Modulators of TNF alpha activity

Abstract

Provided herein are inhibitors of TNF [alpha], pharmaceutical compositions comprising inhibitory compounds, and methods for treating diseases or conditions using TNF [alpha] inhibitory compounds.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 518,062, filed on August 7, 2023, and U.S. Provisional Application No. 63 / 384,919, filed on November 23, 2022, both of which are incorporated herein by reference in their entirety. Background of the Invention

[0003] Tumor necrosis factor alpha (TNFα) is an inflammatory cytokine responsible for a wide range of intracellular signaling events. Aberrant TNFα signaling causes inflammatory disorders and is considered an important component of inflammatory diseases such as rheumatoid arthritis. Summary of the Invention

[0004] Provided herein are inhibitors of TNFα, pharmaceutical compositions comprising the inhibitory compounds, and methods for using the inhibitory compounds to treat inflammatory or autoimmune diseases or disorders.

[0005] One embodiment provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or N - oxide thereof:

[0006]

[0007] Wherein,

[0008] Ring A is selected from wherein the * represents the point of attachment to L, or is an optionally substituted heteroarylene selected from: pyrazolylene, imidazoline, oxazolylene, or thiazolylene;

[0009] V is N or C - R 11 ;

[0010] W is N or C - R 5 ;

[0011] X is N or C - R 6 ;

[0012] Y is N or C - R 7 ;

[0013] Z is N or C - R 8 ;

[0014] L is a bond, -NH -, -(CH2)n -, -C(R 12 )(R 13 ) -, -O(CH2)n - *, or -NH(CH2)n - *, where the * represents the point of attachment to phosphorus;

[0015] n is 1, 2, or 3;

[0016] R 1 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl;

[0017] R 2 is hydrogen or optionally substituted C1-C3 alkyl;

[0018] R 3 is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl;

[0019] R 4 is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl; or R 3 and R 4 are linked to form an optionally substituted 3- to 8-membered phosphorus-containing ring;

[0020] Each R 5 、R 6 、R 7 and R 8 is independently selected from hydrogen, halogen, -CN, -NH2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, or -NH(optionally substituted C1-C3 alkyl);

[0021] R 9 is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl;

[0022] R 10 is selected from hydrogen or halogen;

[0023] R 11 is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; and

[0024] R 12 and R 13 are independently selected from hydrogen, -OH, F, and CH3.

[0025] 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.

[0026] One embodiment provides a method of treating a disease or disorder in a patient in need thereof, the method 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.

[0027] Incorporated by reference

[0028] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference for the specific purposes determined herein. Detailed Description

[0029] As used herein and in the appended claims, the singular forms "a / an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or a plurality of cells) known to those skilled in the art and their equivalents, etc. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formula, all combinations and sub-combinations of the ranges and specific embodiments therein are intended to be included. When referring to a number or numerical range, the term "about" means that the recited number or numerical range is an approximation within experimental variability (or within statistical experimental error), and thus in some cases, the number or numerical range will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude in certain other embodiments, for example, embodiments of any composition of matter, composition, method, or process, etc. described herein "consisting of the recited features" or "consisting essentially of the recited features".

[0030] Definitions

[0031] As used in this specification and the appended claims, unless indicated to the contrary, the following terms have the meanings indicated below.

[0032] "Amino" refers to the -NH2 group.

[0033] "Cyano" refers to the -CN group.

[0034] "Nitro" refers to the -NO2 group.

[0035] "Oxa" refers to the -O- group.

[0036] "Oxo" refers to the ═O group.

[0037] "Thioxo" refers to the ═S group.

[0038] "Imino" refers to the ═N-H group.

[0039] "Oximino" refers to the ═N-OH group.

[0040] "Hydrazino" refers to the ═N-NH2 group.

[0041] "Alkyl" refers to a straight-chain or branched-chain hydrocarbon chain group consisting only of carbon and hydrogen atoms, the straight-chain or branched-chain hydrocarbon chain group having no unsaturation and having from one to fifteen carbon atoms (e.g., C1-C 15 alkyl). In certain embodiments, the alkyl contains from one to thirteen carbon atoms (e.g., C1-C 13 alkyl). In certain embodiments, the alkyl contains from one to eight carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl contains from one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl contains from one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl contains from one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl contains from one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl contains one carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl contains from five to fifteen carbon atoms (e.g., C5-C 15 alkyl). In other embodiments, the alkyl contains from five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl contains from two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl contains from three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the remainder of the molecule by a single bond. Unless specifically stated otherwise in the specification, the alkyl is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oximino, trimethylsilyl, -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 (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) tR a (where t is 1 or 2) and -S(O) t N(R a )2(where t is 1 or 2), wherein each R a is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), carbocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by 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.

[0042] "Alkoxy" refers to a group bonded through an oxygen atom of the formula -O-alkyl, wherein the alkyl is an alkyl chain as defined above.

[0043] "Alkenyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having two to twelve carbon atoms. In certain embodiments, the alkenyl contains two to eight carbon atoms. In other embodiments, the alkenyl contains two to four carbon atoms. The alkenyl is connected to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, etc. Unless specifically stated otherwise in the specification, the alkenyl is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -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 (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a independently is hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), carbocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroaryl alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl).

[0044] "Alkynyl" means a straight-chain or branched hydrocarbon chain group consisting only of carbon atoms and hydrogen atoms, containing at least one carbon-carbon triple bond and having two to twelve carbon atoms. In certain embodiments, alkynyl contains two to eight carbon atoms. In other embodiments, alkynyl contains two to six carbon atoms. In other embodiments, alkynyl contains two to four carbon atoms. Alkynyl is connected to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless specifically stated otherwise in the specification, alkynyl is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oximino, trimethylsilyl, -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 (where t is 1 or 2), -S(O)t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), wherein each R a is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), carbocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl).

[0045] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the remainder of the molecule to a group consisting of only carbon and hydrogen, having no unsaturation and having one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is connected to the remainder of the molecule by a single bond and to the group by a single bond. The points of attachment of the alkylene chain to the remainder of the molecule and to the group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, the alkylene contains one to eight carbon atoms (e.g., C1-C8 alkylene). In other embodiments, the alkylene contains one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, the alkylene contains one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, the alkylene contains one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, the alkylene contains one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, the alkylene contains one carbon atom (e.g., C1 alkylene). In other embodiments, the alkylene contains five to eight carbon atoms (e.g., C5-C8 alkylene). In other embodiments, the alkylene contains one to two carbon atoms (e.g., C2-C5 alkylene). In other embodiments, the alkylene contains one to three carbon atoms (e.g., C3-C5 alkylene). Unless specifically stated otherwise in the specification, the alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oximino, trimethylsilyl, -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 (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), carbocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl).

[0046] "Alkenylene" or "alkenylene chain" refers to a straight-chain or branched-chain divalent hydrocarbon chain that connects the remainder of the molecule to a group consisting of only carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. The alkenylene chain is connected to the remainder of the molecule by a single bond and to the group by a single bond. In certain embodiments, the alkenylene contains two to eight carbon atoms (e.g., C2-C8 alkenylene). In other embodiments, the alkenylene contains two to five carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, the alkenylene contains two to four carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, the alkenylene contains two to three carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, the alkenylene contains two carbon atoms (e.g., C2 alkenylene). In other embodiments, the alkenylene contains five to eight carbon atoms (e.g., C5-C8 alkenylene). In other embodiments, the alkenylene contains three to five carbon atoms (e.g., C3-C5 alkenylene). Unless specifically stated otherwise in the specification, the alkenylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -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 (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R aIndependently is hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), carbocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl).

[0047] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the remainder of the molecule to a group consisting of only carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is connected to the remainder of the molecule by a single bond and to the group by a single bond. In certain embodiments, the alkynylene contains from two to eight carbon atoms (e.g., C2-C8 alkynylene). In other embodiments, the alkynylene contains from two to five carbon atoms (e.g., C2-C5 alkynylene). In other embodiments, the alkynylene contains from two to four carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, the alkynylene contains from two to three carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, the alkynylene contains two carbon atoms (e.g., C2 alkynylene). In other embodiments, the alkynylene contains from five to eight carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, the alkynylene contains from three to five carbon atoms (e.g., C3-C5 alkynylene). Unless specifically stated otherwise in the specification, the alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -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 (where t is 1 or 2), -S(O) t ORa (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), carbocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl).

[0048] "Aryl" means a group derived by removing a hydrogen atom from a ring carbon atom of an aromatic monocyclic or polycyclic hydrocarbon ring system. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon in five to eighteen carbon atoms, wherein at least one of the rings in the ring system is completely unsaturated, i.e., it contains a cyclic, delocalized (4n + 2)π electron system conforming to Hückel theory. The ring system from which the aryl is derived includes, but is not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless specifically stated otherwise in the specification, the term "aryl" or the prefix "ar-(aryl)" (as in "aralkyl") is intended to include aryl optionally substituted by one or more substituents independently selected from the following: 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 -O-Rc -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 (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocycloalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), each R b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and where unless otherwise specified, R a , R b or R c each substituent in the substituents is unsubstituted.

[0049] "Aralkyl" means a group of the formula -R c -aryl, where R c is an alkylene chain as defined above, such as methylene, ethylene, etc. The alkylene chain portion of the aralkyl is optionally substituted as described above for the alkylene chain. The aryl portion of the aralkyl is optionally substituted as described above for the aryl.

[0050] "Arylene" means a group of the formula -R d-aryl group, where R d is an alkenylene chain as defined above. The aryl moiety of the aralkenyl is optionally substituted as described above for aryl. The alkenylene chain moiety of the aralkenyl is optionally substituted as defined above for alkenylene.

[0051] "Arylalkynyl" refers to a group of the formula -R e -aryl, where R e is an alkynylene chain as defined above. The aryl moiety of the arylalkynyl is optionally substituted as described above for aryl. The alkynylene chain moiety of the arylalkynyl is optionally substituted as defined above for alkynylene chain.

[0052] "Arylalkoxy" refers to a group bonded through an oxygen atom of the formula -O-R c -aryl, where R c is an alkylene chain as defined above, such as methylene, ethylene, etc. The alkylene chain moiety of the arylalkyl is optionally substituted as described above for alkylene chain. The aryl moiety of the arylalkyl is optionally substituted as described above for aryl.

[0053] "Carbocyclic group" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, which includes fused ring or bridged ring systems and has three to fifteen carbon atoms. In certain embodiments, the carbocyclic group contains three to ten carbon atoms. In other embodiments, the carbocyclic group contains five to seven carbon atoms. The carbocyclic group is connected to the rest of the molecule by a single bond. The carbocyclic group is saturated (i.e., contains only single C-C bonds) or unsaturated (i.e., contains one or more double bonds or triple bonds). A fully saturated carbocyclic group is also called "cycloalkyl". Examples of monocyclic cycloalkyl include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclic group is also called "cycloalkenyl". Examples of monocyclic cycloalkenyl include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclic groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptyl), norbornenyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Unless specifically stated otherwise in the specification, the term "carbocyclic group" is intended to include a carbocyclic group optionally substituted with one or more substituents independently selected from the following: optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, oxo, thio, 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 -O-R 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 (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2(where t is 1 or 2), where each R a is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), arylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocycloalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), each R b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and where unless otherwise specified, each substituent in the R a , R b or R c substituents is unsubstituted.

[0054] "Carbocycloalkyl" means the formula -R c-a group of cycloalkyl, wherein R c is an alkylene chain as defined above. The alkylene chain and the cycloalkyl are optionally substituted as defined above.

[0055] "Cycloalkynyl" means a group of formula -R c -cycloalkyl, wherein R c is an alkynylene chain as defined above. The alkynylene chain and the cycloalkyl are optionally substituted as defined above.

[0056] "Cycloalkyloxy" means a group bonded through an oxygen atom of formula -O-R c -cycloalkyl, wherein R c is an alkylene chain as defined above. The alkylene chain and the cycloalkyl are optionally substituted as defined above.

[0057] "Halo" or "halogen" means a bromo, chloro, fluoro or iodo substituent.

[0058] "Fluoroalkyl" means an alkyl substituted by one or more fluoro groups 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 is optionally substituted as defined above for alkyl.

[0059] "Heterocyclic group" means a stable 3- to 18-membered non-aromatic ring group containing two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless specifically stated otherwise in the specification, the heterocyclic group is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes a fused ring or bridged ring system. The heteroatoms in the heterocyclic group are optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. The heterocyclic group is partially or fully saturated. The heterocyclic group is attached to the rest of the molecule through any atom of the ring. Examples of such heterocyclic groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithialanyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thioxomorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl. Unless specifically stated otherwise in the specification, the term "heterocyclic group" is intended to include a heterocyclic group optionally substituted by one or more substituents selected from the following: optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, fluoroalkyl, oxo, thio, 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 , -O-R 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 (where t is 1 or 2), -R b , -S(O) t R a (where t is 1 or 2), -R b , -S(O) t OR a (where t is 1 or 2) and -R b , -S(O) t , -N(R a )2(where t is 1 or 2), where each R a is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), arylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocycloalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), each R b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R cis a straight or branched alkylene or alkenylene chain, and wherein unless otherwise indicated, R a 、R b or R c each substituent in the substituents is unsubstituted.

[0060] "N - heterocyclic group" or "N - linked heterocyclic group" means a heterocyclic group as defined above containing at least one nitrogen, and wherein the point of attachment of the heterocyclic group to the rest of the molecule is through a nitrogen atom in the heterocyclic group. The N - heterocyclic group is optionally substituted as described above for the heterocyclic group. Examples of such N - heterocyclic groups include, but are not limited to, 1 - morpholinyl, 1 - piperidinyl, 1 - piperazinyl, 1 - pyrrolidinyl, pyrazolidinyl, and imidazolidinyl.

[0061] "C - heterocyclic group" or "C - linked heterocyclic group" means a heterocyclic group as defined above containing at least one heteroatom, and wherein the point of attachment of the heterocyclic group to the rest of the molecule is through a carbon atom in the heterocyclic group. The C - heterocyclic group is optionally substituted as described above for the heterocyclic group. Examples of such C - heterocyclic groups include, but are not limited to, 2 - morpholinyl, 2 - or 3 - or 4 - piperidinyl, 2 - piperazinyl, 2 - or 3 - pyrrolidinyl, etc.

[0062] "heterocycloalkyl" means a group of the formula - R c -heterocyclic group, wherein R c is an alkylene chain as defined above. If the heterocyclic group is a nitrogen - containing heterocyclic group, the heterocyclic group is optionally attached to the alkyl group at the nitrogen atom. The alkylene chain of the heterocycloalkyl is optionally substituted as defined above for the alkylene chain. The heterocyclic group moiety of the heterocycloalkyl is optionally substituted as defined above for the heterocyclic group.

[0063] "heterocycloalkoxy" means a group bonded through an oxygen atom of the formula - O - R c -heterocyclic group, wherein R c is an alkylene chain as defined above. If the heterocyclic group is a nitrogen - containing heterocyclic group, the heterocyclic group is optionally attached to the alkyl group at the nitrogen atom. The alkylene chain of the heterocycloalkoxy is optionally substituted as defined above for the alkylene chain. The heterocyclic group moiety of the heterocycloalkoxy is optionally substituted as defined above for the heterocyclic group.

[0064] "Heteroaryl" refers to a group derived from a 3- to 18-membered aromatic ring group containing two to seventeen carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π electron system in accordance with Hückel's theory. Heteroaryl includes fused ring or bridged ring systems. The heteroatoms in heteroaryl are optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. Heteroaryl is attached to the remainder of the molecule through any atom of the ring.Examples of heteroaryl include, but are not limited to, azacyclic group, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzodioxepinyl, benzoxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, dibenzodioxinyl, chromenyl, chromenone, benzofuranyl, benzofuranone, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazoline, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothienyl, furanyl, furanone, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolyl, isoindolyl, isoquinolinyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinone, oxadiazolyl, 2-oxoazacyclic group, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl and phenylthio (i.e., thienyl).Unless otherwise specifically stated in the specification, the term "heteroaryl" is intended to include heteroaryl as defined above optionally substituted with one or more substituents selected from the following: 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 -O-R 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 (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2(where t is 1 or 2), where each R aindependently is hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), arylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocycloalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), each R b independently is a direct bond or a straight-chain or branched alkylene or alkenylene chain, and R c is a straight-chain or branched alkylene or alkenylene chain, and wherein unless otherwise specified, R a 、R b or R c each substituent in the substituents is unsubstituted.

[0065] “N-heteroaryl” means a heteroaryl as defined above containing at least one nitrogen, and wherein the point of attachment of the heteroaryl to the rest of the molecule is through a nitrogen atom in the heteroaryl. The N-heteroaryl is optionally substituted as described above for heteroaryl.

[0066] “C-heteroaryl” means a heteroaryl as defined above, and wherein the point of attachment of the heteroaryl to the rest of the molecule is through a carbon atom in the heteroaryl. The C-heteroaryl is optionally substituted as described above for heteroaryl.

[0067] “heteroarylalkyl” means a group of the formula -R c -heteroaryl, wherein 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 at the nitrogen atom. The alkylene chain of the heteroarylalkyl is optionally substituted as defined above for the alkylene chain. The heteroaryl moiety of the heteroarylalkyl is optionally substituted as defined above for heteroaryl.

[0068] “heteroarylalkoxy” means a group bonded through an oxygen atom of the formula -O-R c -heteroaryl, wherein 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 at the nitrogen atom. The alkylene chain of the heteroarylalkoxy is optionally substituted as defined above for the alkylene chain. The heteroaryl moiety of the heteroarylalkoxy is optionally substituted as defined above for heteroaryl.

[0069] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined in terms of absolute stereochemistry as (R)- or (S)-. Unless otherwise stated, the present disclosure is intended to contemplate all stereoisomeric forms of the compounds disclosed herein. When the compounds described herein contain olefinic double bonds, unless otherwise stated, the present disclosure is intended to include the E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term "geometric isomers" refers to the E or Z geometric isomers of an olefinic double bond (e.g., cis or trans). The term "positional isomers" refers to structural isomers around a central ring, such as ortho, meta, and para isomers around a benzene ring.

[0070] As used herein, "carboxylic acid bioisostere" refers to a functional group or moiety that exhibits physical, biological, and / or chemical properties similar to those of a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to, and so on.

[0071] "Tautomers" refer to a molecule in which 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 cases where tautomerism can occur, there will be a chemical equilibrium of tautomers. The exact ratio of tautomers depends on several factors, including physical state, temperature, solubility, and pH. Some examples of tautomeric equilibria include:

[0072]

[0073] In some embodiments, the compounds disclosed herein are used in different enriched isotope forms, e.g., enriched in terms of content 2 H, 3 H, 11 C, 13 C, and / or 14 C. In one specific embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the methods 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 prolonging the duration of drug action.

[0074] Unless otherwise indicated, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotope-enriched atoms. For example, having hydrogen replaced by deuterium or tritium or by13 C or 14 Compounds of the invention in which the carbon of the C or C-enriched carbon displaces a carbon other than carbon in the structure of the invention are within the scope of the present disclosure.

[0075] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms constituting such compounds. For example, the compounds may be labeled with isotopes such as deuterium ( 2 H), tritium ([[]] 3 H), iodine-125 ([[]] 125 I), or carbon-14 ([[]] 14 C). Substitution with 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 I for isotope substitution has been considered in its entirety. In some embodiments, substitution with 18 F is considered. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0076] In certain embodiments, some or all of the 1 H atoms of the compounds disclosed herein are replaced by 2 H atoms. Methods for synthesizing deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0077] Deuterium-substituted compounds are synthesized using various methods such as those described below: 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, p. 110; 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.

[0078] The deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide the synthesis of deuterium-containing compounds. A large number of deuterated reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0079] Deuterium transfer reagents suitable for nucleophilic substitution reactions, such as iodomethane - d3 (CD3I), are readily available and can be used to transfer deuterium-substituted carbon atoms to the reaction substrate under nucleophilic substitution reaction conditions. The use of CD3I is illustrated only by way of example in the reaction schemes below.

[0080]

[0081] Deuterium transfer reagents such as lithium aluminum deuteride (LiAlD4) are used to transfer deuterium to the reaction substrate under reducing conditions. The use of LiAlD4 is illustrated only by way of example in the reaction schemes below.

[0082]

[0083] Deuterium gas and palladium catalysts are used to reduce unsaturated carbon - carbon bonds and to carry out reductive substitution of aryl carbon - halogen bonds, as illustrated only by way of example in the following reaction schemes.

[0084]

[0085] 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 completely substituted with deuterium atoms and do not contain non-exchangeable 1 H hydrogen atoms. 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.

[0086] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. Pharmaceutically acceptable salts of any of the TNFα inhibitory compounds described herein are intended to cover any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0087] "Pharmaceutically acceptable acid addition salts" refers to those salts that retain the biological efficacy and properties of the free base, which salts are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. Also included are salts formed with organic acids such as aliphatic mono- and di-carboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkane diacids, aromatic acids, aliphatic and aromatic sulfonic acids, etc., and include, for example, salts formed with 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, bisulfate, hydrogen sulfate, sulfite, bisulfite, nitrate, phosphate, hydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, etc. Also contemplated are salts of amino acids such as arginine salts, gluconate salts, and galacturonate salts (see, e.g., Berge S.M. et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 66:1-19 (1997)). In some embodiments, the acid addition salts of the basic compound are prepared by contacting the free base form with a sufficient amount of the desired acid according to methods and techniques familiar to those skilled in the art to produce the salt.

[0088] "Pharmaceutically acceptable base addition salts" refer to those salts that retain the biological effectiveness and properties of the free acid and are not biologically or otherwise undesirable. These salts can be prepared by adding an inorganic or organic base to the free acid. In some embodiments, metals or amines such as alkali metals, alkaline earth metals, or organic amines are used to form pharmaceutically acceptable base addition salts. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. 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, hydroxylamine, choline, betaine, ethylenediamine, N-ethyldiphenylamine, N-methylglucosamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., supra.

[0089] "Pharmaceutically acceptable solvates" refer to compositions of a substance in a solvent addition form. In some embodiments, the solvate contains a stoichiometric or non-stoichiometric amount of solvent and is formed during the preparation with a pharmaceutically acceptable solvent (such as water, ethanol, etc.). A hydrate is formed when the solvent is water, or an alcoholate is formed when the solvent is an alcohol. The solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein exist in non-solvated or solvated forms.

[0090] The terms "subject" or "patient" encompass mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees and other ape and monkey species; farm animals such as cows, horses, sheep, goats, pigs, etc.; domestic animals such as rabbits, dogs, and cats, etc.; laboratory animals including rodents such as rats, mice, and guinea pigs. In one aspect, the mammal is a human.

[0091] As used herein, "treatment" or "treating" or "alleviating" or "ameliorating" are used interchangeably. These terms refer to a method of obtaining a beneficial or desired result, including but not limited to a therapeutic benefit and / or a prophylactic benefit. "Therapeutic benefit" means the eradication or amelioration of an underlying disorder being treated. Additionally, a therapeutic benefit is achieved by eradicating or ameliorating one or more of the physiological symptoms associated with the underlying disorder, such that an improvement is observed in a patient, even though the patient still suffers from the underlying disorder. For prophylactic benefits, in some embodiments, the composition is administered to a patient at risk of developing a particular disease or to a patient reporting one or more of the physiological symptoms of the disease, even though a diagnosis of such disease has not yet been made.

[0092] Tumor necrosis factor alpha (TNFα) protein and function

[0093] Tumor necrosis factor alpha (TNFα) protein is a member of the TNF superfamily, which includes various transmembrane proteins having a homologous TNF domain that forms trimers. The TNF superfamily includes 19 family members, including but not limited to tumor necrosis factor alpha (also known as tumor necrosis factor or TNF), lymphotoxin alpha (TNFβ), lymphotoxin beta (TNFγ), OX40 ligand, CD40 ligand, Fas ligand, CD27 ligand, CD30 ligand, CD137 ligand, CD137 ligand, and TNF-related apoptosis-inducing ligand. TNFα protein is a cytokine and an adipokine (a cytokine secreted by adipose tissue).

[0094] TNFα is a transmembrane protein, and soluble TNFα (sTNFα) is released by proteolytic cleavage. sTNFα can transmit signaling by binding to two receptors, TNFR1 and TNFR2. TNFα is a regulator of cellular signaling immune responses and can mediate both cell survival and cell death-inducing signaling. There are two receptors for TNF signaling, TNFR1 and TNFR2. sTNFα-TNFR1 signaling promotes immune cell activation and drives acute and chronic inflammation. Membrane TNFα-TNFR2 signaling promotes inflammation resolution, immune cell regulatory functions, and cell survival.

[0095] The extracellular regions of both TNFR1 and TNFR2 have four homologous cysteine-rich domains, but they have structurally distinct intracellular regions. TNFR1 has a protein-binding region called the death domain, which allows for homotypic and heterotypic interactions with other death domain-containing proteins. In contrast, TNFR2 has TNF receptor-associated factors (TRAFs) that interact with the TRAF signaling adaptor family. The different spectra and differences of the two TNF receptors affect cell activity and physiological functions. TNFR1 can activate NF-κB and MAPK signaling and cell death, and is important for regulating inflammatory diseases. TNFR2 is highly regulated and restricted to specific cell types, such as endothelial cells and T cells. TNFR1 mainly promotes tissue degeneration and inflammation, while TNFR2 usually mediates local homeostasis effects, such as tissue regeneration and cell survival (D. Fresegna et al., Cells, 2020, 9, 2290).

