Inhibitors of TNF alpha activity

Abstract

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

Description

WSGR Ref: 53699-726.601INHIBITORS OF TNF ALPHA ACTIVITYCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of US Provisional Application No. 63 / 723,522, filed November 21, 2024, which is incorporated herein by reference in its entirety.BACKGROUND

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

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

[0004] One embodiment provides a compound of Formula (I), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer:wherein,A is N or C;B is N or C; wherein at least one of A or B is N;V is N or C-R9;W is N or C-R3;X is N or C-R4;Y is N or C-R5;Z is N or C-R6; provided that at least two of W, X, Y and Z are not N;R is an optionally substituted aryl or optionally substituted heteroaryl;R1is hydrogen, -OH, or optionally substituted C1-C6 alkyl; or R1is optionally substituted C1-C6 alkyl, and R and R1join to form optionally substituted spirocyclic ring;WSGR Ref: 53699-726.601 each R2is independently optionally substituted C1 -C6 alkyl; or two R2join to form optionally substituted phosphorus-containing 3- to 8-membered ring;R3, R4, R5, and R6are each independently selected from hydrogen, deuterium, halogen, - CN, or optionally substituted C1 -C3 alkyl;R7, R8, and R9are each independently selected from hydrogen, deuterium, halogen, -CN, or optionally substituted C1 -C3 alkyl;J is -C(R10)2-, or -N(Rn)-;K is absent, -O-, or -C(R12)2-;L is -C(R13)2-, -S-, -SO-, or -SO2-; each R10is independently selected from hydrogen, deuterium, halogen, -CN, -OH, - CO(NR14)2, optionally substituted C1 -C6 alkyl, or optionally substituted C1 -C6 alkoxy; or two R10form an oxo; or two R10form an =N-O-(optionally substituted C1 -C6 alkyl);R11is selected from hydrogen, or optionally substituted C1 -C6 alkyl;R12is selected from hydrogen, deuterium, halogen, -CN, -OH, optionally substituted Cl - C6 alkyl, or optionally substituted C1 -C6 alkoxy; or two R12form an oxo;R13are independently selected from hydrogen, deuterium, halogen, -CN, -OH, - CO(NR14)2, optionally substituted C1 -C6 alkyl, or optionally substituted C1 -C6 alkoxy; or two R13form an oxo; andR14is selected from hydrogen, or optionally substituted C1 -C6 alkyl.

[0005] One embodiment provides a compound of Formula (II) or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer:wherein,A is N or C;B is N or C; wherein at least one of A or B is N;V is N or C-R9;W is N or C-R3;X is N or C-R4;Y is N or C-R5;WSGR Ref: 53699-726.601Z is N or C-R6; provided that at least two of W, X, Y and Z are not N;R is an optionally substituted aryl or optionally substituted heteroaryl;R1is hydrogen, -OH, or optionally substituted C1 -C6 alkyl; or R1is optionally substituted C1-C6 alkyl, and R and R1join to form optionally substituted spirocyclic ring; each R2is independently optionally substituted C1 -C6 alkyl; or two R2join to form optionally substituted phosphorus-containing 3- to 8-membered ring;R3, R4, R5, and R6are each independently selected from hydrogen, deuterium, halogen, - CN, or optionally substituted C1 -C3 alkyl;R7, R8, and R9are each independently selected from hydrogen, deuterium, halogen, -CN, or optionally substituted C1 -C3 alkyl;R20is hydrogen, deuterium, optionally substituted C1 -C3 alkyl, or optionally substituted C1-C6 alkoxy;R21is hydrogen, deuterium, or optionally substituted C1 -C3 alkyl;R22is hydrogen;R23is hydrogen;R24is hydrogen, deuterium, optionally substituted C1 -C3 alkyl, or optionally substituted C1-C6 alkoxy.

[0006] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), (II) or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, and at least one pharmaceutically acceptable excipient.

[0007] One embodiment provides a method of treating a disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I), (II) or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer. Another embodiment provides the method wherein the disease or disorder is rheumatoid arthritis.INCORPORATION BY REFERENCE

[0008] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein.DETAILED DESCRIPTION OF THE INVENTION

[0009] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to thoseWSGR Ref: 53699-726.601 skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, "consist of' or "consist essentially of" the described features.Definitions

[0010] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0011] " Amino" refers to the -NH2radical.

[0012] "Cyano" refers to the -CN radical.

[0013] "Nitro" refers to the -NO2radical.

[0014] " Oxa" refers to the -O- radical.

[0015] " Oxo" refers to the =0 radical.

[0016] " Thioxo" refers to the =S radical.

[0017] " Imino" refers to the =N-H radical.

[0018] " Oximo" refers to the =N-0H radical.

[0019] "Hydrazino" refers to the =N-NH2radical.

[0020] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., Ci-Cg alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., Ci- C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., Ci-C2alkyl). In other embodiments, an alkyl comprisesone carbon atom (e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., Cs-Cs alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5alkyl). In other embodiments, an alkylWSGR Ref: 53699-726.601 comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl ( / / -propyl), 1 -methylethyl ( / .w-propyl), 1 -butyl ( / / -butyl), 1 -methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1 -dimethylethyl (Zc / 7-butyl), 1 -pentyl ( / / -pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -P(O)(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluorom ethyl). In certain embodiments, an optionally substituted alkyl is a haloalkyl. In other embodiments, an optionally substituted alkyl is a fluoroalkyl. In other embodiments, an optionally substituted alkyl is a -CF3group.

[0021] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0022] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon -carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl ( / .<?., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -P(O)(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, cyano,WSGR Ref: 53699-726.601 methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl).

[0023] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon -carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl comprises two to six carbon atoms. In other embodiments, an alkynyl comprises two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -P(O)(Ra)2, -C(O)Ra, - C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluorom ethyl), heterocyclyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or tri fluoromethyl).

[0024] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, w-butylene, and the like. The alkylene chain isWSGR Ref: 53699-726.601 attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., Ci-C8alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., Ci-C2alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., Cs-C8alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -P(O)(Ra)2, -C(O)Ra, - C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluorom ethyl), heterocyclyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or tri fluoromethyl).

[0025] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkenylene comprises two to eight carbon atoms (e.g., C2-C8alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (e.g., C2-C5alkenylene). In other embodiments,WSGR Ref: 53699-726.601 an alkenylene comprises two to four carbon atoms (e.g., C2-C4alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (e.g., C2-C3alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (e.g., C2alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., Cs-C8alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C3-C5alkenylene). Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted by one or more ofthe following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -P(O)(Ra)2, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl).

[0026] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C2-C8alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C2-Cs alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (e.g., C2-C4alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C2-C3alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C2alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C5-C8alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C3-C5alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -P(O)(Ra)2, -C(O)Ra, -WSGR Ref: 53699-726.601C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluorom ethyl), heterocyclyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or tri fluoromethyl).

[0027] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, ie., it contains a cyclic, delocalized (4n+2) 7i-electron system in accordance with the Huckel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb- OC(O)-N(Ra)2, -Rb-N(Ra)2, -P(O)(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc- C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb- S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), -Rb-S(O)tN(Ra)2(where t is 1 or 2), and -P(O)(Ra)2where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, orWSGR Ref: 53699-726.601 trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, andRcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0028] "Aralkyl" refers to a radical of the formula -Rc-aryl where Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0029] "Aralkenyl" refers to a radical of the formula -Rd-aryl where Rdis an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0030] "Aralkynyl" refers to a radical of the formula -Re-aryl, where Reis an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0031] "Aralkoxy " refers to a radical bonded through an oxygen atom of the formula -O-Rc-aryl where Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0032] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused, spiro, or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (i.e., containing single C-C bonds only) or unsaturated ( / .< ., containing one or more double bonds or triple bonds). A fully saturated carbocyclyl radical is also referred to as "cycloalkyl." Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl i.e., bicyclo[2.2.1]heptanyl), norbomenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2. l]heptanyl, and the like. Unless otherwise statedWSGR Ref: 53699-726.601 specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, oxo, thioxo, cyano, nitro, -Rb-0Ra, -Rb-0C(0)-Ra, -Rb-0C(0)-0Ra, -Rb-0C(0)-N(Ra)2, -Rb- N(Ra)2, -P(0)(Ra)2, -Rb-C(0)Ra, -Rb-C(0)0Ra, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb- N(Ra)C(0)0Ra, -Rb-N(Ra)C(0)Ra, -Rb-N(Ra)S(0)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) -Rb-S(0)tN(Ra)2 (where t is 1 or 2), and -P(0)(Ra)2, where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0033] "Carbocyclylalkyl" refers to a radical of the formula -Rc-carbocyclyl where Rcis an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

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

[0035] "Carbocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula - O-Rc-carbocyclyl where Rcis an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0036] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.

[0037] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1 -fluoromethyl-2 -fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.WSGR Ref: 53699-726.601

[0038] "Heterocyclyl" refers to a stable 3 - to 18-membered non-aromatic ring radical that comprises two to twelve carbon atomsand from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes fused, spiro, or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1 -oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alky nyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, - Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -P(O)(Ra)2, -Rb- C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb- N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb- S(O)tORa(where t is 1 or 2) -Rb-S(O)tN(Ra)2 (where t is 1 or 2), and -P(O)(Ra)2, where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluorom ethyl), heterocyclyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.WSGR Ref: 53699-726.601

[0039] "A-heterocyclyl" or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An ^'-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such A-heterocyclyl radicals include, but are not limited to, 1 -morpholinyl, 1- piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, and imidazolidinyl.

[0040] " C-heterocyclyl" or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. A C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2 -morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0041] "Heterocyclylalkyl" refers to a radical of the formula -Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen -containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0042] "Heterocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0043] "Heteroaryl" refers to a radical derived from a 3 - to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, ie., it contains a cyclic, delocalized (4n+2) 7i-electron system in accordance with the Hiickel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[Z>][l,4]dioxepinyl, benzo[b][l,4]oxazinyl,WSGR Ref: 53699-726.6011,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5.6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1.6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10, 10a-octahydrobenzo[h]quinazolinyl, 1 -phenyl- 1 / 7-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5, 6, 7, 8 -tetrahydroquinazolinyl,5.6.7.8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6.7.8.9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, optionally substituted fluoroalkyl, optionally substituted haloalkenyl, optionally substituted haloalkynyl, oxo, thioxo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, - Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -P(O)(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O- Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), - Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) -Rb-S(O)tN(Ra)2 (where t is 1 or 2), and -P(O)(Ra)2, where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), heterocyclylWSGR Ref: 53699-726.601(optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, cyano, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, andRcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0044] "A-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An A-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0045] " C-heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0046] "Heteroarylalkyl" refers to a radical of the formula -Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen -containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0047] "Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula - O-Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0048] The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (A)- or (5 -. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans .) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The termWSGR Ref: 53699-726.601“geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0049] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0050] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,nC,13C and / or14C, or other atoms as appropriate to the molecular formula. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms, referred to herein as “deuteroisotope”, can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As describedin U.S. PatentNos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs .

[0051] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0052] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, theWSGR Ref: 53699-726.601 compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,nC,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35C1,37C1,79Br,81Br,125I are all contemplated. In some embodiments, isotopic substitution with18F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0053] In certain embodiments, the compounds disclosed herein have some or all of theJH atoms replaced with2H atoms. Said compounds with2H replacement are described herein as deuteroisotopes. The methods of synthesis for deuterium -containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0054] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000;6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601 -21 ; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0055] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium -containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0056] Deuterium -transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-d3(CD3I), are readily available and may be employed to transfer a deuterium - substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD3I is illustrated, by way of example only, in the reaction schemes below.

[0057] Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAlD4), are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD4is illustrated, by way of example only, in the reaction schemes below.WSGR Ref: 53699-726.601

[0058] Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbon linkages and to perform a reductive substitution of aryl carbon -halogen bonds as illustrated, by way of example only, in the reaction schemes below.

[0059] In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeableJH hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.

[0060] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the TNF-a inhibitory compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0061] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid,WSGR Ref: 53699-726.601 mandelic acid, methanesulfonic acid, ethanesulfonic acid, p -toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1- 19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0062] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic b ase or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, tri ethylamine, tripropylamine, ethanolamine, diethanolamine, 2 -dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N- dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, A-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0063] "Pharmaceutically acceptable solvate" refers to a composition of matter that is the solvent addition form. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein exist in either unsolvated or solvated forms.WSGR Ref: 53699-726.601

[0064] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non -human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0065] As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and / or a prophylactic benefit. By “therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.Tumor Necrosis Factor alpha (TNFa) Protein and Function

[0066] Tumor necrosis factor alpha (TNFa) proteins are members of the TNF superfamily, comprising various transmembrane proteins with a homologous TNF domain forming trimers. The TNF superfamily comprises 19 family members, including, but not limited to tumor necrosis factor alpha (also known as tumor necrosis factor, or TNF), lymphotoxin alpha (TNFP), lymphotoxin beta (TNFy), 0X40 ligand, CD40 ligand, Fas ligand, CD27 ligand, CD30 ligand, CD137 ligand, CD137 ligand, and TNF-related apoptosis-inducing ligand. TNFa proteins are cytokines and adipokines (cytokines secreted by adipose tissue).

[0067] TNFa is a transmembrane protein, with soluble TNFa (sTNFa) released via protein cleavage. The sTNFa can propagate signaling by binding to two receptors, TNFR1 and TNFR2. TNFa is a regulator of immune responses for cell signaling and can mediate cell survival and cell death inducing signaling. There are two receptors for TNF signaling, TNFR1 and TNFR2. sTNFa - TNFR1 signaling promotes immune cell activation and drives acute and chronic inflammation. Membrane TNFa - TNFR2 signaling promotes inflammation resolution, immune cell regulatory functions and cell survival.

