1), followed by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NHHCO), gradient 25% to 40% in 30 min; detector, 254 nm. This gave (1R,11R)-5-[4-(diethylphosphoryl)-3-fluorophenyl]-18-(difluoromethoxy)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (31 mg, 54%) as a white solid. MS ESI C 28 H 25 Calculated value of F3N3O3P [M+H] + , 540.16, actual value 540.05. 1H NMR (400 MHz, chloroform-d) δ 8.46~8.41(m,1H),8.08~8.00(m,1H),7.82(d,J=8.5Hz,1H),7.74(d,J=1.7 Hz,1H),7.59~7.50(m,2H),7.46(t,J=8.1Hz,1H),7.38(d,J=8.1Hz,1H),7.3 5~7.28(m,1H),6.88(t,J=72.7Hz,1H),6.41(d,J=7.2Hz,1H),5.03(t,J=6. 6Hz,1H),3.58~3.46(m,1H),2.90(d,J=13.3Hz,1H),2.19~1.98(m,4H),1.22 -1.10(m,6H). 19 F NMR (377 MHz, chloroform-d) δ −80.44, −80.88, −80.94, −81.39, −105.34, −105.36. 31 P NMR (162 MHz, chloroform-d) δ 42.11.

[0403] Example 52: (7R,14R)-1-(difluoromethoxy)-11-(4-(dimethylphosphoryl)-2,3-difluorophenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one [ka]

[0404] To a stirred solution of (7R,14R)-1-(difluoromethoxy)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (50 mg, 0.103 mmol) and 1-bromo-4-(dimethylphosphoryl)-2,3-difluorobenzene (42 mg, 0.154 mmol) in 1,4-dioxane (1 mL) and HO (0.2 mL) was added KCO (36 mg, 0.258 mmol) and Pd(dppf)Cl. 2·CHCl (9 mg, 0.010 mmol) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80°C for 3 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (15 / 1), followed by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NHHCO), gradient 25% to 45% in 30 minutes; detector, 254 nm. This gave (7R,14R)-1-(difluoromethoxy)-11-(4-(dimethylphosphoryl)-2,3-difluorophenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (21 mg, 37%) as a white solid. MS ESI C 27 H 19 Calculated value of D3F4N3O3P [M+H] + , 547.15, Actual value 547.15. 1 H NMR (400 MHz, chloroform-d) δ 8.53–8.46 (m, 1H), 7.86–7.71 (m, 3H), 7.49–7.36 (m, 3H), 7.35–7.29 (m, 1H), 7.03–6.62 (m, 1H), 6.31 (d, J = 6.9 Hz, 1H), 5.02 (d, J = 6.8 Hz, 1H), 3.55–3.44 (m, 1H), 2.91 (d, J = 13.4 Hz, 1H), 1.89 (s, 3H), 1.85 (s, 3H). 19 F NMR (377 MHz, chloroform-d) δ −80.11, −80.56, −81.00, −81.45, −131.22, −131.23, −131.28, −131.29, −143.47, −143.48, −143.53, −143.54. 31 P NMR (162 MHz, chloroform-d) δ 29.78.

[0405] Example 53: (7R,14R)-1-(difluoromethoxy)-11-(4-(dimethylphosphoryl)-2-fluorophenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one [ka]

[0406] To a stirred solution of (7R,14R)-1-(difluoromethoxy)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (50 mg, 0.103 mmol) and 1-bromo-4-(dimethylphosphoryl)-2-fluorobenzene (39 mg, 0.154 mmol) in 1,4-dioxane (1 mL) and HO (0.2 mL) was added KCO (36 mg, 0.258 mmol) and Pd(dppf)Cl. 2· CHCl (9 mg, 0.010 mmol) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80°C for 3 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (15 / 1), followed by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NHHCO), gradient 25% to 45% in 30 minutes; detector, 254 nm. This gave (7R,14R)-1-(difluoromethoxy)-11-(4-(dimethylphosphoryl)-2-fluorophenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (28 mg, 51%) as a white solid. MS ESI C 27 H 20 Calculated value of D3F3N3O3P [M+H] +, 529.16, actual value 529.10. 1 H NMR (400 MHz, chloroform-d) δ 8.51–8.47 (m, 1H), 7.84–7.78 (m, 1H), 7.74 (d, J = 1.8 Hz, 1H), 7.64–7.50 (m, 3H), 7.49–7.38 (m, 2H), 7.34–7.27 (m, 1H), 6.81 (t, J = 73.5 Hz, 1H), 6.30 (d, J = 7.2 Hz, 1H), 5.01 (d, J = 7.1 Hz, 1H), 3.55–3.48 (m, 1H), 2.90 (d, J = 13.5 Hz, 1H), 1.81 (s, 3H), 1.78 (s, 3H). 19 F NMR (377 MHz, chloroform-d) δ −79.92, −80.37, −81.12, −81.56, −116.61, −116.62, −116.63. 31 P NMR (162 MHz, chloroform-d) δ 32.93.

[0407] Example 54: (7R,14R)-1-(difluoromethoxy)-11-(4-(dimethylphosphoryl)-2,5-difluorophenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one [ka]

[0408] Preparation 54A: 1-Bromo-4-(dimethylphosphoryl)-2,5-difluorobenzene [ka]

[0409] To a stirred mixture of 1-bromo-2,5-difluoro-4-iodobenzene (1.00 g, 3.136 mmol) and (methylphosphonoyl)methane (0.27 g, 3.450 mmol) in 1,4-dioxane (10 mL), KPO (0.80 g, 3.763 mmol), Xantphos (0.18 g, 0.314 mmol), and Pd(dba) (0.14 g, 0.157 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 16 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (15 / 1) to give 1-bromo-4-(dimethylphosphoryl)-2,5-difluorobenzene (550 mg, 65%) as a brown solid. MS ESI Calculated for C8H8BrF2OP [M+H] + , 268.95 270.94, actual value 268.90 270.90. 1 H NMR (300 MHz, chloroform-d) δ 7.84–7.67 (m, 1H), 7.44–7.33 (m, 1H), 1.84 (d, J = 1.2 Hz, 3H), 1.80 (d, J = 1.2 Hz, 3H). 31 P NMR (121 MHz, chloroform-d) δ 29.75.