[0096] The binding of TNFα to TNFR1 can activate NF-κB to mediate the transcription of various proteins involved in cell survival and proliferation, anti-apoptotic factors, and inflammatory responses. In addition, the MAPK pathway can also be activated by the binding of TNFα to TNFR1, which is involved in cell differentiation and proliferation. When TNFα binds to TNFR1, it triggers receptor trimerization, leading to the assembly of the TNFR1-associated signaling complex. This complex recruits receptor-interacting protein 1 (RIP1) and TNF receptor-associated death domain (TRADD) to TNFR1 through the acceptor death domain. Then, TRADD recruits the adaptor proteins TRAF2 and TRAF5, which can engage the E3 ligase cellular inhibitor of apoptosis (c-IAP1, c-IAP2). c-IAP1 / 2 is important for TNFR1 complex signaling, which can ultimately lead to the recruitment of the signaling kinase complex of kinases IKKα and IKKβ, which are inhibitors of κB kinase 1 and 2, and the conversion of transforming growth factor-β-activated kinase 1 (TAK1), resulting in the activation of NF-κB and MAPK signaling. The activation of these signaling pathways may cause gene activation and expression of pro-inflammatory cytokines and pro-survival proteins.

[0097] TNF signaling is regulated by post-translational ubiquitination, which is crucial for biological processes. Post-translational modification of the TNFR1-associated signaling complex may cause changes from inflammatory gene signaling to cell death. This switch depends on the ubiquitination status of RIP1, which is part of the TNFR1-associated signaling complex formed by TNFα binding.

[0098] For a long time, TNF has been considered a key regulator of the inflammatory response and has recently been known to be involved in brain function (D. Fresegna et al., *Cell*, 2020, 9, 2290). As a regulator of the inflammatory response, TNF can regulate many aspects of T cell biology, including but not limited to proliferation, survival, priming, and apoptotic fate. The ability of TNF to promote cell death in both CD4 and CD8P T cells through TNFR1 is also known to play a role in the conclusion of lymphocyte responses. Specific inflammatory conditions may also cause TNFR2 to promote or support T cell apoptosis.

[0099] In the normal adult brain, TNF is expressed at low levels and this expression is believed to be affected by the presence or absence of cytokines that may cross the blood-brain barrier. TNFRs in the brain are expressed by glial cells and neuronal cells and have regulatory functions, including but not limited to homeostatic synaptic plasticity, astrocyte-mediated synaptic transmission, and neurogenesis. These functions can be used to regulate learning and memory functions as well as other functions.

[0100] TNF is considered a physiological gliotransmitter for communication between neurons and glial cells, which in turn affects synaptic regulation. Glial TNF is important for maintaining normal surface expression of AMPA receptors and homeostatic synaptic scaling, which allows adjustment of the strength of all synapses on neurons.

[0101] Small molecule inhibitors of the prior art

[0102] Diseases treated with biological TNFα inhibitors include but are not limited to rheumatoid arthritis, inflammatory bowel disease, psoriatic arthritis, psoriasis, and ankylosing spondylitis. Patients with neurological and degenerative diseases, including but not limited to Alzheimer's disease, Parkinson's disease, multiple sclerosis, treatment-resistant depression, and tinnitus, may benefit from treatment with oral CNS sTNFα inhibitors by disrupting sTNFα signaling and preserving mTNFα signaling. Previous reports have also shown targeting TNFR2 for the treatment of Alzheimer's disease (N. et al., *Front Neurosci*. 2019; 13:49).

[0103] Small molecules have been developed for the treatment of rheumatoid arthritis because some patients do not respond well to monotherapy with approved anti-TNFα drugs (J.D. Dietrich et al., Journal of Medicinal Chemistry 2021, 64, 417 - 429). Anti-TNFα drugs have also been extended to other chronic autoimmune diseases, including but not limited to Crohn's disease, psoriasis, psoriatic arthritis, ulcerative colitis, inflammatory bowel disease, ankylosing spondylitis, and juvenile rheumatoid arthritis. Small molecules have been developed as an alternative to anti-TNFα biologics because the long-term clinical response rate for rheumatoid arthritis is typically about 60% - 70%.

[0104] Previous studies have also shown that TNFα inhibitors are efficacious for the treatment of multiple sclerosis (D. Fresegna et al., Cells, 2020, 9, 2290). There is evidence that TNF is involved in various pathological problems of multiple sclerosis, including immune dysregulation, demyelination, synaptopathy, and neuroinflammation. TNFα inhibitors have the potential to treat multiple sclerosis and other potential chronic neurodegenerative diseases of the central nervous system.

[0105] More than 50 million Americans struggle with tinnitus, which is the perception of sound without an external source. TNFα has been shown to be required for noise-induced neuroinflammation and synaptic imbalance (W. Wang et al., PLoS Biol. June 18, 2019; 17(6):e3000307; A. Shulman et al., Curr Top Behav Neurosci. 2021; 51:161 - 174). Certain inhibitors of TNFα are believed to have activity for the treatment of tinnitus.

[0106] Recent reports have also shown that TNFα inhibitors can be used alone or in combination for the treatment of inflammatory bowel disease (S.F. Fowler Braga and K.J. Clark, US Pharm. 2021; 46(5):34 - 37). TNFα is a mediator of the abnormal immune response in inflammatory bowel disease, which leads to the disruption of the intestinal mucosal and epithelial wall barriers. Anti-TNF agents can block the activation of TNF-mediated pro-inflammatory pathways to cause a reduction in immune-mediated inflammation.

[0107] In addition to demonstrating efficacy in models of collagen antibody-induced arthritis, small molecule sTNFα inhibitors are also active in pharmacological models of sTNFα / TNFR1 signaling. Currently, there is limited data on the common domain of small molecule sTNFα inhibitors. Some TNFα inhibitors include, but are not limited to, XPro1595, Etanercept, Infliximab, Adalimumab, Certolizumab pegol, Golimumamb, and "TNF-α: The Shape of Small Molecules to Come?" (A. and other inhibitors described in X. Li, Drug Discov Today January 2022; 27(1):3-7) and “Small Molecules that Inhibit TNF Signalling by Stabilising an Asymmetric Form of the Trimer” (J. O'Connell et al., Nature Communications 10, 5795 (2019)). Additional small molecule inhibitors of TNFα include, but are not limited to, those described in “Biologic-like In Vivo Efficacy with Small Molecule Inhibitors of TNFα Identified Using Scaffold Hopping and Structure-Based Drug Design Approaches” (H-Y Xiao et al., Journal of Medicinal Chemistry 2020, 15050-15071), “Development of Orally Efficacious Allosteric Inhibitors of TNFα via Fragment-Based Drug Design” (J.D. Dietrich et al., Journal of Medicinal Chemistry 2021, 64, 417-429), and “Small-Molecule Inhibition of TNF-α” (M.M. He et al., Science, 310 (2015), 1022-1025).

[0108] Small molecule sTNFα inhibitors have the potential to be valuable therapies for patients currently treated with biologic TNFα inhibitors, which can fine-tune oral dose requirements and avoid anti-drug antibody responses that affect mTNFα, thereby improving short-term and long-term responses (A. and X. Li, Drug Discov Today January 2022; 27(1):3-7).

[0109] Novel compounds that inhibit TNFα

[0110] In one aspect, the present disclosure provides TNFα inhibitory compounds.

[0111] One embodiment provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or N-oxide thereof:

[0112]

[0113] Wherein,

[0114] Ring A is selected from wherein the * represents the point of attachment to L, or is an optionally substituted heteroarylene selected from the following: pyrazolylene, imidazoline, oxazolylene or thiazolylene;

[0115] V is N or C-R 11 ;

[0116] W is N or C-R 5 ;

[0117] X is N or C-R 6 ;

[0118] Y is N or C-R 7 ;

[0119] Z is N or C-R 8 ;

[0120] L is a bond, -NH-, -(CH2)n-, -CR 12 R 13 -, -O(CH2)n-*, or -NH(CH2)n-*, where the * represents the point of attachment to phosphorus;

[0121] n is 1, 2 or 3;

[0122] R 1 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl or optionally substituted C4-C7 cycloalkylalkyl;

[0123] R 2 is hydrogen or optionally substituted C1-C3 alkyl;

[0124] R 3 is hydroxy, optionally substituted C1-C3 alkoxy or optionally substituted C1-C6 alkyl;

[0125] 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;

[0126] Each R 5 , R 6 , R7 and R 8 are independently selected from hydrogen, halogen, -CN, -NH2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy or -NH(optionally substituted C1-C3 alkyl);

[0127] R 9 is selected from hydrogen, halogen or optionally substituted C1-C6 alkyl;

[0128] R 10 is selected from hydrogen or halogen;

[0129] R 11 is selected from hydrogen, halogen or optionally substituted C1-C6 alkyl; and

[0130] R 12 and R 13 are independently selected from hydrogen, -OH, F and CH3.

[0131] One embodiment provides a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate or N-oxide thereof:

[0132]

[0133] wherein,

[0134] ring A is selected from wherein the * indicates the point of attachment to L, or is an optionally substituted heteroarylene selected from: pyrazolylene, imidazoline, oxazolylene or thiazolylene;

[0135] V is N or C-R 11 ;

[0136] W is N or C-R 5 ;

[0137] X is N or C-R 6 ;

[0138] Y is N or C-R 7 ;

[0139] Z is N or C-R 8 ;

[0140] L is a bond, -NH-, -(CH2)n-, -O(CH2)n-*, or -NH(CH2)n-*, where the * indicates the point of attachment to phosphorus;

[0141] n is 1, 2 or 3;

[0142] R 1 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl or optionally substituted C4-C7 cycloalkylalkyl;

[0143] R 2 is hydrogen or an optionally substituted C1-C3 alkyl group;

[0144] R 3 is a hydroxyl group, an optionally substituted C1-C3 alkoxy group or an optionally substituted C1-C6 alkyl group;

[0145] R 4 is a hydroxyl group, an optionally substituted C1-C3 alkoxy group or an optionally substituted C1-C6 alkyl group; or R 3 and R 4 are linked to form an optionally substituted 3- to 8-membered phosphorus-containing ring;

[0146] Each R 5 , R 6 , R 7 and R 8 is independently selected from hydrogen, halogen, -CN, an optionally substituted C1-C3 alkyl group, an optionally substituted C1-C3 alkoxy group or -NH(optionally substituted C1-C3 alkyl);

[0147] R 9 is selected from hydrogen, halogen or an optionally substituted C1-C6 alkyl group;

[0148] R 10 is selected from hydrogen or halogen; and

[0149] R 11 is selected from hydrogen, halogen or an optionally substituted C1-C6 alkyl group.

[0150] Another embodiment provides a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein ring A is selected from where * represents the point of attachment to L.

[0151] 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 C-R 5 .

[0152] 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 C-R 6 .

[0153] 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 C-R 7 .

[0154] 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 C-R 8 .

[0155] Another embodiment provides a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein W is C-R 5 , X is C-R 6 , Y is C-R 7 , and Z is C-R 8 . Another embodiment provides a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein W is C-F, X is C-H, Y is C-H, and Z is C-H.

[0156] Another embodiment provides a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein each R 5 , R 6 , R 7 and R 8 is independently selected from hydrogen or halogen.

[0157] Another embodiment provides a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein W is N, X is C-R 6 , Y is C-R 7 , and Z is C-R 8 .

[0158] Another embodiment provides a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein W is C-R 5 , X is N, Y is C-R 7 , and Z is C-R 8 .

[0159] Another embodiment provides a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein W is C-R 5 , X is C-R 6, Y is N, and Z is C-R 8 .

[0160] Another embodiment provides a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein W is C-R 5 , X is C-R 6 , Y is C-R 7 , and Z is N.

[0161] 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.

[0162] Another embodiment provides a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein R 1 is optionally substituted C1-C6 alkyl.

[0163] 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.

[0164] 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.

[0165] Another embodiment provides a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein R 2 is 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 a 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.

[0166] Another embodiment provides a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein one of R 3 or R 4 is hydroxy. 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 hydroxy. 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 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 are 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 or 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 are 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 are each independently 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 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl. 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 each 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 are each 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, isopropyl, n-butyl or isobutyl. 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 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 R 4 is methyl.

[0167] Another embodiment provides a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein R3 and R 4 are linked to form an optionally substituted 3- to 8-membered phosphorus-containing heterocyclic group. 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 3- to 8-membered phosphorus-containing heterocyclic group, said heterocyclic group 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 4- to 6-membered phosphorus-containing heterocyclic group. 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 4-membered phosphorus-containing heterocyclic group. 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 5-membered phosphorus-containing heterocyclic group. 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 6-membered phosphorus-containing heterocyclic group.

[0168] 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 together with the phosphorus atom to which they are attached are linked to form a ring selected from:

[0169] 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 together with the phosphorus atom to which they are attached are linked to form a ring selected from:

[0170] 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 -CH2-. Another embodiment provides a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein L is -OCH2-*. Another embodiment provides a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein L is -NHCH2-*.

[0171] 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. Another embodiment provides a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein R 9 is halogen. 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.

[0172] 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.

[0173] 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, wherein the N-linkage is to the benzimidazole ring of formula (I).

[0174] 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, wherein the C-linkage is to the benzimidazole ring of formula (I).

[0175] 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 C-R 11 . Another embodiment provides a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein V is C-R 11 , and R 11 is hydrogen.

[0176] Another embodiment provides a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein W is C-F, X is C-H, Y is C-H, and Z is C-H; 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 C-F, X is C-H, Y is C-H, and Z is C-H; L is a bond; and R 3 and R 4 are each methyl.

[0177] 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 a C1-C3 alkyl group substituted with a 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.

[0178] 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, R 10 is hydrogen, and V is C-H. 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, R 10 is hydrogen, and V is C-H. 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, R 10 is hydrogen, and V is C-F.

[0179] 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; R 2 is a C1-C3 alkyl group substituted with a halogen; R 9 is hydrogen; R 10 is hydrogen; and V is C-H. 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; R2 is a C1-C3 alkyl group substituted by halogen; R 9 is F; R 10 is hydrogen; and V is C-H. 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; R 2 is a C1-C3 alkyl group substituted by halogen; R 9 is hydrogen; R 10 is hydrogen; and V is C-F.

[0180] One embodiment provides a TNFα inhibitory compound or a pharmaceutically acceptable salt, solvate or N-oxide thereof, having the structure presented in Table 1.

[0181] Table 1

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217] Another embodiment provides a TNFα inhibitory compound or a pharmaceutically acceptable salt, solvate or N-oxide thereof, which has the structure presented in Table 2.

[0218] Table 2

[0219]

[0220]

[0221] Preparation of the compound

[0222] Starting from commercially available chemicals and / or compounds described in the chemical literature, compounds for use in the synthetic chemical reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art. “Commercially available chemicals” are obtained from standard commercial sources, including Acros Organics (Pittsburgh, Pennsylvania), Aldrich Chemical Company (Milwaukee, Wisconsin, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (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 (Leicestershire, UK), Frontier Scientific (Logan, Utah), ICN Biomedicals, Inc. (Costa Mesa, California), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, New Hampshire), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, Utah), Pfaltz & Bauer, Inc. (Waterbury, Connecticut), Polyorganix (Houston, Texas), Pierce Chemical Co. (Rockford, Illinois), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc.)(New Brunswick, New Jersey), TCI America (Portland, Oregon), Trans World Chemicals, Inc. (Rockville, Maryland), and Wako Chemicals USA, Inc. (Richmond, Virginia).

[0223] Suitable reference books and treatises that detail the synthesis of reactants useful for preparing the compounds described herein or that provide references to articles describing such preparations include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations", 2nd ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd ed., W. A. Benjamin, Inc., Menlo Park, Calif., 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatises that detail the synthesis of reactants useful for preparing the compounds described herein or that provide references to articles describing such preparations include, for example, Fuhrhop, J. and Penzlin, G., "Organic Synthesis: Concepts, Methods, Starting Materials", Second Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C."Comprehensive Organic Transformations: A Guide to Functional Group Preparations", 2nd Edition (1999), Wiley-VCH Verlag GmbH & Co. KGaA, ISBN: 0-471-19031-4; March, J., "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 4th Edition (1992), John Wiley & Sons, Inc., ISBN: 0-471-60180-2; Otera, J. (Editor), "Modern Carbonyl Chemistry" (2000), Wiley-VCH Verlag GmbH & Co. KGaA, ISBN: 3-527-29871-1; Patai, S., "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992), Interscience Publishers, Inc., ISBN: 0-471-93022-9; Solomons, T.W.G., "Organic Chemistry", 7th Edition (2000), John Wiley & Sons, Inc., 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, Inc., ISBN: 3-527-29645-X, 8 volumes; "Organic Reactions" (1942 - 2000), John Wiley & Sons, Inc., over 55 volumes; and "Chemistry of Functional Groups", John Wiley & Sons, Inc., 73 volumes in total.

[0224] Optionally, specific and analogous reactants are identified by an index of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which is available in most libraries and university libraries and through online databases (contact the American Chemical Society in Washington, D.C. for more details). Chemicals known in the catalog but not commercially available are optionally prepared by custom chemical synthesis companies, and many standard chemical supply companies (such as those listed above) offer custom synthesis services. References useful for the preparation and selection of the pharmaceutical salts of the compounds described herein are P. H. Stahl and C. G. Wermuth, "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, Switzerland, 2002.

[0225] Pharmaceutical composition

[0226] In certain embodiments, the TNFα inhibitory compounds described herein are administered in the form of pure chemicals. In other embodiments, the TNFα inhibitory compounds described herein are 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), and the carrier is selected according to the chosen route of administration and standard pharmaceutical practices described in the following references: for example, "Remington: The Science and Practice of Pharmacy" (Gennaro, 21st edition, Mack Pub. Co., Easton, PA (2005)).

[0227] Provided herein is a pharmaceutical composition comprising at least one TNFα inhibitory compound or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, as described herein, and one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other components of the composition and harmless to the recipient of the composition (i.e., the subject or patient).

[0228] 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.

[0229] One embodiment provides a method for preparing a pharmaceutical composition, the method comprising mixing a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate or N-oxide thereof and a pharmaceutically acceptable carrier.

[0230] In certain embodiments, the TNFα inhibitory compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate or N-oxide thereof is substantially pure as it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1% of other organic small molecules, such as unreacted intermediates or synthetic by-products generated in one or more steps of the synthetic method.

[0231] 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.

[0232] One embodiment provides a method for preparing a pharmaceutical composition, the method 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.

[0233] In certain embodiments, the TNFα inhibitory compound of Table 1 or Table 2 or a pharmaceutically acceptable salt, solvate or N-oxide thereof is substantially pure as it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1% of other organic small molecules, such as unreacted intermediates or synthetic by-products generated in one or more steps of the synthetic method.

[0234] Suitable oral dosage forms include, for example, tablets, pills, cachets or capsules of hard or soft gelatin, methylcellulose or another suitable material that readily dissolves in the digestive tract. In some embodiments, a suitable non-toxic solid carrier is used, which includes, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, etc. See, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21st ed. Mack Pub. Co., Easton, PA (2005)).

[0235] In some embodiments, a TNFα inhibitory compound or a pharmaceutically acceptable salt or solvate thereof, as described by formula (I) or (Ia) or in Table 1 or Table 2, is formulated for administration by injection. In some cases, the injection formulation is an aqueous formulation. In some cases, the injection formulation is a non-aqueous formulation. In some cases, the injection formulation is an oil-based formulation such as sesame oil.

[0236] The dosage of a composition comprising at least one TNFα inhibitory compound as described herein varies according to the condition of the subject or patient (e.g., human). In some embodiments, such factors include general health status, age, and other factors.

[0237] The pharmaceutical composition is administered in a manner suitable for the disease to be treated (or prevented). The appropriate dosage, appropriate duration, and frequency of administration will be determined by factors such as the condition of the patient, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. Generally, the appropriate dosage and treatment regimen provide one or more compositions in an amount sufficient to provide a therapeutic and / or prophylactic benefit (e.g., improvement in clinical outcomes such as more frequent complete or partial remission, or longer disease-free and / or overall survival or reduced symptom severity). The optimal dosage is typically determined using experimental models and / or clinical trials. The optimal dosage depends on the body mass, weight, or blood volume of the patient.

[0238] The oral dosage range is generally from about 1.0 mg to about 1000 mg per day, one to four or more times.

[0239] Methods of treatment

[0240] 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 treating a human or animal body.

[0241] 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 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 of 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 of treating an autoimmune disease or disorder.

[0242] 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 excipient for use in a method of treating an inflammatory or autoimmune disease or disorder.

[0243] One embodiment provides the use of a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate or N-oxide thereof for the preparation of a medicament for the treatment of an inflammatory or autoimmune disease or disorder.

[0244] 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 formula (I) or (Ia) 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 formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate or N-oxide thereof and a pharmaceutically acceptable excipient. One embodiment provides a method of treating an inflammatory disease or disorder. Another embodiment provides a method of treating an autoimmune disease or disorder.

[0245] 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 treating the human or animal body.

[0246] 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 treating an inflammatory or autoimmune disease or disorder.

[0247] 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 excipient for use in a method of treating an inflammatory or autoimmune disease or disorder.

[0248] One embodiment provides the use of a compound of Table 1 or Table 2 or a pharmaceutically acceptable salt, solvate or N-oxide thereof for the preparation of a medicament for the treatment of an inflammatory or autoimmune disease or disorder.

[0249] 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.

[0250] In some embodiments, the inflammatory and autoimmune diseases or disorders are selected from, but not limited to: rheumatoid arthritis, psoriatic arthritis, systemic juvenile idiopathic arthritis, multiple sclerosis, lupus nephritis, systemic lupus erythematosus, psoriasis, Crohn's disease, colitis, asthma, graft-versus-host disease, allograft rejection, chronic obstructive pulmonary disease, multiple sclerosis, Alzheimer's disease, Graves' disease, cutaneous lupus, ankylosing spondylitis, cryopyrin-associated periodic syndromes (CAPS), gout and gouty arthritis, ulcerative TNF receptor-associated periodic syndromes (TRAPS), Wegener's granulomatosis, sarcoidosis, familial Mediterranean fever (FMF), neuropathic pain, and adult onset stills disease.

[0251] Methods are provided herein for administering the pharmaceutical compositions orally. Methods are provided herein for administering the pharmaceutical compositions by injection.

[0252] One embodiment provides a method of inhibiting TNFα activity, the method comprising contacting the TNFα protein with a compound of formula (I) or (Ia) or Tables 1 or 2. Another embodiment provides a method of inhibiting TNFα activity, wherein the TNFα protein is contacted in a in vivo environment. Another embodiment provides a method of inhibiting TNFα activity, wherein the TNFα protein is contacted in a in vitro environment.

[0253] Other embodiments and uses will be apparent to those skilled in the art in light of the present disclosure. The following examples are provided only as illustrations of the various embodiments and should not be construed as limiting the invention in any way.

[0254] Examples

[0255] I. Chemical Synthesis

[0256] In some embodiments, the TNFα inhibitory compounds disclosed herein are synthesized according to the following examples. Unless otherwise indicated, as used herein and throughout the specification of the present invention, the following abbreviations are to be understood to have the following meanings:

[0257] ACN Acetonitrile

[0258] °C Degrees Celsius

[0259] δ H Chemical shift in parts per million relative to the low field of tetramethylsilane

[0260] DCM Dichloromethane (CH2Cl2)

[0261] DIAD Diisopropyl azodicarboxylate

[0262] DIEA Diisopropylethylamine

[0263] DMF N,N-Dimethylformamide

[0264] DMSO Dimethyl sulfoxide

[0265] EA Ethyl acetate

[0266] EtOAc Ethyl acetate

[0267] ESI Electrospray ionization

[0268] Et Ethyl

[0269] g Gram

[0270] h Hour

[0271] HPLC High performance liquid chromatography

[0272] Hz Hertz

[0273] J Coupling constant (in NMR spectroscopy)

[0274] LCMS Liquid chromatography mass spectrometry

[0275] μ Micro

[0276] m Multiplet (spectrum); meter; milli

[0277] M Mole

[0278] M + Parent molecular ion

[0279] Me Methyl

[0280] MsCl Methanesulfonyl chloride

[0281] MHz Megahertz

[0282] min Minute

[0283] mol Mole; molecule (in molwt)

[0284] mL Milliliter

[0285] MS Mass spectrometry

[0286] nm Nanometer

[0287] NMR Nuclear magnetic resonance

[0288] pH Hydrogen potential; amount of acidity or alkalinity of an aqueous solution

[0289] PE Petroleum ether

[0290] RT Room temperature

[0291] s Singlet (spectrum)

[0292] t Triplet (spectrum)

[0293] SFC Supercritical fluid chromatography

[0294] T Temperature

[0295] TFA Trifluoroacetic acid

[0296] THF Tetrahydrofuran

[0297] TPP Triphenylphosphine

[0298] Example 1: (7R,14R)-1-(Difluoromethoxy)-11-(2-(dimethylphosphoryl)pyrimidin-5-yl)-6,7-dihydro-7,14-methanobenz[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-5(14H)-one

[0299]

[0300] Synthesis scheme

[0301]

[0302] Preparation 1A: 2-Bromo-6-(difluoromethoxy)benzaldehyde

[0303]

[0304] At room temperature, a solution of NaOH (107.44 g, 2686.314 mmol) in H2O (900 mL) was added dropwise to a stirred solution of 2-bromo-6-hydroxybenzaldehyde (90.00 g, 447.719 mmol) in 1,4-dioxane (900 mL). The mixture was heated at 65 °C and chlorodifluoromethane (gas) was passed through the solution. The reaction mixture was cooled to room temperature. The resulting mixture was filtered and the cake was washed with EtOAc (3 x 100 mL). The filtrate was extracted with EtOAc (3 x 500 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (20:1) to give 2-bromo-6-(difluoromethoxy)benzaldehyde as a yellow oil (80.00 g, 71%). 11H 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).