[0068] The extracellular region of both TNFR1 and TNFR2 have four homologous cysteine-rich domains, but they have structurally different intracellular regions. TNFR1 has a protein binding region called a death domain which allows homo- and hetero-typic interactions with other death domain-containing proteins. In contrast, TNFR2 has a TNF Receptor Associated Factor TRAF) that interacts with TRAF family of signaling adaptors. The distinct profiles and differences ofWSGR Ref: 53699-726.601 the two TNF receptors influence the cellular activity and physiological roles. TNFR1 can activate NF-KB and MAPK signaling, and cell death, and is important to regulate for inflammatory diseases. TNFR2 is highly regulated and restricted to specific cell types such as endothelial cells and T cells. TNFR1 primarily promotes tissue degeneration and inflammation and TNFR2 typically mediates local homestatic effects such as tissue regeneration and cell survival (D. Fresegna et al., Cells, 2020, 9, 2290).

[0069] Binding of TNFa to TNFR1 can activate NF-KB for mediating transcription of various proteins involved in cell survival and proliferation, anti -ap opto tic factors, and inflammatory response. Further, the MAPK pathway can also be activated by binding of TNFa to TNFR1, which is involved in cell differentiation and proliferation. When TNF binds to TNFR1, it triggers receptor trimerization, leading to the assembly of a TNFR1 -associated signaling complex. This complex recruits the receptor interacting protein 1 (RIP2) and TNF receptor associated death domain (TRADD) to the TNFR1 through the receptive death domains. TRADD then recruits adaptor proteins TRAF2 and TRAF5, which can engage the E3 ligases cellular inhibitors of apoptosis (c-IAPl, C-IAP2). C-IAP1 / 2 are important for TNFR1 complex signaling which can eventually lead to the recruitment of the signaling kinase complexes of kinase IKKa and IKKP, which are inhibitors of kappa B kinase 1 and 2, and transforming growth factor betaactivated kinase 1 (TAK1) leading to activation of NF-KB and MAPK signaling. Activation of these signaling pathways can result in gene activation and expression of pro -inflammatory cytokines and pro-survival proteins.

[0070] TNF signaling is regulated by post-translational ubiquitination, which is essential for my biological processes. Post-translational modifications of TNFR1 -associated signaling complexes can result in a change from inflammatory gene signaling to cell death. This switch is dependent upon the ubiquitination status of RIP1, which is formed as part of the TNFR1 -associated signaling complex from TNFa binding.

[0071] TNF has long been known to be a key regulator of the inflammatory response, and recently has been known to be involved in brain functioning (D. Fresegna et al., Cells, 2020, 9, 2290). As a regulator of the inflammatory response, TNF can regulate many aspects of T cell biology including, but not limited to proliferation, survival, priming, and apoptotic fate. TNF is also known to play a role in conclusion of lymphocyte response, by the ability to promote cell death in both CD4 and CD8P T cells, through TNFR1 . Specific inflammatory conditions can also result in TNFR2 promoting or supporting T cell apoptosis.

[0072] In normal adult brains, TNF is expressed at low levels, and it is believed that the expression could be influenced by presence or absence of cytokines that can cross the blood brain barrier. TNFRs in the brain are expressed by glia and neurons cells, and have regulatoryWSGR Ref: 53699-726.601 functions, including, but not limited to homeostatic synaptic plasticity, astrocyte -mediated synaptic transmission, and neurogenesis. These functions are useful for regulating learning and memory functions amongst other roles.

[0073] TNF is recognized to be physiological gliotransmitter for the communication between neurons and glial cells, which in turn affects synaptic regulation. Glial TNF is important for maintenance of normal surface expression of AMPA receptors, and for homeostatic synaptic scaling, which allows for adjustment of the strength of all synapses on a neuron.Prior Art Small Molecules Inhibitors

[0074] Diseases treated with biologic TNFa inhibitors include, but are not limited to rheumatoid arthritis, inflammatory bowel disease, psoriatic arthritis, psoriasis, and ankylosing spondylitis. Patients with neuroinflammatory conditions and degenerative disease, including, but not limited to Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, treatment resistant depression, and tinnitus, may benefit from treatment with oral CNS sTNFa inhibitors by disrupting the sTNFa signaling and sparing the mTNFa signaling. Previous reports have also indicated targeting TNFR2 for treating Alzheimer’s Disease (N. Orti-Casan et al., Front Neurosci. 2019; 13 : 49).

[0075] Small molecules have been developed for treatment of rheumatoid arthritis as some patients have responded poorly to monotherapy of approved anti -TNFa drugs (J. D. Dietrich et al., J. Med. Chem. 2021, 64, 417-429). Anti-TNFa drugs have also been expanded for use in other chronic autoimmune diseases, including, but not limited to, Crohn’s disease, psoriasis, psoriatic arthritis, ulcerative colitis inflammatory bowel disease, ankylosing spondylitis, and juvenile rheumatoid arthritis. Small molecules have been developed as an alternative to anti- TNFa biologies since the long-term clinical response rate is generally around 60-70% for rheumatoid arthritis.

[0076] Previous research has also indicated that TNFa inhibitors can be therapeutic for treatment of multiple sclerosis (D. Fresegna et al., Cells, 2020, 9, 2290). There has been evidence of the involvement of TNF in various pathological issues of multiple sclerosis, including immune dysregulation, demylination, synaptopathy, and neuroinflammation. TNFa inhibitors have the potential for treatment of multiple sclerosis, other potential chronic neurodegenerative diseases of the central nervous system.

[0077] More than 50 million Americans struggle with tinnitus, which is the hearing of a sound with no external source. It has been shown that TNFa is necessary for noise -induced neuroinflammation and synaptic imbalance (W. Wang et al., PLoS Biol. 2019 Jun 18;17(6):e3000307; A. Shulman et al., Curr Top Behav Neurosci. 2021 ;51 : 161 -174). It is believed that certain inhibitors of TNFa have activities for treating tinnitus.WSGR Ref: 53699-726.601

[0078] Recent reports also indicate that TNFa inhibitors can be used alone or in combination for treatment with inflammatory bowel disease (S. F. Fowler Braga and K. J. Clark, US Pharm. 2021; 46(5):34-37). TNFa is a mediator of the abnormal immune response of inflammatory bowel disease, which leads to disruption of the intestinal mucosa and epithelial wall barrier. The anti-TNF agents can block TNF-mediated activation of the proinflammatory pathways to result in decreased immune-mediated inflammation.

[0079] Small molecule sTNF-a inhibitors are active in pharmacology models of sTNF-a / TNFR1 signaling in addition to demonstrating efficacy in a model of collagen antibody induced arthritis. There is currently limited data in the public domain for small molecule sTNF-a inhibitors. Some TNFa inhibitors include, but are not limited to XProl595, Etanercept, Infliximab, Adalimumab, Certolizumab pegol, Golimumamb, and other inhibitors described in “TNF-a: The Shape of Small Molecules to Come?” (A. Dbmling and X. Li, Drug Discov Today 2022 Jan; 27(l):3-7) and “Small Molecules that Inhibit TNF Signalling by Stabilising an Asymmetric Form of the Trim er (J. O’Connell et al., Nature Communications 10, 5795 (2019)). Additional small molecule inhibitors of TNFa include, but are not limited to the inhibitors described in “Biologic-like In Vivo Efficacy with Small Molecule Inhibitors of TNFa Identified Using Scaffold Hopping and Structure-Based Drug Design Approaches” (H-Y Xiao et al., J. Med. Chem. 2020, 15050-15071), “Development of Orally Efficacious Allosteric Inhibitors of TNF-a via Fragment-Based Drug Design” (J. D. Dietrich et al., J. Med. Chem. 2021, 64, 417- 429), and “Small-Molecule Inhibition of TNF-a” (M.M. He et al., Science, 310 (2015), 1022- 1025). Other recent publications in the filed of small molecule sTNF-a inhibitors include PCT Publication No. WO 2024 / 129763.

[0080] Small molecule sTNF-a inhibitors have potential as a valuable therapy for patients currently treated with biologic TNFa inhibitors which affect mTNFa with the ability to fine tune oral dosing requirements and avoid anti -drug antibody responses, thereby improving short and long responses (A. Dbmling and X. Li, Drug Discov Today 2022 Jan; 27(1):3 -7).Novel Compounds Inhibiting TNF-a

[0081] In one aspect, provided herein are TNF-a inhibitory compounds.

[0082] One embodiment provides a compound of Formula (I), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer:WSGR Ref: 53699-726.601wherein,A is N or C;B is N or C; wherein at least one of A or B is N;V is N or C-R9;W is N or C-R3;X is N or C-R4;Y is N or C-R5;Z is N or C-R6; provided that at least two of W, X, Y and Z are not N;R is an optionally substituted aryl or optionally substituted heteroaryl;R1is hydrogen, -OH, or an optionally substituted C1 -C6 alkyl; or R1is an optionally substituted C1-C6 alkyl, and R and R1join to form an optionally substituted spirocyclic ring; each R2is independently an optionally substituted C1 -C6 alkyl; or two R2join to form optionally substituted phosphorus-containing 3- to 8-membered ring;R3, R4, R5, and R6are each independently selected from hydrogen, deuterium, halogen, - CN, or optionally substituted C1 -C3 alkyl;R7, R8, and R9are each independently selected from hydrogen, deuterium, halogen, -CN, or optionally substituted C1 -C3 alkyl;J is -C(R10)2-, or -N(Rn)-;K is absent, -O-, or -C(R12)2-;L is -C(R13)2-, -S-, -SO-, or -SO2-; each R10is independently selected from hydrogen, deuterium, halogen, -CN, -OH, - CO(NR14)2, optionally substituted C1 -C6 alkyl, or optionally substituted C1 -C6 alkoxy; or two R10form an oxo; or two R10form an =N-O-(optionally substituted C1 -C6 alkyl);R11is selected from hydrogen, or optionally substituted C1 -C6 alkyl;R12is selected from hydrogen, deuterium, halogen, -CN, -OH, optionally substituted Cl - C6 alkyl, or optionally substituted C1 -C6 alkoxy; or two R12form an oxo;R13are independently selected from hydrogen, deuterium, halogen, -CN, -OH, - CO(NR14)2, optionally substituted C1 -C6 alkyl, or optionally substituted C1 -C6 alkoxy; or two R13form an oxo; andWSGR Ref: 53699-726.601R14is selected from hydrogen, or optionally substituted C1 -C6 alkyl.

[0083] One embodiment provides a compound of Formula (II) or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer:wherein,A is N or C;B is N or C; wherein at least one of A or B is N;V is N or C-R9;W is N or C-R3;X is N or C-R4;Y is N or C-R5;Z is N or C-R6; provided that at least two of W, X, Y and Z are not N;R is an optionally substituted aryl or optionally substituted heteroaryl;R1is hydrogen, -OH, or optionally substituted C1 -C6 alkyl; or R1is optionally substituted C1-C6 alkyl, and R and R1join to form optionally substituted spirocyclic ring; each R2is independently optionally substituted C1 -C6 alkyl; or two R2join to form optionally substituted phosphorus-containing 3- to 8-membered ring;R3, R4, R5, and R6are each independently selected from hydrogen, deuterium, halogen, - CN, or optionally substituted C1 -C3 alkyl;R7, R8, and R9are each independently selected from hydrogen, deuterium, halogen, -CN, or optionally substituted C1 -C3 alkyl;R20is hydrogen, deuterium, optionally substituted C1 -C3 alkyl, or optionally substituted C1-C6 alkoxy;R21is hydrogen, deuterium, or optionally substituted C1 -C3 alkyl;R22is hydrogen;R23is hydrogen;R24is hydrogen, deuterium, optionally substituted C1 -C3 alkyl, or optionally substituted C1-C6 alkoxy.WSGR Ref: 53699-726.601

[0084] One embodiment provides a compound of Formula (I), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein A is C.

[0085] One embodiment provides a compound of Formula (I), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein A is N.

[0086] One embodiment provides a compound of Formula (I), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein B is C.

[0087] One embodiment provides a compound of Formula (I), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein B is N.

[0088] One embodiment provides a compound of Formula (I), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein R is an optionally substituted heteroaryl. One embodiment provides a compound of Formula (I), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein the optionally substituted heteroaryl is an optionally substituted pyridinyl.

[0089] One embodiment provides a compound of Formula (I), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein R is an optionally substituted aryl. One embodiment provides a compound of Formula (I), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein the optionally substituted aryl is an optionally substituted phenyl. One embodiment provides a compound of Formula (I), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein the optionally substituted phenyl is a structure provided in Formula (a):wherein,R15is selected from hydrogen, halogen, -CN, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 alkoxy, or optionally substituted C1-C6 alkynyl;R16, R17, and R18is selected from hydrogen, or halogen; andWSGR Ref: 53699-726.601R19is selected from hydrogen, halogen, -CN, optionally substituted C1-C6 alkoxy, or optionally substituted C1-C3 alkyl.

[0090] One embodiment provides a compound of Formula (I), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein R1is optionally substituted C1-C6 alkyl, and R and R1join to form optionally substituted spirocyclic ring.

[0091] One embodiment provides a compound of Formula (I), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein the optionally substituted spirocyclic ring has the structure provided in Formula (b):wherein,G is an optionally substituted alkylene.

[0092] One embodiment provides a compound of Formula (b), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein Gis an optionally substituted C2-C7 alkylene. One embodiment provides a compound of Formula (b), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein G is an optionally substituted C2 alkylene. One embodiment provides a compound of Formula (b), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein Gis an optionally substituted C3 alkylene. One embodiment provides a compound of Formula (b), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein G is an optionally substituted C4 alkylene. One embodiment provides a compound of Formula (b), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein G is an optionally substituted C5 alkylene.