[0410] Example 54: (7R,14R)-1-(difluoromethoxy)-11-(4-(dimethylphosphoryl)-2,5-difluorophenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one [ka]

[0411] To a stirred solution of (7R,14R)-1-(difluoromethoxy)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (50 mg, 0.103 mmol) and 1-bromo-4-(dimethylphosphoryl)-2,5-difluorobenzene (42 mg, 0.154 mmol) in 1,4-dioxane (1 mL) and HO (0.2 mL) was added KCO (35.67 mg, 0.258 mmol) and Pd(dppf)Cl. 2· CHCl (9 mg, 0.010 mmol) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80°C for 3 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (15 / 1), followed by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NHHCO), gradient 25% to 40% in 30 min; detector, 254 nm. This gave (7R,14R)-1-(difluoromethoxy)-11-(4-(dimethylphosphoryl)-2,5-difluorophenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (20 mg, 35%) as a white solid. MS ESI C 27 H 19 Calculated value of D3F4N3O3P [M+H] + , 547.15, actual value 547.10. 1H NMR (400 MHz, chloroform-d) δ 8.52–8.46 (m, 1H), 7.87–7.69 (m, 3H), 7.48–7.39 (m, 2H), 7.32 (d, J = 8.1 Hz, 1H), 7.25–7.18 (m, 1H), 6.83 (t, J = 72.1 Hz, 1H), 6.31 (d, J = 7.2 Hz, 1H), 5.03 (d, J = 7.1 Hz, 1H), 3.55–3.45 (m, 1H), 2.91 (d, J = 13.6 Hz, 1H), 1.86 (s, 3H), 1.83 (s, 3H). 19 F NMR (377 MHz, chloroform-d) δ −80.04, −80.48, −81.26, −81.70, −111.88, −111.89, −111.93, −111.95, −122.27, −122.32. 31 P NMR (162 MHz, chloroform-d) δ 29.76.

[0412] Example 55: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2,3-difluorophenyl]-6-fluoro-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0413] Preparation 55A Ethyl (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-[(5-chloro-4-fluoro-2-nitrophenyl)amino]propanoate [ka]

[0414] To a stirred solution of ethyl (3R)-3-amino-3-[2-bromo-6-(difluoromethoxy)phenyl]propanoate hydrochloride (30.00 g, 80.084 mmol) and 1-chloro-2,5-difluoro-4-nitrobenzene (15.50 g, 80.084 mmol) in ACN (300 mL) was added K2CO3 (33.20 g, 240.252 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h. The resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with EtOAc (3 × 800 mL). The combined organic phase was washed with brine (1 × 800 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give ethyl (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-[(5-chloro-4-fluoro-2-nitrophenyl)amino]propanoate (30.00 g, 73%) as a yellow oil. MS ESI C 18 H 15 Calculated value for BrClF3N2O5 [M+H] + , 510.98 512.98, actual values ​​511.00 513.00. 1 H NMR (400 MHz, chloroform-d) δ 8.78–8.74 (m, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.48–7.44 (m, 1H), 7.21–7.14 (m, 2H), 6.65 (t, J = 72.2 Hz, 1H), 5.83–5.77 (m, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.27–3.20 (m, 1H), 2.94–2.89 (m, 1H), 1.23 (t, J = 7.1 Hz, 3H).

[0415] Preparation 55B: (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-[(5-chloro-4-fluoro-2-nitrophenyl)amino]propanal [ka]

[0416] To a stirred solution of ethyl (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-[(5-chloro-4-fluoro-2-nitrophenyl)amino]propanoate (29.00 g, 56.676 mmol) in DCM (300 mL) was added dropwise a 1.5 N solution of DIBAL-H (45 mL, 68.011 mmol) in toluene at −78° C. under a nitrogen atmosphere. The resulting mixture was stirred at −78° C. for 2 hours under a nitrogen atmosphere. The reaction was then quenched by the addition of saturated NH4Cl(aq) (50 mL) at −78° C. The mixture was allowed to warm to room temperature. The resulting mixture was filtered, and the filter cake was washed with DCM (3×100 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3×500 mL). The combined organic phase was washed with brine (1 x 500 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (6:1) to give (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-[(5-chloro-4-fluoro-2-nitrophenyl)amino]propanal (16.10 g, 60%) as a yellow solid. MS ESI C 16 H 11 Calculated value for BrClF3N2O4 [M+H] + , 466.95 468.95, actual values ​​467.00 469.00. 1 H NMR (400 MHz, chloroform-d) δ 9.81 (s, 1H), 8.68 (d, J = 9.1 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.50–7.43 (m, 1H), 7.22–7.15 (m, 3H), 6.67 (t, J = 72.2 Hz, 1H), 5.93–5.87 (m, 1H), 3.54–3.47 (m, 1H), 3.09–3.04 (m, 1H).

[0417] Preparation 55C: (4R)-4-[2-bromo-6-(difluoromethoxy)phenyl]-4-[(5-chloro-4-fluoro-2-nitrophenyl)amino]-2-[(trimethylsilyl)oxy]butanenitrile [ka]

[0418] To a stirred solution of (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-[(5-chloro-4-fluoro-2-nitrophenyl)amino]propanal (15.00 g, 32.077 mmol) in DCM (150 mL) was added ZnI (1.02 g, 3.208 mmol), TEA (324 mg, 3.208 mmol), and TMSCN (6.36 g, 64.154 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic phase was washed with brine (1 × 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was used directly in the next step without further purification. MS ESI C 20 H 20 Calculated value for BrClF3N3O4Si [M+H] + , 566.00 568.00, Actual values ​​566.10 568.10.