[0305] Preparation 1B: (S)-N-{[2-Bromo-6-(difluoromethoxy)phenyl]methylene}-2-methylpropane-2-sulfinamide

[0306]

[0307] At room temperature, Cs2CO3 (207.67 g, 637.382 mmol) was added 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 CH2Cl2 (800 mL). 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 x 500 mL). The combined organic layers were washed with brine (1 x 1 L), 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 (10:1) to afford (S)-N-{[2-bromo-6-(difluoromethoxy)phenyl]methylene}-2-methylpropane-2-sulfinamide as a yellow oil (90.00 g, 80%). C 12 H 14 BrF2NO2S [M+H] + The calculated MS ESI values for 353.99 355.99, experimental values 353.80 355.75. 1 1H 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).

[0308] Preparation 1C: (3R)-3-[2-Bromo-6-(difluoromethoxy)phenyl]-3-{[(S)-2-methylpropane-2-sulfinyl]amino}propanoic acid ethyl ester

[0309]

[0310] At room temperature, anhydrous CuCl (5.59 g, 56.464 mmol) was added to a stirred mixture of Zn powder (36.92 g, 564.640 mmol) in THF (200 mL). The resulting mixture was stirred at 70 °C for 0.5 h. The mixture was cooled to room temperature. At room temperature, a solution of ethyl bromoacetate (23.57 g, 141.160 mmol) in THF (200 mL) was added dropwise to the above mixture. The resulting mixture was stirred at 50 °C for an additional 0.5 h. The resulting mixture was filtered. At 0 °C, a solution of (S)-N-{[2-bromo-6-(difluoromethoxy)phenyl]methylene}-2-methylpropane-2-sulfinamide (20.00 g, 56.464 mmol) in THF (20 mL) was added dropwise to the above filtrate. The resulting mixture was stirred at room temperature for an additional 2 h. The reaction solution was quenched with saturated NH4Cl (aqueous solution) 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 layers 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 CH2Cl2 / MeOH (10:1) to give ethyl (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-{[(S)-2-methylpropane-2-sulfinyl]amino}propionate (21.00 g, 84%) as a yellow oil. C 16 H 22 BrF2NO4S[M+H] + The calculated values of MS ESI for 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).

[0311] Preparation 1D: Ethyl (3R)-3-amino-3-[2-bromo-6-(difluoromethoxy)phenyl]propionate hydrochloride

[0312]

[0313] At room temperature, 4N HCl (gas) in 1,4-dioxane (70 mL) was added to a stirred solution of ethyl (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-{[(S)-2-methylpropan-2-ylsulfinyl]amino}propanoate (24.00 g, 54.259 mmol) in Et2O (50 mL) and EtOH (25 mL). The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure. This gave ethyl (3R)-3-amino-3-[2-bromo-6-(difluoromethoxy)phenyl]propanoate hydrochloride as a yellow oil (20.00 g, 98%). C 12 H 14 BrF2NO3[M+H] + The calculated MS ESI values for 338.01 340.01, experimental values 338.00 340.00.

[0314] Preparation 1E: Ethyl (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-[(5-chloro-2-nitrophenyl)amino]propanoate

[0315]

[0316] At room temperature, potassium carbonate (22.30 g, 160.167 mmol) was added 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). The mixture was stirred at 80 °C for 16 h. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (1 x 500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (10:1) to give ethyl (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-[(5-chloro-2-nitrophenyl)amino]propanoate as a yellow oil (20.00 g, 76%). C 18 H 16 BrClF2N2O5[M+H] + The calculated MS ESI values for 492.99 494.99, experimental values 492.95 494.85. 11H 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).

[0317] Preparation 1F: (3R)-3-[2-Bromo-6-(difluoromethoxy)phenyl]-3-[(5-chloro-2-nitrophenyl)amino]propanal

[0318]

[0319] At -78 °C under a nitrogen atmosphere, a solution of ethyl (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-[(5-chloro-2-nitrophenyl)amino]propionate (18.00 g, 36.460 mmol) in CH2Cl2 (200 mL) was stirred and a solution of 1N DIBAl-H in THF (73 mL, 73.000 mmol) was added dropwise. The reaction mixture was stirred at -78 °C under a nitrogen atmosphere for 3 hours. The resulting mixture was quenched with saturated NH4Cl (aqueous solution) at -78 °C and extracted with CH2Cl2 (3 x 500 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (10:1), to give (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-[(5-chloro-2-nitrophenyl)amino]propanal as a yellow oil (12.00 g, 73%). C 16 H 12 BrClF2N2O4 [M+H] + The calculated MS ESI values for 448.96 450.96, and the experimental values were 448.95 450.95. 11H 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).

[0320] Preparation 1G: (4R)-4-[2-Bromo-6-(difluoromethoxy)phenyl]-4-[(5-chloro-2-nitrophenyl)amino]-2-[(trimethylsilyl)oxy]butyronitrile

[0321]

[0322] At room temperature, ZnI2 (852 mg, 2.669 mmol) and TMSCN (5.30 g, 53.378 mmol) were added 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 CH2Cl2 (120 mL). The mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with water (50 mL) and extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford (4R)-4-[2-bromo-6-(difluoromethoxy)phenyl]-4-[(5-chloro-2-nitrophenyl)amino]-2-[(trimethylsilyl)oxy]butyronitrile as a yellow oil (13.00 g, 89%). The crude product was used directly in the next step without further purification. C 20 H 21 BrClF2N3O4Si [M+H] + The calculated value of MS ESI for BrClF2N3O4Si [M+H] is 548.01550.01, and the experimental value is 548.05550.00.

[0323] Preparation 1H: (3R)-3-[2-Bromo-6-(difluoromethoxy)phenyl]-11-chloro-2,7-diazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-5-ol

[0324]

[0325] At room temperature, SnCl2·2H2O (26.96 g, 118.430 mmol) was added to a stirred solution of (4R)-4-[2-bromo-6-(difluoromethoxy)phenyl]-4-[(5-chloro-2-nitrophenyl)amino]-2-[(trimethylsilyl)oxy]butyronitrile (13.00 g, 23.686 mmol) in EtOH (100 mL). The mixture was stirred at 80 °C for 16 h. The reaction was quenched by the addition of water (50 mL) at room temperature and basified to pH 8 with 1N KOH (aqueous solution). The mixture was filtered, the cake was washed with EtOAc (3 x 50 mL), and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:2) to give (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-11-chloro-2,7-diazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-5-ol (7.00 g, 69%) as a yellow solid. C 17 H 12 BrClF2N2O2[M+H] + The calculated MS ESI values for BrClF2N2O2[M+H] are 428.97 and 430.97, and the experimental values are 429.00 and 431.00.

[0326] Preparation 1I: (3R)-5-azido-3-[2-bromo-6-(difluoromethoxy)phenyl]-11-chloro-2,7-diazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraene

[0327]

[0328] At 0 °C, DPPA (16.91 g, 61.445 mmol) and DBU (15.59 g, 102.408 mmol) were added to a stirred solution of (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-11-chloro-2,7-diazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-5-ol (22.00 g, 51.204 mmol) in THF (200 mL). The mixture was stirred at room temperature for 16 h. The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (1 x 500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (20:1) to afford the desired mixture of (3R)-5-azido-3-[2-bromo-6-(difluoromethoxy)phenyl]-11-chloro-2,7-diazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraene as a green oil (15.00 g, 64%). C 17 H 11 BrClF2N5O[M+H] + The calculated MS ESI values for 453.98 455.98, and the experimental values were 454.05 456.05.

[0329] Preparation 1J: (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-11-chloro-2,7-diazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-5-amine

[0330]

[0331] At room temperature, PPh3 (12.98 g, 49.488 mmol) was added to a stirred solution of (3R)-5-azido-3-[2-bromo-6-(difluoromethoxy)phenyl]-11-chloro-2,7-diazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraene (15.00 g, 32.992 mmol) in THF (50 mL) and H2O (5 mL). 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 CH2Cl2 / MeOH (12:1) to afford (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-11-chloro-2,7-diazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-5-amine as a yellow solid (10 g, 71%). C 17 H13 BrClF2N3O[M+H] + The calculated MSESI values of BrClF2N3O[M+H] are 427.99 and 429.99, and the experimental values are 428.00 and 430.00. 1 1H 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).

[0332] Preparation 1K: (1R,11R)-5-chloro-18-(difluoromethoxy)-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0333]

[0334] In a pressure vessel, K2CO3 (806 mg, 5.830 mmol), XantPhos (34 mg, 0.058 mmol), and Pd(OAc)2 (13 mg, 0.058 mmol) were added 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). The mixture was purged with nitrogen for 5 minutes and then pressurized with carbon monoxide to 1 atm at 100 °C for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1) to give (1R,11R)-5-chloro-18-(difluoromethoxy)-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one as a white solid (200 mg, 46%). C 18 H 12 ClF2N3O2[M+H] + The calculated MSESI value of ClF2N3O2[M+H] is 376.06, and the experimental value is 375.95. 1HNMR (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).

[0335] Preparation of 1L: (1R,11R)-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0336]

[0337] At room temperature under a nitrogen atmosphere, to a stirred solution of (1R,11R)-5-chloro-18-(difluoromethoxy)-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icos-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) were added KOAc (39 mg, 0.399 mmol, Pd2(dba)3 (12 mg, 0.013 mmol) and PCy3.HBF4 (5 mg, 0.013 mmol). 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 CH2Cl2 / MeOH (10:1) to give (1R,11R)-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one as a yellow oil (22 mg, 35%). C 24 H 24 BF2N3O4 [M+H] + The calculated value of MS ESI for BF2N3O4 [M+H] is 468.18, and the experimental value is 467.95.

[0338] 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]diazacyclooctatetraen-5(14H)-one

[0339]

[0340] At room temperature under a nitrogen atmosphere, a solution of K3PO4 (30 mg, 0.141 mmol) in H2O (0.5 mL) was added 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}]icos-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). At room temperature, Pd(dppf)Cl2.CH2Cl2 (4 mg, 0.005 mmol) was added to the above mixture. The resulting mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. 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}]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one (15 mg, 64%) as a white solid. C 24 H 20 F2N5O3P[M+H] + The calculated value of MS ESI for F2N5O3P[M+H] is 496.13, and the experimental value is 496.20. 1 H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 2H), 9.16 (d, J = 6.8 Hz, 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). 1919F NMR (377 MHz, DMSO-d6) δ -81.53 (d, J = 169.3 Hz) (1F), -82.84 (d, J = 169.3 Hz) (1F). 31 31P NMR (162 MHz, DMSO-d6) δ 33.89.

[0341] Example 2: (7R,14R)-1-(Difluoromethoxy)-11-(6-(dimethylphosphoryl)pyridin-3-yl)-6-methyl-6,7-dihydro-7,14-methano-benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazacyclooctatetraen-5(14H)-one

[0342]

[0343] Preparation 2A: (1R,11R)-5-Chloro-18-(difluoromethoxy)-12-methyl-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0344]

[0345] Under nitrogen atmosphere at -78 °C, to a stirred solution of (1R,11R)-5-chloro-18-(difluoromethoxy)-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (120 mg, 0.319 mmol) in dry THF (2 mL) was added dropwise THF containing 1 N KHMDS (0.4 mL, 0.40 mmol). The reaction mixture was stirred at -78 °C under nitrogen atmosphere for 1 hour. At -78 °C, CH3I (68 mg, 0.479 mmol) was added dropwise to the above solution within 2 minutes. The mixture was stirred at room temperature for 1 hour. The reaction was quenched at room temperature by adding saturated NH4Cl (aqueous solution) (1 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1) to give (1R,11R)-5-chloro-18-(difluoromethoxy)-12-methyl-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one as a yellow solid (85 mg, 68%). C 19 H 14ClF2N3O2[M+H] + The calculated MS ESI values of + are 390.07 and 392.07, and the experimental values are 390.25 and 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).

[0346] Preparation 2B: (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0347]

[0348] At room temperature under a nitrogen atmosphere, PCy3·HBF4 (8 mg, 0.022 mmol) and Pd2(dba)3 (20 mg, 0.022 mmol) were added to a stirred mixture of (1R,11R)-5-chloro-18-(difluoromethoxy)-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-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). 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 CH2Cl2 / MeOH (10:1) to afford (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (65 mg, 62%) as a yellow oil. C 25 H 26 Calculated MS ESI for BF2N3O4[M+H] 482.20, found 481.90. +

[0349] Example 2: (7R,14R)-1-(Difluoromethoxy)-11-(6-(dimethylphosphoryl)pyridin-3-yl)-6-methyl-6,7-dihydro-7,14-methanobenz[f]benzo[4,5]imidazo[1,2-a][1,4]diazacyclooctatetraen-5(14H)-one

[0350]

[0351] At room temperature under a nitrogen atmosphere, a solution of K3PO4 (79 mg, 0.375 mmol) in H2O (1 mL) was added 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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-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). At room temperature under a nitrogen atmosphere, Pd(dppf)Cl 2· CH2Cl2 (10 mg, 0.013 mmol) was added to the above solution. 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), and the fraction containing the desired product was collected at 33% B, concentrated under reduced pressure to give (1R,11R)-18-(difluoromethoxy)-5-[6-(dimethylphosphoryl)pyridin-3-yl]-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (40 mg, 63%) as an off-white solid. C 26 H 23 F2N4O3P[M+H] + The MS ESI calculated value for 509.15, experimental 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 - 7.29 (m, 1H), 6.86 (t, J = 72.9 Hz, 1H), 6.31 (d, J = 7.1 Hz, 1H), 5.02 (d, J = 7.0 Hz, 1H), 3.54 (s, 3H), 3.53 - 3.45 (m, 1H), 2.91 (d, J = 13.6 Hz, 1H), 1.84 (s, 3H), 1.81 (s, 3H).19 19F NMR (377 MHz, chloroform-d) δ -80.73 (2F). 31 31P NMR (162 MHz, chloroform-d) δ 36.56.

[0352] Example 3: (7R,14R)-1-(Difluoromethoxy)-11-(6-(dimethylphosphoryl)pyridin-3-yl)-6,7-dihydro-7,14-methano-benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazacyclooctatetraen-5(14H)-one

[0353]

[0354] At room temperature under a nitrogen atmosphere, a solution of K3PO4 (68 mg, 0.321 mmol) in H2O (0.5 mL) was added 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[9.8.1.02,10.03,8.014,19]icos-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). Under a nitrogen atmosphere at room temperature, Pd(dppf)Cl 2· CH2Cl2 (9 mg, 0.011 mmol) was added to the above mixture. The mixture was stirred at 100 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 column 40 g; 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 afford (1R,11R)-18-(difluoromethoxy)-5-[6-(dimethylphosphoryl)pyridin-3-yl]-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one (25 mg, 47%) as a white solid. C 25 H 21 F2N4O3P [M+H] + The calculated value of MS ESI for 495.13, the experimental value 495.00. 11H 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 = 72.7 Hz, 1H), 6.42 (d, J = 7.2 Hz, 1H), 5.07 (t, J = 6.6 Hz, 1H), 3.57 - 3.47 (m, 1H), 2.91 (d, J = 13.3 Hz, 1H), 1.85 (s, 3H), 1.82 (s, 3H). 19 19F NMR (377 MHz, chloroform-d) δ -80.82 (1F), -80.83 (1F). 31 31P NMR (162 MHz, chloroform-d) δ 36.48.

[0355] Example 4: (7R,14R)-1-(Difluoromethoxy)-11-(6-(dimethylphosphoryl)-5-fluoropyridin-3-yl)-6-methyl-6,7-dihydro-7,14-methano-benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazacyclooctatetraen-5(14H)-one

[0356]

[0357] Preparation 4A: 5-Bromo-2-(dimethylphosphoryl)-3-fluoropyridine

[0358]

[0359] At room temperature, Pd2(dba)3 (898 mg, 0.981 mmol) and TEA (3.3 mL, 23.540 mmol) were added to a stirred solution of 2,5-dibromo-3-fluoropyridine (5.00 g, 19.617 mmol) and (methylphosphoryl)methane (1.68 g, 21.579 mmol) in 1,4-dioxane (50 mL). 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 CH2Cl2 / MeOH (10:1) to give 5-bromo-2-(dimethylphosphoryl)-3-fluoropyridine as a brown solid (1.78 g, 36%). C7H8BrFNOP [M+H] + The calculated values of MS ESI for 251.95 253.95, the experimental values 251.95 253.95.1 1H NMR (300 MHz, chloroform-d) δ 8.65 (s, 1H), 7.76 - 7.69 (m, 1H), 1.90 (s, 3H), 1.87 (s, 3H).

[0360] Example 4: (7R,14R)-1-(Difluoromethoxy)-11-(6-(dimethylphosphoryl)-5-fluoropyridin-3-yl)-6-methyl-6,7-dihydro-7,14-methano-benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazacyclooctatetraen-5(14H)-one

[0361]

[0362] At room temperature under a nitrogen atmosphere, 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-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-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 H2O (0.5 mL). At room temperature under a nitrogen atmosphere, to the above solution was added Pd(dppf)Cl 2· CH2Cl2 (8 mg, 0.010 mmol). The resulting mixture was stirred at 100 °C for 2 h. The mixture was cooled 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 afford (1R,11R)-18-(difluoromethoxy)-5-[6-(dimethylphosphoryl)-5-fluoropyridin-3-yl]-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one as a white solid (16 mg, 29%). C 26 H 22 F3N4O3P [M+H] +The calculated value of MS ESI is 527.14, and the experimental value is 527.20. 1 H NMR (300 MHz, 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 = 72.8 Hz, 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).

[0363] Example 5: (1R,11R)-18-(difluoromethoxy)-12-methyl-5-[6-(1-oxo-1λ5-phospholane-1-yl)pyridin-3-yl]-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0364]

[0365] Preparation 5A: 1λ5-Phospholane-1-one

[0366]

[0367] To a solution of 1,4-dibromobutane (19.62 g, 90.868 mmol) in THF (100 mL) was added active magnesium powder (4.42 g, 181.736 mmol) portionwise. The mixture was stirred at <30 °C for 2 h. At <30 °C, 50 mL of THF containing dimethyl phosphite (5.00 g, 45.434 mmol) was added dropwise to the above mixture over 0.5 h. The resulting mixture was stirred at room temperature for an additional 1 h. The reaction solution was quenched by adding an aqueous solution (50 mL) containing 20 g of K2CO3 at 20 °C. The resulting mixture was filtered, and the filter cake was washed with EtOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. This gave 1λ5-phospholane-1-one (3.10 g, 51%) as a colorless oil. 3131P NMR (162 MHz, chloroform-d) δ 47.62 (1P).

[0368] Preparation of 5B: 1-(5-Bromopyridin-2-yl)-1λ5-phospholane-1-one

[0369]

[0370] 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 for 15 minutes under a nitrogen atmosphere. At room temperature under a nitrogen atmosphere, 5-bromo-2-iodopyridine (1.00 g, 3.522 mmol) and 1λ5-phospholane-1-one (1.47 g, 14.088 mmol) were added to the above mixture. The resulting mixture was stirred at 80 °C for an additional overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (20:1) to afford 1-(5-bromopyridin-2-yl)-1λ5-phospholane-1-one as a yellow solid (218 mg, 23%). C9H 11 BrNOP [M+H] + The calculated values of MS ESI for 259.98 261.98, experimental values 259.90 261.90. 1 1H 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).

[0371] Example 5: (1R,11R)-18-(Difluoromethoxy)-12-methyl-5-[6-(1-oxo-1λ5-phospholane-1-yl)pyridin-3-yl]-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0372]

[0373] At room temperature, a solution of K3PO4 (66 mg, 0.312 mmol) in H2O (0.5 mL) was added 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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.104 mmol) and 1-(5-bromopyridin-2-yl)-1λ5-phospholane-1-one (27 mg, 0.104 mmol) in 1,4-dioxane (2 mL). Under a nitrogen atmosphere at room temperature, Pd(dppf)Cl 2· CH2Cl2 (8 mg, 0.010 mmol) was added to the above solution. The resulting mixture was stirred at 100 °C for an additional 2 h. The mixture was cooled 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%), and then 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 afford (1R,11R)-18-(difluoromethoxy)-12-methyl-5-[6-(1-oxo-1λ5-phospholan-1-yl)pyridin-3-yl]-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (25 mg, 45%) as a white solid. C 28 H 25 F2N4O3P[M+H] + The calculated value of MS ESI for 535.16, the experimental 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). 1919F NMR (282 MHz, chloroform-d) δ -80.73 (2F). 31 31P NMR (122 MHz, chloroform-d) δ 62.17 (1P).

[0374] Example 6: (1R,11R)-18-(difluoromethoxy)-12-methyl-5-[6-(4-oxo-1,4λ5-oxaphosphinan-4-yl)pyridin-3-yl]-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0375]

[0376] Preparation 6A: 4-Hydroxy-1,4λ5-oxaphosphinan-4-one

[0377]

[0378] A mixture of ammonium hypophosphite (3.49 g, 43.119 mmol) and hexamethyldisilazane (13.92 g, 86.238 mmol) was stirred at 120 °C under a nitrogen atmosphere for 4 h. At 120 °C, 1-bromo-2-(2-bromoethoxy)ethane (10.00 g, 43.119 mmol) was added dropwise to the above mixture over 10 min. The resulting mixture was stirred at 120 °C for an additional 4 h. The mixture was cooled to room temperature and EtOH (20 mL) was added. The resulting mixture was stirred at 100 °C for an additional 1 h. The resulting mixture was allowed to cool to room temperature. The mixture was filtered and the cake was washed with dichloromethane (2 x 10 mL). The filtrate was concentrated under reduced pressure to afford crude 4-hydroxy-1,4λ5-oxaphosphinan-4-one as a yellow liquid (7.40 g, 25%). The crude product was used directly in the next step without further purification.

[0379] Preparation 6B: 4-Chloro-1,4λ5-oxaphosphinan-4-one

[0380]

[0381] At 0 °C under a nitrogen atmosphere, oxalyl chloride (9.20 g, 72.454 mmol) was added dropwise to a stirred solution of 4-hydroxy-1,4λ5-oxaphosphinan-4-one (5.80 g, 42.620 mmol) in DCM (60 mL). 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 under vacuum to give crude 4-chloro-1,4λ5-oxaphosphinan-4-one as a yellow liquid (6.00 g, 91%). The crude product was used directly in the next step without further purification.

[0382] Preparation of 6C: 1,4λ5-oxaphosphinan-4-one

[0383]

[0384] At -78 °C under a nitrogen atmosphere, 1N DIBAL-H (36.24 mL, 36.239 mmol) was added dropwise to a stirred solution of 4-chloro-1,4λ5-oxaphosphinan-4-one (5.60 g, 36.239 mmol) in DCM (60 mL). The resulting mixture was stirred at -78 °C for 2 h. The reaction solution was quenched by adding CH3OH (6 mL) at -78 °C, and then this reaction solution was stirred at -78 °C for 5 min. The mixture was warmed to 0 °C, and 10% aqueous acetic acid solution (50 mL) was added. The resulting mixture was extracted with DCM (5 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give crude 1,4λ5-oxaphosphinan-4-one as a yellow oil (2.50 g, 57%). C4H9O2P [M+H] + The calculated value of MS ESI for 121.03, the experimental value is 121.25.

[0385] Preparation of 6D: 4-(5-bromopyridin-2-yl)-1,4λ5-oxaphosphinan-4-one

[0386]

[0387] 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 for 10 minutes at room temperature under a nitrogen atmosphere. At room temperature, 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) was added to the above mixture. The resulting mixture was stirred for an additional 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 CH2Cl2 / MeOH (20:1) to afford 4-(5-bromopyridin-2-yl)-1,4λ5-oxaphosphinan-4-one (260 mg, 33%) as a white solid. C9H 11 BrNO2P[M+H] + The calculated MS ESI values for 275.97 277.97, found 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).

[0388] Example 6: (1R,11R)-18-(difluoromethoxy)-12-methyl-5-[6-(4-oxo-1,4λ5-oxaphosphinan-4-yl)pyridin-3-yl]-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0389]

[0390] At room temperature under a nitrogen atmosphere, a solution of K3PO4 (66 mg, 0.312 mmol) in H2O (0.5 mL) was added 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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.104 mmol) and 4-(5-bromopyridin-2-yl)-1,4λ5-oxaphosphinan-4-one (29 mg, 0.104 mmol) in 1,4-dioxane (2 mL). At room temperature under a nitrogen atmosphere, Pd(dppf)Cl 2· CH2Cl2 (8 mg, 0.010 mmol) was added to the above solution. The resulting mixture was stirred at 100 °C for an additional 2 h. The mixture was cooled 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%), and then by preparative HPLC (column: 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 afford (1R,11R)-18-(difluoromethoxy)-12-methyl-5-[6-(4-oxo-1,4λ5-oxaphosphinan-4-yl)pyridin-3-yl]-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one as a white solid (25 mg, 44%). C 28 H 25 F2N4O4P[M+H] + The calculated value of MS ESI for 551.16, the experimental value is 551.05. 11H NMR (300 MHz, 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 = 73.1 Hz, 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 19F NMR (282 MHz, chloroform-d) δ -80.71 (2F). 31 31P NMR (122 MHz, chloroform-d) δ 25.96 (1P).