[0093] One embodiment provides a compound of Formula (I), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein R15is hydrogen, halogen, or optionally substituted C1-C6 alkoxy. One embodiment provides a compound of Formula (I), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein R15is -OCHF2.WSGR Ref: 53699-726.601

[0094] One embodiment provides a compound of Formula (I), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein J is -CH2-, -CF2-, -CHF-, -C(H)OCH3-, -CHCN-, or -C(H)CH3-. One embodiment provides a compound of Formula (I), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein J is -NH-, or -NCH3-.

[0095] One embodiment provides a compound of Formula (I), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein K is absent. One embodiment provides a compound of Formula (I), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein K is -O-. One embodiment provides a compound of Formula (I), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein K is -C(R12)2-. One embodiment provides a compound of Formula (I), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein K is -CH2-.

[0096] One embodiment provides a compound of Formula (I), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein L is -S-, -SO-, or -SO2-. One embodiment provides a compound of Formula (I), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein L is -C(R13)2-. One embodiment provides a compound of Formula (I), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein L is -CH2-, -C(H)OH-, -C(H)OCH3-, -CHCN-, or - C(H)CH3-.

[0097] One embodiment provides a compound of Formula (II) or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer:wherein,V is N or C-R9;W is N or C-R3;X is N or C-R4;WSGR Ref: 53699-726.601Y is N or C-R5;Z is N or C-R6; provided that at least two of W, X, Y and Z are not N;R is an optionally substituted aryl or optionally substituted heteroaryl;R1is hydrogen, -OH, or optionally substituted C1 -C6 alkyl; or R1is optionally substituted C1-C6 alkyl, and R and R1join to form optionally substituted spirocyclic ring; each R2is independently optionally substituted C1 -C6 alkyl; or two R2join to form optionally substituted phosphorus-containing 3- to 8-membered ring;R3, R4, R5, and R6are each independently selected from hydrogen, deuterium, halogen, - CN, or optionally substituted C1 -C3 alkyl;R7, R8, and R9are each independently selected from hydrogen, deuterium, halogen, -CN, or optionally substituted C1 -C3 alkyl;R20is hydrogen, deuterium, optionally substituted C1 -C3 alkyl, or optionally substituted C1-C6 alkoxy;R21is hydrogen, deuterium, or optionally substituted C1 -C3 alkyl;R22is hydrogen;R23is hydrogen;R24is hydrogen, deuterium, optionally substituted C1 -C3 alkyl, or optionally substituted C1-C6 alkoxy.

[0098] One embodiment provides a compound of Formula (I), (II), or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein each R2is independently optionally substituted C1 -C6 alkyl.

[0099] One embodiment provides a compound of Formula (I), (II), or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein each R2is CH3.

[0100] One embodiment provides a compound of Formula (I), (II), or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein W is N. One embodiment provides a compound of Formula (I), (II), or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein W is C-R11.

[0101] One embodiment provides a compound of Formula (I), (II), or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein X is N. One embodiment provides a compound of Formula (I), (II), or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein X is C-R12.WSGR Ref: 53699-726.601

[0102] One embodiment provides a compound of Formula (I), (II), or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein Y is N. One embodiment provides a compound of Formula (I), (II), or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein Y is C-R13.

[0103] One embodiment provides a compound of Formula (I), (II), or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein Z is N. One embodiment provides a compound of Formula (I), (II), or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein Z is C-R14.

[0104] One embodiment provides a compound of Formula (I), (II), or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein each R11, R12, R13, and R14is independently selected from H, D, or halogen.

[0105] One embodiment provides a compound of Formula (I), (II), or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein V is C-H.

[0106] One embodiment provides a compound of Formula (I), (II), or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein R7, R8, and R9are each independently selected from hydrogen, deuterium, or halogen.

[0107] One embodiment provides a TNF-a inhibitory compound, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, having a structure presented in Table 1.WSGRRef: 53699-726.601Table 1WSGRRef: 53699-726.601WSGRRef: 53699-726.601WSGRRef: 53699-726.601WSGRRef: 53699-726.601WSGRRef: 53699-726.601WSGRRef: 53699-726.601WSGRRef: 53699-726.601WSGRRef: 53699-726.601WSGR Ref: 53699-726.601

[0108] Another embodiment provides a TNF-a inhibitory compound, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, having a structure presented in Table 2.Table 2WSGR Ref: 53699-726.601Preparation of Compounds

[0109] The compounds used in the synthetic chemistry reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and / or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservicelnc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak CompanyWSGR Ref: 53699-726.601(Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0110] Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley -Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527- 29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley -Interscience, ISBN: 0-471- 57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[0111] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databasesWSGR Ref: 53699-726.601(contact the American Chemical Society, Washington, D.C. for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference useful for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002. Pharmaceutical Compositions

[0112] In certain embodiments, the TNF-a inhibitory compound described herein is administered as a pure chemical. In other embodiments, the TNF-a inhibitory compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0113] Provided herein is a pharmaceutical composition comprising at least one TNF-a inhibitory compound as described herein, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or the patient) of the composition.

[0114] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), (II) or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer.

[0115] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I), (II) or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, and a pharmaceutically acceptable carrier.

[0116] In certain embodiments, the TNF-a inhibitory compound as described by Formula (I), (II) or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, is substantially pure, in that it contains less than about 5%, or less than about2%, or less than about 1%, orless than about 0.5%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.WSGR Ref: 53699-726.601

[0117] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 1 or Table 2, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer.

[0118] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Table 1 or Table 2, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, and a pharmaceutically acceptable carrier.

[0119] In certain embodiments, the TNF-a inhibitory compound as described by Table 1 or Table 2, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, is substantially pure, in that it contains less than about 5%, or less than about 2%, orless than about 1%, orless than about 0.5%, orless than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0120] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. See, e.g., Remington: The Science andPractice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0121] In some embodiments, the TNF-a inhibitory compound as described by Formula (I) or Table 1 or Table 2, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, is formulated for administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a non-aqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like.

[0122] The dose of the composition comprising at least one TNF-a inhibitory compound as described herein differs dependingupon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors.

[0123] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g.,WSGR Ref: 53699-726.601 an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0124] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.Methods of Treatment

[0125] One embodiment provides a compound of Formula (I), (II) or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, for use in a method of treatment of the human or animal body.

[0126] One embodiment provides a compound of Formula (I), (II) or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, for use in a method of treatment of inflammatory or autoimmune disease or disorder. Another embodiment provides a compound of Formula (I), (II) or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, for use in a method of treatment of inflammatory disease or disorder. Yet another embodiment provides a compound of Formula (I), (II) or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, for use in a method of treatment of autoimmune disease or disorder.

[0127] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), (II) or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, and a pharmaceutically acceptable excipient for use in a method of treatment of inflammatory or autoimmune disease or disorder.

[0128] One embodiment provides a use of a compound of Formula (I), (II) or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, in the manufacture of a medicament for the treatment of inflammatory or autoimmune disease or disorder.

[0129] In some embodiments is provided a method of treating an inflammatory or autoimmune disease or disorder, in a patient in need thereof, comprising administering to the patient a compound of Formula (I), (II) or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer. In some embodiments is provided a method of treating inflammatory or autoimmune disease or disorder, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I), (II) or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, and a pharmaceutically acceptable excipient. OneWSGR Ref: 53699-726.601 embodiment provides a method of treating an inflammatory disease or disorder. Another embodiment provides a method of treating an autoimmune disease or disorder.

[0130] One embodiment provides a compound of Table 1 or Table 2, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, for use in a method of treatment of the human or animal body.

[0131] One embodiment provides a compound of Table 1 or Table 2, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, for use in a method of treatment of inflammatory or autoimmune disease or disorder.

[0132] One embodiment provides a pharmaceutical composition comprising a compound of Table 1 or Table 2, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, and a pharmaceutically acceptable excipient for use in a method of treatment of inflammatory or autoimmune disease or disorder.

[0133] One embodiment provides a use of a compound of Table 1 or Table 2, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, in the manufacture of a medicament for the treatment of inflammatory or autoimmune disease or disorder.

[0134] In some embodiments is provided a method of treating an inflammatory or autoimmune disease or disorder in a patient in need thereof, comprising administering to the patient a compound of Table 1 or Table 2, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer. In some embodiments is provided a method of treating an inflammatory or autoimmune disease or disorder, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Table 1 or Table 2, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, and a pharmaceutically acceptable excipient.

[0135] In some embodiments the inflammatory and autoimmune disease or disorder is selected from, but are not limited to: rheumatoid arthritis, psoriatic arthritis, systemic onset juvenile idiopathic arthritis, multiple sclerosis, lupus nephritis, systemic lupus erythematosus, psoriasis, Crohn's disease, colitis, asthma, graft versus host disease, allograft rejection, chronic obstructive pulmonary disease, multiple sclerosis, Alzheimer’s disease, Graves' disease, cutaneous lupus, ankylosing spondylitis, cryopyrin-associated periodic syndromes (CAPS), gout, and gouty arthritis, ulcerative TNF receptor associated periodic syndrome (TRAPS), Wegener’s granulomatosis, sarcoidosis, familial Mediterranean fever (FMF), neuropathic pain, and adult onset stills.WSGR Ref: 53699-726.601

[0136] In some embodiments the inflammatory and autoimmune disease or disorder is selected from Rheumatoid Arthritis (RA), Psoriatic Arthritis (PsA), Psoriasis, Juvenile Idiopathic Arthritis (JIA), Ankylosing Spondylitis (AS) Inflammatory Bowel Diseases (IBD) including Crohn’s disease and ulcerative colitis. Systemic Lupus Erythematosus (SLE), Spondyloarthritis (SpA). Behget's Disease, Sarcoidosis, Multiple Sclerosis (MS), Palmoplantar Pustulosis (PPP), Palmoplantar Pustulosis (PPP), Atopic Dermatitis, graft versus host disease, Sepsis, Neuropathic pain, Fibromyalgia, Schnitzler Syndrome, Blau Syndrome, TNF Receptor -Associated Periodic Syndrome (TRAPS), Pyogenic Arthritis, Pyoderma Gangrenosum, chronic Recurrent Multifocal Osteomyelitis (CRMO).

[0137] Provided herein is the method wherein the pharmaceutical composition is administered orally. Provided herein is the method wherein the pharmaceutical composition is administered by injection.

[0138] One embodiment provides a method of inhibiting TNF-a activity comprising contacting the TNF-a protein with a compound of Formula (I), (II) or (III), or Table 1 or Table 2, or tautomer thereof, or deuteroisotope of said compound or tautomer. Another embodiment provides the method of inhibiting TNF-a activity, wherein the TNF-a protein is contacted in an in vivo setting. Another embodiment provides the method of inhibiting TNF-a activity, wherein the TNF-a protein is contacted in an in vitro setting.Determination of blood-brain barrier penetration by small molecules

[0139] In drug development, CNS drug candidates have lower success rates and longer development times than those in the other therapeutic areas. (Di, L. et al. Expert Opinion on Drug Discovery (2008) 3 :6, 677-687. DOI: 10. 1517 / 17460441 .3.6.677) Low brain penetration of small molecules can be due to several factors, including, but not limited to, low blood-brain barrier (BBB) permeability, P-glycoprotein (Pgp) efflux, or high plasma protein binding.

[0140] There are multiple mechanisms that affect brain penetration of molecules. Compounds may enter the brain by transcellular passive diffusion, which is driven by a concentration gradient between the blood and the brain. Brain penetration of compounds may be enhanced by influx transporters, such as the large neutral amino acid transporter 1 (LAT1) for L-dopa and gabapentin (Ohtsuki,et al. Pharm. Res. 2007, 24, 1745 -58; Gynther, et al. J. Med. Chem. 2008, 51(4), 932-936). This requires that the compoundshave a certain structural motif to bind to the transporter. Only a few examples have been reported in which this pathway was purposely used to increase brain penetration. Efflux transporters move molecules out of cells. Of primary importance for brain penetration is the efflux transporter Pgp. Plasma protein binding, which reduces the free drug concentration available for BBB penetration, and metabolism and renal excretion, which reduces the total blood concentration, also affect brain penetration. Overall,WSGR Ref: 53699-726.601 passive diffusion is the major driving force moving most molecules into the brain; however, the other mechanisms discussed above can reduce brain penetration, depending on the structure and properties of the compound.