[0419] Preparation 55D: (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-11-chloro-10-fluoro-2,7-diazatricyclo[6.4.0.0^{2,6}]dodeca-1(8),6,9,11-tetraen-5-ol [ka]

[0420] To a stirred solution of (4R)-4-[2-bromo-6-(difluoromethoxy)phenyl]-4-[(5-chloro-4-fluoro-2-nitrophenyl)amino]-2-[(trimethylsilyl)oxy]butanenitrile (19.00 g, 33.520 mmol) in EtOH (150 mL) was added SnCl (32.12 g, 167.600 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with water (100 mL). The mixture was basified to pH 8 with KOH (1 N). The resulting mixture was diluted with EtOAc (500 mL). The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (10:1) to give (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-11-chloro-10-fluoro-2,7-diazatricyclo[6.4.0.0^{2,6}]dodeca-1(8),6,9,11-tetraen-5-ol (14.02 g, 93%) as a yellow solid. MS ESI C 17 H 11 Calculated value for BrClF3N2O2 [M+H] + 446.96 448.96, actual values ​​447.00 449.00.

[0421] Preparation 55E: (3R,5S)-3-[2-bromo-6-(difluoromethoxy)phenyl]-11-chloro-10-fluoro-2,7-diazatricyclo[6.4.0.0^{2,6}]dodeca-1(8),6,9,11-tetraen-5-ol [ka]

[0422] A mixture of (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-11-chloro-10-fluoro-2,7-diazatricyclo[6.4.0.0^{2,6}]dodeca-1(8),6,9,11-tetraen-5-ol (14 g, 31.275 mmol) was purified using the following conditions: Column: XB-C18 Purification by HPLC using a 101 x 650 mm, 10 μm column; mobile phase A: water (0.1% TFA), mobile phase B: ACN; flow rate: 350 mL / min; gradient: 30% B to 50% B in 40 min; 254 / 220 nm yielded (3R,5S)-3-[2-bromo-6-(difluoromethoxy)phenyl]-11-chloro-10-fluoro-2,7-diazatricyclo[6.4.0.0^{2,6}]dodeca-1(8),6,9,11-tetraen-5-ol (8.10 g, 57%) as a yellow solid. 17 H 11 BrClF3N2O2[M+H] + , 446.96 448.96, actual values ​​447.00 449.00. 1 H NMR (400 MHz, chloroform-d) δ 7.66–7.47 (m, 2H), 7.43–7.34 (m, 1H), 7.05–5.99 (m, 4H), 5.85–5.77 (m, 1H), 3.41–3.18 (m, 2H).

[0423] Preparation 55F: (3R,5R)-5-Azido-3-[2-bromo-6-(difluoromethoxy)phenyl]-11-chloro-10-fluoro-2,7-diazatricyclo[6.4.0.0^{2,6}]dodeca-1(8),6,9,11-tetraene [ka]

[0424] To a stirred solution of (3R,5S)-3-[2-bromo-6-(difluoromethoxy)phenyl]-11-chloro-10-fluoro-2,7-diazatricyclo[6.4.0.0^{2,6}]dodeca-1(8),6,9,11-tetraen-5-ol (6.01 g, 13.404 mmol) and DPPA (4.43 g, 16.085 mmol) in THF (20 mL) was added DBU (10.20 g, 67.020 mmol) at 0 °C. The resulting mixture was stirred at 30 °C for 24 h. The resulting mixture was diluted with EtOAc (50 mL) and HO (100 mL). The resulting mixture was extracted with EtOAc (2 × 50 mL). The combined organic phase was washed with saturated NH4Cl (1 x 100 mL) and saturated NaHCO3 (1 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. MS ESI C 17 H 10 Calculated value for BrClF3N5O [M+H] + , 471.97 473.97, actual values ​​471.95 473.95.

[0425] Preparation 55G: (3R,5R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-11-chloro-10-fluoro-2,7-diazatricyclo[6.4.0.0^{2,6}]dodeca-1(8),6,9,11-tetraen-5-amine [ka]

[0426] To a stirred solution of (3R,5R)-5-azido-3-[2-bromo-6-(difluoromethoxy)phenyl]-11-chloro-10-fluoro-2,7-diazatricyclo[6.4.0.0^{2,6}]dodeca-1(8),6,9,11-tetraene (10 g, crude) in THF (100 mL) and HO (10 mL) was added PPh (4.00 g, 15.250 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (10:1) to give (3R,5R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-11-chloro-10-fluoro-2,7-diazatricyclo[6.4.0.0^{2,6}]dodeca-1(8),6,9,11-tetraen-5-amine (5.02 g) as a black oil. MS ESI C 17 H 12 Calculated value for BrClF3N3O [M+H] + , 445.98 447.98, actual values ​​446.00 448.00.

[0427] Preparation 55H: (1R,11R)-5-chloro-18-(difluoromethoxy)-6-fluoro-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0428] To a solution of (3R,5R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-11-chloro-10-fluoro-2,7-diazatricyclo[6.4.0.0^{2,6}]dodeca-1(8),6,9,11-tetraen-5-amine (2.00 g, 4.478 mmol) in 1,4-dioxane (20 mL) was added K2CO3 (3.09 g, 22.390 mmol), Xantphos (129 mg, 0.224 mmol), and Pd(OAc)2 (50 mg, 0.224 mmol) in a pressure tank. The mixture was purged with nitrogen for 2 minutes and then pressurized to 1 atmosphere with carbon monoxide at 100 °C for 16 hours. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (10:1) to give (1R,11R)-5-chloro-18-(difluoromethoxy)-6-fluoro-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (0.70 g, 39%) as a brown solid. MS ESI C 18 H 11 Calculated value for ClF3N3O2 [M+H] + , 394.05 396.05, actual value 394.00 396.00. 1 H NMR (400 MHz, chloroform-d) δ 8.44–8.42 (m, 1H), 7.66 (d, J = 6.6 Hz, 1H), 7.51–7.38 (m, 4H), 6.85 (t, J = 72.6 Hz, 1H), 6.29–6.27 (m, 1H), 4.97–4.93 (m, 1H), 3.50–3.43 (m, 1H), 2.87–2.83 (m, 1H).