[0391] Example 7: (1R,11R)-18-(Difluoromethoxy)-5-{6-[(dimethylphosphoryl)methoxy]pyridin-3-yl}-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0392]

[0393] Preparation 7A: 5-Bromo-2-[(dimethylphosphoryl)methoxy]pyridine

[0394]

[0395] At room temperature, K2CO3 (5.48 g, 39.657 mmol) was added 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). The mixture was stirred overnight at 100 °C. The resulting mixture was cooled to room temperature and purified by reverse-phase flash chromatography to afford 5-bromo-2-[(dimethylphosphoryl)methoxy]pyridine as a yellow solid (538 mg, 29%). C8H 11 BrNO2P [M+H] + The calculated MS ESI values for 263.97 265.97, found 264.00 266.00. 11H 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).

[0396] Example 7: (1R,11R)-18-(Difluoromethoxy)-5-{6-[(dimethylphosphoryl)methoxy]pyridin-3-yl}-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0397]

[0398] At room temperature under a nitrogen atmosphere, a solution of K3PO4 (66 mg, 0.312 mmol) in H2O (0.5 mL) was added 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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-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). At room temperature under a nitrogen atmosphere, Pd(dppf)Cl 2· CH2Cl2 (8 mg, 0.010 mmol) was added to the above solution. The resulting mixture was stirred at 100 °C for 2 h. The mixture was cooled 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 afford (1R,11R)-18-(difluoromethoxy)-5-{6-[(dimethylphosphoryl)methoxy]pyridin-3-yl}-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one as a white solid (20 mg, 36%). C27 H 25 F2N4O4P[M+H] + The calculated value of MS ESI is 539.16, and the experimental value is 539.20. 1 H NMR (300 MHz, 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 = 72.9 Hz, 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).

[0399] Example 8: (1R,11R)-18-(Difluoromethoxy)-5-[2-(dimethylphosphoryl)pyrimidin-5-yl]-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0400]

[0401] At room temperature under a nitrogen atmosphere, 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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icos-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 K3PO4 (66 mg, 0.312 mmol) in H2O (0.5 mL). At room temperature under a nitrogen atmosphere, to the above solution was added Pd(dppf)Cl 2·CH2Cl2 (8 mg, 0.010 mmol). The resulting mixture was stirred at 100 °C for 2 h. The mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (0% to 10%), followed by purification 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 afford (1R,11R)-18-(difluoromethoxy)-5-[2-(dimethylphosphoryl)pyrimidin-5-yl]-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one as a white solid (20 mg, 38%). C 25 H 22 F2N5O3P [M+H] + The calculated MS ESI value of F2N5O3P [M+H] is 510.14, and the experimental value is 510.15. 1 1H NMR (300 MHz, 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 = 72.7 Hz, 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 19F NMR (282 MHz, chloroform-d) δ -80.68 (1F), -80.76 (1F). 31 31P NMR (162 MHz, chloroform-d) δ 34.60 (1P).

[0402] Example 9: (1R,11R)-18-(difluoromethoxy)-5-{2-[(dimethylphosphoryl)methoxy]pyrimidin-5-yl}-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0403]

[0404] Preparation 9A: 5-Bromo-2-[(dimethylphosphoryl)methoxy]pyrimidine

[0405]

[0406] At room temperature, K2CO3 (7.50 g, 54.282 mmol) was added 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). The resulting mixture was stirred at 80 °C for 16 h. The resulting mixture was diluted with water (250 mL) and extracted with CH2Cl2 (3 x 100 mL). The combined organic layers were washed with brine (5 x 50 mL), 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 (10:1) to afford 5-bromo-2-[(dimethylphosphoryl)methoxy]pyrimidine as a white solid (3.90 g, 81%). C7H 10 BrN2O2P[M+H] + The calculated MS ESI value of 264.97 266.97 for 1 H NMR (300 MHz, MeOD) δ 8.70 (s, 2H), 4.78 (d, J = 5.5 Hz, 2H), 1.69 (s, 3H), 1.65 (s, 3H).[[ID=...]] [[ID=...]]

[0407] [[ID=...]] [[ID=...]]

[0408] [[ID=...]] [[ID=...]] [[ID=...]]

[0409] ​Under a nitrogen atmosphere at room temperature, a solution of K3PO4 (66 mg, 0.312 mmol) in H2O (0.5 mL) was added 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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-hepten-13-one (50 mg, 0.104 mmol) and 4-(5-bromopyridin-2-yl)-1,4λ5-oxaphosphinan-4-one (29 mg, 0.104 mmol) in 1,4-dioxane (2 mL). Under a nitrogen atmosphere at room temperature, Pd(dppf)Cl 2· CH2Cl2 (8 mg, 0.010 mmol) was added to the above solution. The resulting mixture was stirred at 100 °C for an additional 2 h. The mixture was cooled 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%), and then purified by preparative HPLC under the following conditions: column: 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-{2-[(dimethylphosphoryl)methoxy]pyrimidin-5-yl}-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-hepten-13-one (25 mg, 45%) as a white solid. C 26 H 24 F2N5O4P[M+H] + The calculated value of MSESI for is 540.15, and the experimental value is 540.20. 11H NMR (400 MHz, chloroform-d) δ 8.75 (s, 2H), 8.53 - 8.47 (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 = 72.8 Hz, 1H), 6.32 (d, J = 7.2 Hz, 1H), 5.10 (d, J = 7.1 Hz, 1H), 4.81 (d, J = 6.9 Hz, 2H), 3.52 - 3.48 (m, 4H), 2.92 (d, J = 13.6 Hz, 1H), 1.74 (s, 3H), 1.70 (s, 3H). 19 19F NMR (377 MHz, chloroform-d) δ -80.73 (1F), -80.90 (1F). 31 31P NMR (162 MHz, chloroform-d) δ 43.56 (1P).

[0410] Example 10: (1R,11R)-18-(Difluoromethoxy)-5-{6-[(dimethylphosphoryl)methoxy]-5-fluoropyridin-3-yl}-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0411]

[0412] Preparation 10A: 5-Bromo-2-[(dimethylphosphoryl)methoxy]-3-fluoropyridine

[0413]

[0414] 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 minutes. At room temperature, 5-bromo-2,3-difluoropyridine (100 mg, 0.516 mmol) was added to the above mixture. The resulting mixture was stirred at room temperature for an additional 3 hours. The reaction solution was quenched with water and purified by reverse-phase flash chromatography (C18 silica gel; mobile phase, aqueous CH3CN solution (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 minutes; detector, 254 nm) to obtain 5-bromo-2-[(dimethylphosphoryl)methoxy]-3-fluoropyridine as a white solid (120 mg, 82%). C8H 10 BrFNO2P [M+H] +The calculated value of MS ESI is 281.96, and the experimental value is 281.9. 1 1H 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).

[0415] Example 10: (1R,11R)-18-(Difluoromethoxy)-5-{6-[(dimethylphosphoryl)methoxy]-5-fluoropyridin-3-yl}-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0416]

[0417] To a solution of 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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.104 mmol) in dioxane (0.5 mL) and H2O (0.1 mL) was added K3PO4 (66 mg, 0.312 mmol) and Pd(dppf)Cl2.CH2Cl2 (8 mg, 0.010 mmol). After stirring at 100 °C for 2 h under a nitrogen atmosphere, the mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH, 0% to 10%) and then by preparative HPLC (C18 silica; mobile phase, aqueous CH3CN solution (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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one as a white solid (19 mg, 32%). C 27 H 24 F3N4O4P [M+H]+ The calculated value of MS ESI is 557.15, and the experimental value is 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 = 72.9 Hz, 1H), 6.29 (d, J = 7.1 Hz, 1H), 4.99 (d, J = 7.1 Hz, 1H), 4.79 (d, J = 6.4 Hz, 2H), 3.53 (s, 3H), 3.52 - 3.42 (m, 1H), 2.90 (d, J = 13.5 Hz, 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).

[0418] Example 11: (1R,11R)-18-(Difluoromethoxy)-5-{6-[(dimethylphosphoryl)methoxy]pyridin-3-yl}-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0419]

[0420] At room temperature, to a stirred solution of (1R,11R)-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icosane

[0421] -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 K3PO4 (82 mg, 0.384 mmol) in H2O (0.5 mL). At room temperature under a nitrogen atmosphere, to the above solution was added Pd(dppf)Cl 2·CH2Cl2 (10 mg, 0.013 mmol). The resulting mixture was stirred at 100 °C for 2 h. The mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH, 0% to 10%) and then 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-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (35 mg, 52%) as a white solid.

[0422] C 26 H 23 F2N4O4P[M+H] + The calculated value of MS ESI for 23 is 525.14, and the experimental value is 525.20. 1 1H NMR (400 MHz, 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 = 7.2 Hz, 1H), 4.99 (t, J = 6.6 Hz, 1H), 4.75 (d, J = 6.0 Hz, 2H), 3.55 - 3.40 (m, 1H), 2.88 (d, J = 13.3 Hz, 1H), 1.66 (s, 3H), 1.63 (s, 3H). 19 19F NMR (377 MHz, chloroform-d) δ -80.79 (2F). 31 31P NMR (162 MHz, chloroform-d) δ 41.85 (1P).

[0423] Example 12: (1R,11R)-18-(difluoromethoxy)-5-{2-[(dimethylphosphoryl)methoxy]pyrimidin-5-yl}-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0424]

[0425] At room temperature, a solution of K3PO4 (82 mg, 0.384 mmol) in H2O (0.5 mL) was added to a stirred solution of (1R,11R)-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-hepten-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). Under a nitrogen atmosphere at room temperature, Pd(dppf)Cl 2· CH2Cl2 (10 mg, 0.013 mmol) was added to the above solution. The resulting mixture was stirred at 100 °C for 2 h. The mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH, 0% to 10%) and then 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 afford (1R,11R)-18-(difluoromethoxy)-5-{2-[(dimethylphosphoryl)methoxy]pyrimidin-5-yl}-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-hepten-13-one (35 mg, 52%) as a white solid. C 25 H 22 F2N5O4P[M+H] + The calculated value of MS ESI for 526.14, the experimental value is 526.05. 1 H NMR (400 MHz, DMSO-d6) δ 9.15 (d, J = 6.9 Hz, 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 = 7.1 Hz, 1H), 4.89 (t, J = 6.8 Hz, 1H), 4.70 (d, J = 5.2 Hz, 2H), 3.53 - 3.44 (m, 1H), 2.75 (d, J = 13.3 Hz, 1H), 1.56 (s, 3H), 1.52 (s, 3H). 1919F NMR (377 MHz, DMSO-d6) δ -81.89 (1F), -82.58 (1F). 31 31P NMR (162 MHz, DMSO-d6) δ 37.61 (1P).

[0426] Example 13: (1R,11R)-18-(Difluoromethoxy)-5-[4-(dimethylphosphoryl)phenyl]-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0427]

[0428] Preparation 13A: 1-Bromo-4-(dimethylphosphoryl)benzene

[0429]

[0430] At room temperature under a nitrogen atmosphere, Xantphos (4.09 g, 7.069 mmol), TEA (8.58 g, 84.834 mmol), and Pd2(dba)3 (3.24 g, 3.535 mmol) were added to a stirred solution of 4-bromoiodobenzene (20.00 g, 70.695 mmol) and (methylhydrogenphosphorylidene)methane (5.52 g, 70.695 mmol) in 1,4-dioxane (200 mL). The resulting mixture was stirred at 100 °C for 4 h under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH, 10:1) to afford 1-bromo-4-(dimethylphosphoryl)benzene (14.10 g, 85%) as a yellow solid. C8H 10 BrOP [M+H] + The calculated MS ESI values for 232.97 234.97, and the experimental values were 233.00 235.00. 1 1H NMR (300 MHz, chloroform-d) δ 7.69 - 7.48 (m, 4H), 1.74 (s, 3H), 1.70 (s, 3H).

[0431] Example 13: (1R,11R)-18-(Difluoromethoxy)-5-[4-(dimethylphosphoryl)phenyl]-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0432]

[0433] A mixture of (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (60 mg, 0.125 mmol), 1-bromo-4-(dimethylphosphoryl)benzene (34 mg, 0.150 mmol), K3PO4 (79 mg, 0.375 mmol) and Pd(dppf)Cl2.CH2Cl2 (10 mg, 0.013 mmol) in dioxane (1 mL) and H2O (0.2 mL) was stirred at 100 °C for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH, 0% to 10%) and then 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 afford (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)phenyl]-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one as a white solid (23 mg, 36%). C 27 H 24 F2N3O3P [M+H] + The calculated value of MS ESI for F2N3O3P [M+H] is 508.15, and the experimental value is 508.25. 1 1H NMR (300 MHz, 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 = 8.2 Hz, 1H), 7.37 - 7.30 (m, 1H), 6.87 (t, J = 72.8 Hz, 1H), 6.34 (d, J = 6.9 Hz, 1H), 5.08 (d, J = 6.7 Hz, 1H), 3.57 (s, 3H), 3.56 - 3.43 (m, 1H), 2.93 (d, J = 13.5 Hz, 1H), 1.83 (s, 3H), 1.79 (s, 3H). 19 19F NMR (282 MHz, chloroform-d) δ -80.70 (2F). 3131P NMR (121 MHz, chloroform-d) δ 34.00 (1P).

[0434] Example 14: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3-fluorophenyl]-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0435]

[0436] Preparation 14A: 4-bromo-1-(dimethylphosphoryl)-2-fluorobenzene

[0437]

[0438] At room temperature under a nitrogen atmosphere, TEA (0.81 g, 7.976 mmol), Xantphos (0.38 g, 0.665 mmol) and Pd2(dba)3 (0.30 g, 0.332 mmol) were added to a solution of 4-bromo-2-fluoro-1-iodobenzene (2.00 g, 6.647 mmol) and (methylhydrophosphorylidene)methane (0.57 g, 7.312 mmol) in 1,4-dioxane (20 mL). 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 layer was extracted with CH2Cl2 (3 x 100 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4. 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. C8H9BrFOP [M+H] + The calculated value of MS ESI for 250.96 252.96, the experimental value 250.90 252.90. 1 1H 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).

[0439] Example 14: (1R,11R)-18-(Difluoromethoxy)-5-[4-(dimethylphosphoryl)-3-fluorophenyl]-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icos-3(8),4,6,9,14(19),15,17-hepten-13-one

[0440]

[0441] A mixture of (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icos-3(8),4,6,9,14(19),15,17-hepten-13-one (60 mg, 0.125 mmol), 4-bromo-1-(dimethylphosphoryl)-2-fluorobenzene (37 mg, 0.150 mmol), K3PO4 (79 mg, 0.375 mmol) and Pd(dppf)Cl2.CH2Cl2 (10 mg, 0.013 mmol) in 1,4-dioxane (1 mL) and H2O (0.2 mL) was stirred at 100 °C for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH, 0% to 10%) and then 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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icos-3(8),4,6,9,14(19),15,17-hepten-13-one as a white solid (17 mg, 26%). C 27 H 23 F3N3O3P[M+H] + The calculated value of MS ESI for F3N3O3P[M+H] is 526.14, and the experimental value is 526.30. 11H NMR (300 MHz, chloroform-d) δ 8.52 (d, J = 8.2 Hz, 1H), 8.14 - 7.98 (m, 1H), 7.89 - 7.76 (m, 2H), 7.62 - 7.52 (m, 2H), 7.47 (t, J = 8.2 Hz, 1H), 7.41 - 7.31 (m, 2H), 6.89 (t, J = 72.9 Hz, 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 19F NMR (282 MHz, chloroform-d) δ -80.79 (2F), -105.70 (1F). 31 31P NMR (121 MHz, chloroform-d) δ 30.54 (1P).

[0442] Example 15: (7R,14R)-1-(Difluoromethoxy)-11-(6-((dimethylphosphoryl)methoxy)pyridin-3-yl)-6-(methyl-d3)-6,7-dihydro-7,14-methano-benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-5(14H)-one

[0443]

[0444] Preparation 15A: (7R,14R)-11-Chloro-1-(difluoromethoxy)-6-(methyl-d3)-6,7-dihydro-7,14-methano-benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-5(14H)-one

[0445]

[0446] At -78 °C under a nitrogen atmosphere, a solution of 1N KHMDS (0.96 mL, 0.958 mmol) in THF was added dropwise to a stirred solution of (1R,11R)-5-chloro-18-(difluoromethoxy)-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (300 mg, 0.798 mmol) in dry THF (6 mL). The resulting solution was stirred at -78 °C under a nitrogen atmosphere for 1 hour. At -78 °C, iodomethane-d3 (231 mg, 1.596 mmol) was added dropwise to the above solution over 2 minutes. The resulting mixture was slowly warmed to room temperature and stirred at room temperature under a nitrogen atmosphere for 3 hours. The resulting solution was quenched by the addition of saturated NH4Cl (aqueous solution) (10 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with brine (20 mL), 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 (CH2Cl2 / MeOH, 10:1) to give (7R,14R)-11-chloro-1-(difluoromethoxy)-6-(methyl-d3)-6,7-dihydro-7,14-methano-benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazacyclooctatetraen-5(14H)-one (290 mg, 92%) as a white solid. C 19 H 11 D3ClF2N3O2[M+H] + The calculated values of MS ESI for D3ClF2N3O2[M+H] are 393.09 and 395.09, and the experimental values are 393.05 and 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

[0447] -2.84 (m, 1H).

[0448] Preparation of 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-methanobenz[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-5(14H)-one

[0449]

[0450] At room temperature under a nitrogen atmosphere, PCy3.HBF4 (28 mg, 0.076 mmol) and Pd2(dba)3 (70 mg, 0.076 mmol) were added to a stirred mixture of (1R,11R)-5-chloro-18-(difluoromethoxy)-12-(2H3)methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-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). The resulting mixture was stirred at 140 °C for 16 h 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 CH2Cl2 / MeOH (10:1) to afford (7R,14R)-1-(difluoromethoxy)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenz[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-5(14H)-one (300 mg, 81%). C 25 H 23 D3BF2N3O4[M+H] + The calculated value of MS ESI for 485.22, the experimental value 485.20.

[0451] Example 15: (7R,14R)-1-(Difluoromethoxy)-11-(6-((dimethylphosphoryl)methoxy)pyridin-3-yl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenz[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-5(14H)-one

[0452]

[0453] At room temperature under a nitrogen atmosphere, a solution of K3PO4 (66 mg, 0.309 mmol) in H2O (0.5 mL) was added 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]diazocine-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). At room temperature under a nitrogen atmosphere, Pd(dppf)Cl 2· CH2Cl2 (8 mg, 0.010 mmol) was added to the above solution. The resulting mixture was stirred at 100 °C for an additional 2 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH, 0% to 10%) and then 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]diazocine-5(14H)-one (20 mg, 36%) as a white solid. C 27 H 22 D3F2N4O4P [M+H] + The calculated value of MS ESI for 542.18 and the experimental value was 542.25. 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 2.5 Hz, 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), 6.30 - 6.28 (m, 1H), 5.23 - 5.21 (m, 1H), 4.63 (d, J = 5.2 Hz, 2H), 3.48 - 3.40 (m, 1H), 2.83 - 2.80 (m, 1H), 1.54 (s, 3H), 1.51 (s, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -82.00 (1F), -82.15 (1F). 3131P NMR (162 MHz, DMSO-d6) δ 39.72 (1P).

[0454] Example 16: (1R,11R)-18-(difluoromethoxy)-5-(6-{[(dimethylphosphoryl)methyl]amino}-5-fluoropyridin-3-yl)-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0455]

[0456] Preparation 16A: 5-Bromo-N-[(dimethylphosphoryl)methyl]-3-fluoropyridin-2-amine

[0457]

[0458] At room temperature, sodium hydride (120 mg, 3.011 mmol, 60% in oil) was added portionwise to a solution of 5-bromo-3-fluoropyridin-2-amine (500 mg, 2.618 mmol) in THF (10 mL). The mixture was stirred at room temperature for 30 minutes. Then chloro(dimethylphosphoryl)methane (380 mg, 3.011 mmol) was added and the mixture was warmed to 50 °C and stirred for 3 hours. The reaction mixture was quenched with water and extracted with DCM (3 x 25 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 minutes; detector, 254 nm. This gave 5-bromo-N-[(dimethylphosphoryl)methyl]-3-fluoropyridin-2-amine as a white solid (227 mg, 30%). C8H 11 BrFN2OP [M+H] + The calculated value of MS ESI for 280.98, the experimental value 280.9. 1 1H 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).

[0459] Example 16: (1R,11R)-18-(difluoromethoxy)-5-(6-{[(dimethylphosphoryl)methyl]amino}-5-fluoropyridin-3-yl)-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-hepten-13-one

[0460]

[0461] To a solution of 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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-hepten-13-one (50 mg, 0.104 mmol) in 1,4-dioxane (0.5 mL) and H2O (0.1 mL) was added K3PO4 (66 mg, 0.312 mmol) and Pd(dppf)Cl2.CH2Cl2 (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, and the cake was washed with CH3OH (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 min; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-(6-{[(dimethylphosphoryl)methyl]amino}-5-fluoropyridin-3-yl)-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-hepten-13-one as a white solid (30 mg, 52%). C 27 H 25 F3N5O3P[M+H] + The calculated MSESI value for 556.16, experimental value 556.10. 11H NMR (300 MHz, 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 = 72.9 Hz, 1H), 6.27 (d, J = 7.2 Hz, 1H), 5.36 - 5.26 (m, 1H), 4.97 (d, J = 7.1 Hz, 1H), 4.03 (t, J = 6.0 Hz, 2H), 3.52 (s, 3H), 3.51 - 3.41 (m, 1H), 2.88 (d, J = 13.6 Hz, 1H), 1.61 (s, 3H), 1.57 (s, 3H). 19 19F NMR (282 MHz, chloroform-d) δ -80.68 (1F), -80.73 (1F), -140.77 (1F). 31 31P NMR (122 MHz, chloroform-d) δ 42.22 (1P).

[0462] Example 17: (7R,14R)-1-(Difluoromethoxy)-11-(6-(dimethylphosphoryl)pyridin-3-yl)-6-(methyl-d3)-6,7-dihydro-7,14-methano-benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazacyclooctatetraen-5(14H)-one

[0463]

[0464] At room temperature under a nitrogen atmosphere, 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-methano-benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazacyclooctatetraen-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 H2O (0.5 mL). At room temperature under a nitrogen atmosphere, to the above solution was added Pd(dppf)Cl 2·CH2Cl2 (8 mg, 0.010 mmol). The resulting mixture was stirred at 100 °C for 2 h. The mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (0% to 10%), followed by purification by preparative HPLC under the following conditions: column: 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)pyridin-3-yl)-6-(methyl-d3)-6,7-dihydro-7,14-methano-benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazacyclotetradecin-5(14H)-one as a white solid (20 mg, 38%). C 26 H 20 D3F2N4O3P [M+H] + The calculated value of MS ESI for D3F2N4O3P [M+H] is 512.17, and the experimental value is 512.20. 1 1H NMR (400 MHz, 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). 19 19F NMR (377 MHz, DMSO-d6) δ -81.82 (1F), -82.28 (1F). 31 31P NMR (162 MHz, DMSO-d6) δ 34.01 (1P).

[0465] Example 18: (1R,11R)-18-(difluoromethoxy)-5-{4-[(dimethylphosphoryl)methoxy]-3-fluorophenyl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0466]

[0467] Preparation 18A: 4-bromo-1-[(dimethylphosphoryl)methoxy]-2-fluorobenzene

[0468]

[0469] At room temperature, a solution of 4-bromo-2-fluorophenol (200 mg, 1.047 mmol) in CH3CN (4 mL) was treated with K2CO3 (434 mg, 3.141 mmol) and NaI (16 mg, 0.105 mmol) 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 CH2Cl2 / MeOH (12 / 1) to give 4-bromo-1-[(dimethylphosphoryl)methoxy]-2-fluorobenzene as an off-white solid (252 mg, 85%). C9H 11 BrFO2P[M+H] + The calculated MS ESI value for 280.97 and the experimental value was 280.80. 1 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).

[0470] Example 18: (1R,11R)-18-(Difluoromethoxy)-5-{4-[(dimethylphosphoryl)methoxy]-3-fluorophenyl}-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0471]

[0472] Under a nitrogen atmosphere at room temperature, 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-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-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 H2O (0.2 mL) was added K2CO3 (57 mg, 0.415 mmol) and Pd(dppf)Cl2· CH2Cl2 (14 mg, 0.017 mmol). The resulting mixture was stirred at 80 °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 CH2Cl2 / MeOH (12 / 1), and then purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous CH3CN solution (10 mmol / L NH4HCO3), 30% to 50% gradient in 30 min; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-{4-[(dimethylphosphoryl)methoxy]-3-fluorophenyl}-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (48 mg, 52%) as a white solid. C 28 H 25 F3N3O4P [M+H] + The calculated MS ESI value of 556.15 and the experimental value of 556.10. 1 H NMR (400 MHz, chloroform-d) δ 8.52 - 8.48 (m, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.66 (d, J = 1.7 Hz, 1H), 7.49 - 7.40 (m, 2H), 7.38 - 7.29 (m, 3H), 7.16 - 7.08 (m, 1H), 6.86 (t, J = 72.9 Hz, 1H), 6.31 (d, J = 6.9 Hz, 1H), 5.08 (d, J = 6.8 Hz, 1H), 4.36 (d, J = 8.2 Hz, 2H), 3.55 (s, 3H), 3.53 - 3.43 (m, 1H), 2.91 (d, J = 13.4 Hz, 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).