[0141] Bioanalytical methods and screening strategies provide the rationale for design and evaluation of compounds with desirable BBB distribution properties. (Di, L. et al. Expert Opinion on Drug Discovery (2008) 3 :6, 677-687; Summerfield et al. J. Pharmacol. Exp. Ther. (2016) 358:294-305) A superior representation of brain distribution is based on the ratio of unbound compound in the brain extracellular fluid to the unbound blood concentration, represented a Kp,uii. (Liu and Chen, Blood-Brain Barrier in Drug Discovery: Optimizing Brain Exposure of CNS Drugs and Minimizing Brain Side Effects for Peripheral Drugs (2015), p. 42- 65, Wiley & Sons). Kp,uu is a steady-state distribution term denotingthe unbound concentration gradient across the BBB. If Kp,uu is lower than 1, then drug passage across the BBB is restricted by some factor. If Kp,uu is larger than 1, then drug passage across the BBB is assisted by some factor. Kp,uu value of about 1 indicates passive diffusion across the BBB is predominate, or that active pathways (e.g., influx and efflux) are balanced. (Summerfield et al. vide supra)

[0142] In some embodiments, the TNF-a inhibitory compound described herein, or tautomer thereof, or deuteroisotope of said compound or tautomer, exhibits a. Kp,uu of 1. In some embodiments, the TNF-a inhibitory compound described herein, or tautomer thereof, or deuteroisotope of said compound or tautomer, exhibits a Kp,im of larger than 1. In some embodiments, the TNF-a inhibitory compound described herein, or tautomer thereof, or deuteroisotope of said compound or tautomer, exhibits a Kp,im of larger than 1.1. In some embodiments, the TNF-a inhibitory compound described herein, or tautomer thereof, or deuteroisotope of said compound or tautomer, exhibits a Kp,im of larger than 1.2. In some embodiments, the TNF-a inhibitory compound described herein, or tautomer thereof, or deuteroisotope of said compound or tautomer, exhibits a Kp,im of larger than 1.3. In some embodiments, the TNF-a inhibitory compound described herein, or tautomer thereof, or deuteroisotope of said compound or tautomer, exhibits a Kp,im of larger than 1.4. In some embodiments, the TNF-a inhibitory compound described herein, or tautomer thereof, or deuteroisotope of said compound or tautomer, exhibits a Kp,im of larger than 1.5. In some embodiments, the TNF-a inhibitory compound described herein, or tautomer thereof, or deuteroisotope of said compound or tautomer, exhibits a Kp,im of larger than 1.6.In some embodiments, the TNF-a inhibitory compound described herein, or tautomer thereof, or deuteroisotope of said compound or tautomer, exhibits a Kp,im of larger than 1.7. In some embodiments, the TNF-a inhibitory compound described herein, or tautomer thereof, orWSGR Ref: 53699-726.601 deuteroisotope of said compound or tautomer, exhibits a. Kp,uu of larger than 1.8. In some embodiments, the TNF-a inhibitory compound described herein, or tautomer thereof, or deuteroisotope of said compound ortautomer, a Kp,uu of larger than 1.9. In some embodiments, the TNF-a inhibitory compound described herein, or tautomer thereof, or deuteroisotope of said compound or tautomer, exhibits a Kp,uu of larger than 2.0.

[0143] Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way.EXAMPLESI. Chemical Synthesis

[0144] In some embodiments, the TNF-a inhibitory compounds disclosed herein are synthesized according to the following examples. As used below, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:ACN acetonitrile°C degrees Celsius bHchemical shift in parts per million downfield from tetramethyl silaneDCM dichloromethane (CH2CI2)DIAL) diisopropyl azodicarboxylateDIEA diisopropylethylamineDMF dimethylformamideDMSO dimethylsulfoxideEA ethyl acetateEtOAc ethyl acetateESI electrospray ionizationEt ethyl g gram(s) h hour(s)HPLC high performance liquid chromatographyHz hertzJ coupling constant (in NMR spectrometry)LCMS liquid chromatography mass spectrometry micro m multiplet (spectral); meter(s); milliWSGR Ref: 53699-726.601M molarM+parent molecular ionMe methylMsCl methanesulfonyl chlorideMHz megahertz min minute(s) mol mole(s); molecular (as in mol wt) mL milliliterMS mass spectrometry nm nanometer(s)NMR nuclear magnetic resonance pH potential of hydrogen; a measure of the acidity or basicity of an aqueous solutionPE petroleum etherRT room temperature s singlet (spectral) t triplet (spectral)SFC Supercritical fluid chromatographyT temperatureTFA trifluoroacetic acidTHF tetrahydrofuranTPP Triphenylphosphine

[0145] Example 1 : (R)-(5-(l-(2,6-difluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazol-7-yl)pyridin-2-yl)dimethylphosphine oxideWSGR Ref: 53699-726.601Preparation 1 A: (S)-N-[(2,6-difluorophenyl)methylidene]-2-methylpropane-2-sulfinamide A mixture of 2,6-difluorobenzaldehyde (49.00 g, 344.815 mmol), (5)-2-methylpropane-2- sulfinamide (50.15 g, 413 mmol) and CS2CO3 (123.58 g, 379.297 mmol) in DCM (490 mL) was stirred at room temperature for 2 h. The resulting mixture was washed with 3 x 300 mL of water. The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10 / 1) to afford (S)-N-[(2,6-difluorophenyl)methylidene]-2- methylpropane-2-sulfinamide (82.40 g, 97%) as light yellow oil. MS ESI calculated for CnHi3F2NOS [M + H]+, 246.07 found 246.20. TI NMR ^OO MHz, Chloroform -d) 8 8.82 (s, 1H), 7.50 - 7.41 (m, 1H), 7.04- 6.96 (m, 2H), 1.28 (s, 9H).19FNMR(377 MHz, Chloroform^ / )6 -110.71.Preparation IB: tert-butyl (3R)-3-(2,6-difluorophenyl)-3-{[(S)-2-methylpropane-2- sulfinyl]amino}propanoateA mixture of Zinc (151.13 g, 2311.547 mmol) and CuCl (49.04 g, 495.332 mmol) in THF (820 mL) was stirred at 60 °C for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. To the above mixture was added tert -butyl 2-bromoacetate (161.03 g, 825.553 mmol) dropwise at room temperature. The resulting mixture was stirred at 60 °C for additional 2 h. The mixture was allowed to cool down to 0 °C followed by the addition of (S)-N- [(2,6-difluorophenyl)methylidene]-2-methylpropane-2-sulfinamide (81.00 g, 330.221 mmol) at room temperature. The resulting mixture was stirred at room temperature for additional 16 h. The resulting mixture was filtered, the filter cake was washed with water (3 x 100 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers wereWSGR Ref: 53699-726.601 washed with citric acid (0.3g / mL in water) (1 L). The organic layer was washed with NaHCO3(aq.) (1 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl (3R)-3-(2,6-difluorophenyl)-3-{[(S)-2-methylpropane-2- sulfinyl]amino}propanoate (100.00 g, 84%) as a light yellow oil. MS ESI calculated for CI7H25F2NO3S [M + H]+, 362.15 found 362.30. 'H NMR (400 MHz, Chloroform -d) 6 7.26 - 7.20 (m, 1H), 6.88 (t, = 8.4 Hz, 2H), 5.26 - 5.16 (m, 1H), 4.19 - 4.08 (m, 1H), 3.16- 3.04 (m, 1H), 2.92 - 2.82 (m, 1H), 1.37 (s, 9H), 1.15 (s, 9H).19F NMR (377 MHz, Chloroform -d) 6 - 113.09.Preparation 1C: (lR)-3-(tert-butoxy)-l-(2,6-difluorophenyl)-3-oxopropan-l-aminium (S)- hydroxy(phenyl)ac etateTo a stirred solution of tert-butyl (3R)-3-(2,6-difluorophenyl)-3-{[(S)-2-methylpropane-2- sulfinyl]amino}propanoate (97.50 g, 269.747 mmol) in THF (500 mL) and H2O (100 mL) was added Iodine (17.12 g, 67.437 mmol) atroom temperature. The resulting mixture was stirred at room temperature for 12 h. The reaction was quenched with sat. NaHCO3(aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was diluted with MTBE (500 mL). To the above mixture was added (2 S)-2 -hydroxy-2 -phenylacetic acid (41.04 g, 269.747 mmol) atroom temperature. The resulting mixture was stirred at room temperature for additional 30 min. The precipitated solids were collected by filtration and washed with MTBE (3 x 100 mL). The precipitated solids were dried to afford (lR)-3-(tert-butoxy)-l-(2,6- difluorophenyl)-3 -oxopropan- 1-aminium (S)-hydroxy(phenyl)acetate (80.70 g, 73%) as a white solid. 'HNMR (400 MHz, Chloroform-; / , free base) 8 7.23 - 7.14 (m, 1H), 6.86 (t, J= 8.3 Hz, 2H), 4.76 - 4.70 (m, 1H), 2.91 - 2.81 (m, 1H), 2.76 - 2.66 (m, 1H), 1.39 (s, 9H).19F NMR (377 MHz, Chloroform-; / ) 6 -113.04.Preparation ID: tert-butyl (3R)-3-[(5-chloro-2-nitrophenyl)amino]-3-(2,6- difluorophenyl)propanoateA solution of (lR)-3-(tert-butoxy)-l-(2,6-difluorophenyl)-3-oxopropan-l-aminium (S)- hydroxy(phenyl)acetate (80.70 g, 197.103 mmol), 4 -chloro-2-fluoro-l -nitrobenzene (34.60 g, 197.103 mmol) and DIEA (52 mL, 295.654 mmol) in DMAc (400 mL) was stirred at 80 °C for 16 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and diluted with water (320 mL). The resulting mixture was extracted with MTBE (3 x 480 mL). The combined organic layers were washed with water (3 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in tert-butyl (3R)-3-[(5-chloro-2-nitrophenyl)amino]-3-(2,6-difluorophenyl)propanoate (80.20 g,WSGR Ref: 53699-726.601 crude) as yellow oil. MS ESI calculated for C19H19CIF2N2O4 [M + H]+, 413.10 found 413.10.JH NMR (400 MHz, Chloroform-; / ) 68.65 (d, J= 8.8 Hz, 1H), 8.10 (d, = 9.2 Hz, 1H), 7.31 - 7.26 (m, 1H), 7.01 (d, J= 2.1 Hz, 1H), 6.93 (t, J= 8.4 Hz, 2H), 6.65 - 6.60 (m, 1H), 5.52 - 5.43 (m, 1H), 3.14 - 3.05 (m, 1H), 2.98 - 2.86 (m, 1H), 1.38 (s, 9H).Preparation IE: (3R)-3-[(5-chloro-2-nitrophenyl)amino]-3-(2,6-difluorophenyl)propanal To a stirred solution of tert-butyl (3R)-3-[(5-chloro-2-nitrophenyl)amino]-3-(2,6- difluorophenyl)propanoate (80.00 g, 193.789 mmol) in DCM (800 mL) was added Diisobutylaluminum hydride (1.0M in DCM) (213 mL, 213.168 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 3 h under nitrogen atmosphere. The reaction was quenched with HC1 (IM) at 0 °C. The resulting mixture was extracted with CH2C12(3 x 1 L). The combined organic layers were washed with brine (1 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5 / 1) to afford (3R)-3-[(5-chloro-2-nitrophenyl)amino]-3-(2,6-difluorophenyl)propanal (50.00 g, 76%) as yellow oil. MS ESI calculated for CI5HHC1F2N2O3[M + H]+, 341.04 found 341.05. iH NMR (400 MHz, Chloroform-; / ) 8 9.80 (s, 1H), 8.59 (d, J= 9.1 Hz, 1H), 8.10 (d, J= 9.1 Hz, 1H), 7.33 - 7.26 (m, 1H), 7.05 (d, J= 2.1 Hz, 1H), 6.94 (t, J= 8.4 Hz, 2H), 6.67 - 6.62 (m, 1H), 5.67 - 5.59 (m, 1H), 3.47 - 3.36 (m, 1H), 3.23 - 3.14 (m, 1H).19F NMR (377 MHz, Chloroform -d) 8 -114.60.Preparation IF: (4R)-4-[(5-chloro-2-nitrophenyl)amino]-4-(2,6-difluorophenyl)-2- [(trimethylsilyl)oxy]butanenitrileTo a stirred solution of (3R)-3-[(5-chloro-2-nitrophenyl)amino]-3-(2,6-difluorophenyl)propanal (8.60 g, 25.241 mmol) and TMSCN (5.01 g, 50.482 mmol) in DCM (100 mL) were added Et3N (255 mg, 2.524 mmol) and Znl2(806 mg, 2.524 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction was quenched with sat. NH4C1 (aq.) at room temperature. The resulting mixture was extracted with CH2Q2 (3 x 200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford (4R)-4-[(5-chloro-2-nitrophenyl)amino]-4-(2,6- difluorophenyl)-2-[(trimethylsilyl)oxy]butanenitrile (10.80 g, 97%) as a green solid. MS ESI calculated for Ci9H2oClF2N303Si [M + H]+, 440.09 found 440.00.Preparation 1G: (lR)-7-chloro-l-(2,6-difluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazol-3-olA solution of (4R)-4-[(5-chloro-2-nitrophenyl)amino]-4-(2,6-difluorophenyl)-2- [(trimethylsilyl)oxy]butanenitrile (10.00 g, 22.731 mmol) and Titanium(III) chloride, 15 -20% inWSGR Ref: 53699-726.601HC1) (160.26 g, 181.848 mmol) in EtOH (300 mL) was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with water (200 mL). The mixture was basified to pH 8 with saturated NaHCCL (aq.). The resulting mixture was filtered, the filter cake was washed with EtOAc (3 x 300 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) to afford (lR)-7-chloro-l-(2,6- difluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-3-ol (4.30 g, 59%) as a green solid. MS ESI calculated for CI6HHC1F2N2O [M + H]+, 321.05 found 320.95.Preparation 1H: (R)-7-chloro-l-(2,6-difluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazoleA solution of (lR)-7-chloro-l-(2,6-difluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazol-3-ol (1 .00 g, 3.118 mmol) and DIEA (0.81 g, 6.236 mmol) in phosphoroyl trichloride (5 mL) was stirred at 60 °C for 1 h. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (50 mL) followed by extraction with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (12 / 1) to afford yellow oil. The crude product was dissolved in EtOH (10 mL) added Raney nickel (92 mg, 1.559 mmol) under nitrogen atmosphere in a 50 mL round-bottom flask. The mixture was hydrogenated at room temperature for overnight under hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) to afford (R)-7- chloro-l-(2,6-difluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole (350 mg, 37%) as a light yellow solid. MS ESI calculated for Ci6HnClF2N2[M + H]+, 305.06 found 305.20. 'H NMR (400 MHz, Chloroform-; / ) 87.60 (d, J = 8.6 Hz, 1H), 7.39 - 7.30 (m, 1H), 7.18 - 7. 12 (m, 1H), 6.95 (t, J= 8.7 Hz, 2H), 6.88 (d, J= 2.0 Hz, 1H), 5.93 - 5.86 (m, 1H), 3.46 - 3.34 (m, 1H), 3.28 - 3.13 (m, 2H), 2.90 - 2.79 (m, 1H).19F NMR (377 MHz, Chloroform-; / ) 6 -115.09.Example 1 : (R)-(5-(l-(2,6-difluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-7- yl)pyridin-2-yl)dimethylphosphine oxideTo a stirred solution of (R)-7-chloro-l-(2,6-difluorophenyl)-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazole (70 mg, 0.230 mmol) and 2-(dimethylphosphoryl)-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (194 mg, 0.690 mmol) in 1,4-dioxane (1 mL) and H2O (0.2 mL) were added Sphos (19 mg, 0.046 mmol), Sphos Pd G3(18 mg, 0.023 mmol) and K3PO4 (146 mg, 0.690 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture wasWSGR Ref: 53699-726.601 concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in water (10 mmol / L NH4HCO3), 30% to 70% gradient in 20 min; detector, 254 nm. This resulted in (R)-(5-(l-(2,6- difluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-7-yl)pyridin-2- yl)dimethylphosphine oxide (28 mg, 28%) as a white solid. MS ESI calculated for C23H20F2N3OP [M + H]+, 424.13 found 424.15. 'HNMR (400 MHz, Chloroform -d) 8 8.82 (d, J = 2.2 Hz, 1H), 8.15 - 8.10 (m, 1H), 7.94 - 7.88 (m, 1H), 7.83 (d, J= 8.5 Hz, 1H), 7.47 - 7.43 (m, 1H), 7.40 - 7.30 (m, 1H), 7.11 (s, 1H), 6.96 (t, J= 8.7 Hz, 2H), 6.07 - 5.97 (m, 1H), 3.55 - 3.41 (m, 1H), 3.36 - 3.22 (m, 2H), 2.97 - 2.85 (m, 1H), 1.81 (s, 3H), 1.78 (s, 3H).19F NMR (377 MHz, Chloroform-; / ) 6 -114.97.