[0429] Preparation 55I: (1R,11R)-5-chloro-18-(difluoromethoxy)-6-fluoro-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0430] To a stirred solution of (1R,11R)-5-chloro-18-(difluoromethoxy)-6-fluoro-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (300 mg, 0.762 mmol) in anhydrous THF (3 mL) was added dropwise a solution of 1 N KHMDS (0.91 mL, 0.914 mmol) in THF at −78°C under a nitrogen atmosphere. The resulting mixture was stirred at −78°C for 1 hour under a nitrogen atmosphere. To the above mixture was added dropwise CHI (162 mg, 1.143 mmol) at −78°C. The resulting mixture was stirred for an additional 16 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (10:1) to give (1R,11R)-5-chloro-18-(difluoromethoxy)-6-fluoro-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (220 mg, 70%) as a yellow solid. MS ESI C 19 H 13 Calculated value for ClF3N3O2 [M+H] + , 408.06 410.06, actual value 408.05 410.05. 1 H NMR (400 MHz, chloroform-d) δ 8.52–8.44 (m, 1H), 7.50–7.42 (m, 3H), 7.34 (d, J = 8.2 Hz, 1H), 6.84 (t, J = 72.7 Hz, 1H), 6.20–6.18 (m, 1H), 4.96–4.94 (m, 1H), 3.50–3.41 (m, 4H), 2.88–2.85 (m, 1H).

[0431] Preparation 55J: (1R,11R)-18-(difluoromethoxy)-6-fluoro-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0432] To a stirred solution of (1R,11R)-5-chloro-18-(difluoromethoxy)-6-fluoro-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (210 mg, 0.515 mmol), KOAc (152 mg, 1.545 mmol), and BPD (196 mg, 0.772 mmol) in 1,4-dioxane (5 mL), PCy3.HBF4 (19 mg, 0.052 mmol) and Pd2(dba)3 (47 mg, 0.052 mmol) were added under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 140°C under a nitrogen atmosphere for 16 hours. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (10:1) to give (1R,11R)-18-(difluoromethoxy)-6-fluoro-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (210 mg, 81%) as a yellow solid. MS ESI C 25 H 25 Calculated value for BF3N3O4 [M+H] + , 500.19, actual value 500.30.

[0433] Example 55: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2,3-difluorophenyl]-6-fluoro-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0434] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-6-fluoro-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (70 mg, 0.140 mmol) and 1-bromo-4-(dimethylphosphoryl)-2,3-difluorobenzene (38 mg, 0.140 mmol) in 1,4-dioxane (2 mL) was added a solution of K3PO4 (89 mg, 0.420 mmol) in HO (0.5 mL) under a nitrogen atmosphere at room temperature. To the above mixture, Pd(dppf)Cl.CHCl (11 mg, 0.014 mmol) was added at room temperature. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (10:1), followed by reverse-phase flash chromatography using the following conditions: Column: C18 column 120 g; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 50 mL / min; Gradient: 25% B to 50% B in 25 min; 254 / 220 nm to give a white solid. (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2,3-difluorophenyl]-6-fluoro-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (35 mg, 44%) was obtained. MS ESI C 27 H 21 Calculated value of F5N3O3P [M+H] + , 562.12, actual value 562.20. 1H NMR(400MHz,chloroform-d)δ 8.50(d,J=8.2Hz,1H),7.82~7.75(m,1H),7.53(d,J=10.4Hz,1H),7.48(d,J=6.3Hz,1H),7.44(t,J=8.2Hz,1H),7.34~7.30(m,2H) ),6.79(t,J=72.8Hz,1H),6.26~6.24(m,1H),4.99~4.97(m,1H),3.52~3.44(m,4H),2.91~2.87(m,1H),1.89(s,3H),1.86(s,3H). 19 F NMR (377 MHz, chloroform-d) δ −80.33, −80.78, −80.89, −81.34, −120.15, −120.20, −131.22, −131.23, −131.28, −131.29, −139.01, −139.02, −139.06, −139.07, −139.08, −139.12, −139.14. 31 P NMR (162 MHz, chloroform-d) δ 29.90.

[0435] Example 56: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2,5-difluorophenyl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0436] (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one(50 To a solution of 1-bromo-4-(dimethylphosphoryl)-2,5-difluorobenzene (28 mg, 0.104 mmol) and 1-bromo-4-(dimethylphosphoryl)-2,5-difluorobenzene (28 mg, 0.104 mmol) in 1,4-dioxane (0.5 mL) and HO (0.1 mL) was added KPO (66 mg, 0.312 mmol) and Pd(dppf)Cl.CHCl (8 mg, 0.010 mmol). After stirring at 80 °C for 2 h under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The resulting mixture was filtered. The filter cake was washed with MeOH (3 × 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NHHCO), gradient 20% to 50% in 30 min; detector, UV 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2,5-difluorophenyl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (34 mg, 59%) as a white solid. MS ESI C 27 H 22 Calculated value of F4N3O3P [M+H] + ,544.13, actual value 544.05. 1H NMR(300MHz,chloroform-d)δ 8.56~8.47(m,1H),7.90~7.73(m,3H),7.52~7.40(m,2H),7.34(d,J=8.2Hz,1H),7.26~7.20(m,1H),7.14~6.58(m,1 H),6.35(d,J=6.1Hz,1H),5.13~5.04(m,1H),3.62~3.45(m,4H),2.94(d,J=13.2Hz,1H),1.89(s,3H),1.85(s,3H). 19 F NMR (282 MHz, chloroform-d) δ −79.97, −80.57, −81.21, −81.81, −111.82, −111.83, −111.88, −111.90, −122.26, −122.33. 31 P NMR (121 MHz, chloroform-d) δ 29.66.