[0473] Example 19: (1R,11R)-18-(difluoromethoxy)-5-[6-(dimethylphosphoryl)pyridin-3-yl]-12-ethyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0474]

[0475] Preparation 19A: (1R,11R)-5-chloro-18-(difluoromethoxy)-12-ethyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0476]

[0477] At -78 °C under a nitrogen atmosphere, KHMD (0.3 mL, 0.319 mmol, 1 M in THF) was added dropwise to a stirred solution of (1R,11R)-5-chloro-18-(difluoromethoxy)-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (100 mg, 0.266 mmol) in THF (3 mL). The resulting mixture was stirred for 0.5 h at -78 °C under a nitrogen atmosphere. At -78 °C, iodoethane (62 mg, 0.399 mmol) was added dropwise to the above mixture. The resulting mixture was stirred at room temperature overnight. The reaction solution was quenched with 1 mL of saturated NH4Cl (aqueous solution) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (20 / 1) to give (1R,11R)-5-chloro-18-(difluoromethoxy)-12-ethyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (75 mg, 64%) as a white solid. C 20 H 16 ClF2N3O2[M+H] + The calculated value of MS ESI for ClF2N3O2[M+H] is 404.09, and the experimental value is 403.95. 11H NMR (400 MHz, chloroform-d) δ 8.52 (d, J = 8.3 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.43 (t, J = 8.2 Hz, 1H), 7.37 - 7.31 (m, 1H), 7.24 - 7.20 (m, 1H), 6.83 (t, J = 73.1 Hz, 1H), 6.22 (d, J = 7.1 Hz, 1H), 5.02 (d, J = 7.1 Hz, 1H), 4.13 - 4.05 (m, 1H), 3.90 - 3.80 (m, 1H), 3.53 - 3.42 (m, 1H), 2.82 (d, J = 13.5 Hz, 1H), 1.44 (t, J = 7.1 Hz, 3H).

[0478] Preparation 19B: (1R,11R)-18-(difluoromethoxy)-12-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0479]

[0480] At room temperature under a nitrogen atmosphere, Pd2(dba)3 (17 mg, 0.019 mmol) and PCy3.HBF4 (7 mg, 0.019 mmol) were added to a stirred mixture of (1R,11R)-5-chloro-18-(difluoromethoxy)-12-ethyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-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). The resulting mixture was stirred at 140 °C for 16 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10 / 1) to afford (1R,11R)-18-(difluoromethoxy)-12-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (100 mg, 86%) as a yellow oil. C 26 H 28 Calculated MSESI for BF2N3O4[M+H] 496.21, found 496.05. + Example 19: (1R,11R)-18-(Difluoromethoxy)-5-[6-(dimethylphosphoryl)pyridin-3-yl]-12-ethyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0481]

[0482]

[0483] ​To a solution of (1R,11R)-18-(difluoromethoxy)-12-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one (100 mg, 0.202 mmol) and 5-bromo-2-(dimethylphosphoryl)pyridine (47 mg, 0.202 mmol) in 1,4-dioxane (2 mL) and H2O (0.4 mL) was added K3PO4 (128 mg, 0.606 mmol) and Pd(dppf)Cl 2· CH2Cl2 (16 mg, 0.020 mmol). After stirring for 2 h at 100 °C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10 / 1), followed by purification by reverse phase flash chromatography under the following conditions: column, C18 silica; mobile phase, aqueous CH3CN (0.1% FA), 15% to 40% gradient in 25 min; detector, 254 nm, to afford (1R,11R)-18-(difluoromethoxy)-5-[6-(dimethylphosphoryl)pyridin-3-yl]-12-ethyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one as a white solid (50 mg, 47%). C 27 H 25 F2N4O3P [M+H] + The MS ESI calculated value for 523.16, found 523.15. 11H 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 = 72.9 Hz, 1H), 6.32 (d, J = 7.0 Hz, 1H), 5.05 (d, J = 7.1 Hz, 1H), 4.16 - 4.03 (m, 1H), 3.92 - 3.81 (m, 1H), 3.56 - 3.46 (m, 1H), 2.86 (d, J = 13.4 Hz, 1H), 1.84 (s, 3H), 1.81 (s, 3H), 1.47 (t, J = 7.1 Hz, 3H). 19 19F NMR (377 MHz, chloroform-d) δ -80.76 (1F), -80.77 (1F). 31 31P NMR (162 MHz, chloroform-d) δ 36.52.

[0484] Example 20: (1R,11R)-18-(Difluoromethoxy)-5-{6-[(dimethylphosphoryl)amino]pyridin-3-yl}-12-methyl-2,9,12-triazatricyclo[9.8.1.0²,¹⁰.0³,⁸.0¹⁴,¹⁹]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0485]

[0486] Preparation 20A: 5-Bromo-N-(dimethylphosphoryl)pyridin-2-amine

[0487]

[0488] A mixture of dimethylphosphoryl 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 CH₂Cl₂ / MeOH (9 / 1) to afford 5-bromo-N-(dimethylphosphoryl)pyridin-2-amine as a white solid (220 mg, 23%). C₇H 10 BrN₂OP [M+H] +The calculated value of MS ESI is 248.97, and the experimental value is 248.80. 1 1H 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).

[0489] Example 20: (1R,11R)-18-(Difluoromethoxy)-5-{6-[(dimethylphosphoryl)amino]pyridin-3-yl}-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0490]

[0491] To a solution of 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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.104 mmol) in 1,4-dioxane (1 mL) and H2O (0.1 mL) was added K3PO4 (66 mg, 0.312 mmol) and Pd(dppf)Cl2.CH2Cl2 (8 mg, 0.010 mmol). After stirring for 2 hours at 100 °C 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%), and then purified by preparative HPLC under the following conditions: column, C18 silica; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 minutes; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-{6-[(dimethylphosphoryl)amino]pyridin-3-yl}-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one as a white solid (50 mg, 92%). C 26 H 24 F2N5O3P[M+H] +The calculated value of MS ESI is 524.16, and the experimental value is 524.10. 1 H NMR (400 MHz, chloroform-d) δ 8.49 (d, J = 8.2 Hz, 1H), 8.40 (d, J = 2.5 Hz, 1H), 7.80 - 7.71 (m, 2H), 7.60 (s, 1H), 7.46 - 7.36 (m, 2H), 7.30 (d, J = 8.1 Hz, 1H), 6.86 (d, J = 73.0 Hz, 1H), 6.85 - 6.82 (m, 1H), 6.27 (d, J = 7.2 Hz, 1H), 5.78 (s, 1H), 4.97 (d, J = 7.1 Hz, 1H), 3.52 (s, 3H), 3.51 - 3.40 (m, 1H), 2.88 (d, J = 13.6 Hz, 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).

[0492] Example 21: (1R,11R)-18-(difluoromethoxy)-5-{1-[(dimethylphosphoryl)methyl]pyrazol-4-yl}-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0493]

[0494] Preparation 21A: 4-bromo-1-[(dimethylphosphoryl)methyl]pyrazole

[0495]

[0496] At 0 °C, sodium hydride (30 mg, 0.748 mmol, 60% in oil) was added to a solution of 4-bromopyrazole (100 mg, 0.680 mmol) in THF (2 mL). The mixture was stirred for 30 minutes. Then, chloro(dimethylphosphoryl)methane (86 mg, 0.680 mmol) was added to the above solution. The mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with water and extracted with DCM (3 x 10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 minutes; detector, 254 nm. This gave 4-bromo-1-[(dimethylphosphoryl)methyl]pyrazole (100 mg, 62%) as a white solid. C6H 10 BrN2OP[M+H] + The calculated MS ESI values for 236.97 238.97, and the experimental values were 236.90 238.90. 1 1H 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).

[0497] Example 21: (1R,11R)-18-(Difluoromethoxy)-5-{1-[(dimethylphosphoryl)methyl]pyrazol-4-yl}-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0498]

[0499] To a solution of 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-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.104 mmol) in 1,4-dioxane (1 mL) and H2O (0.1 mL) was added K3PO4 (66 mg, 0.312 mmol) and Pd(dppf)Cl2.CH2Cl2 (8 mg, 0.010 mmol). After stirring at 100 °C for 2 h under a nitrogen atmosphere. The mixture was cooled 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 purification by preparative HPLC under the following conditions: column, C18 silica; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 min; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-{1-[(dimethylphosphoryl)methyl]pyrazol-4-yl}-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one (38 mg, 72%) as a white solid. C 25 H 24 F2N5O3P[M+H] + The calculated MS ESI value for + F2N5O3P[M+H] is 512.16, and the experimental value is 512.05. 1 H NMR (400 MHz, chloroform-d) δ 8.51 (d, J = 8.2 Hz, 1H), 7.83 (s, 2H), 7.78 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.52 - 7.43 (m, 2H), 7.33 (d, J = 8.2 Hz, 1H), 6.94 (t, J = 72.8 Hz, 1H), 6.36 (d, J = 6.3 Hz, 1H), 5.26 (s, 1H), 4.61 (d, J = 7.3 Hz, 2H), 3.62 (s, 3H), 3.59 - 3.48 (m, 1H), 2.95 (d, J = 13.3 Hz, 1H), 1.61 (d, J = 3.9 Hz, 3H), 1.57 (d, J = 3.9 Hz, 3H). 1919F NMR (376 MHz, chloroform-d) δ -80.78 (1F), -80.97 (1F). 31 31P NMR (162 MHz, chloroform-d) δ 40.53.

[0500] Example 22: (1R,11R)-18-(difluoromethoxy)-5-{6-[(dimethylphosphoryl)methyl]pyridin-3-yl}-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0501] Preparation 22A: 5-bromo-2-(chloromethyl)pyridine

[0502]

[0503] At 0 °C under a nitrogen atmosphere, thionyl chloride (4.75 g, 39.888 mmol) was added dropwise to a stirred solution of (5-bromopyridin-2-yl)methanol (5.00 g, 26.592 mmol) in DCM (50 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 h. The reaction solution was quenched by the addition of saturated sodium bicarbonate (50 mL) at 0 °C. The resulting mixture was extracted with CH2Cl2 (3 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. 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 1H 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).

[0504] Preparation 22B: 5-bromo-2-[(dimethylphosphoryl)methyl]pyridine

[0505]

[0506] At 0 °C under a nitrogen atmosphere, a solution of (methylhydrophosphinylidene)methane (756 mg, 9.687 mmol) in THF (5 mL) was treated with NaHMDS (4.9 mL, 9.687 mmol, 2 N in THF) for 0.5 h, and then a solution of 5-bromo-2-(chloromethyl)pyridine (2.00 g, 9.687 mmol) in THF (20 mL) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 h. The reaction solution was quenched at room temperature by adding water (50 mL). The resulting mixture was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), 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 (10:1) to give 5-bromo-2-[(dimethylphosphoryl)methyl]pyridine as a pale yellow oil (270 mg, 11%). C8H 11 BrNOP[M+H] + The calculated values of MS ESI for 247.98 249.98, and the experimental values were 247.90 249.90. 1 1H 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).

[0507] Example 22: (1R,11R)-18-(difluoromethoxy)-5-{6-[(dimethylphosphoryl)methyl]pyridin-3-yl}-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0508]

[0509] At room temperature under a nitrogen atmosphere, 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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-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) was added H2O (0.5 mL) containing K3PO4 (56 mg, 0.267 mmol) and Pd(dppf)Cl 2· CH2Cl2 (7 mg, 0.009 mmol). The resulting mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. The mixture was cooled 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 purification by preparative HPLC under the following conditions: column: C18 column 120 g; 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 afford (1R,11R)-18-(difluoromethoxy)-5-{6-[(dimethylphosphoryl)methyl]pyridin-3-yl}-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (29 mg, 63%) as a white solid. C 27 H 25 F2N4O3P[M+H] + The calculated value of MS ESI for 523.16, the experimental value 523.20. 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J = 2.4 Hz, 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 = 7.1 Hz, 1H), 5.25 (d, J = 7.1 Hz, 1H), 3.57 - 3.47 (m, 1H), 3.39 (d, J = 15.3 Hz, 2H), 3.36 (s, 3H), 2.83 (d, J = 13.8 Hz, 1H), 1.45 (s, 3H), 1.42 (s, 3H).19 F NMR (377 MHz, DMSO-d6) δ -81.53, -81.98, -82.38, -82.83. 31 P NMR (162 MHz, DMSO) δ 38.92.

[0510] Example 23: (1R,11R)-18-(Difluoromethoxy)-5-(6-{[(dimethylphosphoryl)methyl]amino}pyridin-3-yl)-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0511]

[0512] Preparation 23A: 5-Bromo-N-[(dimethylphosphoryl)methyl]pyridin-2-amine

[0513]

[0514] At 0 °C, sodium hydride (60% in oil, 64 mg) was added to a solution of 5-bromopyridin-2-amine (250 mg, 1.445 mmol) in THF (5 mL). The mixture was stirred for 30 minutes. Chlorodimethylphosphorylmethane (183 mg, 1.445 mmol) was added and the mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched with water and extracted with DCM (3 x 25 mL). The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 minutes; detector, 254 nm. This gave 5-bromo-N-[(dimethylphosphoryl)methyl]pyridin-2-amine as a white solid (50 mg, 13%). C8H 12 BrN2OP [M+H] + The calculated MS ESI values for + BrN2OP [M+H] are 262.99 and 264.99, and the experimental values are 263.00 and 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).

[0515] Example 23: (1R,11R)-18-(Difluoromethoxy)-5-(6-{[(dimethylphosphoryl)methyl]amino}pyridin-3-yl)-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-hepten-13-one

[0516]

[0517] To a solution of 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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-hepten-13-one (50 mg, 0.104 mmol) in 1,4-dioxane (0.5 mL) and H2O (0.1 mL) was added K3PO4 (66 mg, 0.312 mmol) and Pd(dppf)Cl2.CH2Cl2 (8 mg, 0.010 mmol). After stirring for 2 h at 100 °C 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 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 min; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-(6-{[(dimethylphosphoryl)methyl]amino}pyridin-3-yl)-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-hepten-13-one as a white solid (22 mg, 39%). C 27 H 26 F2N5O3P[M+H] + The calculated value of MS ESI for 538.17 and the experimental value was 538.05. 11H 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 = 7.2 Hz, 1H), 5.49 (s, 1H), 4.96 (d, J = 7.1 Hz, 1H), 3.95 (t, J = 5.7 Hz, 2H), 3.52 (s, 3H), 3.51 - 3.42 (m, 1H), 2.87 (d, J = 13.5 Hz, 1H), 1.61 (s, 3H), 1.58 (s, 3H). 19 19F NMR (377 MHz, chloroform-d) δ -80.09, -80.54, -80.71, -81.15. 31 31P NMR (162 MHz, chloroform-d) δ 42.08.

[0518] Example 24: (7R,14R)-1-(Difluoromethoxy)-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methano-benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazacyclotetradecin-5(14H)-one

[0519]

[0520] At room temperature, (7R,14R)-1-(difluoromethoxy)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methano-benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-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·CH2Cl2 (10 mg, 0.014 mmol), 1,4-dioxane (2 mL) and water (0.6 mL) were added to an 8 mL vial. The resulting mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The mixture was cooled 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%), and then purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous CH3CN solution (10 mmol / L NH4HCO3), 35% to 60% gradient in 20 minutes; 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-methano-benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-5(14H)-one as a white solid (28 mg, 35%). C 27 H 20 D3F3N3O3P[M+H] + The calculated value of MS ESI for D3F3N3O3P[M+H] is 529.16, and the experimental value is 529.30. 1 H NMR (400 MHz, chloroform-d) δ 8.52 - 8.47 (m, 1H), 8.07 - 7.98 (m, 1H), 7.79 (d, J = 8.5 Hz, 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 = 8.2 Hz, 1H), 7.39 - 7.28 (m, 2H), 6.87 (t, J = 72.9 Hz, 1H), 6.30 (d, J = 7.2 Hz, 1H), 4.98 (d, J = 7.1 Hz, 1H), 3.54 - 3.43 (m, 1H), 2.90 (d, J = 13.6 Hz, 1H), 1.86 (s, 3H), 1.82 (s, 3H). 19 F NMR (377 MHz, chloroform-d) δ -80.77, -105.83, -105.84.31 31P NMR (162 MHz, chloroform-d) δ 30.76.

[0521] Example 25: (1R,11R)-18-(difluoromethoxy)-5-{2-[(dimethylphosphoryl)methoxy]-1,3-thiazol-5-yl}-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0522]

[0523] Preparation 25A: 5-bromo-2-[(dimethylphosphoryl)methoxy]-1,3-thiazole

[0524]

[0525] Under a nitrogen atmosphere at 0 °C, NaH (111 mg, 2.771 mmol, 60%) was added to a stirred solution of 5-bromo-2-chloro-1,3-thiazole (500 mg, 2.519 mmol) in DMF (5 mL). The resulting mixture was stirred for 30 minutes under a nitrogen atmosphere at room temperature. At 0 °C, (dimethylphosphoryl)methanol (272 mg, 2.519 mmol) was added to the above mixture. The resulting mixture was stirred for an additional overnight at room temperature. The resulting mixture was diluted with EtOAc (100 mL). The resulting mixture was washed with 3 x 30 mL of water. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (12 / 1) to give 5-bromo-2-[(dimethylphosphoryl)methoxy]-1,3-thiazole (135 mg, 20%) as a yellow solid. C6H9BrNO2PS [M+H] + MS ESI calculated for 269.93 271.93, found 269.95 271.95. 1 1H 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 31P NMR (162 MHz, chloroform-d) δ 40.02.

[0526] Example 25: (1R,11R)-18-(Difluoromethoxy)-5-{2-[(dimethylphosphoryl)methoxy]-1,3-thiazol-5-yl}-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0527]

[0528] At room temperature under a nitrogen atmosphere, Pd(dppf)Cl 2· CH2Cl2 (9 mg, 0.010 mmol) and K2CO3 (36 mg, 0.260 mmol) were added 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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-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 H2O (0.2 mL). 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 CH2Cl2 / MeOH (15 / 1), and then purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 25% to 40% gradient over 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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one as a white solid (37 mg, 65%). C 25 H 23 F2N4O4PS[M+H] + The calculated value of MS ESI for 11H NMR (400 MHz, chloroform-d) δ 8.52 - 8.47 (m, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 1.7 Hz, 1H), 7.43 (t, J = 8.3 Hz, 1H), 7.38 - 7.27 (m, 3H), 6.87 (t, J = 72.9 Hz, 1H), 6.26 (d, J = 7.2 Hz, 1H), 4.97 (d, J = 7.1 Hz, 1H), 4.79 (d, J = 6.0 Hz, 2H), 3.52 (s, 3H), 3.50 - 3.41 (m, 1H), 2.88 (d, J = 13.6 Hz, 1H), 1.68 (s, 3H), 1.65 (s, 3H). 19 19F NMR (377 MHz, chloroform-d) δ -80.54. 31 31P NMR (162 MHz, chloroform-d) δ 40.06.

[0529] Example 26: (1R,11R)-18-(difluoromethoxy)-5-{2-[(dimethylphosphoryl)amino]pyrimidin-5-yl}-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0530]

[0531] Preparation 26A: 5-bromo-N-(dimethylphosphoryl)pyrimidin-2-amine

[0532]

[0533] At 50 °C under a nitrogen atmosphere, 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%) for 30 minutes, followed by the addition of dimethylphosphoryl chloride (100 mg, 0.889 mmol) at 0 °C. The resulting mixture was stirred for 2 hours at room temperature under a nitrogen atmosphere. The reaction solution was quenched with water at room temperature. The aqueous layer was extracted with EtOAc (3 x 100 mL). The aqueous layer was concentrated under reduced pressure to give 5-bromo-N-(dimethylphosphoryl)pyrimidin-2-amine as a yellow solid (80 mg, 9%). C6H9BrN3OP [M+H] + MS ESI calculated value for 249.97 251.97, experimental value 250.10 252.10. 11H NMR (400 MHz, chloroform-d) δ 8.50 (s, 2H), 1.86 (s, 3H), 1.82 (s, 3H).

[0534] Example 26: (1R,11R)-18-(Difluoromethoxy)-5-{2-[(dimethylphosphoryl)amino]pyrimidin-5-yl}-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0535]

[0536] At room temperature under a nitrogen atmosphere, 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-triazatricyclo[9.8.1.02,10.03,8.014,19]eicosa-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 H2O (0.2 mL) was added K3PO4 (66 mg, 0.312 mmol) and Pd(dppf)Cl 2· CH2Cl2 (9 mg, 0.010 mmol). The resulting mixture was stirred 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 CH2Cl2 / MeOH (15 / 1), and then purified by reverse-phase flash chromatography under the following conditions: column, C18 silica; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 25% to 40% gradient over 30 min; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-{2-[(dimethylphosphoryl)amino]pyrimidin-5-yl}-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one as a white solid (10 mg, 18%). C 25 H 23 F2N6O3P [M+H] + The calculated value of MS ESI for 525.15, the experimental value 525.10. 11H NMR (400 MHz, chloroform-d) δ 8.71 (s, 2H), 8.51 - 8.47 (m, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 1.7 Hz, 1H), 7.47 - 7.36 (m, 2H), 7.35 - 7.31 (m, 1H), 7.21 - 6.80 (m, 1H), 6.30 (d, J = 7.2 Hz, 1H), 4.99 (d, J = 7.1 Hz, 1H), 3.53 (s, 3H), 3.52 - 3.43 (m, 1H), 2.90 (d, J = 13.5 Hz, 1H), 1.93 (d, J = 3.2 Hz, 3H), 1.89 (d, J = 3.2 Hz, 3H). 19 19F NMR (377 MHz, chloroform-d) δ -80.44, -80.88, -81.30, -81.75. 31 31P NMR (162 MHz, chloroform-d) δ 41.11.

[0537] Example 27: (1R,11R)-5-[2-chloro-4-(dimethylphosphoryl)phenyl]-18-(difluoromethoxy)-12-methyl-2,9,12-triazatricyclo[9.8.1.0²,¹⁰.0³,⁸.0¹⁴,¹⁹]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0538]

[0539] Preparation 27A: 1-bromo-2-chloro-4-(dimethylphosphoryl)benzene

[0540]

[0541] A mixture of 1-bromo-2-chloro-4-iodobenzene (1.00 g, 3.1�1 mmol), (methylphosphonato)methane (270 mg, 3.466 mmol), Pd₂(dba)₃ (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 CH₂Cl₂ / MeOH (12 / 1) to afford 1-bromo-2-chloro-4-(dimethylphosphoryl)benzene as a yellow solid (800 mg, 95%). C₈H₉BrClOP [M+H] + Calculated MSESI values for 266.93 268.92, experimental values 267.00 269.00.1 1H 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 31P NMR (162 MHz, chloroform-d) δ 33.00.

[0542] Example 27: (1R,11R)-5-[2-chloro-4-(dimethylphosphoryl)phenyl]-18-(difluoromethoxy)-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0543]

[0544] Under a nitrogen atmosphere at room temperature, 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-triazatricyclo[9.8.1.02,10.03,8.014,19]eicosa-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 H2O (0.2 mL) was added K2CO3 (36 mg, 0.260 mmol) and Pd(dppf)Cl 2· CH2Cl2 (9 mg, 0.010 mmol). The resulting mixture was stirred under a nitrogen atmosphere at 80 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (15 / 1), followed by purification by reverse-phase flash chromatography under the following conditions: column, C18 silica; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 25% to 40% gradient over 30 min; detector, 254 nm. This gave (1R,11R)-5-[2-chloro-4-(dimethylphosphoryl)phenyl]-18-(difluoromethoxy)-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one as a white solid (37 mg, 65%). C 27 H 23 ClF2N3O3P [M+H]+ The calculated value of MS ESI is 542.11, and the experimental value is 542.00. 1 1H NMR (400 MHz, 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 = 8.2 Hz, 1H), 7.36 - 7.27 (m, 2H), 6.78 (d, J = 72.3 Hz, 1H), 6.28 (d, J = 7.2 Hz, 1H), 5.01 (d, J = 7.1 Hz, 1H), 3.54 (s, 3H), 3.51 - 3.42 (m, 1H), 2.90 (d, J = 13.6 Hz, 1H), 1.82 (s, 3H), 1.78 (s, 3H). 19 19F NMR (377 MHz, chloroform-d) δ -80.04, -80.48, -80.93, -81.37. 31 31P NMR (162 MHz, chloroform-d) δ 33.04.

[0545] Example 28: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2-fluorophenyl]-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0546]

[0547] Preparation 28A: 1-bromo-4-(dimethylphosphoryl)-2-fluorobenzene

[0548]

[0549] A mixture of 1-bromo-2-fluoro-4-iodobenzene (1.00 g, 3.323 mmol), (methylphosphonato)methane (285 mg, 3.655 mmol), Pd2(dba)3 (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 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (12 / 1) to give 1-bromo-4-(dimethylphosphoryl)-2-fluorobenzene as a yellow solid (820 mg, 98%). C8H9BrFOP [M+H]+ The calculated MS ESI values are 250.96 and 252.98, and the experimental values are 251.00 and 253.00. 1 1H 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 31P NMR (162 MHz, chloroform-d) δ 33.08.