[0146] Example 2: (R)-(5-(l-(2-(difluoromethoxy)-6-fluorophenyl)-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazol-7-yl)pyridin-2-yl)dimethylphosphine oxidePreparation 2A: 2-(difluoromethoxy)-6-fluorobenzaldehydeA mixture of 2-fluoro-6-hydroxybenzaldehyde (44.00 g, 314.032 mmol) and KOH (114.52 g,WSGR Ref: 53699-726.6012041.208 mmol) in 1,4-dioxane (500 mL) and H2O (500 mL) was stirred at 60 °C, then chlorodifluoromethane gas pass through above mixture at 60 °C for 1 h. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (2.5 L). The resulting mixture was extracted with EtOAc (3 x 1 L). The combined organic layers were washed with brine (2 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, eluted with EA in PE (0-10%) to afford 2-(difluoromethoxy)-6- fluorobenzaldehyde (43.40 g, 73%yield) as a yellow liquid. MS ESI calculated for C8H5F3O2[M + H]+, 191.02 found N / A.1HNMR(400 MHz, Chloroform -d) 8 10.39 (s, 1H), 7.65 - 7.53 (m, 1H), 7.10 - 7.04 (m, 2H), 6.84- 6.45 (m, 1H).19F NMR (377 MHz, Chloroform -t / ) 6 -82.26, - 114.04.Preparation 2B: (S)-N-{[2-(difluoromethoxy)-6-fluorophenyl]methylidene}-2-methylpropane-2- sulfinamideTo a stirred solution of 2-(difluorornethoxy)-6-fluorobenzaldehyde (43.40 g, 228.276 mmol) in DCM (500 mL) were added (S)-2-methylpropane-2-sulfinamide (33.20 g, 273.931 mmol) and Cs2CO3(81.81 g, 251.104 mmol) at room temperature. The mixture was stirred for 16 h at room temperature. The resulting mixture was filtered, the filter cake was washed with DCM (500 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0-20%) to afford (S)-N-{[2-(difluoromethoxy)- 6-fluorophenyl]methylidene}-2-methylpropane-2-sulfinamide (55.40 g, 83%yield) as yellow liquid. MS ESI calculated for CI2HI4F3NO2S [M + H]+, 294.07 found 294.05. TI NMR (400 MHz, Chloroform -t / ) 68.84 (s, 1H), 7.53 - 7.43 (m, 1H), 7.12 - 7.03 (m, 2H), 6.62 (t, J= 72.6 Hz, 1H), 1.28 (s, 9H).19F NMR (377 MHz, Chloroform -d) 6 -81.50, -81.94, -82.04, -82.48, - 109.92.Preparation 2C: tert-butyl (3R)-3-[2-(difluoromethoxy)-6-fluorophenyl]-3-{[(S)-2- methylpropane-2-sulfinyl]amino}propanoateA mixture of Zinc powder (31.99 g, 489.258 mmol) and CuCl (10.38 g, 104.841 mmol) in THF (250 mL) was stirred at 60 °C for 2 h under nitrogen atmosphere, tert -butyl 2-bromoacetate (34.08 g, 174.735 mmol) was added to the above mixture below 40 °C and stirred for additional 2 h at 60 °C. (S)-N-{[2-(difluoromethoxy)-6-fluorophenyl]methylidene}-2-methylpropane-2- sulfinamide (20.50 g, 69.894 mmol) in THF (50 mL) was added to above mixture dropwise at 10 °C and stirred for 16 h at room temperature. The resulting mixture was filtered, the filter cake was washed with EA (3 x 50 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with 25%~30 % citric acid (aq.) (1 L). The resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with sat.WSGR Ref: 53699-726.601NaHCO3(aq.) (2 x 200 mL) and brine (1 x 1 L), dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography, eluted with EA in PE (0-50%) to afford tert -butyl (3R)-3-[2-(difluoromethoxy)-6-fluorophenyl]-3-{[(S)-2-methylpropane-2- sulfinyl]amino}propanoate (23.50 g, 82%) as colorless oil. MS ESI calculated for CI8H26F3NO4S [M + H]+, 410.15 found 410.20. !H NMR (400 MHz, Chloroform-t ) 8 7.33 - 7.23 (m, 1H), 7.00 - 6.88 (m, 2H), 6.6172.6 Hz, 1H), 5.34 - 5.23 (m, 1H), 4.20 (d, J =8.0 Hz, 1H), 3.18 - 3.08 (m, 1H), 2.92 - 2.82 (m, 1H), 1.36 (s, 9H), 1.14 (s, 9H).19F NMR (377 MHz, Chloroform-; / ) 6 -79.58, -80.02, -80.46, -80.91, -112.12.Preparation 2D: tert-butyl (3S)-3-amino-3-[2-(difluoromethoxy)-6-fluorophenyl]propanoate To a stirred mixture of tert-butyl (3R)-3-[2-(difluoromethoxy)-6-fluorophenyl]-3-{[(S)-2- methylpropane-2-sulfinyl]amino}propanoate (45.00 g, 109.901 mmol) in THF (250 mL) and H2O (50 mL) was added Iodine (6.97 g, 27.475 mmol) at room temperature. The mixture was stirred for 16 h at 50 °C. The mixture was allowed to cool down to room temperature. The reaction was quenched by addition of sat. NaHCO3(aq.) (0.5 L) at room temperature. The resulting mixture was extracted with MTBE (3 x 500 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in tert -butyl (3S)-3-amino-3-[2- (difluoromethoxy)-6-fluorophenyl]propanoate (38.80 g) as light yellow liquid. The crude was dissolved in MTBE (400 mL) and added (2 S)-2 -hydroxybutanedioic acid (17.04 g, 127.089 mmol) at room temperature. The mixture was stirred for 4 h at 50 °C. The mixture was allowed to cool down to room temperature. The precipitated solids were collected by filtration and washed with MTBE (550 mL). The filter cake was dissolved in sat. NaHCO3(1.5 L) and extracted with MTBE (3 x 800 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. This resulted in tert-butyl (3S)-3-amino-3-[2-(difluoromethoxy)-6- fluorophenyl]propanoate (29.27 g, 75%) as light yellow liquid. MS ESI calculated for Ci4Hi8F3NO3[M + H]+, 306.12 found 306.20. !HNMR(400 MHz, Chloroform-^ 67.25 - 7.17 (m, 1H), 6.97 - 6.87 (m, 2H), 6.58 (t, J = 73.4 Hz, 1H), 4.80 - 4.72 (m, 1H), 2.90 - 2.80 (m, 1H), 2.74 - 2.64 (m, 1H), 1.36 (s, 9H).19F NMR (377 MHz, Chloroform -d) 6 -80.52, -113.77. Preparation 2E: tert-butyl (3R)-3-[(5-chloro-2-nitrophenyl)amino]-3-[2-(difluoromethoxy)-6- fluorophenyl]propanoateA mixture of tert-butyl (3R)-3-amino-3-[2-(difluoromethoxy)-6-fluorophenyl]propanoate (18.50 g, 60.597 mmol), 4-chloro-2 -fluoro- 1 -nitrobenzene (11.70 g, 66.657 mmol) and DIEA (15.83 mL, 90.895 mmol) in N,N-Dimethylacetamide (200 mL) was stirred at 80 °C for 16 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resultingWSGR Ref: 53699-726.601 mixture was diluted with water (0.5 L). The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (3 x 1 L), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0~l 5%) to afford tert -butyl (3R)-3-[(5-chloro-2-nitrophenyl)amino]-3-[2-(difluoromethoxy)-6-fluorophenyl]propanoate (25.40 g, 9 l%yield) as yellow oil. MS ESI calculated for C20H20CIF3N2O5 [M + H]+, 461.10 found 461.15. !HNMR (400 MHz, Chloroform-t ) 8 8.70 (d, J= 9.0 Hz, 1H), 8.08 (d, J= 9.1 Hz, 1H), 7.34 - 7.27 (m, 1H), 7.04 (d, J = 2.1 Hz, 1H), 7.02 - 6.93 (m, 2H), 6.87 - 6.47 (m, 2H), 5.61 - 5.50 (m, 1H), 3.16 - 3.05 (m, 1H), 2.95 - 2.85 (m, 1H), 1.37 (s, 9H).19F NMR (377 MHz, Chloroform-; / ) 6 -80.98, -113.51.Preparation 2F: (3R)-3-[(5-chloro-2-nitrophenyl)amino]-3-[2-(difluoromethoxy)-6- fluorophenyl]propanalTo a stirred solution of tert-butyl (3R)-3-[(5-chloro-2-nitrophenyl)amino]-3-[2- (difluoromethoxy)-6-fluorophenyl]propanoate (7.10 g, 15.407 mmol) in DCM (110 mL) was added Diisobutylaluminum hydride (1 M in DCM) (71.65 mL, 71.653 mmol) dropwise slowly at -78 °C under nitrogen atmosphere. The mixture was stirred for 1 h at -78 °C . The reaction was quenched by the addition of sat. NH4C1 (aq.) (20 mL) at -78 °C. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 50 mL). The filtrate was extracted and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0-30%) to afford (3R)-3-[(5-chloro-2- nitrophenyl)amino]-3-[2-(difluoromethoxy)-6-fluorophenyl]propanal (15.40 g, 72%yield) as a yellow solid. MS ESI calculated for C16H12CIF3N2O4 [M + H]+, 389.04 found 389.10. iH NMR (400 MHz, Chloroform-; / ) 69.79 (s, 1H), 8.64 (d, J=9.1 Hz, 1H), 8.09 (d, = 9.1 Hz, 1H), 7.35 - 7.25 (m, 1H), 7.08 (d, = 2.1 Hz, 1H), 7.02 - 6.95 (m, 2H), 6.90 - 6.50 (m, 2H), 5.76 - 5.65 (m, 1H), 3.51 - 3.37 (m, 1H), 3.23 - 3.12 (m, 1H).19F NMR (377 MHz, Chloroform-; / ) 6 - 80.30, -80.75, -81.23, -81.67, -113.71.Preparation 2G: (4R)-4-[(5-chloro-2-nitrophenyl)amino]-4-[2-(difluoromethoxy)-6- fluorophenyl]-2-[(trimethylsilyl)oxy]butanenitrileTo a stirred mixture of (3R)-3-[(5-chloro-2-nitrophenyl)amino]-3-[2-(difluoromethoxy)-6- fluorophenyl]propanal (3.80 g, 9.775 mmol) and ZnL (312 mg, 0.978 mmol) in DCM (40 mL) were added TEA (99 mg, 0.987 mmol) and TMSCN (1.94 g, 19.550 mmol) dropwise at room temperature under nitrogen atmosphere. The mixture was stirred for 3 h at room temperature. The resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with CH2CI2 (3 x 300 mL). The combined organic layers were washed with brine (2 x 500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reducedWSGR Ref: 53699-726.601 pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0-100%) to afford (4R)-4-[(5-chloro-2-nitrophenyl)amino]-4-[2-(difluoromethoxy)-6- fluorophenyl]-2-[(trimethylsilyl)oxy]butanenitrile (4.10 g, 84%yield) as yellow oil. MS ESI calculated for C2oH2iClF3N304Si [M + H]+, 488.09 found 488.15. !H NMR (400 MHz, Chloroform -6 88.51 (dd, J = 42.1, 9.4 Hz, 1H), 7.99 - 7.90 (m, 1H), 7.22 - 7.11 (m, 1H), 6.91 - 6.77 (m, 3H), 6.73 - 6.29 (m, 2H), 5.33 - 5.21 (m, 1H), 4.52 - 4.25 (m, 1H), 2.57 - 2.42 (m, 1H), 2.40 - 2.16 (m, 1H), -0.03 (s, 9H).Preparation 2H: (3R)-1 l-chloro-3-[2-(difluoromethoxy)-6-fluorophenyl]-2,7- diazatricyclo[6.4.0.0A{2,6}]dodeca-l(8),6,9,l l-tetraen-5-olTo a stirred mixture of (4R)-4-[(5-chloro-2-nitrophenyl)amino]-4-[2-(difluoromethoxy)-6- fluorophenyl]-2-[(trimethylsilyl)oxy]butanenitrile (17.50 g, 35.865 mmol) in EtOH (200 mL) was added Titanium(III) chloride, 15-20% in HCl) (221.24 g, 286.920 mmol, 20%) dropwise at room temperature. The mixture was stirred for 16 h at 80 °C. The resulting mixture was diluted with water (1 L). The mixture was basified to pH 8-9 with saturated Na2CO3(aq.). The resulting mixture was extracted with EtOAc (3 x 0.5 L). The combined organic layers were washed with brine (3 x 0.5 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0-70%) to afford (3R)-ll-chloro-3-[2-(difluoromethoxy)-6-fluorophenyl]-2,7- diazatricyclo[6.4.0.0A{2,6}]dodeca-l(8),6,9,ll-tetraen-5-ol (8.80 g, 67%yield) as a light yellow solid. MS ESI calculated for CI7HI2C1F3N2O2[M + H]+, 369.05 found 368.95. 'H NMR (400 MHz, Chloroform -t / ) 67.72 - 7.63 (m, IH), 7.45 - 7.35 (m, IH), 7.23 - 7.16 (m, IH), 7.13 - 6.96 (m, 2H), 6.83 - 6.71 (m, IH), 6.23 - 5.83 (m, IH), 5.75 - 5.56 (m, IH), 3.66 - 3.54 (m, IH), 3.28 - 3.13 (m, IH), 2.95 - 2.86 (m, IH).19F NMR (377 MHz, Chloroform-; / ) 6 -80.58, - 81.02, -81.93, -82.37, -114.13.Preparation 21: (3R)-1 l-chloro-3-[2-(difluoromethoxy)-6-fluorophenyl]-2,7- diazatricyclo[6.4.0.0A{2,6}]dodeca-l(8),6,9,l 1 -tetraeneTo a stirred solution of (3R)-l l-chloro-3-[2-(difluoromethoxy)-6-fluorophenyl]-2,7- diazatricyclo[6.4.0.0A{2,6}]dodeca-l(8),6,9,l l-tetraen-5-ol (200 mg, 0.542 mmol) in phosphoroyl trichloride (0.5 mL) was added DIEA (140 mg, 1.084 mmol) dropwise at 0 °C. The mixture was stirred for 3 h at room temperature. The resulting mixture was diluted with water (50 mL ) at 0 °C. The mixture was basified to pH 8 with saturated NaHCO3(aq.). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was dissolved in EtOH (5 mL) added raney nickel (100 mg, 1.704 mmol) under nitrogen atmosphere in a 50 mL round -bottom flask. The mixtureWSGR Ref: 53699-726.601 was hydrogenated at room temperature overnight under hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 25% to 50% gradient in 30 min; detector, 254 nm. This resulted in (3R)-l l-chloro-3-[2-(difluoromethoxy)-6-fluorophenyl]-2,7- diazatricyclo[6.4.0.0A{2,6}]dodeca-l(8), 6, 9, 11 -tetraene (110 mg, 57%yield) as a light yellow solid. MS ESI calculated for Ci7Hi2ClF3N2O [M + H]+, 353.06 found 353.10. !H NMR (400 MHz, Chloroform -d) 67.61 (d, J = 8.6 Hz, 1H), 7.42 - 7.33 (m, 1H), 7.18 - 7.12 (m, 1H), 7.06 - 6.95 (m, 2H), 6.80 (d, J = 2.0 Hz, 1H), 6.43 (t, J = 72.6 Hz, 1H), 6.05 - 5.94 (m, 1H), 3.48 - 3.34 (m, 1H), 3.28 - 3.13 (m, 2H), 2.90 - 2.73 (m, 1H).19FNMR (377 MHz, Chloroform -t / ) 6 - 80.31, -80.75, -81.73, -82.17, -114.12.Example 2: (R)-(5-(l-(2-(difluoromethoxy)-6-fluorophenyl)-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazol-7-yl)pyridin-2-yl)dimethylphosphine oxide A mixture of (3R)-l l-chloro-3-[2-(difluoromethoxy)-6-fluorophenyl]-2,7- diazatricyclo[6.4.0.0A{2,6}]dodeca-l(8), 6, 9,11-tetraene (45 mg, 0.128 mmol), 2- (dimethylphosphoryl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (54 mg, 0.192 mmol), Sphos (11 mg, 0.026 mmol), Sphos Pd G3 (10 mg, 0.013 mmol) and K2CO3(44 mg, 0.320 mmol) in H2O (0.1 mL) and 1,4-dioxane (0.9 mL) was stirred at 80 °C for 3 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with MeOH / DCM (0-10%) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 25% to 50% gradient in 30 min; detector, 254 nm. This resulted in (R)-(5-(l-(2- (difluoromethoxy)-6-fluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-7- yl)pyridin-2-yl)dimethylphosphine oxide (28 mg, 47%yield) as a white solid. MS ESI calculated for C24H2IF3N3O2P [M + H]+, 472.13 found 472.10. 'H NMR (400 MHz, Chloroform -d) 6 8.80 (d, J = 2.2 Hz, 1H), 8.17 - 8.09 (m, 1H), 7.95 - 7.87 (m, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.49 - 7.43 (m, 1H), 7.42 - 7.34 (m, 1H), 7.08 - 6.95 (m, 3H), 6.49 (t, J = 72.7 Hz, 1H), 6.13 - 6.04 (m, 1H), 3.55 - 3.42 (m, 1H), 3.38 - 3.21 (m, 2H), 2.96 - 2.78 (m, 1H), 1.80 (s, 3H), 1.77 (s, 3H).19F NMR (377 MHz, Chloroform -d) 6 -80.36, -80.80, -81.87, -82.31, -113.87.31P NMR (162 MHz, Chloroform-; / ) 8 36.22.