[0437] Example 57: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3-fluorophenyl]-6-fluoro-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0438] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-6-fluoro-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (70 mg, 0.140 mmol) and 4-bromo-1-(dimethylphosphoryl)-2-fluorobenzene (35 mg, 0.140 mmol) in 1,4-dioxane (2 mL) was added a solution of K3PO4 (89 mg, 0.420 mmol) in HO (0.5 mL) under a nitrogen atmosphere at room temperature. The above solution was added with Pd(dppf)Cl at room temperature under a nitrogen atmosphere. 2· CH2Cl2 (11 mg, 0.014 mmol) was added. The resulting mixture was stirred at 80 °C for an additional 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (0% to 10%) followed by preparative HPLC using the following conditions: Column: C18 120g; Mobile phase A: water (0.1% FA), Mobile phase B: CH3CN; Flow rate: 50 mL / min; Gradient: 20B to 40B in 40 min; 254 / 220 nm to give (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3-fluorophenyl]-6-fluoro-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (18 mg, 23%) as a white solid. MS ESI C 27 H 22 Calculated value of F4N3O3P [M+H] + , 544.13, actual value 544.00. 1H NMR (400 MHz, chloroform-d) δ 8.53–8.47 (m, 1H), 8.07–8.01 (m, 1H), 7.56–7.31 (m, 6H), 6.83 (t, J = 73.3 Hz, 1H), 6.29–6.25 (m, 1H), 5.04–4.98 (m, 1H), 3.56–3.47 (m, 4H), 2.93–2.87 (m, 1H), 1.88–1.79 (m, 6H). 19 F NMR (377 MHz, chloroform-d) δ −80.81, −80.90, −106.04, −122.36. 31 P NMR (162 MHz, chloroform-d) δ 30.70.

[0439] Example 58: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2-fluorophenyl]-6-fluoro-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0440] To a stirred solution of (1R,11R)-18-(difluoromethoxy)-6-fluoro-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (70 mg, 0.140 mmol) and 1-bromo-4-(dimethylphosphoryl)-2-fluorobenzene (35 mg, 0.140 mmol) in 1,4-dioxane (2 mL) was added a solution of K3PO4 (89 mg, 0.420 mmol) in HO (0.5 mL) at room temperature under a nitrogen atmosphere. The above solution was added with Pd(dppf)Cl at room temperature under a nitrogen atmosphere. 2·CH2Cl2 (11 mg, 0.014 mmol) was added. The resulting mixture was stirred at 80 °C for an additional 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (0%-10%), followed by preparative HPLC using the following conditions: Column: C18 120g; Mobile phase A: water (0.1% FA), Mobile phase B: CH3CN; Flow rate: 50 mL / min; Gradient: 20B to 40B in 40 min; 254 / 220 nm to give (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2-fluorophenyl]-6-fluoro-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (30 mg, 39%) as a white solid. MS ESI C 27 H 22 Calculated value of F4N3O3P [M+H] + , 544.13, Actual value 544.20. 1 H NMR (400 MHz, chloroform-d) δ 8.52–8.48 (m, 1H), 7.58–7.28 (m, 7H), 6.78 (t, J = 73.0 Hz, 1H), 6.27–6.23 (m, 1H), 5.00–4.96 (m, 1H), 3.55–3.44 (m, 4H), 2.91–2.85 (m, 1H), 1.83–1.78 (m, 6H). 19 F NMR (377 MHz, chloroform-d) δ −80.19, −80.64, −81.04, −81.49, −113.44, −113.48, −120.55, −120.59. 31 P NMR (162 MHz, chloroform-d) δ 33.69.

[0441] Example 59: (7R,14R)-1-(difluoromethoxy)-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-10-fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one [ka]

[0442] Preparation 59A: (7R,14R)-11-chloro-1-(difluoromethoxy)-10-fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one [ka]

[0443] To a stirred solution of (1R,11R)-5-chloro-18-(difluoromethoxy)-6-fluoro-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (400 mg, 1.016 mmol) in anhydrous THF (10 mL) was added dropwise a solution of 1 N KHMDS (1.22 mL, 1.219 mmol) in THF at −78°C under a nitrogen atmosphere. The resulting solution was stirred at −78°C for 1 h under a nitrogen atmosphere. To the above solution, CD3I (295 mg, 2.032 mmol) was added dropwise over 2 min at −78°C. The resulting mixture was allowed to warm slowly to room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The reaction was then quenched by adding saturated NH4Cl (aq) (5 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl2 / MeOH (10 / 1) to give (7R,14R)-11-chloro-1-(difluoromethoxy)-10-fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (380 mg, 91%) as an off-white solid. MS ESI C 19 H 10 Calculated value for D3ClF3N3O2 [M+H] + , 411.08, actual value 410.90.1 H NMR (400 MHz, chloroform-d) δ 8.50 (d, J = 8.2 Hz, 1H), 7.53–7.42 (m, 3H), 7.37–7.31 (m, 1H), 6.84 (t, J = 72.7 Hz, 1H), 6.21 (d, J = 7.2 Hz, 1H), 4.97 (d, J = 7.2 Hz, 1H), 3.51–3.41 (m, 1H), 2.87 (d, J = 13.6 Hz, 1H). 19 F NMR (376 MHz, chloroform-d) δ −80.21, −80.65, −80.99, −81.43, −120.18.