[0550] Example 28: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2-fluorophenyl]-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0551]

[0552] At room temperature under a nitrogen atmosphere, 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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-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 H2O (0.2 mL) was added K2CO3 (36 mg, 0.260 mmol) and Pd(dppf)Cl 2·CH2Cl2 (9 mg, 0.010 mmol). 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 CH2Cl2 / MeOH (15 / 1), and then purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 25% to 40% gradient over 30 min; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2-fluorophenyl]-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (20 mg, 36%) as a white solid. C 27 H 23 F3N3O3P [M+H] + The calculated value of MS ESI for 526.14, the experimental value 526.15. 1 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 19F NMR (377 MHz, chloroform-d) δ -79.94, -80.39, -81.12, -81.57, -116.60. 31 31P NMR (162 MHz, chloroform-d) δ 33.07.

[0553] Example 29: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2-methylphenyl]-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0554]

[0555] Preparation 29A: 1-Bromo-4-(dimethylphosphoryl)-2-methylbenzene

[0556]

[0557] A solution of 1-bromo-4-iodo-2-methylbenzene (1.00 g, 3.368 mmol), (methylhydrophosphinylidene)methane (289 mg, 3.705 mmol), Pd2(dba)3 (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 CH2Cl2 / MeOH (15 / 1) to afford 1-bromo-4-(dimethylphosphoryl)-2-methylbenzene (453 mg, 54%) as a yellow solid. C9H 12 BrOP[M+H] + The MS ESI calculated values for 246.98 248.98, found 247.05 249.15. 1 1H 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 31P NMR (162 MHz, chloroform-d) δ 33.90.

[0558] Example 29: (1R,11R)-18-(Difluoromethoxy)-5-[4-(dimethylphosphoryl)-2-methylphenyl]-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0559]

[0560] At room temperature under a nitrogen atmosphere, 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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-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 H2O (0.2 mL) was added K3PO4 (66 mg, 0.312 mmol) and Pd(dppf)Cl 2· CH2Cl2 (9 mg, 0.010 mmol). The resulting mixture was stirred at 100 °C for 16 under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (15 / 1), and then purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 25% to 40% gradient over 30 minutes; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2-methylphenyl]-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (12 mg, 21%) as a white solid. C 28 H 26 F2N3O3P[M+H] + The calculated value of MS ESI for 522.17, the experimental value 522.20. 1 H NMR (400 MHz, chloroform-d) δ 8.54 - 8.47 (m, 1H), 7.77 (d, J = 8.4 Hz, 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 = 72.8 Hz, 1H), 6.25 (d, J = 7.1 Hz, 1H), 5.00 (d, J = 7.0 Hz, 1H), 3.54 (s, 3H), 3.52 - 3.43 (m, 1H), 2.89 (d, J = 13.6 Hz, 1H), 2.30 (s, 3H), 1.80 (s, 3H), 1.77 (s, 3H). 1919F NMR (377 MHz, chloroform-d) δ -80.16, -80.61, -80.73, -81.17. 31 31P NMR (162 MHz, chloroform-d) δ 34.08.

[0561] Example 30: (1R,11R)-18-(difluoromethoxy)-5-(6-{[(dimethylphosphoryl)methyl](methyl)amino}pyridin-3-yl)-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0562]

[0563] Preparation 30A: 5-bromo-N-[(dimethylphosphoryl)methyl]-N-methylpyridin-2-amine

[0564]

[0565] At 0 °C, sodium hydride (60% in oil, 64 mg) was added to a solution of 5-bromopyridin-2-amine (250 mg, 1.445 mmol) in THF (5 mL). The mixture was stirred for 30 minutes. Chlorodimethylphosphorylmethane (183 mg, 1.445 mmol) was added and the mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched with water and extracted with DCM (3 x 25 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 minutes; detector, 254 nm. This gave 5-bromo-N-[(dimethylphosphoryl)methyl]-N-methylpyridin-2-amine as a white solid (50 mg, 12%). C9H 14 BrN2OP [M+H] + MS ESI calculated value for 277.00, experimental value 277.01. 1 1H 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 31P NMR (162 MHz, chloroform-d) δ 43.67.

[0566] Example 30: (1R,11R)-18-(Difluoromethoxy)-5-(6-{[(dimethylphosphoryl)methyl](methyl)amino}pyridin-3-yl)-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-hepten-13-one

[0567]

[0568] To a solution of 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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-hepten-13-one (50 mg, 0.104 mmol) in 1,4-dioxane (0.5 mL) and H2O (0.1 mL) was added K3PO4 (66 mg, 0.312 mmol) and Pd(dppf)Cl2.CH2Cl2 (8 mg, 0.010 mmol). After stirring for 2 h at 100 °C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The resulting mixture was filtered and the cake was washed with MeOH (3 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 10% to 50% gradient over 30 min; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-(6-{[(dimethylphosphoryl)methyl](methyl)amino}pyridin-3-yl)-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-hepten-13-one as a white solid (21 mg, 36%). C 28 H 28 F2N5O3P[M+H] + The MS ESI calculated value for is 552.19, found 552.10. 11H NMR (400 MHz, chloroform-d) δ 8.51 - 8.46 (m, 1H), 8.36 (d, J = 2.4 Hz, 1H), 7.80 - 7.72 (m, 2H), 7.60 (d, J = 1.7 Hz, 1H), 7.46 - 7.36 (m, 2H), 7.33 - 7.28 (m, 1H), 7.07 - 6.62 (m, 2H), 6.27 (d, J = 7.1 Hz, 1H), 4.96 (d, J = 7.0 Hz, 1H), 4.26 (s, 2H), 3.52 (s, 3H), 3.51 - 3.41 (m, 1H), 3.28 (s, 3H), 2.88 (d, J = 13.5 Hz, 1H), 1.57 (s, 3H), 1.54 (s, 3H). 19 19F NMR (376 MHz, chloroform-d) δ -80.11, -80.56, -80.74, -81.19. 31 31P NMR (162 MHz, chloroform-d) δ 43.95.

[0569] Example 31: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2-fluorophenyl]-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0570]

[0571] To a solution of 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-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-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 H2O (0.1 mL) was added K3PO4 (68 mg, 0.321 mmol) and Pd(dppf)Cl2.CH2Cl2 (9 mg, 0.011 mmol). After stirring for 1 h at 100 °C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The resulting mixture was filtered, and the filter cake was washed with MeOH (3x 4 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 20% to 60% gradient in 30 min; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2-fluorophenyl]-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (16 mg, 29%) as a white solid. C 26 H 21 F3N3O3P [M+H] + The calculated MS ESI value for was 512.13, the experimental value was 512.05. 1 H NMR (400 MHz, chloroform-d) δ 8.46 - 8.40 (m, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 1.8 Hz, 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 = 73.3 Hz, 1H), 6.39 (d, J = 7.2 Hz, 1H), 5.00 (t, J = 6.6 Hz, 1H), 3.55 - 3.45 (m, 1H), 2.89 (d, J = 13.3 Hz, 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 PNMR (162 MHz, chloroform-d) δ 33.04.

[0572] Example 32: (1R,11R)-18-(Difluoromethoxy)-5-[4-(dimethylphosphoryl)-2-methylphenyl]-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0573]

[0574] To a solution of 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-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-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 H2O (0.1 mL) was added K3PO4 (68 mg, 0.321 mmol) and Pd(dppf)Cl2·CH2Cl2 (9 mg, 0.011 mmol). After stirring for 1 h at 100 °C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 20% to 60% gradient in 10 min; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2-methylphenyl]-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one as a white solid (39 mg, 70%). C 27 H 24 F2N3O3P [M+H] + The calculated value of MS ESI for F2N3O3P [M+H] is 508.15, and the experimental value is 508.10. 11H NMR (400 MHz, chloroform-d) δ 8.49 - 8.42 (m, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 12.0 Hz, 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 = 8.0 Hz, 1H), 6.77 (t, J = 72.6 Hz, 1H), 6.37 (d, J = 6.6 Hz, 1H), 5.10 (s, 1H), 3.56 - 3.48 (m, 1H), 2.90 (d, J = 13.1 Hz, 1H), 2.29 (s, 3H), 1.81 (s, 3H), 1.77 (s, 3H). 19 19F NMR (377 MHz, chloroform-d) δ -80.32, -80.77, -80.80, -81.25. 31 31P NMR (162 MHz, chloroform-d) δ 33.88.

[0575] Example 33: (1R,11R)-18-(Difluoromethoxy)-5-{4-[(dimethylphosphoryl)methyl]phenyl}-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0576]

[0577] Preparation 33A: 1-Bromo-4-[(dimethylphosphoryl)methyl]benzene

[0578]

[0579] At 0 °C under a nitrogen atmosphere, a solution of (methylhydrophosphinylidene)methane (172 mg, 2.201 mmol) in THF (5 mL) was treated with NaHMDS (1 mL, 2.001 mmol, 1 N in THF) for 15 minutes, and then a solution of 1-bromo-4-(bromomethyl)benzene (500 mg, 2.001 mmol) in THF (3 mL) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction solution was quenched with water at 0 °C. The resulting mixture was extracted with CH2Cl2 (3 x 100 mL). The combined organic layers were washed with brine (2 x 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 CH2Cl2 / MeOH (10:1) to give 1-bromo-4-[(dimethylphosphoryl)methyl]benzene as a white solid (240 mg, 48%). C9H 12 BrOP[M+H] + The calculated values of MS ESI for 246.98 248.98, and the experimental values were 247.05 249.05. 1 1H 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).

[0580] 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}]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0581]

[0582] At room temperature under a nitrogen atmosphere, 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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-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 H2O (0.5 mL) containing K3PO4 (57 mg, 0.267 mmol) and Pd(dppf)Cl 2· CH2Cl2 (7 mg, 0.009 mmol). The resulting mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. The mixture was cooled 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%), and then purified by preparative HPLC under the following conditions: column: C18 column 120 g; 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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one as a white solid (28 mg, 59%). C 28 H 26 F2N3O3P [M+H] + The calculated value of MS ESI for 522.17, the experimental value 522.15. 11H NMR (400 MHz, chloroform-d) δ 8.53 - 8.46 (m, 1H), 7.80 - 7.75 (m, 1H), 7.69 (d, J = 1.7 Hz, 1H), 7.57 (d, J = 7.8 Hz, 2H), 7.52 - 7.46 (m, 1H), 7.42 (t, J = 8.2 Hz, 1H), 7.37 - 7.28 (m, 3H), 6.84 (t, J = 72.8 Hz, 1H), 6.29 (d, J = 7.1 Hz, 1H), 5.00 (d, J = 7.0 Hz, 1H), 3.54 (s, 3H), 3.52 - 3.42 (m, 1H), 3.21 (d, J = 15.1 Hz, 2H), 2.89 (d, J = 13.5 Hz, 1H), 1.51 (s, 3H), 1.48 (s, 3H). 19 19F NMR (377 MHz, chloroform-d) δ -80.20, -80.64, -80.86, -81.30. 31 31P NMR (162 MHz, chloroform-d) δ 40.86.

[0583] Example 34: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2,3-difluorophenyl]-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0584]

[0585] Preparation 34A: 1-bromo-4-(dimethylphosphoryl)-2,3-difluorobenzene

[0586]

[0587] At room temperature under a nitrogen atmosphere, K3PO4 (0.80 g, 3.763 mmol), XantPhos (0.18 g, 0.314 mmol) and Pd2(dba)3 (0.14 g, 0.157 mmol) were added to a stirred mixture of 1-bromo-2,3-difluoro-4-iodobenzene (1.00 g, 3.136 mmol) and (methylphosphonato)methane (0.27 g, 3.450 mmol) in 1,4-dioxane (10 mL). 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 CH2Cl2 / MeOH (15:1) to give 1-bromo-4-(dimethylphosphoryl)-2,3-difluorobenzene as a yellow solid (650 mg, 77%). C8H8BrF2OP [M+H] + The calculated values of MS ESI for + are 268.95 270.94, and the experimental values are 268.80 270.80. 1 1H 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 31P NMR (162 MHz, chloroform-d) δ 30.19.

[0588] Example 34: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2,3-difluorophenyl]-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0589]

[0590] At room temperature under a nitrogen atmosphere, K2CO3 (37 mg, 0.268 mmol) and Pd(dppf)Cl were added to a stirred solution of (1R,11R)-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-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 H2O (0.2 mL). 2·CH2Cl2 (9 mg, 0.011 mmol). 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 CH2Cl2 / MeOH (15 / 1), and then purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 25% to 40% gradient over 30 min; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2,3-difluorophenyl]-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (17 mg, 30%) as a white solid. C 26 H 20 F4N3O3P [M+H] + The calculated value of MS ESI for F4N3O3P [M+H] is 530.12, and the experimental value is 529.95. 1 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 19F 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 31P NMR (162 MHz, chloroform-d) δ 29.81.

[0591] Example 35: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3,5-difluorophenyl]-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0592]

[0593] Preparation 35A: 5-Bromo-2-(dimethylphosphoryl)-1,3-difluorobenzene

[0594]

[0595] At room temperature under a nitrogen atmosphere, K3PO4 (0.80 g, 3.763 mmol), XantPhos (0.18 g, 0.314 mmol), and Pd2(dba)3 (0.14 g, 0.157 mmol) were added to a stirred mixture of (methylhydrogenphosphonato)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). The resulting mixture was stirred at 60 °C for 16 h under a nitrogen atmosphere. The reaction solution was quenched with saturated NaHCO3 (aqueous solution) at room temperature. The aqueous layer was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), 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 (20 / 1) to give 5-bromo-2-(dimethylphosphoryl)-1,3-difluorobenzene as a pale yellow solid (170 mg, 20%). C8H8BrF2OP [M+H] + The calculated values of MS ESI for C8H8BrF2OP [M+H] are 268.95 and 270.94, and the experimental values are 268.80 and 270.80. 1 1H 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 31P NMR (162 MHz, chloroform-d) δ 30.03.

[0596] Example 35: (1R,11R)-18-(Difluoromethoxy)-5-[4-(dimethylphosphoryl)-3,5-difluorophenyl]-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0597]

[0598] At room temperature under a nitrogen atmosphere, to a stirred solution of (1R,11R)-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-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 H2O (0.2 mL) was added K2CO3 (37 mg, 0.268 mmol) and Pd(dppf)Cl 2· CH2Cl2 (9 mg, 0.011 mmol). 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 CH2Cl2 / MeOH (15 / 1), followed by purification by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 25% to 40% gradient over 30 min; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3,5-difluorophenyl]-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (17 mg, 30%) as a white solid. C 26 H 20 F4N3O3P[M+H] + The calculated value of MS ESI for 530.12, the experimental value is 529.95. 1 H NMR (400 MHz, chloroform-d) δ 8.46 - 8.42 (m, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.69 (d, J = 1.8 Hz, 1H), 7.49 - 7.43 (m, 2H), 7.42 - 7.35 (m, 2H), 7.22 - 7.15 (m, 2H), 6.89 (t, J = 72.8 Hz, 1H), 6.41 (d, J = 7.1 Hz, 1H), 5.04 (t, J = 6.6 Hz, 1H), 3.59 - 3.47 (m, 1H), 2.90 (d, J = 13.4 Hz, 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 PNMR (162 MHz, chloroform-d) δ 30.76.

[0599] Example 36: (1R,11R)-18-(Difluoromethoxy)-5-[4-(dimethylphosphoryl)-2,3-difluorophenyl]-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0600]

[0601] At room temperature under a nitrogen atmosphere, 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-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-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 H2O (0.2 mL) was added K2CO3 (36 mg, 0.260 mmol) and Pd(dppf)Cl 2· CH2Cl2 (9 mg, 0.010 mmol). 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 CH2Cl2 / MeOH (15 / 1), and then purified by reverse-phase flash chromatography under the following conditions: column, C18 silica; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 25% to 40% gradient over 30 min; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2,3-difluorophenyl]-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one as a white solid (17 mg, 31%). C 27 H 22 F4N3O3P [M+H] + Calculated MS ESI 544.13, found 544.00. 11H 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 19F 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 31P NMR (162 MHz, chloroform-d) δ 29.83.

[0602] Example 37: (1R,11R)-18-(Difluoromethoxy)-5-[4-(dimethylphosphoryl)-3,5-difluorophenyl]-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0603]

[0604] At room temperature under a nitrogen atmosphere, 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-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-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 H2O (0.2 mL) was added K2CO3 (36 mg, 0.260 mmol) and Pd(dppf)Cl 2·CH2Cl2 (8 mg, 0.010 mmol). 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 CH2Cl2 / MeOH (15 / 1), and then purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 25% to 40% gradient over 30 min; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3,5-difluorophenyl]-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (22 mg, 39%) as a white solid. C 27 H 22 F4N3O3P [M+H] + The calculated value of MS ESI for 544.13, the experimental value 544.05. 1 1H NMR (400 MHz, chloroform-d) δ 8.52 - 8.47 (m, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 1.7 Hz, 1H), 7.52 - 7.41 (m, 2H), 7.36 - 7.30 (m, 1H), 7.24 - 7.16 (m, 2H), 6.88 (t, J = 72.9 Hz, 1H), 6.32 (d, J = 7.1 Hz, 1H), 5.06 (d, J = 7.0 Hz, 1H), 3.55 (s, 3H), 3.54 - 3.45 (m, 1H), 2.92 (d, J = 13.6 Hz, 1H), 1.98 (s, 3H), 1.94 (s, 3H). 19 19F NMR (377 MHz, chloroform-d) δ -80.38, -80.83, -80.91, -81.36, -101.70. 31 31P NMR (162 MHz, chloroform-d) δ 30.80.

[0605] Example 38: (1R,11R)-18-(difluoromethoxy)-5-{4-[(dimethylphosphoryl)methoxy]phenyl}-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0606]

[0607] Preparation of 38A: 1-Bromo-4-[(dimethylphosphoryl)methoxy]benzene

[0608]

[0609] At room temperature, a solution of 4-bromophenol (200 mg, 1.156 mmol) in MeCN (4 mL) was treated with K2CO3 (367 mg, 3.468 mmol) and NaI (17 mg, 0.116 mmol) for 10 minutes, and then chloro(dimethylphosphoryl)methane (146 mg, 1.156 mmol) was added dropwise 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 CH2Cl2 / MeOH (12:1) to afford 1-bromo-4-[(dimethylphosphoryl)methoxy]benzene as an off-white solid (190 mg, 62.48%). C9H 12 BrO2P[M+H] + The calculated MS ESI values for 262.98 264.98, and the experimental values were 262.80 264.80. 1 1H 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 31P NMR (162 MHz, chloroform-d) δ 42.12.

[0610] Example 38: (1R,11R)-18-(Difluoromethoxy)-5-{4-[(dimethylphosphoryl)methoxy]phenyl}-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0611]

[0612] At room temperature under a nitrogen atmosphere, 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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-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 H2O (0.2 mL) was added K2CO3 (36 mg, 0.260 mmol) and Pd(dppf)Cl 2· CH2Cl2 (9 mg, 0.010 mmol). 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 CH2Cl2 / MeOH (15 / 1), followed by purification by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 25% to 40% gradient in 30 min; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-{4-[(dimethylphosphoryl)methoxy]phenyl}-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (20 mg, 35%) as a white solid. C 28 H 26 F2N3O4P[M+H] + The MS ESI calculated value for 538.16, experimental value 538.05. 1 H NMR (400 MHz, chloroform-d) δ 8.52 - 8.47 (m, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.66 (d, J = 1.7 Hz, 1H), 7.59 - 7.52 (m, 2H), 7.48 - 7.39 (m, 2H), 7.30 (d, J = 8.3 Hz, 1H), 7.08 - 6.99 (m, 2H), 6.74 (t, J = 72.9 Hz, 1H), 6.30 (d, J = 7.1 Hz, 1H), 5.02 (d, J = 7.0 Hz, 1H), 4.30 (d, J = 8.3 Hz, 2H), 3.54 (s, 3H), 3.52 - 3.41 (m, 1H), 2.89 (d, J = 13.5 Hz, 1H), 1.70 (s, 3H), 1.67 (s, 3H). 1919F NMR (377 MHz, chloroform-d) δ -80.14, -80.59, -80.67, -81.12. 31 31P NMR (162 MHz, chloroform-d) δ 42.08.

[0613] Example 39: (1R,11R)-18-(difluoromethoxy)-5-{6-[2-(dimethylphosphoryl)ethoxy]pyridin-3-yl}-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0614]

[0615] Preparation 39A: {[2-(dimethylphosphoryl)ethoxy]methyl}benzene

[0616]

[0617] Under a nitrogen atmosphere at 0 °C, NaHMDS (11.62 mL, 23.246 mmol, 2 N in THF) was added dropwise to a stirred solution of (methylphosphonato)methane (1.81 g, 23.246 mmol) in THF (20 mL). The resulting mixture was stirred for 15 minutes at room temperature under a nitrogen atmosphere. At room temperature under a nitrogen atmosphere, a solution of [(2-bromoethoxy)methyl]benzene (5.00 g, 23.246 mmol) in THF (30 mL) was added dropwise above the solution. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction solution was quenched with water at room temperature. The resulting mixture was extracted with CH2Cl2 (3 x 100 mL). The combined organic layers were washed with brine (1 x 200 mL), 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 (7 / 1) to give {[2-(dimethylphosphoryl)ethoxy]methyl}benzene (3.44 g, 69%) as a colorless liquid. 1 1H 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).

[0618] Preparation 39B: 2-(dimethylphosphoryl)ethanol

[0619]

[0620] Under a nitrogen atmosphere, in a 100 mL round-bottom flask, Pd / C (10%, 300 mg) was added to a solution of {[2-(dimethylphosphoryl)ethoxy]methyl}benzene (3.44 g, 16.209 mmol) in 30 mL of MeOH. The mixture was hydrogenated overnight under a hydrogen atmosphere using a hydrogen balloon at room temperature, filtered through a Celite pad, and concentrated under reduced pressure to give 2-(dimethylphosphoryl)ethanol (1.95 g, 98%) as a colorless oil. 1 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).

[0621] Preparation 39C: 5-Bromo-2-[2-(dimethylphosphoryl)ethoxy]pyridine

[0622]

[0623] At 0 °C, NaH (117 mg, 2.948 mmol, 60%) was added to a stirred solution of 2-(dimethylphosphoryl)ethanol (300 mg, 2.457 mmol) in THF (3 mL). The resulting mixture was stirred at room temperature for 15 minutes. At 0 °C, 5-bromo-2-fluoropyridine (432 mg, 2.457 mmol) was added dropwise to the above mixture. The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction solution was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The 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. C9H 13 BrNO2P [M+H] + The calculated values of MS ESI for 277.99 279.99, the experimental values 278.00 279.00. 1 1H 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).

[0624] Example 39: (1R,11R)-18-(Difluoromethoxy)-5-{6-[2-(dimethylphosphoryl)ethoxy]pyridin-3-yl}-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0625]

[0626] A mixture of 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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.104 mmol), Pd(dppf)Cl2.CH2Cl2 (8 mg, 0.010 mmol), and K3PO4 (66 mg, 0.312 mmol) in 1,4-dioxane (1 mL) and H2O (0.2 mL) was stirred at 100 °C under a nitrogen atmosphere for 2 h. The mixture was cooled 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%), and then purified by preparative HPLC 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-{6-[2-(dimethylphosphoryl)ethoxy]pyridin-3-yl}-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one as a white solid (24 mg, 42%). C 28 H 27 F2N4O4P[M+H] + The calculated value of MS ESI for F2N4O4P[M+H] is 553.17, and the experimental value is 553.20. 11H NMR (400 MHz, chloroform-d) δ 8.50 (d, J = 8.2 Hz, 1H), 8.36 (d, J = 2.2 Hz, 1H), 7.83 - 7.76 (m, 2H), 7.65 - 7.61 (m, 1H), 7.42 (t, J = 8.2 Hz, 2H), 7.31 (d, J = 7.9 Hz, 1H), 7.04 - 6.65 (m, 2H), 6.29 (d, J = 7.1 Hz, 1H), 5.00 (d, J = 7.0 Hz, 1H), 4.77 - 4.67 (m, 2H), 3.54 (s, 3H), 3.51 - 3.44 (m, 1H), 2.89 (d, J = 13.6 Hz, 1H), 2.37 - 2.30 (m, 2H), 1.63 (s, 3H), 1.60 (s, 3H); 19 19F NMR (377 MHz, chloroform-d) δ -80.18, -80.63, -80.74, -81.19. 31 31P NMR (162 MHz, chloroform-d) δ 40.68.

[0627] Example 40: (1R,11R)-18-(Difluoromethoxy)-5-{6-[3-(dimethylphosphoryl)propoxy]pyridin-3-yl}-12-methyl-2,9,12-triazatricyclo[9.8.1.0²,¹⁰.0³,⁸.0¹⁴,¹⁹]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0628]

[0629] Preparation 40A: {[3-(Dimethylphosphoryl)propoxy]methyl}benzene

[0630]

[0631] At about 0 °C under a nitrogen atmosphere, NaHMDS (4.36 mL, 8.729 mmol, 2N in THF) was added dropwise to a stirred solution of (methylhydrogenphosphonato)methane (0.68 g, 8.729 mmol) in THF (30 mL). The mixture was stirred for <15 minutes. The above mixture was added dropwise to THF (30 mL) containing [(3-bromopropoxy)methyl]benzene (2.00 g, 8.729 mmol) 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 CH2Cl2 / MeOH (10 / 1) to give {[3-(dimethylphosphoryl)propoxy]methyl}benzene (1.20 g, 60%) as a colorless oil. C 12 H19 O2P[M+H] + The calculated value of MS ESI for it is 227.11, and the experimental value is 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).