[0147] Example 3 : (R)-(4-(l-(2-(difluoromethoxy)-6-fluorophenyl)-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazol-7-yl)-2-fluorophenyl)dimethylphosphine oxideWSGR Ref: 53699-726.601A mixture of (R)-7-chloro-l-(2-(difluoromethoxy)-6-fluorophenyl)-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazole (60 mg, 0.170 mmol), (2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)dimethylphosphine oxide(76 mg, 0.255 mmol), Sphos (14 mg, 0.034 mmol), Sphos Pd G3 (13 mg, 0.017 mmol) and K2CO3 (59 mg, 0.425 mmol) in 1,4-dioxane (1 mL) and H2O (0.1 mL) was stirred at 80 °C for overnight under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0-10%) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 25% to 50% gradient in 30 min; detector, 254 nm. This resulted in (R)-(4-(l-(2-(difluoromethoxy)-6-fluorophenyl)-2,3- dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-7-yl)-2-fluorophenyl)dimethylphosphine oxide (35 mg, 42%yield) as a white solid. MS ESI calculated for C25H21F4N2O2P [M + H]+, 489.13 found 489.10. 'HNMR (400 MHz, Chloroform -d) 68.03 - 7.89 (m, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.45 - 7.32 (m, 3H), 7.23 - 7.15 (m, 1H), 7.08 - 7.01 (m, 2H), 6.98 (t, J = 9.2 Hz, 1H), 6.47 (t, J = 72.7 Hz, 1H), 6.11 - 6.00 (m, 1H), 3.51 - 3.33 (m, 1H), 3.31 - 3.16 (m, 2H), 2.94 - 2.77 (m, 1H), 1.82 (s, 3H), 1.79 (s, 3H).19F NMR (377 MHz, Chloroform -t / ) 8 -80.21, -80.65, -81.89, - 82.33, -106.03, -106.04, -113.85.31P NMR (162 MHz, Chloroform -d) 6 30.39, 30.37.

[0148] Example 4: (R)-(4-(l-(2,6-difluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazol-7-yl)-2-fluorophenyl)dimethylphosphine oxideTo a stirred solution of (R)-7-chloro-l-(2,6-difluorophenyl)-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazole (50 mg, 0.164 mmol) and 2-[4-(dimethylphosphoryl)-3- fluorophenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (147 mg, 0.492 mmol) in 1,4-dioxane (1WSGR Ref: 53699-726.601 mL) and H20 (0.2 mL) were added Sphos (13 mg, 0.033 mmol), Sphos Pd G3(13 mg, 0.016 mmol) and K3PO4(104 mg, 0.492 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 1 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) followed by reversed -phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in water (10 mmol / L NH4HCO3), 30% to 70% gradient in 20 min; detector, 254 nm. This resulted in (R)-(4-(l-(2,6- difluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-7-yl)-2- fluorophenyl)dimethylphosphine oxide (14 mg, 19%) as a white solid. MS ESI calculated for C24H20F3N2OP [M + H]+, 441.13 found 441.15. !H NMR (400 MHz, DMSO-t / 6) 5 7.81 - 7.72 (m, 1H), 7.67 (d, J= 8.5 Hz, 1H), 7.53 - 7.42 (m, 4H), 7.19- 7.10 (m, 3H), 6.09 - 6.02 (m, 1H), 3.30 - 3.11 (m, 3H), 2.76 - 2.65 (m, 1H), 1.73 (s, 3H), 1.69 (s, 3H).19F NMR (377 MHz, DMSO-t / 6) 5 -105.67, -115.64.

[0149] Example 5: (R)-(2-fluoro-4-(l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol- 7 -yl)pheny l)dimethy Iphosphine oxidePreparation 5 A: (5R)-l-(5-chloro-2-nitrophenyl)-5-phenylpyrrolidin-2-oneTo a stirred mixture of (5R)-5-phenylpyrrolidin-2-one (1.95 g, 12.096mmol) and Cs2CO3(11.82 g, 36.288 mmol) in DMF (20 mL) was added 4-chloro-2-fhioro-l-nitrobenzene (3.19 g, 18.144 mmol) at room temperature under nitrogen atmosphere. 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 (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (12:1) to afford (5R)-l-(5-chloro-2-nitrophenyl)-5-phenylpyrrolidin-2-one (1.60 g, 42%yield) as a yellow solid. MS ESI calculated for CI6HI3C1N2O3[M + H]+, 317.06 found 317.05.1HNMR(400 MHz, Chloroform -d) 57.85 (d, J = 8.8 Hz, 1H), 7.44 - 7.18 (m, 6H), 6.98 (d, J = 2.2 Hz, 1H), 5.28 - 5.09 (m, 1H), 2.83 - 2.56 (m, 3H), 2.31 - 2.15 (m, 1H).Preparation 5B: (R)-7-chloro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole A solution of (5R)-l-(5-chloro-2-nitrophenyl)-5-phenylpyrrolidin-2-one (900 mg, 2.841 mmol) and Titanium(III) chloride, 15-20% in HCl) (17.53 g, 22.728 mmol) in EtOH (8 mL) was stirredWSGR Ref: 53699-726.601 at 80 °C for 3 h under nitrogen atmosphere. The reaction was quenched by the addition of sat. NaHCO3(aq.) (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in (R)-7-chloro-l-phenyl-2,3-dihydro- lH-benzo[d]pyrrolo[l,2-a]imidazole (720 mg, 94%yield) as a yellow solid. MS ESI calculated for CI6HI3C1N2[M + H]+, 269.08 found 269.05. 'HNMR (400 MHz, Chloroform-; / ) 87.62 (d, J = 8.6 Hz, 1H), 7.44 - 7.32 (m, 3H), 7.21 - 7.09 (m, 3H), 6.79 (d, J = 2.1 Hz, 1H), 5.40 (t, J = 6.8 Hz, 1H), 3.32 - 3.03 (m, 3H), 2.70 - 2.48 (m, 1H).Example 5: (R)-(2-fluoro-4-(l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-7- yl)phenyl)dimethylphosphine oxideTo a stirred solution of (R)-7-chloro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole (50 mg, 0.186 mmol) and 2-[4-(dimethylphosphoryl)-3-fluorophenyl]-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (83 mg, 0.279 mmol) in 1,4-dioxane (2 mL) and H2O (0.5 mL) were added K2CO3(77 mg, 0.558 mmol), Sphos Pd G3 (15 mg, 0.019 mmol) and Sphos (16 mg, 0.037 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CH2C12 / MeOH (12:1) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 5% to 40% gradient in 25 min; detector, 254 nm to afford (R)-(2-fluoro-4-(l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l, 2- a]imidazol-7-yl)phenyl)dimethylphosphine oxide (25 mg, 33%yield) as a white solid. MS ESI calculated for C24H22FN2OP [M + H]+, 405.15 found 405.15. !H NMR (400 MHz, DMSO-^6) 6 7.81 - 7.72 (m, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.55 - 7.48 (m, 2H), 7.48 - 7.42 (m, 1H), 7.41 - 7.29 (m, 3H), 7.28 - 7.22 (m, 2H), 7.20 (d, J = 1.8 Hz, 1H), 5.73 - 5.66 (m, 1H), 3.26 - 3.03 (m, 3H), 2.60 - 2.53 (m, 1H), 1.72 (s, 3H), 1.68 (s, 3H).19FNMR (377 MHz, DMSO-66) 6 -105.74.31P NMR (162 MHz, DMSC 628.22.