[0444] Preparation 59B: (7R,14R)-1-(difluoromethoxy)-10-fluoro-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one [ka]

[0445] To a stirred mixture of (7R,14R)-11-chloro-1-(difluoromethoxy)-10-fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (380 mg, 0.925 mmol), KOAc (272 mg, 2.775 mmol), and BPD (470 mg, 1.850 mmol) in 1,4-dioxane (10 mL) was added PCy. 3·HBF (51 mg, 0.139 mmol) and Pd(dba) (85 mg, 0.093 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 140 °C for 16 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / EtOH / PE (3 / 1 / 6) to give (7R,14R)-1-(difluoromethoxy)-10-fluoro-6-(methyl-d)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (370 mg, 80%) as an off-white solid. MS ESI C 25 H 22 Calculated value for D3BF3N3O4 [M+H] + , 503.21, actual value 503.30.

[0446] Example 59: (7R,14R)-1-(difluoromethoxy)-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-10-fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one [ka]

[0447] To a stirred solution of (7R,14R)-1-(difluoromethoxy)-10-fluoro-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (60 mg, 0.119 mmol) and 4-bromo-1-(dimethylphosphoryl)-2-fluorobenzene (45 mg, 0.178 mmol) in 1,4-dioxane (1 mL) and HO (0.2 mL) was added KCO (41 mg, 0.297 mmol) and Pd(dppf)Cl. 2·CHCl (10 mg, 0.012 mmol) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80°C under a nitrogen atmosphere for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (15 / 1), followed by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NHHCO), gradient 25% to 40% in 30 minutes; detector, 254 nm. This gave (7R,14R)-1-(difluoromethoxy)-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-10-fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (22 mg, 34%) as a white solid. MS ESI C 27 H 19 Calculated value of D3F4N3O3P [M+H] + , 547.15, actual value 547.00. 1 H NMR(400MHz,chloroform-d)δ 8.53~8.46(m,1H),8.10~8.01(m,1H),7.60~7.50(m,2H),7.50~7.41(m,2H),7.37~7.29(m,2H),6.83(t,J=72.8Hz,1H ),6.29(d,J=7.0Hz,1H),5.05(d,J=7.0Hz,1H),3.57~3.45(m,1H),2.91(d,J=13.6Hz,1H),1.87(s,3H),1.83(s,3H). 19 F NMR (377 MHz, chloroform-d) δ −80.37, −80.82, −80.95, −81.39, −105.97, −105.98, −121.63. 31 P NMR (162 MHz, chloroform-d) δ 30.43.

[0448] Example 60: (7R,14R)-1-(difluoromethoxy)-11-(4-(dimethylphosphoryl)-3,5-difluorophenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one [ka]

[0449] (7R,14R)-1-(difluoromethoxy)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (50 mg, 0.103 mmol), 5-bromo-2-(dimethylphosphoryl)-1,3-difluorobenzene (36 mg, 0.134 mmol), K2CO3 (43 mg, 0.309 mmol), and Pd(dppf)Cl 2· A mixture of CHCl (8 mg, 0.010 mmol) in 1,4-dioxane (1 mL) and HO (0.2 mL) was stirred at 80°C for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (8:1), followed by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NHHCO), gradient 20% to 50% in 30 minutes; detector, 254 nm. This gave (7R,14R)-1-(difluoromethoxy)-11-(4-(dimethylphosphoryl)-3,5-difluorophenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (30 mg, 53%) as a white solid. MS ESI C 27 H 19 Calculated value of D3F4N3O3P [M+H] + , 547.15, actual value 547.00. 1H NMR(400MHz,chloroform-d)δ 8.52~8.47(m,1H),7.81(d,J=8.5Hz,1H),7.72(d,J=1.8Hz,1H),7.51~7.40(m,2H),7.36~7.29(m,1H),7.24~7.15(m,2H),6.88(t, J=72.9Hz,1H),6.31(d,J=7.2Hz,1H),5.02(d,J=7.1Hz,1H),3.55~3.45(m,1H),2.92(d,J=13.6Hz,1H),1.98(s,3H),1.94(s,3H). 19 F NMR (377 MHz, chloroform-d) δ −80.37, −80.82, −80.88, −81.32, −101.77. 31 P NMR (162 MHz, chloroform-d) δ 30.79.

[0450] Example 61: (7R,14R)-1-(difluoromethoxy)-11-(4-(dimethylphosphoryl)-2-fluorophenyl)-10-fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one [ka]

[0451] To a stirred solution of (7R,14R)-1-(difluoromethoxy)-10-fluoro-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (60 mg, 0.119 mmol) and 1-bromo-4-(dimethylphosphoryl)-2-fluorobenzene (45 mg, 0.178 mmol) in 1,4-dioxane (1 mL) and HO (0.2 mL) was added KCO (41 mg, 0.297 mmol) and Pd(dppf)Cl. 2·CHCl (10 mg, 0.012 mmol) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80°C under a nitrogen atmosphere for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (15 / 1), followed by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NHHCO), gradient 25% to 40% in 30 minutes; detector, 254 nm. This gave (7R,14R)-1-(difluoromethoxy)-11-(4-(dimethylphosphoryl)-2-fluorophenyl)-10-fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (21 mg, 32%) as a white solid. MS ESI C 27 H 19 Calculated value of D3F4N3O3P [M+H] + , 547.15, actual value 547.05. 1 H NMR (400 MHz, chloroform-d) δ 8.54–8.48 (m, 1H), 7.64–7.49 (m, 5H), 7.45 (t, J = 8.2 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 6.79 (t, J = 72.7 Hz, 1H), 6.30 (d, J = 7.1 Hz, 1H), 5.09 (d, J = 7.0 Hz, 1H), 3.58–3.47 (m, 1H), 2.91 (d, J = 13.5 Hz, 1H), 1.82 (s, 3H), 1.79 (s, 3H). 19 F NMR (377 MHz, chloroform-d) δ −80.29, −80.73, −81.04, −81.49, −113.52, −113.53, −113.56, −113.57, −118.96. 31 P NMR (162 MHz, chloroform-d) δ 32.98.