[0632] Preparation of 40B: 3-(Dimethylphosphoryl)propan-1-ol

[0633]

[0634] Under a nitrogen atmosphere, Pd / C (0.42 g, 0.398 mmol, 10%) was added to a solution of {[3-(dimethylphosphoryl)propoxy]methyl}benzene (1.80 g, 7.956 mmol) in MeOH (20 mL). The mixture was hydrogenated overnight at room temperature under a hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad, and concentrated under reduced pressure. This gave 3-(dimethylphosphoryl)propan-1-ol (1.00 g, 92%) as a colorless oil. 1 H 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).

[0635] Preparation of 40C: 5-Bromo-2-[3-(dimethylphosphoryl)propoxy]pyridine

[0636]

[0637] At 0 °C, NaH (105 mg, 2.645 mmol, 60%) was added to a solution of 3-(dimethylphosphoryl)propan-1-ol (300 mg, 2.204 mmol) in DMF (10 mL). The mixture was stirred for 15 minutes. 5-Bromo-2-fluoropyridine (388 mg, 2.204 mmol) was added and the mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with water and purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 10% to 50% gradient in 20 minutes; detector, 254 nm. This gave 5-bromo-2-[3-(dimethylphosphoryl)propoxy]pyridine (380 mg, 59%) as a colorless oil. C 10 H 15 BrNO2P[M+H] +The calculated MS ESI value is 292.00 - 294.00, and the experimental value is 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).

[0638] Example 40: (1R,11R)-18-(difluoromethoxy)-5-{6-[3-(dimethylphosphoryl)propoxy]pyridin-3-yl}-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0639]

[0640] 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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.104 mmol), Pd(dppf)Cl 2·A mixture of CH2Cl2 (8 mg, 0.010 mmol) and K3PO4 (66 mg, 0.312 mmol) in 1,4 - dioxane (1 mL) and H2O (0.2 mL) was stirred at 100 °C under a nitrogen atmosphere for 2 h. The mixture was cooled 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%), and then purified by preparative HPLC 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-{6-[3-(dimethylphosphoryl)propoxy]pyridin - 3 - yl}-12 - methyl - 2,9,12 - triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icos - 3(8),4,6,9,14(19),15,17 - heptaen - 13 - one (20 mg, 34%) as a white solid. C 29 H 29 F2N4O4P[M + H] + The calculated value of MS ESI for is 567.19, and the experimental value is 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 = 7.1 Hz, 1H), 4.44 (t, J = 6.1 Hz, 2H), 3.55 (s, 3H), 3.53 - 3.45 (m, 1H), 2.91 (d, J = 13.5 Hz, 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.

[0641] Example 41: (1R,11R)-5-[2-chloro-4-(dimethylphosphoryl)phenyl]-18-(difluoromethoxy)-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-hepten-13-one

[0642]

[0643] To a solution of 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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-hepten-13-one (50 mg, 0.107 mmol) in 1,4-dioxane (0.5 mL) and H2O (0.1 mL) was added K3PO4 (68 mg, 0.321 mmol) and Pd(dppf)Cl2.CH2Cl2 (9 mg, 0.011 mmol). After stirring for 1 h at 100 °C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The resulting mixture was filtered, and the cake was washed with MeOH (3x 4 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 20% to 60% gradient in 30 min; detector, 254 nm. This gave (1R,11R)-5-[2-chloro-4-(dimethylphosphoryl)phenyl]-18-(difluoromethoxy)-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-hepten-13-one as a white solid (23 mg, 41%). C 26 H 21 ClF2N3O3P[M+H] + The calculated value of MS ESI for ClF2N3O3P[M+H] is 528.10, and the experimental value is 527.95. 11H NMR (400 MHz, 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 = 1.6 Hz, 1H), 7.51 - 7.41 (m, 2H), 7.39 - 7.32 (m, 2H), 6.79 (t, J = 72.6 Hz, 1H), 6.39 (d, J = 7.2 Hz, 1H), 5.07 (t, J = 6.6 Hz, 1H), 3.57 - 3.44 (m, 1H), 2.90 (d, J = 13.3 Hz, 1H), 1.82 (s, 3H), 1.79 (s, 3H). 19 19F NMR (377 MHz, chloroform-d) δ -80.23, -80.68, -80.99, -81.43. 31 31P NMR (162 MHz, chloroform-d) δ 33.28.

[0644] Example 42: (1R,11R)-18-(Difluoromethoxy)-5-{2-[(dimethylphosphoryl)methoxy]-1,3-thiazol-5-yl}-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0645]

[0646] Preparation 42A: 5-Bromo-2-[(dimethylphosphoryl)methoxy]-1,3-thiazole

[0647]

[0648] Under a nitrogen atmosphere at 0 °C, NaH (111 mg, 2.771 mmol, 60%) was added to a stirred solution of (dimethylphosphoryl)methanol (272 mg, 2.519 mmol) in DMF (5 mL). The resulting mixture was stirred for 30 minutes at room temperature under a nitrogen atmosphere. At 0 °C, 5-bromo-2-chloro-1,3-thiazole (500 mg, 2.519 mmol) was added to the above mixture. The resulting mixture was stirred for an additional overnight at room temperature. The resulting mixture was diluted with water and extracted with EtOAc (3 x 50 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (12:1) to afford 5-bromo-2-[(dimethylphosphoryl)methoxy]-1,3-thiazole (135 mg, 20%) as a yellow solid. C6H9BrNO2PS [M+H] +The calculated MS ESI value is 269.93 - 271.93, and the experimental value is 269.95 - 272.00. 1 1H 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).

[0649] Example 42: (1R,11R)-18-(Difluoromethoxy)-5-{2-[(dimethylphosphoryl)methoxy]-1,3-thiazol-5-yl}-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0650]

[0651] At room temperature under a nitrogen atmosphere, to a stirred mixture of (1R,11R)-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-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 an aqueous solution of Pd(dppf)Cl 2· CH2Cl2 (7 mg, 0.009 mmol) and K3PO4 (57 mg, 0.267 mmol) in H2O (0.5 mL). The resulting mixture was stirred under a nitrogen atmosphere at 100 °C for 16 h. The mixture was cooled 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 15%), and then purified by preparative HPLC under the following conditions: column: C18 column 120 g; 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 afford (1R,11R)-18-(difluoromethoxy)-5-{2-[(dimethylphosphoryl)methoxy]-1,3-thiazol-5-yl}-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one as a white solid (15 mg, 32%). C24 H 21 F2N4O4PS[M+H] + The calculated MS ESI value of is 531.10, and the experimental value is 530.95. 1 H 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.

[0652] Example 43: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3-fluorophenyl]-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0653]

[0654] At room temperature under a nitrogen atmosphere, to a stirred mixture of (1R,11R)-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-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·H2O (0.5 mL) of CH2Cl2 (7 mg, 0.009 mmol) and K3PO4 (56 mg, 0.264 mmol). The resulting mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. The mixture was cooled 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 15%), followed by purification by preparative HPLC under the following conditions: column: C18 column 120 g; 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 afford (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3-difluorophenyl]-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (10 mg, 21%) as a white solid. C 26 H 21 F3N3O3P [M+H] + Calculated MSESI value 512.13, experimental value 512.00. 1 1H NMR (400 MHz, chloroform-d) δ 8.44 (d, J = 8.0 Hz, 1H), 8.06 - 8.02 (m, 1H), 7.81 (d, J = 7.9 Hz, 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 = 6.7 Hz, 1H), 5.03 (s, 1H), 3.51 (t, J = 7.0 Hz, 1H), 3.01 - 2.81 (m, 1H), 1.87 (s, 3H), 1.83 (s, 3H). 19 19F NMR (377 MHz, chloroform-d) δ -80.41, -80.86, -80.92, -81.36, -105.79. 31 31P NMR (162 MHz, chloroform-d) δ 30.56.

[0655] Example 44: (1R,11R)-18-(difluoromethoxy)-5-{4-[(dimethylphosphoryl)methoxy]phenyl}-12-ethyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0656]

[0657] At room temperature, K3PO4 (64 mg, 0.303 mmol) and Pd(dppf)Cl2.CH2Cl2 (8 mg, 0.010 mmol) were added to a stirred solution of (1R,11R)-18-(difluoromethoxy)-12-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-hepten-13-one (50 mg, 0.101 mmol) and 1-bromo-4-[(dimethylphosphoryl)methoxy]benzene (26 mg, 0.101 mmol) in 1,4-dioxane (2 mL) and H2O (0.4 mL). The resulting mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1), and then purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 20% to 50% gradient in 30 min; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-{4-[(dimethylphosphoryl)methoxy]phenyl}-12-ethyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-hepten-13-one (15 mg, 26%) as a white solid. C 29 H 28 F2N3O4P[M+H] + The calculated MS ESI value for F2N3O4P[M+H] is 552.18, and the experimental value is 552.15. 1 H NMR (400 MHz, 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 = 7.1 Hz, 1H), 5.28 (d, J = 7.2 Hz, 1H), 4.36 (d, J = 6.7 Hz, 2H), 3.90 - 3.73 (m, 2H), 3.57 - 3.45 (m, 1H), 2.78 (d, J = 13.6 Hz, 1H), 1.54 (s, 3H), 1.51 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H). 1919F NMR (377 MHz, DMSO-d6) δ -81.72, -82.64. 31 31P NMR (162 MHz, DMSO-d6) δ 38.42.

[0658] Example 45: (1R,11R)-18-(Difluoromethoxy)-5-[4-(dimethylphosphoryl)-3-fluorophenyl]-12-ethyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0659]

[0660] At room temperature, K3PO4 (64 mg, 0.303 mmol) and Pd(dppf)Cl2·CH2Cl2 (8 mg, 0.010 mmol) were added to a stirred solution of (1R,11R)-18-(difluoromethoxy)-12-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.101 mmol) and 4-bromo-1-(dimethylphosphoryl)-2-fluorobenzene (25 mg, 0.101 mmol) in 1,4-dioxane (2 mL) and H2O (0.4 mL). The resulting mixture was stirred at 100 °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 CH2Cl2 / MeOH (10:1), and then purified by reverse-phase flash chromatography under the following conditions: column, C18 silica; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 20% to 50% gradient over 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-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one as a white solid (26 mg, 47%). C 28 H 25 F3N3O3P [M+H] + The calculated value of MS ESI for 540.16, the experimental value 540.10. 11H NMR (400 MHz, 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 = 8.5 Hz, 1H), 7.71 - 7.46 (m, 6H), 6.31 (d, J = 7.0 Hz, 1H), 5.30 (d, J = 7.2 Hz, 1H), 3.89 - 3.76 (m, 2H), 3.58 - 3.48 (m, 1H), 2.80 (d, J = 13.7 Hz, 1H), 1.76 (s, 3H), 1.73 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H). 19 19F NMR (377 MHz, DMSO-d6) δ -81.77, -82.23, -82.38, -82.83, -105.69. 31 31P NMR (162 MHz, DMSO-d6) δ 28.34.

[0661] Example 46: (1R,11R)-18-(Difluoromethoxy)-5-[4-(dimethylphosphoryl)-3,5-difluorophenyl]-12-ethyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0662]

[0663] At room temperature, K3PO4 (64 mg, 0.303 mmol) and Pd(dppf)Cl2.CH2Cl2 (8 mg, 0.010 mmol) were added to a stirred solution of (1R,11R)-18-(difluoromethoxy)-12-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.101 mmol) and 5-bromo-2-(dimethylphosphoryl)-1,3-difluorobenzene (27 mg, 0.101 mmol) in 1,4-dioxane (2 mL) and H2O (0.4 mL). The resulting mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1), and then purified by reverse-phase flash chromatography under the following conditions: column, C18 silica; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 20% to 50% gradient over 30 min; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3,5-difluorophenyl]-12-ethyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (19 mg, 34%) as a white solid. C 28 H 24 F4N3O3P[M+H] + The calculated MS ESI value for F4N3O3P[M+H] is 558.15, and the experimental value is 558.10. 1 H NMR (400 MHz, 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 = 7.0 Hz, 1H), 5.31 (d, J = 7.3 Hz, 1H), 3.90 - 3.75 (m, 2H), 3.57 - 3.48 (m, 1H), 2.80 (d, J = 13.8 Hz, 1H), 1.88 (s, 3H), 1.84 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -81.82, -82.27, -82.49, -82.95, -102.26. 311P NMR (162 MHz, DMSO-d6) δ 29.10.

[0664] Example 47: (1R,11R)-12-Cyclopropyl-18-(difluoromethoxy)-5-[6-(dimethylphosphoryl)pyridin-3-yl]-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0665]

[0666] Preparation 47A: (1R,11R)-5-Chloro-12-cyclopropyl-18-(difluoromethoxy)-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0667]

[0668] At room temperature, Na2CO3 (135 mg, 1.278 mmol) and copper(I) acetate (157 mg, 1.278 mmol) were added to a solution of (1R,11R)-5-chloro-18-(difluoromethoxy)-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-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). The mixture was purged with nitrogen for 5 minutes and then pressurized with oxygen to 1 to 2 atmospheres 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-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one (210 mg, 59%) as a pale yellow solid. C 21 H 16 ClF2N3O2 [M+H] + The calculated value of MS ESI for ClF2N3O2 [M+H] is 416.09, and the experimental value is 415.90. 11H 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 = 8.2 Hz, 1H), 7.34 - 7.24 (m, 1H), 7.23 - 7.15 (m, 1H), 6.81 (t, J = 72.7 Hz, 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 = 13.5 Hz, 1H), 1.53 - 1.41 (m, 1H), 1.14 - 1.02 (m, 2H), 0.76 - 0.60 (m, 1H).

[0669] Preparation of 47B: (1R,11R)-12-Cyclopropyl-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-hepten-13-one

[0670]

[0671] To a solution of (1R,11R)-5-chloro-12-cyclopropyl-18-(difluoromethoxy)-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-hepten-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 afford (1R,11R)-12-cyclopropyl-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-hepten-13-one as a pale yellow oil (250 mg, 97%). C 27 H28 BF2N3O4[M+H] + The calculated value of MS ESI for it is 508.21, and the experimental value is 508.15.

[0672] Example 47: (1R,11R)-12-Cyclopropyl-18-(difluoromethoxy)-5-[6-(dimethylphosphoryl)pyridin-3-yl]-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0673]

[0674] A solution of (1R,11R)-12-cyclopropyl-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (60 mg, 0.118 mmol), 5-bromo-2-(dimethylphosphoryl)pyridine (41 mg, 0.177 mmol), K3PO4 (75 mg, 0.354 mmol) and Pd(dppf)Cl2.CH2Cl2 (9 mg, 0.012 mmol) in 1,4-dioxane (2 mL) and H2O (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%), and then purified by preparative HPLC 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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one as a white solid (21 mg, 33%). C 28 H 25 F2N4O3P[M+H] + The calculated value of MS ESI for it is 535.16, and the experimental value is 535.15. 11H 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 = 72.9 Hz, 1H), 6.28 (d, J = 7.0 Hz, 1H), 5.27 (d, J = 7.2 Hz, 1H), 3.56 - 3.44 (m, 1H), 3.31 - 3.24 (m, 1H), 2.88 (d, J = 13.5 Hz, 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 19F NMR (376 MHz, chloroform-d) δ -80.28, -80.72, -80.81 -81.26. 31 31P NMR (162 MHz, chloroform-d) δ 36.29.

[0675] Example 48: (1R,11R)-12-Cyclopropyl-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3-fluorophenyl]-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0676]

[0677] (1R,11R)-12-Cyclopropyl-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (60 mg, 0.118 mmol), 4-bromo-1-(dimethylphosphoryl)-2-fluorobenzene (44 mg, 0.177 mmol), K3PO4 (75 mg, 0.354 mmol), and Pd(dppf)Cl2.CH2Cl2 (9 mg, 0.012 mmol) in a mixture of 1,4-dioxane (2 mL) and H2O (0.4 mL) were 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%), and then purified by preparative HPLC 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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one as a white solid (20 mg, 30%). C 29 H 25 F3N3O3P[M+H] + The calculated value of MS ESI for it is 552.16, and the experimental value is 552.20. 1HNMR (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 = 7.0 Hz, 1H), 5.26 (d, J = 7.4 Hz, 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.

[0678] Example 49: (1R,11R)-18-(Difluoromethoxy)-5-[4-(dimethylphosphoryl)phenyl]-12-ethyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0679]

[0680] Preparation 49A: 1-Bromo-4-(dimethylphosphoryl)benzene

[0681]

[0682] At room temperature under a nitrogen atmosphere, to a stirred solution of 4-bromoiodobenzene (20.00 g, 70.695 mmol) and (methylhydrophosphorylidene)methane (5.52 g, 70.695 mmol) in 1,4-dioxane (500 mL) was added XantPhos (4.09 g, 7.069 mmol), Et3N (8.58 g, 84.834 mmol) and Pd2(dba)3 (3.24 g, 3.535 mmol). The resulting mixture was stirred at 100 °C for 4 hours under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1) to give 1-bromo-4-(dimethylphosphoryl)benzene as a yellow solid (14.01 g, 85%).1 1H NMR (300 MHz, chloroform-d) δ 7.63 - 7.50 (m, 4H), 1.71 (s, 3H), 1.67 (s, 3H).

[0683] Example 49: (1R,11R)-18-(Difluoromethoxy)-5-[4-(dimethylphosphoryl)phenyl]-12-ethyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0684]

[0685] At room temperature, to a stirred solution of (1R,11R)-18-(difluoromethoxy)-12-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 mg, 0.101 mmol) and 1-bromo-4-(dimethylphosphoryl)benzene (23 mg, 0.101 mmol) in 1,4-dioxane (2 mL) and H2O (0.4 mL) was added K3PO4 (64 mg, 0.303 mmol) and Pd(dppf)Cl2·CH2Cl2 (8 mg, 0.010 mmol). The resulting mixture was stirred 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 CH2Cl2 / MeOH (10:1), and then purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 20% to 50% gradient in 30 min; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)phenyl]-12-ethyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one as a white solid (27 mg, 51%). C 28 H 26 F2N3O3P [M+H]+ + The calculated value of MS ESI for F2N3O3P [M+H]+ is 522.17, and the experimental value is 522.10. 11H NMR (400 MHz, 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 = 7.0 Hz, 1H), 5.30 (d, J = 7.2 Hz, 1H), 3.93 - 3.75 (m, 2H), 3.58 - 3.47 (m, 1H), 2.80 (d, J = 13.7 Hz, 1H), 1.71 (s, 3H), 1.68 (s, 3H), 1.36 (t, J = 7.0 Hz, 3H). 19 19F NMR (377 MHz, DMSO-d6) δ -81.68, -82.13, -82.19, -82.64. 31 31P NMR (162 MHz, DMSO-d6) δ 32.30.

[0686] Example 50: (1R,11R)-18-(Difluoromethoxy)-5-{4-[(dimethylphosphoryl)amino]phenyl}-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0687]

[0688] Preparation 50A: 4-Bromo-N-(dimethylphosphoryl)aniline

[0689]

[0690] At 0 °C, sodium hydride (60% in oil, 38 mg) was added to a solution of 4-bromoaniline (150 mg, 0.872 mmol) in THF (4 mL). The mixture was stirred for 20 minutes. Dimethylphosphoryl chloride (108 mg, 0.959 mmol) was added and the mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with water and extracted with DCM (3 x 10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (9 / 1) to give 4-bromo-N-(dimethylphosphoryl)aniline as a yellow solid (37 mg, 17%). C8H 11 BrNOP [M+H] + The calculated MS ESI values for 247.98 249.98, experimental values 248.00 250.00.1 1H 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).

[0691] Example 50: (1R,11R)-18-(Difluoromethoxy)-5-{4-[(dimethylphosphoryl)amino]phenyl}-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0692]

[0693] To a solution of 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-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-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 H2O (0.1 mL) was added K3PO4 (66 mg, 0.312 mmol) and Pd(dppf)Cl2·CH2Cl2 (8 mg, 0.010 mmol). After stirring for 2 h at 100 °C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (9 / 1), and then purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 20% to 50% gradient in 30 min; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-{4-[(dimethylphosphoryl)amino]phenyl}-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one as a white solid (22 mg, 38%). C 27 H 25 F2N4O3P [M+H] + The calculated value of MS ESI for F2N4O3P [M+H] is 523.16, and the experimental value is 523.10. 11H NMR (400 MHz, chloroform-d) δ 8.50 - 8.43 (m, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 1.7 Hz, 1H), 7.49 - 7.33 (m, 4H), 7.32 - 7.25 (m, 1H), 7.17 - 7.11 (m, 2H), 6.82 (t, J = 72.9 Hz, 1H), 6.22 (d, J = 7.2 Hz, 1H), 5.26 (d, J = 9.4 Hz, 1H), 4.97 (d, J = 7.1 Hz, 1H), 3.52 (s, 3H), 3.50 - 3.42 (m, 1H), 2.86 (d, J = 13.5 Hz, 1H), 1.74 (s, 3H), 1.71 (s, 3H). 19 19F NMR (377 MHz, chloroform-d) δ -80.10, -80.55, -80.74, 81.19. 31 31P NMR (162 MHz, chloroform-d) δ 34.53.

[0694] Example 51: (1R,11R)-5-[4-(Diethylphosphoryl)-3-fluorophenyl]-18-(difluoromethoxy)-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0695]

[0696] Preparation 51A: 4-Bromo-1-(diethylphosphoryl)-2-fluorobenzene

[0697]

[0698] At room temperature under nitrogen atmosphere, to a stirred mixture of 4-bromo-2-fluoro-1-iodobenzene (1.00 g, 3.323 mmol) and (ethyl hydrogen phosphono) 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 Pd2(dba)3 (0.15 g, 0.166 mmol). The resulting mixture was stirred at 80 ° C for 16 hours under a nitrogen atmosphere. The mixture was basified to pH 8 with saturated NaHCO3 (aqueous solution). The aqueous layer was extracted with CH2Cl2 (3x 100 mL). The combined organic layers were washed with brine (3x 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 CH2Cl2 / MeOH (20 / 1) to give 4-bromo-1-(diethylphosphoryl)-2-fluorobenzene (778 mg, 83%) as a yellow solid. 10 H 13 BrFOP[M+H] + MS ESI calculated values were 278.99-280.99, found values were 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.

[0699] 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}]eicos-3(8),4,6,9,14(19),15,17-hepten-13-one

[0700]

[0701] At room temperature under a nitrogen atmosphere, to a stirred solution of (1R,11R)-18-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-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 H2O (0.2 mL) was added K2CO3 (37 mg, 0.268 mmol) and Pd(dppf)Cl 2· CH2Cl2 (9 mg, 0.011 mmol). The resulting mixture was stirred at 80 °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 CH2Cl2 / MeOH (15 / 1), and then purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 25% to 40% gradient over 30 min; detector, 254 nm. This gave (1R,11R)-5-[4-(diethylphosphoryl)-3-fluorophenyl]-18-(difluoromethoxy)-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (31 mg, 54%) as a white solid. C 28 H 25 F3N3O3P [M+H] + The calculated MS ESI value for 540.16, experimental value 540.05. 1 H NMR (400 MHz, chloroform-d) δ 8.46 - 8.41 (m, 1H), 8.08 - 8.00 (m, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 1.7 Hz, 1H), 7.59 - 7.50 (m, 2H), 7.46 (t, J = 8.1 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.35 - 7.28 (m, 1H), 6.88 (t, J = 72.7 Hz, 1H), 6.41 (d, J = 7.2 Hz, 1H), 5.03 (t, J = 6.6 Hz, 1H), 3.58 - 3.46 (m, 1H), 2.90 (d, J = 13.3 Hz, 1H), 2.19 - 1.98 (m, 4H), 1.22 - 1.10 (m, 6H). 1919F NMR (377 MHz, chloroform-d) δ -80.44, -80.88, -80.94, -81.39, -105.34, -105.36. 31 31P NMR (162 MHz, chloroform-d) δ 42.11.

[0702] Example 52: (7R,14R)-1-(Difluoromethoxy)-11-(4-(dimethylphosphoryl)-2,3-difluorophenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methano-benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazacyclooctatetraen-5(14H)-one

[0703]

[0704] At room temperature under a nitrogen atmosphere, 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-methano-benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazacyclooctatetraen-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 H2O (0.2 mL) was added K2CO3 (36 mg, 0.258 mmol) and Pd(dppf)Cl 2· CH2Cl2 (9 mg, 0.010 mmol). The resulting mixture was stirred under a nitrogen atmosphere at 80 °C for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (15 / 1), followed by purification by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 25% to 45% gradient over 30 min; detector, 254 nm. This gave (7R,14R)-1-(difluoromethoxy)-11-(4-(dimethylphosphoryl)-2,3-difluorophenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methano-benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazacyclooctatetraen-5(14H)-one as a white solid (21 mg, 37%). C 27 H 19 D3F4N3O3P [M+H] + The calculated value of MS ESI for 547.15, the experimental value 547.15. 1HNMR (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.

[0705] Example 53: (7R,14R)-1-(Difluoromethoxy)-11-(4-(dimethylphosphoryl)-2-fluorophenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methano-benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazacyclotetradecin-5(14H)-one

[0706]

[0707] At room temperature under a nitrogen atmosphere, 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-methano-benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazacyclotetradecin-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 H2O (0.2 mL) was added K2CO3 (36 mg, 0.258 mmol) and Pd(dppf)Cl 2·CH2Cl2 (9 mg, 0.010 mmol). The resulting mixture was stirred at 80 °C for 3 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (15 / 1), and then purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 25% to 45% gradient in 30 min; detector, 254 nm. This gave (7R,14R)-1-(difluoromethoxy)-11-(4-(dimethylphosphoryl)-2-fluorophenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methano-benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-5(14H)-one as a white solid (28 mg, 51%). C 27 H 20 D3F3N3O3P [M+H] + The calculated value of MS ESI for is 529.16, and the experimental value is 529.10. 1 1H 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 19F NMR (377 MHz, chloroform-d) δ -79.92, -80.37, -81.12, -81.56, -116.61, -116.62, -116.63. 31 31P NMR (162 MHz, chloroform-d) δ 32.93.