[0150] Example 6: (2-fluoro-4-(l-phenyl-l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2-a]pyridin-8- yl)phenyl)dimethylphosphine oxide Synthetic SchemePreparation 6 A: l-(5-chloro-2-nitrophenyl)-6-phenylpiperidin-2-oneTo a stirred solution of 6-phenylpiperidin -2-one (200 mg, 1.141 mmol) in THF (2 mL) wasWSGR Ref: 53699-726.601 added NaH (68 mg, 1.712 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 15 min. To the above mixture was added 4-chloro-2-fluoro-l -nitrobenzene (301 mg, 1.712 mmol) at 0 °C. The resulting mixture was stirred at room temperature for additional 1 h. The reaction was quenched by the addition of water (10 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3 :l)to afford l-(5-chloro-2-nitrophenyl)-6-phenylpiperidin-2-one (217 mg, 57%) as a yellow solid. MS ESI calculated for CI7HI5C1N2O3 [M + H]+, 331.08 found 331.10. E NMR (400 MHz, Chloroform-; / ) 88.05 - 7.71 (m, 1H), 7.50 - 6.77 (m, 7H), 5.11 - 4.68 (m, 1H), 2.69 (t, J = 6.8 Hz, 2H), 2.53 - 1.86 (m, 4H).Preparation 6B: 8-chloro-l-phenyl-l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2-a]pyridine To a stirred solution of l-(5-chloro-2-nitrophenyl)-6-phenylpiperidin-2-one (200 mg, 0.605 mmol) in EtOH (2 mL) was added Titanium(III) chloride, 15-20% in 2N Hydrochloric acid (3.73 g, 4.840 mmol) dropwise at room temperature. The resulting mixture was stirred at 80 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (30 mL). The mixture was basified to pH 8 with saturated Na2CO3 (aq.). The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (3 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, eluted with PEZEA (3 :1) to afford 8-chloro-l-phenyl-l, 2,3,4- tetrahydrobenzo[4,5]imidazo[l,2-a]pyridine (58 mg, 34%) as an off-white solid. MS ESI calculated for CI7HI5C1N2[M + H]+, 283.09 found 283.20.1H NMR (400 MHz, Chloroform -d) 8 7.60 (d, J = 8.6 Hz, 1H), 7.38 - 7.26 (m, 3H), 7.19 - 7.12 (m, 1H), 7.03 - 6.94 (m, 2H), 6.71 (d, J = 2.0 Hz, 1H), 5.43 (t, J = 5.5 Hz, 1H), 3.29 - 3.09 (m, 2H), 2.53 - 2.40 (m, 1H), 2.21 - 2.09 (m, 1H), 2.08 - 1.84 (m, 2H).Example 6: (2-fluoro-4-(l-phenyl-l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2-a]pyridin-8- yl)phenyl)dimethylphosphine oxideWSGR Ref: 53699-726.601To a stirred mixture of 8-chloro-l-phenyl-l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2-a]pyridine (48 mg, 0.170 mmol) and 2-[4-(dimethylphosphoryl)-3-fhiorophenyl]-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (61 mg, 0.204 mmol) in H2O (0.2 mL) and 1,4-dioxane (1.0 mL) were added K3PO4 (108 mg, 0.510 mmol), Sphos Pd G3 (13 mg, 0.017 mmol) and Sphos (14 mg, 0.034 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 1 h under nitrogen atmosphere. The resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 10% to 55% gradient in 40 min; detector, 254 nm to afford (2-fluoro-4-(l-phenyl-l,2,3,4- tetrahydrobenzo[4,5]imidazo[l,2-a]pyridin-8-yl)phenyl)dimethylphosphine oxide (18 mg, 25%) as a white solid. MS ESI calculated for C25H24FN2OP [M + H]+, 419.16 found 419.10. ^ NMR (400 MHz, Chloroform-; / ) 87.95 - 7.85 (m, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.45 - 7.39 (m, 1H), 7.37 - 7.28 (m, 4H), 7.14 - 7.08 (m, 1H), 7.07 - 7.02 (m, 2H), 6.89 - 6.83 (m, 1H), 5.53 (t, J = 5.6 Hz, 1H), 3.33 - 3.14 (m, 2H), 2.57 - 2.44 (m, 1H), 2.25 - 2.14 (m, 1H), 2.10 - 2.01 (m, 1H), 1.99 - 1.94 (m, 1H), 1.81 (s, 3H), 1.77 (s, 3H).19F NMR (377 MHz, Chloroform-; / ) 6 -106.12.31P NMR (162 MHz, Chloroform-; / ) 6 30.66.

[0151] Example 7: (2-fluoro-4-(4-phenyl-3,4-dihydro-lH-benzo[4,5]imidazo[2,l-c][l,4]oxazin- 7 -yl)pheny l)dimethy Iphosphine oxidePreparation 7 A: 4-(5-chloro-2-nitrophenyl)-5-phenylmorpholin-3-oneTo a stirred solution of 5-phenylmorpholin-3-one (500 mg, 2.822 mmol) and 4-chloro-2-fluoro- 1 -nitrobenzene (594 mg, 3.386 mmol) in DMF (5 mL) was added Cs2CO3(2.76 g, 8.466 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL) and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PEZEA (5:1) to afford 4-(5- chloro-2-nitrophenyl)-5-phenylmorpholin-3-one (570 mg, 60%) as a light yellow solid. MS ESI calculated for CI6HI3C1N2O4[M + H]+, 333.06 found 333.05. >HNMR (400 MHz, Chloroform- d) 6 8.12 - 7.94 (m, 1H), 7.47 - 7.31 (m, 7H), 5.39 - 5.15 (m, 1H), 4.53 - 4.41 (m, 2H), 4.05 (d, J = 12.1 Hz, 2H).Preparation 7B: 7-chloro-4-phenyl-3,4-dihydro-lH-benzo[4,5]imidazo[2,l-c][l,4]oxazineWSGR Ref: 53699-726.601To a stirred solution of 4-(5-chloro-2-nitrophenyl)-5-phenylmorpholin-3-one (220 mg, 0.661 mmol) in EtOH (2 mL) was added Titanium(III) chloride, 15-20% in 2N Hydrochloric acid) (4.08 g, 5.288 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 1 h. The mixture was basified to pH 8 with saturated Na2COs (aq.) at 0 °C. The resulting mixture was diluted with water (50 mL) followed by extraction with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL) and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 :1) to afford 7-chloro-4-phenyl-3,4-dihydro-lH- benzo[4,5]imidazo[2,l-c][l,4]oxazine (187 mg, 99%) as a yellow solid. MS ESI calculated for CI6HI3C1N2O [M + H]+, 285.07 found 285.10. !HNMR(400 MHz, Chloroform -d) 87.63 (d, J = 8.6 Hz, 1H), 7.42 - 7.37 (m, 3H), 7.21 - 7.15 (m, 3H), 6.69 (d, J = 1.9 Hz, 1H), 5.39 - 5.34 (m, 1H), 5.13 (s, 2H), 4.40 - 4.32 (m, 1H), 4.04 - 3.96 (m, 1H).Example 7: (2-fluoro-4-(4-phenyl-3,4-dihydro-lH-benzo[4,5]imidazo[2,l-c][l,4]oxazin-7- yl)phenyl)dimethylphosphine oxideTo a stirred mixture of 7-chloro-4-phenyl-3,4-dihydro-lH-benzo[4,5]imidazo[2,l-c][l,4]oxazine (60 mg, 0.211 mmol) and 2-[4-(dimethylphosphoryl)-3-fluorophenyl]-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (75 mg, 0.253 mmol) in 1,4-dioxane (1 mL) and H2O (0.1 mL) were added K3PO4 (134 mg, 0.633 mmol), Sphos (17 mg, 0.042 mmol) and Sphos Pd G3 (16 mg, 0.021 mmol) at room temperature. The resulting mixture was stirred at 80 °C for2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 10% to 34% gradientin 10 min; detector, 254 nm to afford (2-fluoro-4-(4-phenyl-3,4-dihydro- lH-benzo[4,5]imidazo[2,l-c][l,4]oxazin-7-yl)phenyl)dimethylphosphine oxide (40 mg, 46%) as a white solid. MS ESI calculated for C24H22FN2O2P [M + H]+, 421.14 found 421.20. TI NMR (400 MHz, Chloroform-; / ) 67.96 - 7.87 (m, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.49 - 7.45 (m, 1H), 7.43 - 7.38 (m, 3H), 7.29 (d, J = 1.4 Hz, 1H), 7.25 - 7.21 (m, 2H), 7.13 - 7.07 (m, 1H), 6.86 (d, J = 1.7 Hz, 1H), 5.50 - 5.46 (m, 1H), 5.19 (s, 2H), 4.45 - 4.39 (m, 1H), 4.09 - 4.02 (m, 1H),WSGR Ref: 53699-726.6011.81 (s, 3H), 1.78 (s, 3H).19F NMR (377 MHz, Chloroform -t / ) 6 -105.95, -105.96.31P NMR (162 MHz, Chloroform-t / ) 6 30.47.

[0152] Example 8: (S)-(2-fluoro-4-(4-(2-fluorophenyl)-3,4-dihydro-lH-benzo[4,5]imidazo[2,l-Preparation 8 A: (S)-2-chloro-N-(l -(2 -fluorophenyl)-2 -hydroxy ethyl)acetamideA solution of (S)-2-amino-2-(2-fluorophenyl)ethanol hydrochloride (2.00 g, 10.437 mmol) in DCM (30 mL) was treated with EtN (1.60 g, 15.655 mmol) at 0 °C for 5 min followed by the addition of chloroacetyl chloride (1.20 g, 10.448 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was quenched with water (10 mL) followed by extraction with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 20 mL) and dried overNa2SO4. After filtrated, and concentrated under reduced pressure to afford (S)-2-chloro-N-(l-(2-fluorophenyl)-2-hydroxyethyl)acetamide (2.01 g) as a white solid. The crude product was used in the next step directly. MS ESI calculated for CIOHHC1FN02[M + H]+, 232.05 found 232.00.Preparation 8B: (S)-5-(2-fluorophenyl)morpholin-3-oneA solution of 2-chloro-N-[(l S)-l-(2-fluorophenyl)-2-hydroxyethyl]acetamide (2.01 g, 8.634 mmol) in THF (30 mL) was treated with NaH (518 mg, 12.951 mmol, 60%) at 0 °C for 5 min under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The resulting mixture was quenched with water (5 mL) followed by extraction with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 10 mL) and dried over Na2SO4. After filtrated, and concentrated under reduced pressure to afford (S)-5-(2-fluorophenyl)morpholin-3-one (1.50 g, 89%) as a white solid. MS ESI calculated for CIOHI0FN02[M + H]+, 196.07 found 196.05.XH NMR (400 MHz, Chloroform-d) 8 7.45 - 7.38 (m, 1H), 7.37 - 7.30 (m, 1H), 7.25 - 7.17 (m, 1H), 7.12 - 7.04 (m, 1H), 6.62 (s, 1H), 5.14 -WSGR Ref: 53699-726.6015.05 (m, 1H), 4.65 - 4.54 (m, 2H), 4.15 - 4.05 (m, 1H), 3.74 - 3.62 (m, 1H).Preparation 8C: (S)-4-(5-chloro-2-nitrophenyl)-5-(2-fluorophenyl)morpholin-3-oneTo a solution of (S)-5 -(2 -fluorop henyl)morpholin-3 -one (1.50 g, 7.684 mmol) andCs2CC>3 (7.50 g, 23.054 mmol) in DMF (15 mL) was added 4-chloro-2-fluoro-l -nitrobenzene (2.01 g, 11.527 mmo) at room temperature. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The resulting mixture was diluted with water (5 mL) followed by extraction with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (3 x 20 mL) and dried over Na2SO4. After filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PEZEA (30% to 40%) to afford (S)-4-(5-chloro-2-nitrophenyl)-5-(2-fluorophenyl)morpholin-3-one (1.50 g, 59%) as a yellow solid. MS ESI calculated for CI6HI2C1FN2O4[M + H]+, 351.00 found 351.05. ENMR (400 MHz, Chloroform-d) 88.17 - 7.87 (m, 2H), 7.81 - 7.71 (m, 1H), 7.67 - 7.48 (m, 1H), 7.47 - 6.66 (m, 3H), 6.11 - 4.98 (m, 1H), 4.48 (d, J = 16.9 Hz, 1H), 4.36 (d, J = 16.9 Hz, 1H), 4.30 - 4.22 (m, 1H), 4.13 - 4.02 (m, 1H).Preparation 8D: (S)-7-chloro-4-(2-fluorophenyl)-3,4-dihydro-lH-benzo[4,5]imidazo[2,l- c][l,4]oxazineTo a solution of (S)-4-(5-chloro-2-nitrophenyl)-5-(2-fluorophenyl)morpholin-3-one (500 mg, 1.462 mmol) in EtOH (10 mL) was added Titanium(III) chloride, 15 -20% in 2N Hydrochloric acid) (1.80 g, 11.408 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 1 h. The resulting mixture was diluted with water (10 mL) followed by extraction with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 20 mL) and dried over Na2SO4. After filtrated, concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (40% to 50%) to afford (S)-7- chloro-4-(2-fluorophenyl)-3,4-dihydro-lH-benzo[4,5]imidazo[2,l-c][l,4]oxazine (420 mg, 97%) as a white solid. MS ESI calculated for CI6HI2C1FN2O [M + H]+, 303.06 found 302.90.JH NMR (400 MHz, Chloroform-t ) 67.65 (d, J = 8.6 Hz, 1H), 7.43 - 7.32 (m, 1H), 7.25 - 7.14 (m, 2H), 7.11 - 7.03 (m, 1H), 6.85 (d, J = 2.0 Hz, 1H), 6.83 - 6.74 (m, 1H), 5.73 (t, J = 4.4 Hz, 1H), 5.20 - 5.04 (m, 2H), 4.42 - 4.29 (m, 1H), 4.24 - 4.09 (m, 1H).Example 8: (S)-(2-fluoro-4-(4-(2-fluorophenyl)-3,4-dihydro-lH-benzo[4,5]imidazo[2,l- c][l,4]oxazin-7-yl)phenyl)dimethylphosphine oxideWSGR Ref: 53699-726.601A solution of (S)-7-chloro-4-(2-fluorophenyl)-3,4-dihydro-lH-benzo[4,5]imidazo[2,l- c][l,4]oxazine (lOOmg, 0.330mmol) and (2-fhioro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)phenyl)dimethylphosphine oxide (118 mg, 0.396 mmol) in 1,4-dioxane (2 mL) and H2O (0.5 mL) were added K3PO4 (210 mg, 0.990 mmol), Sphos Pd G3 (26 mg, 0.033 mmol) and Sphos (27 mg, 0.066 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / LNH^HCCL), 35% to 45% gradient in 15 min; detector, 254 nm to afford (S)-(2-fluoro-4- (4-(2-fluorophenyl)-3,4-dihydro-lH-benzo[4,5]imidazo[2,l-c][l,4]oxazin-7- yl)phenyl)dimethylphosphine oxide (60 mg, 41%) as a white solid. MS ESI calculated for C24H2IF2N2O2P [M + H]+, 439.13 found 439.15. !H NMR (400 MHz, Chloroform-t ) 8 8.01 - 7.89 (m, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.56 - 7.46 (m, 1H), 7.43 - 7.33 (m, 2H), 7.25 - 7.14 (m, 2H), 7.11 - 6.99 (m, 2H), 6.91 - 6.80 (m, 1H), 5.84 (t, J = 4.4 Hz, 1H), 5.29 - 5.09 (m, 2H), 4.50 - 4.37 (m, 1H), 4.29 - 4.18 (m, 1H), 1.82 (s, 3H), 1.79 (s, 3H).19F NMR (377 MHz, Chloroform -t / ) 6 -105.87, -105.88, -119.13.3 JP NMR (162 MHz, Chloroform -d) 6 30.43.