[0452] Example 62: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2,6-difluorophenyl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0453] Preparation 62A: 2-Bromo-5-(dimethylphosphoryl)-1,3-difluorobenzene [ka]

[0454] A mixture of 2-bromo-1,3-difluoro-5-iodobenzene (1.00 g, 3.136 mmol), (methylphosphonoyl)methane (367 mg, 4.704 mmol), Pd(dba) (143 mg, 0.157 mmol), Xantphos (181 mg, 0.314 mmol), and TEA (476 mg, 4.704 mmol) in 1,4-dioxane (10 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (12 / 1) to give 2-bromo-5-(dimethylphosphoryl)-1,3-difluorobenzene (500 mg, 59%) as a white solid. MS ESI calculated for CHBrFOP [M+H] + , 268.95,270.95,Actual values ​​268.80,270.80. 1 H NMR (300MHz, DMSO-d6) δ 7.70~7.60 (m, 2H), 1.73 (s, 3H), 1.69 (s, 3H).

[0455] Example 62: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2,6-difluorophenyl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one [ka]

[0456] 2-Bromo-5-(dimethylphosphoryl)-1,3-difluorobenzene (40 mg, 0.150 mmol), (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (60 mg, 0.125 mmol), K3PO4 (79 mg, 0.375 mmol), and Pd(dppf)Cl 2· A mixture of CHCl (10 mg, 0.013 mmol) in 1,4-dioxane (1 mL) and HO (0.2 mL) was stirred at 80°C for 16 hours under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (0% to 10%), followed by elution under the following conditions: Column: C18 column 120 g; Mobile phase A: water (10 mmol / L) NH4HCO3), mobile phase B: CH3CN; flow rate: 60 mL / min; gradient: 30% B to 70% B in 20 min; 254 / 220 nm to give (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2,6-difluorophenyl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or N-oxide thereof: 【Chemistry 421】 During the ceremony, In ring A, * represents the attachment point to L. 【Chemistry 422】 or an optionally substituted heteroarylene selected from pyrazolene, imidazoline, oxazolene or thiazolene; V is N or C-R １１ and W is N or C-R ５ and X is N or C-R ６ and Y is N or C-R ７ and Z is N or C-R ８ and L is a bond, —NH—, —(CH ２ )n-, -C(R １２ ) (R １３ ) -, -O(CH ２ )n-*, or -NH(CH ２ )n-*, where * represents the point of attachment to phosphorus; n is 1, 2, or 3; R １ is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl; R ２ is hydrogen or optionally substituted C1-C3 alkyl; R ３ is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl; R ４ is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl, or R ３ and R ４ are joined to form an optionally substituted phosphorus-containing 3- to 8-membered ring; R ５ , R ６ , R ７ and R ８ are each independently hydrogen, halogen, —CN, or —NH ２ , optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, or —NH(optionally substituted C1-C3 alkyl); R ９ is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; R １０ is selected from hydrogen or halogen; R １１ is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; and R １２ and R １３ are independently hydrogen, —OH, F, and CH ３ or a pharmaceutically acceptable salt, solvate or N-oxide thereof.

2. A compound of formula (Ia), or a pharmaceutically acceptable salt, solvate or N-oxide thereof: 【Chemistry 423】 During the ceremony, In ring A, * represents the attachment point to L. 【Chemistry 424】 or an optionally substituted heteroarylene selected from pyrazolene, imidazoline, oxazolene or thiazolene; V is N or C-R １１ and W is N or C-R ５ and X is N or C-R ６ and Y is N or C-R ７ and Z is N or C-R ８ and L is a bond, —NH—, —(CH ２ )n-, -O(CH ２ )n-*, or -NH(CH ２ )n-*, where * represents the point of attachment to phosphorus; n is 1, 2, or 3; R １ is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl; R ２ is hydrogen or optionally substituted C1-C3 alkyl; R ３ is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl; R ４ is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl, or R ３ and R ４ are joined to form an optionally substituted phosphorus-containing 3- to 8-membered ring; R ５ , R ６ , R ７ , and R ８ are each independently selected from hydrogen, halogen, —CN, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, or —NH(optionally substituted C1-C3 alkyl); R ９ is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; R １０ is selected from hydrogen or halogen, and R １１ is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl, or a pharmaceutically acceptable salt, solvate, or N-oxide thereof.

3. Ring A is 【Chemical 425】 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, selected from: wherein * represents the point of attachment to L.

4. 4. The compound of claim 3, or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein W is N.

5. 5. The compound of claim 3 or 4, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein X is N.

6. The compound of any one of claims 3 to 5, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein Y is N.

7. The compound of any one of claims 3 to 6, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein Z is N.

8. W is C-R ５ 8. The compound of any one of claims 3 or 5 to 7, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein:

9. X is C-R ６ 9. The compound of any one of claims 3, 4, or 6 to 8, or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein:

10. Y is C-R ７ 10. The compound of any one of claims 3 to 5 or 7 to 9, wherein:

11. Z is C-R ８ 11. The compound of any one of claims 3 to 6 or 8 to 10, wherein:

12. R ５ , R ６ , R ７ and R ８ are each independently selected from hydrogen or halogen, or a pharmaceutically acceptable salt, solvate or N-oxide thereof.

13. R １ The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein is hydrogen.

14. R １ The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein: is optionally substituted C1-C6 alkyl.

15. R ２ 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein: is optionally substituted C1-C3 alkyl.

16. 16. The compound of claim 15, or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein said optionally substituted C1-C3 alkyl is substituted with halogen.

17. The optionally substituted C1-C3 alkyl is —CHF ２ 16. The compound of claim 15, wherein:

18. R ３ or R ４ 18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein one of is hydroxy.

19. R ３ and R ４ The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein is hydroxy.

20. R ３ or R ４ 18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein one of is optionally substituted C1-C3 alkoxy.

21. R ３ and R ４ 18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein:

22. R ３ or R ４ 17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein one of is optionally substituted C1-C3 alkoxy.

23. R ３ and R ４ 17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein:

24. R ３ and R ４ are each independently an optionally substituted C1-C6 alkyl, or a pharmaceutically acceptable salt, solvate, or N-oxide thereof.