[0708] Example 54: (7R,14R)-l-(difluoromethoxy)-ll-(4-(dimethylphosphoryl)-2,5-difluorophenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methano-benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-5(14H)-one

[0709]

[0710] Preparation 54A: 1-Bromo-4-(dimethylphosphoryl)-2,5-difluorobenzene

[0711]

[0712] At room temperature under a nitrogen atmosphere, K3PO4 (0.80 g, 3.763 mmol), XantPhos (0.18 g, 0.314 mmol), and Pd2(dba)3 (0.14 g, 0.157 mmol) were added to a stirred mixture of 1-bromo-2,5-difluoro-4-iodobenzene (1.00 g, 3.136 mmol) and (methylphosphonato)methane (0.27 g, 3.450 mmol) in 1,4-dioxane (10 mL). 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 CH2Cl2 / MeOH (15 / 1) to afford 1-bromo-4-(dimethylphosphoryl)-2,5-difluorobenzene as a brown solid (550 mg, 65%). C8H8BrF2OP [M+H] + The calculated MS ESI values for 268.95 270.94, and the experimental values were 268.90 270.90. 1 1H 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 31P NMR (121 MHz, chloroform-d) δ 29.75.

[0713] Example 54: (7R,14R)-1-(difluoromethoxy)-11-(4-(dimethylphosphoryl)-2,5-difluorophenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methano-benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-5(14H)-one

[0714]

[0715] At room temperature under a nitrogen atmosphere, 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]diazocine-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 H2O (0.2 mL) was added K2CO3 (35.67 mg, 0.258 mmol) and Pd(dppf)Cl 2· CH2Cl2 (9 mg, 0.010 mmol). The resulting mixture was stirred at 80 °C for 3 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (15 / 1), and then purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 25% to 40% gradient over 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]diazocine-5(14H)-one (20 mg, 35%) as a white solid. C 27 H 19 D3F4N3O3P [M+H] + The calculated value of MS ESI for 547.15, the experimental value 547.10. 1 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 19F 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 1P NMR (162 MHz, chloroform-d) δ 29.76.

[0716] Example 55: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2,3-difluorophenyl]-6-fluoro-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0717]

[0718] Preparation 55A: Ethyl (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-[(5-chloro-4-fluoro-2-nitrophenyl)amino]propionate

[0719]

[0720] At room temperature, K2CO3 (33.20 g, 240.252 mmol) was added to a stirred solution of ethyl (3R)-3-amino-3-[2-bromo-6-(difluoromethoxy)phenyl]propionate 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). 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 x 800 mL). The combined organic layers were washed with brine (1 x 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]propionate as a yellow solid (30.00 g, 73%). C 18 H 15 BrClF3N2O5 [M+H] + The calculated MS ESI values for 510.98 512.98, the experimental values 511.00 513.00. 11H 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).

[0721] Preparation of 55B: (3R)-3-[2-Bromo-6-(difluoromethoxy)phenyl]-3-[(5-chloro-4-fluoro-2-nitrophenyl)amino]propanal

[0722]

[0723] At -78 °C under a nitrogen atmosphere, to a stirred solution of ethyl (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-[(5-chloro-4-fluoro-2-nitrophenyl)amino]propionate (29.00 g, 56.676 mmol) in DCM (300 mL) was added dropwise toluene containing 1.5 N DIBAL-H (45 mL, 68.011 mmol). The resulting mixture was stirred at -78 °C under a nitrogen atmosphere for 2 hours. The reaction solution was quenched at -78 °C by the addition of saturated NH4Cl (aqueous solution) (50 mL). The mixture was allowed to warm to room temperature. The resulting mixture was filtered, and the filter cake was washed with DCM (3 x 100 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (1 x 500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (6:1) to give (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-[(5-chloro-4-fluoro-2-nitrophenyl)amino]propanal as a yellow solid (16.10 g, 60%). C 16 H 11 BrClF3N2O4 [M+H] + The calculated value of MS ESI for 466.95468.95, the experimental value 467.00 469.00. 11H 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).

[0724] Preparation of 55C: (4R)-4-[2-Bromo-6-(difluoromethoxy)phenyl]-4-[(5-chloro-4-fluoro-2-nitrophenyl)amino]-2-[(trimethylsilyl)oxy]butanenitrile

[0725]

[0726] At room temperature, ZnI2 (1.02 g, 3.208 mmol), TEA (324 mg, 3.208 mmol) and TMSCN (6.36 g, 64.154 mmol) were added 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). The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was used directly in the next step without further purification. C 20 H 20 BrClF3N3O4Si [M+H] + The calculated MS ESI values for BrClF3N3O4Si [M+H] are 566.00568.00, and the experimental values are 566.10 568.10.

[0727] Preparation of 55D: (3R)-3-[2-Bromo-6-(difluoromethoxy)phenyl]-11-chloro-10-fluoro-2,7-diazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-5-ol

[0728]

[0729] At room temperature, SnCl2 (32.12 g, 167.600 mmol) was added to a stirred solution of (4R)-4-[2-bromo-6-(difluoromethoxy)phenyl]-4-[(5-chloro-4-fluoro-2-nitrophenyl)amino]-2-[(trimethylsilyl)oxy]butyronitrile (19.00 g, 33.520 mmol) in EtOH (150 mL). The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with water (100 mL). The mixture was basified to pH 8 with KOH (1N). The resulting mixture was diluted with EtOAc (500 mL). The resulting mixture was filtered and the cake was washed with EtOAc (3 x 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (10:1) to afford (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. C 17 H 11 BrClF3N2O2[M+H] + The calculated MS ESI values for BrClF3N2O2[M+H] are 446.96 and 448.96, and the experimental values are 447.00 and 449.00.

[0730] 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

[0731]

[0732] 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 by HPLC under the following conditions: column: XB-C18 101 x 650 mm, 10 μm; 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 to afford (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. C17 H 11 BrClF3N2O2[M+H] + , 446.96 - 448.96, experimental 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).

[0733] Preparation of 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

[0734]

[0735] At 0 °C, DBU (10.20 g, 67.020 mmol) was added 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 - tetraene - 5 - ol (6.01 g, 13.404 mmol) and DPPA (4.43 g, 16.085 mmol) in THF (20 mL). The resulting mixture was stirred at 30 °C for 24 h. The resulting mixture was diluted with EtOAc (50 mL) and H2O (100 mL). The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were 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. C 17 H 10 BrClF3N5O[M+H] + The calculated MS ESI values for 471.97 - 473.97, experimental values 471.95 - 473.95.

[0736] Preparation of 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 - tetraene - 5 - amine

[0737]

[0738] At room temperature under a nitrogen atmosphere, PPh3 (4.00 g, 15.250 mmol) was added 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 a solution of THF (100 mL) and H2O (10 mL). 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 CH2Cl2 / MeOH (10:1) to afford (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-tetraene-5-amine (5.02 g) as a black oil. C 17 H 12 BrClF3N3O[M+H] + The calculated MS ESI values for 445.98 447.98, experimental values 446.00 448.00.

[0739] Preparation of 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}]eicos-3(8),4,6,9,14(19),15,17-heptaene-13-one

[0740]

[0741] In a pressure vessel, K2CO3 (3.09 g, 22.390 mmol), XantPhos (129 mg, 0.224 mmol), and Pd(OAc)2 (50 mg, 0.224 mmol) were added 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). The mixture was purged with nitrogen for 2 minutes and then pressurized with carbon monoxide to 1 atmosphere 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 CH2Cl2 / MeOH (10:1) to afford (1R,11R)-5-chloro-18-(difluoromethoxy)-6-fluoro-2,9,12-triazapentacyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one (0.70 g, 39%) as a brown solid. C 18 H 11 ClF3N3O2[M+H] + The calculated MS ESI values for 394.05 396.05, experimental values 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).

[0742] Preparation of 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}]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0743]

[0744] At -78 °C under a nitrogen atmosphere, a solution of 1N KHMDS (0.91 mL, 0.914 mmol) in THF was added dropwise to a stirred solution of (1R,11R)-5-chloro-18-(difluoromethoxy)-6-fluoro-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (300 mg, 0.762 mmol) in dry THF (3 mL). The resulting mixture was stirred at -78 °C under a nitrogen atmosphere for 1 hour. At -78 °C, CH3I (162 mg, 1.143 mmol) was added dropwise to the above mixture. 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 CH2Cl2 / MeOH (10:1) to give (1R,11R)-5-chloro-18-(difluoromethoxy)-6-fluoro-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicosa-3(8),4,6,9,14(19),15,17-heptaen-13-one (220 mg, 70%) as a yellow solid. C 19 H 13 ClF3N3O2[M+H] + The calculated MS ESI values for ClF3N3O2[M+H] are 408.06 and 410.06, and the experimental values are 408.05 and 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).

[0745] 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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicosa-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0746]

[0747] At room temperature under a nitrogen atmosphere, PCy3·HBF4 (19 mg, 0.052 mmol) and Pd2(dba)3 (47 mg, 0.052 mmol) were added to a stirred solution of (1R,11R)-5-chloro-18-(difluoromethoxy)-6-fluoro-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-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). The resulting mixture was stirred at 140 °C for 16 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / 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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (210 mg, 81%) as a yellow solid. C 25 H 25 Calculated MS ESI for BF3N3O4[M+H] 500.19, found 500.30. +

[0748] Example 55: (1R,11R)-18-(Difluoromethoxy)-5-[4-(dimethylphosphoryl)-2,3-difluorophenyl]-6-fluoro-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0749]

[0750] Under nitrogen atmosphere at room temperature, a solution of K3PO4 (89 mg, 0.420 mmol) in H2O (0.5 mL) was added 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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-hepten-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). At room temperature, Pd(dppf)Cl2.CH2Cl2 (11 mg, 0.014 mmol) was added to the above mixture. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1), and then purified by reverse phase flash chromatography under 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 (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2,3-difluorophenyl]-6-fluoro-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-hepten-13-one (35 mg, 44%) as a white solid. C 27 H 21 F5N3O3P[M+H] + The calculated value of MS ESI for F5N3O3P[M+H] is 562.12, and the experimental value is 562.20. 1 H NMR (400 MHz, chloroform-d) δ 8.50 (d, J = 8.2 Hz, 1H), 7.82 - 7.75 (m, 1H), 7.53 (d, J = 10.4 Hz, 1H), 7.48 (d, J = 6.3 Hz, 1H), 7.44 (t, J = 8.2 Hz, 1H), 7.34 - 7.30 (m, 2H), 6.79 (t, J = 72.8 Hz, 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). 1919F 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 31P NMR (162 MHz, chloroform-d) δ 29.90.

[0751] Example 56: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2,5-difluorophenyl]-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0752]

[0753] To a solution of (1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one (50 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 H2O (0.1 mL) was added K3PO4 (66 mg, 0.312 mmol) and Pd(dppf)Cl2.CH2Cl2 (8 mg, 0.010 mmol). After stirring for 2 h at 80 °C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 20% to 50% gradient in 30 min; detector, 254 nm. This gave (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2,5-difluorophenyl]-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]icos-3(8),4,6,9,14(19),15,17-heptaen-13-one (34 mg, 59%) as a white solid. C 27 H 22 F4N3O3P[M+H] + The calculated value of MS ESI for F4N3O3P[M+H] is 544.13, and the experimental value is 544.05. 1 1H NMR (300 MHz, 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 = 8.2 Hz, 1H), 7.26 - 7.20 (m, 1H), 7.14 - 6.58 (m, 1H), 6.35 (d, J = 6.1 Hz, 1H), 5.13 - 5.04 (m, 1H), 3.62 - 3.45 (m, 4H), 2.94 (d, J = 13.2 Hz, 1H), 1.89 (s, 3H), 1.85 (s, 3H). 1919F 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 31P NMR (121 MHz, chloroform-d) δ 29.66.

[0754] Example 57: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3-fluorophenyl]-6-fluoro-12-methyl-2,9,12-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0755]

[0756] At room temperature under a nitrogen atmosphere, 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-triazatricyclo[9.8.1.02,10.03,8.014,19]eicos-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 H2O (0.5 mL). At room temperature under a nitrogen atmosphere, to the above solution was added Pd(dppf)Cl 2·CH2Cl2 (11 mg, 0.014 mmol). The resulting mixture was stirred for an additional 2 h at 80 °C. The mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (0% to 10%), followed by purification by preparative HPLC under the following conditions: column: 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 afford (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3-fluorophenyl]-6-fluoro-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one (18 mg, 23%) as a white solid. C 27 H 22 F4N3O3P [M+H] + The calculated value of MS ESI for 544.13, the experimental value is 544.00. 1 H 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.

[0757] Example 58: (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2-fluorophenyl]-6-fluoro-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one

[0758]

[0759] At room temperature under a nitrogen atmosphere, 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-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-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 H2O (0.5 mL). At room temperature under a nitrogen atmosphere, to the above solution was added Pd(dppf)Cl 2· CH2Cl2 (11 mg, 0.014 mmol). The resulting mixture was stirred at 80 °C for an additional 2 h. The mixture was cooled 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%), and then purified by preparative HPLC under the following conditions: column: 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 afford (1R,11R)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2-fluorophenyl]-6-fluoro-12-methyl-2,9,12-triazatricyclo[9.8.1.0^{2,10}.0^{3,8}.0^{14,19}]eicos-3(8),4,6,9,14(19),15,17-heptaen-13-one as a white solid (30 mg, 39%). C 27 H 22 F4N3O3P [M+H] + The calculated value of MS ESI for 544.13, the experimental 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.

[0760] Example 59: (7R,14R)-1-(Difluoromethoxy)-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-10-fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methano-benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazacyclotetradecin-5(14H)-one

[0761]

[0762] Preparation 59A: (7R,14R)-11-Chloro-1-(difluoromethoxy)-10-fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methano-benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazacyclotetradecin-5(14H)-one

[0763]

[0764] Under a nitrogen atmosphere at -78 °C, a solution of 1N KHMDS (1.22 mL, 1.219 mmol) in THF was added dropwise to a stirred solution of (1R,11R)-5-chloro-18-(difluoromethoxy)-6-fluoro-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014,19]eicos-3(8),4,6,9,14(19),15,17-heptaene-13-one (400 mg, 1.016 mmol) in dry THF (10 mL). The resulting solution was stirred for 1 hour at -78 °C under a nitrogen atmosphere. At -78 °C, CD3I (295 mg, 2.032 mmol) was added dropwise to the above solution over 2 minutes. The resulting mixture was slowly warmed to room temperature. The resulting mixture was stirred for 3 hours at room temperature under a nitrogen atmosphere. The reaction mixture was quenched at room temperature by the addition of saturated NH4Cl (aqueous solution) (5 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10 / 1) to afford (7R,14R)-11-chloro-1-(difluoromethoxy)-10-fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methano-benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazacyclotetradecin-5(14H)-one as an off-white solid (380 mg, 91%). C 19 H 10 D3ClF3N3O2 [M+H] + The calculated value of MS ESI for 411.08, experimental value 410.90.1 1H 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 19F NMR (376 MHz, chloroform-d) δ -80.21, -80.65, -80.99, -81.43, -120.18.

[0765] Preparation of 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]diazacyclooctatetraen-5(14H)-one

[0766]

[0767] At room temperature under a nitrogen atmosphere, 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]diazacyclooctatetraen-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) were added PCy3·HBF4 (51 mg, 0.139 mmol) and Pd2(dba)3 (85 mg, 0.093 mmol). The resulting 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 EtOAc / EtOH / PE (3 / 1 / 6) to give (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]diazacyclooctatetraen-5(14H)-one (370 mg, 80%). C 25 H 22 D3BF3N3O4 [M+H] +The calculated value of MS ESI is 503.21, and the experimental value is 503.30.

[0768] Example 59: (7R,14R)-1-(Difluoromethoxy)-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-10-fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methano-benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazacyclooctatetraen-5(14H)-one

[0769]

[0770] At room temperature under a nitrogen atmosphere, 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-methano-benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazacyclooctatetraen-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 H2O (0.2 mL) was added K2CO3 (41 mg, 0.297 mmol) and Pd(dppf)Cl 2· CH2Cl2 (10 mg, 0.012 mmol). The resulting mixture was stirred at 80 °C for 3 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (15 / 1), followed by purification by reverse-phase flash chromatography under the following conditions: column, C18 silica; mobile phase, aqueous CH3CN (10 mmol / L NH4HCO3), 25% to 40% gradient in 30 min; detector, 254 nm. This gave (7R,14R)-1-(difluoromethoxy)-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-10-fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methano-benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazacyclooctatetraen-5(14H)-one as a white solid (22 mg, 34%). C 27 H 19 D3F4N3O3P [M+H] + The calculated value of MS ESI is 547.15, and the experimental value is 547.00. 11H NMR (400 MHz, 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 = 72.8 Hz, 1H), 6.29 (d, J = 7.0 Hz, 1H), 5.05 (d, J = 7.0 Hz, 1H), 3.57 - 3.45 (m, 1H), 2.91 (d, J = 13.6 Hz, 1H), 1.87 (s, 3H), 1.83 (s, 3H). 19 19F NMR (377 MHz, chloroform-d) δ -80.37, -80.82, -80.95, -81.39, -105.97, -105.98, -121.63. 31 31P NMR (162 MHz, chloroform-d) δ 30.43.

[0771] Example 60: (7R,14R)-1-(Difluoromethoxy)-11-(4-(dimethylphosphoryl)-3,5-difluorophenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methano-benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-5(14H)-one

[0772]

[0773] (7R,14R)-1-(Difluoromethoxy)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methano-benzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-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 CH2Cl2 (8 mg, 0...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or N-oxide thereof: Wherein, Ring A is selected from wherein * represents a point of attachment to L, or is an optionally substituted heteroarylene selected from the following: pyrazolylene, imidazoline, oxazolylene or thiazolylene; V is N or C-R 11 ; W is N or C-R 5 ; X is N or C-R 6 ; Y is N or C-R 7 ; Z is N or C-R 8 ; L is a bond, -NH-, -(CH2)n-, -C(R 12 )(R 13 )-, -O(CH2)n-*, or -NH(CH2)n-*, where the * represents the point of attachment to phosphorus; n is 1, 2 or 3; R 1 selected from hydrogen, an optionally substituted C1-C6 alkyl group, an optionally substituted C3-C6 cycloalkyl group, or an optionally substituted C4-C7 cycloalkylalkyl group; R 2 is hydrogen or an optionally substituted C1-C3 alkyl group; R 3 is a hydroxyl group, an optionally substituted C1-C3 alkoxy group or an optionally substituted C1-C6 alkyl group; R 4 is a hydroxyl group, an optionally substituted C1-C3 alkoxy group or an optionally substituted C1-C6 alkyl group; or R 3 and R 4 are linked to form an optionally substituted 3- to 8-membered phosphorus-containing ring; Each R 5 , R 6 , R 7 and R 8 is independently selected from hydrogen, halogen, -CN, -NH2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy or -NH(optionally substituted C1-C3 alkyl); R 9 selected from hydrogen, a halogen or an optionally substituted C1-C6 alkyl group; R 10 selected from hydrogen or a halogen; R 11 selected from hydrogen, a halogen or an optionally substituted C1-C6 alkyl group; and R 12 and R 13 are independently selected from hydrogen, -OH, F and CH3.

2. A compound of formula (Ia) or a pharmaceutically acceptable salt, solvate or N-oxide thereof: Wherein, Ring A is selected from wherein * represents the connection point to L, is an optionally substituted heteroarylene selected from the following: pyrazolylene, imidazoline, oxazolylene or thiazolylene; V is N or C-R 11 ; W is N or C-R 5 ; X is N or C-R 6 ; Y is N or C-R 7 ; Z is N or C-R 8 ; L is a bond, -NH-, -(CH2)n-, -O(CH2)n-* or -NH(CH2)n-*, wherein the * represents the point of attachment to phosphorus; n is 1, 2 or 3; R 1 selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl or optionally substituted C4-C7 cycloalkylalkyl; R 2 is hydrogen or an optionally substituted C1-C3 alkyl group; R 3 is a hydroxyl group, an optionally substituted C1-C3 alkoxy group or an optionally substituted C1-C6 alkyl group; R 4 is a hydroxyl group, an optionally substituted C1-C3 alkoxy group or an optionally substituted C1-C6 alkyl group; or R 3 and R 4 are linked to form an optionally substituted 3- to 8-membered phosphorus-containing ring; Each R 5 , R 6 , R 7 and R 8 is 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 selected from hydrogen, a halogen or an optionally substituted C1-C6 alkyl group; R 10 selected from hydrogen or a halogen; and R 11 Selected from hydrogen, a halogen or an optionally substituted C1-C6 alkyl group.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein ring A is selected from wherein the * represents the point of attachment to L.

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

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

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

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

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

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

10. A compound or a pharmaceutically acceptable salt, solvate or N-oxide thereof according to any one of claims 3 to 5 or 7 to 9, wherein Y is C-R 7 .

11. A compound or a pharmaceutically acceptable salt, solvate or N-oxide thereof according to any one of claims 3 to 6 or 8 to 10, wherein Z is C-R 8 .

12. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein each R 5 , R 6 , R 7 and R 8 is independently selected from hydrogen or halogen.

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

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

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

16. The compound or a pharmaceutically acceptable salt, solvate or N-oxide thereof according to claim 15, wherein the optionally substituted C1-C3 alkyl is substituted by halogen.

17. The compound or a pharmaceutically acceptable salt, solvate or N-oxide thereof according to claim 15, wherein the optionally substituted C1-C3 alkyl is -CHF2.

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

19. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein R 3 and R 4 are hydroxyl groups.

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

21. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein R 3 and R 4 are optionally substituted C1-C3 alkoxy groups.

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

23. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein R 3 and R 4 are optionally substituted C1-C3 alkoxy groups.

24. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein R 3 and R 4 are each independently an optionally substituted C1-C6 alkyl group.

25. The compound according to claim 24 or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein R 3 and R 4 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.

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

27. The compound according to claim 24, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein R 3 and R 4 are each ethyl.

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

29. The compound according to claim 24, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein R 3 and R 4 are linked to form an optionally substituted 3- to 8-membered heterocyclic group containing phosphorus.

30. The compound according to claim 29, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein R 3 and R 4 are linked to form an optionally substituted 3- to 8-membered heterocyclic group containing phosphorus, said heterocyclic group containing one or two additional heteroatoms each independently selected from N, O and S.

31. A compound or a pharmaceutically acceptable salt, solvate or N-oxide thereof according to claim 29 or 30, wherein R 3 and R 4 are linked to form an optionally substituted 4- to 6-membered heterocyclic group containing phosphorus.

32. A compound or a pharmaceutically acceptable salt, solvate or N-oxide thereof according to claim 29 or 30, wherein R 3 and R 4 are linked to form an optionally substituted phosphorus-containing 4-membered heterocyclic group.

33. A compound or a pharmaceutically acceptable salt, solvate or N-oxide thereof according to claim 29 or 30, wherein R 3 and R 4 are linked to form an optionally substituted phosphorus-containing 5-membered heterocyclic group.

34. A compound according to claim 29 or 30, 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 heterocyclic group.

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

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

37. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein R 3 and R 4 together with the phosphorus atom to which they are attached are joined to form a ring selected from:

38. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate or N - oxide thereof, wherein R 3 and R 4 together with the phosphorus atom to which they are attached are joined to form a ring selected from the following:

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

40. The compound or a pharmaceutically acceptable salt, solvate or N-oxide thereof according to any one of claims 1 to 38, wherein L is -CH2-.

41. The compound or a pharmaceutically acceptable salt, solvate or N-oxide thereof according to any one of claims 1 to 38, wherein L is -OCH2-*.

42. The compound or a pharmaceutically acceptable salt, solvate or N-oxide thereof according to any one of claims 1 to 38, wherein L is -NHCH2-*.

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

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

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

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

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

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

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

50. A compound or a pharmaceutically acceptable salt, solvate or N-oxide thereof according to any one of claims 1 to 48, wherein V is C-R 11 .

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

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

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

54. A pharmaceutical composition comprising a compound as claimed in 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. A method for preparing a pharmaceutical composition, the method comprising mixing a compound as claimed in 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.

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

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

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

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

60. 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 therapeutically effective amount of a compound as claimed in any one of claims 1 to 53 or a pharmaceutically acceptable salt or solvate or N-oxide thereof, or a pharmaceutical composition as claimed in claim 54.

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

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

63. A method for treating or preventing a condition that is amenable to treatment or prevention by inhibiting TNFα in a patient, the method 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.

64. A pharmaceutical composition comprising a compound according to any one of claims 1 to 53 or a pharmaceutically acceptable salt or solvate or N-oxide thereof, the pharmaceutical composition being for treating or preventing a condition that is amenable to treatment or prevention by inhibiting TNFα in a patient.

65. 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 treating or preventing a condition that is amenable to treatment or prevention by inhibiting TNFα in a patient.

66. A compound according to any one of claims 1 to 53 or a pharmaceutically acceptable salt or solvate or N-oxide thereof or The use of a pharmaceutical composition according to claim 54 for the manufacture of a medicament for treating or preventing a condition that is amenable to treatment or prevention by inhibiting TNFα in a patient.

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