25. R ３ and R ４ is each independently methyl, ethyl, n-propyl, iso-propyl, n-butyl, or iso-butyl, or a pharmaceutically acceptable salt, solvate, or N-oxide thereof.

26. R ３ and R ４ 25. The compound of claim 24, or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein each is methyl.

27. R ３ and R ４ and n is 0 or 1; and n is 1 or 2; and n is 2 or 3; and n is 3 or 4; and n is 4 or 5; and n is 5 or 6; and n is 6 or 7;

28. R ３ is hydroxy, and R ４ 18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein is methyl, ethyl, n-propyl, iso-propyl, n-butyl, or iso-butyl.

29. R ３ and R ４ and R are linked to form an optionally substituted phosphorus-containing 3- to 8-membered heterocyclyl, or a pharmaceutically acceptable salt, solvate, or N-oxide thereof.

30. R ３ and R ４ are linked to form an optionally substituted phosphorus-containing 3-8 membered heterocyclyl, said heterocyclyl containing one or two additional heteroatoms each independently selected from N, O and S, or a pharmaceutically acceptable salt, solvate or N-oxide thereof.

31. R ３ and R ４ and R are linked to form an optionally substituted phosphorus-containing 4-6 membered heterocyclyl, or a pharmaceutically acceptable salt, solvate or N-oxide thereof.

32. R ３ and R ４ or a pharmaceutically acceptable salt, solvate, or N-oxide thereof.

33. R ３ and R ４ or a pharmaceutically acceptable salt, solvate, or N-oxide thereof.

34. R ３ and R ４ or a pharmaceutically acceptable salt, solvate, or N-oxide thereof.

35. R ３ and R ４ The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein each is methyl or ethyl.

36. R ３ is OH, and R ４ 18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein is methyl.

37. R ３ and R ４ are grouped together with a phosphorus atom to which they are attached, 【Chemistry 426】 18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, which cooperate to form a ring selected from:

38. R ３ and R ４ are grouped together with a phosphorus atom to which they are attached, 【Chemistry 427】 18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, which cooperate to form a ring selected from:

39. 39. The compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein L is a bond.

40. L is -CH ２ 39. The compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein

41. L is -OCH ２ 39. The compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein: -*.

42. L is -NHCH ２ 39. The compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein: -*.

43. R ９ 43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein: is hydrogen.

44. R ９ 43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein: is halogen.

45. R １０ 45. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein: is hydrogen.

46. 46. ​​The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein Ring A is optionally substituted heteroarylene.

47. 47. The compound of claim 46, or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein the optionally substituted heteroarylene is an N-linked heteroarylene, and the N-linked is the bond to the benzimidazole ring of formula (I).

48. 47. The compound of claim 46, or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein the optionally substituted heteroarylene is a C-linked heteroarylene, and the C-linked heteroarylene is the bond to the benzimidazole ring of formula (I).

49. 49. The compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein V is N.

50. V is C-R １１ 49. The compound of any one of claims 1 to 48, wherein:

51. V is C-R １１ and R １１ 49. The compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein: is hydrogen.

52. A compound set forth in Table 1, or a pharmaceutically acceptable salt, solvate or N-oxide thereof.

53. A compound set forth in Table 2, or a pharmaceutically acceptable salt, solvate, or N-oxide thereof.

54. 54. A pharmaceutical composition comprising a compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt or solvate or N-oxide thereof, and a pharmaceutically acceptable excipient or carrier.

55. 54. A method for preparing a pharmaceutical composition, comprising mixing a compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt or solvate or N-oxide thereof, with a pharmaceutically acceptable excipient or carrier.

56. 55. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt or solvate or N-oxide thereof, or a pharmaceutical composition according to claim 54, for use in a method of treatment of the human or animal body.

57. 55. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt or solvate or N-oxide thereof, or a pharmaceutical composition according to claim 54, for use in a method for the treatment of an inflammatory or autoimmune disease or disorder.

58. 55. Use of a compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt or solvate or N-oxide thereof, or a pharmaceutical composition according to claim 54, in the manufacture of a medicament for the treatment of an inflammatory or autoimmune disease or disorder.

59. 54. A pharmaceutical composition comprising a compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt or solvate or N-oxide thereof, for use in treating an inflammatory or autoimmune disease or disorder in a patient in need thereof.

60. 54. A method of treating an inflammatory or autoimmune disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt or solvate or N-oxide thereof, or a pharmaceutical composition according to claim 54.

61. 54. A method of inhibiting TNFa activity, comprising contacting a TNFa protein with a compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt or solvate or N-oxide thereof, or a pharmaceutical composition of claim 54, wherein the TNFa protein is contacted under in vitro conditions.

62. 54. A method of inhibiting TNFa activity, comprising contacting the TNFa protein with a compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt or solvate or N-oxide thereof, or the pharmaceutical composition of claim 54, wherein the TNFa protein is contacted under in vivo conditions.

63. 54. A method of treating or preventing a condition in a patient induced by the inhibition of TNFa, said method comprising administering to said patient a therapeutically effective amount of a compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt or solvate or N-oxide thereof, or a pharmaceutical composition according to claim 54.

64. 54. A pharmaceutical composition comprising a compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt or solvate or N-oxide thereof, for use in treating or preventing in a patient a condition induced by the inhibition of TNFa.

65. 55. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt or solvate or N-oxide thereof, or a pharmaceutical composition according to claim 54, for use in treating or preventing in a patient a condition induced by the inhibition of TNFa.

66. 55. Use of a compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt or solvate or N-oxide thereof, or a pharmaceutical composition according to claim 54, in the preparation of a medicament for treating or preventing in a patient a condition induced by the inhibition of TNFa.

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