[0153] Example 9: (4-((lR)-l-(2,6-difluorophenyl)-3-fluoro-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazol-7-yl)-2-fluorophenyl)dimethylphosphine oxidePreparation 9 A: (1 R)-7 -chloro- 1 -(2, 6-difluoropheny l)-3 -fluoro-2, 3 -dihydro- 1 H- benzo[d]pyrrolo[l,2-a]imidazoleTo a stirred solution of (lR)-7-chloro-l-(2,6-difluorophenyl)-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazol-3-ol (100 mg, 0.312 mmol) in DCM (2 mL) was added diethylaminosulfur trifluoride (151 mg, 0.936 mmol) dropwise at 0 °C under nitrogenWSGR Ref: 53699-726.601 atmosphere. The resulting mixture was stirred at room temperature for additional 2 h. The reaction was quenched with water (0.2 mL) at 0 °C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (12:1) to afford (lR)-7-chloro-l-(2,6-difluorophenyl)-3-fluoro-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazole (58 mg, 58%) as a purple solid. MS ESI calculated for C16H10CIF3N2 [M + H]+, 323.05 found 323.05. 'HNMR (400 MHz, Chloroform -d) 57.76 (d, J= 8.8 Hz, 1H), 7.45 - 7.36 (m, 1H), 7.24 (t, J= 1.6 Hz, 1H), 7.02 - 6.94 (m, 2H), 6.88 (d, J= 1.9 Hz, 1H), 6.33 - 6.11 (m, 2H), 3.44 - 3.19 (m, 2H).19F NMR (377 MHz, Chloroform -d) 8 - 115.10, -170.94.Example 9: (4-((lR)-l-(2,6-difluorophenyl)-3-fluoro-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazol-7-yl)-2-fluorophenyl)dimethylphosphine oxideA mixture of (lR)-7-chloro-l-(2,6-difluorophenyl)-3-fluoro-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazole (55 mg, 0.170 mmol), 2-[4-(dimethylphosphoryl)-3- fluorophenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (76 mg, 0.255 mmol), Sphos Pd G3 (13 mg, 0.017 mmol), Sphos (14 mg, 0.034 mmol) andK3PO4(90 mg, 0.425 mmol) in 1,4-dioxane (1 mL) and H2O (0.1 mL) was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (12:1) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 20% to 50% gradient in 10 min; detector, 254 nm. This resulted in (4-((lR)-l-(2,6-difluorophenyl)-3-fluoro-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-7- yl)-2-fluorophenyl)dimethylphosphine oxide (31 mg, 40%) as a white solid. MS ESI calculated for C24Hi9F4N2OP [M + H]+, 459.12 found459.10. !HNMR(400 MHz, Chloroform-; / ) 6 8.00 - 7.91 (m, 2H), 7.54 - 7.48 (m, 1H), 7.45 - 7.35 (m, 2H), 7.22 - 7.16 (m, 1H), 7.05 (d, J= 1.8 Hz, 1H), 6.98 (t, J= 8.9 Hz, 2H), 6.38 - 6.19 (m, 2H), 3.48 - 3.24 (m, 2H), 1.82 (s, 3H), 1.79 (s, 3H).19F NMR (377 MHz, Chloroform-; / ) 6 -105.73, -115.00, -170.95.31P NMR (162 MHz, Chloroform -d) 8 30.45.

[0154] Example 10: (2-fluoro-4-(l-(pyridin-2-yl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazol-7 -yl)pheny l)dimethy Iphosphine oxidePreparation 10 A: l-(5-chloro-2-nitrophenyl)-5-(pyridin-2-yl)pyrrolidin-2-oneA mixture of 5-(pyridin-2-yl)pyrrolidin-2-one (100 mg, 0.617 mmol), 4-chloro-2-fluoro-l-WSGR Ref: 53699-726.601 nitrobenzene (130 mg, 0.740 mmol) and CS2CO3 (603 mg, 1.851 mmol) in DMF (1 mL) was stirred at room temperature overnight. The resulting mixture was diluted with water (30 mL) followed by extraction with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 30 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PEZEA (1 :2) to afford l-(5-chloro-2-nitrophenyl)-5-(pyridin-2- yl)pyrrolidin-2-one (90 mg, 46%) as a yellow solid. MS ESI calculated for C15H12CIN3O3 [M + H]+, 318.06 found 317.95. !H NMR (400 MHz, DMSO-t / 6) 8 8.59 - 8.50 (m, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.80 - 7.73 (m, 1H), 7.52 - 7.44 (m, 2H), 7.34 (d, J= 2.2 Hz, 1H), 7.32 - 7.27 (m, 1H), 5.59 - 5.53 (m, 1H), 2.74 - 2.54 (m, 3H), 2.21 - 2.10 (m, 1H).Preparation 10B: 7-chloro-l-(pyridin-2-yl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole A solution of l-(5-chloro-2-nitrophenyl)-5-(pyridin-2-yl)pyrrolidin-2-one (80 mg, 0.252 mmol) in EtOH (10 mL) was treated with TiCh in 15-20% HC1 (2.07 g, 2.013 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 1 h under nitrogen atmosphere. The mixture was neutralized to pH 7 with saturated NaHCO3(aq.) followed by extraction with CH2CI2 (3 x 30 mL). The combined organic layers were washed with brine (3 x 20 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (20:1) to afford 7-chloro-l-(pyridin-2-yl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole (65 mg, 96%) as a light yellow solid. MS ESI calculated for C15H12CIN3 [M + H]+, 270.07 found 270.00. 'H NMR (400 MHz, Methanol-^) 68.63 - 8.49 (m, 1H), 7.95 - 7.83 (m, 1H), 7.59 - 7.50 (m, 1H), 7.45 - 7.33 (m, 2H), 7.21 - 7.12 (m, 1H), 6.92 - 6.85 (m, 1H), 5.73 - 5.63 (m, 1H), 3.29 - 3.10 (m, 3H), 2.82 - 2.70 (m, 1H).Example 10: (2-fluoro-4-(l-(pyridin-2-yl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-7- yl)phenyl)dimethylphosphine oxideA mixture of 7-chloro-l-(pyridin-2-yl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole (50 mg, 0.185 mmol), (2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)dimethylphosphine oxide (66 mg, 0.222 mmol), Sphos (15 mg, 0.037 mmol), Sphos Pd G3 (15 mg, 0.018 mmol), K3PC>4 (118 mg, 0.555 mmol) and H2O (0.2 mL) in 1,4-dioxane (2 mL) was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was diluted with water (20 mL) followed by extraction with CH2Q2 (2 x 30 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with C ECh / MeOH (10:1) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN inWSGR Ref: 53699-726.601Water (10 mmol / L NH4HCO3), 20% to 50% gradient in 30 min; detector, 254 nm. This resulted in (2-fluoro-4-(l-(pyridin-2-yl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-7- yl)phenyl)dimethylphosphine oxide (9 mg, 12%) as a white solid. MS ESI calculated for C23H21FN3OP [M + H]+, 406.14 found 406.15. !H NMR (400 MHz, DMSO-t / 6) 8 8.56 - 8.50 (m, 1H), 7.87 - 7.79 (m, 1H), 7.79- 7.73 (m, 1H), 7.66 (d, = 8.6 Hz, 1H), 7.59 - 7.54 (m, 1H), 7.54 - 7.48 (m, 2H), 7.44 - 7.37 (m, 2H), 7.36 - 7.30 (m, 1H), 5.83 - 5.74 (m, 1H), 3.28 - 3.00 (m, 3H), 2.77 - 2.62 (m, 1H), 1.73 (s, 3H), 1.69 (s, 3H).19F NMR (377 MHz, DMSO-t / 6) 8 - 105.77, -105.78.

[0155] Example 11 : (2-fluoro-4-(l-(pyridin-3-yl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazol-7 -yl)pheny l)dimethy Iphosphine oxidePreparation 11 A: l-(5-chloro-2-nitrophenyl)-5-(pyridin-3-yl)pyrrolidin-2-oneA mixture of 5-(pyridin-3-yl)pyrrolidin-2-one (100 mg, 0.617 mmol), 4-chloro-2-fluoro-l- nitrobenzene (130 mg, 0.740 mmol) and CS2CO3 (603 mg, 1.851 mmol) in DMF (1 mL) was stirred at room temperature for 3 h. The resulting mixture was diluted with water (30 mL) followed by extraction with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PEZEA (1 :2) to afford l-(5-chloro-2-nitrophenyl)-5-(pyridin-3- yl)pyrrolidin-2-one (130 mg, 66%) as a yellow solid. MS ESI calculated for C15H12CIN3O3 [M + H]+, 318.06 found 317.95. 'HNMR (400 MHz, Methanol-^) 88.66 (d, J= 2.3 Hz, 1H), 8.48 - 8.40 (m, 1H), 8.08 - 8.02 (m, 1H), 8.00 - 7.88 (m, 1H), 7.46 - 7.34 (m, 3H), 5.65 - 5.44 (m, 1H), 2.81 - 2.69 (m, 3H), 2.29 - 2.16 (m, 1H).Preparation 1 IB: 7-chloro-l-(pyridin-3-yl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole A solution of l-(5-chloro-2-nitrophenyl)-5-(pyridin-3-yl)pyrrolidin-2-one (120mg, 0.378 mmol) in EtOH (4 mL) was treated with TiCh in 15-20% HC1 (466 mg, 3.024 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The mixture was neutralized to pH 7 with saturated NaHCCL (aq.) followed by extraction with CH2CI2 (2 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with C LCh / MeOH (10:1) to afford 7-chloro-l-(pyridin-3 -yl)-2,3-dihydro-lH-benzo[d]pyrrolo[l, 2-WSGR Ref: 53699-726.601 a]imidazole (80 mg, 79%) as a white solid. MS ESI calculated for C15H12CIN3 [M + H]+, 270.07 found 269.95. 'HNMR (400 MHz, Methanol-^) 88.60- 8.56 (m, 1H), 8.54 (d, J= 1.5 Hz, 1H), 7.69 - 7.62 (m, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.51 - 7.43 (m, 1H), 7.23 - 7.16 (m, 1H), 6.86 (d, J = 2.0 Hz, 1H), 5.75 - 5.67 (m, 1H), 3.27 - 3.10 (m, 3H), 2.71 - 2.57 (m, 1H).Example 11 : (2-fluoro-4-(l-(pyridin-3-yl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-7- yl)phenyl)dimethylphosphine oxideA mixture of 7-chloro-l-(pyridin-3-yl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole (40 mg, 0.148 mmol), (2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)dimethylphosphine oxide (53 mg, 0.178 mmol), Sphos (12 mg, 0.030 mmol), Sphos Pd G3 (12 mg, 0.015 mmol), KsPO4 (95 mg, 0.444 mmol) and H2O (0.2 mL) in 1,4-dioxane (2 mL) was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was diluted with water (20 mL) followed by extraction with CH2Q2 (2 x 30 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) followed by reversed -phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 min; detector, 254 nm. This resulted in (2-fluoro-4-(l-(pyridin-3-yl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-7- yl)phenyl)dimethylphosphine oxide (8 mg, 13%) as a white solid. MS ESI calculated for C23H21FN3OP [M + H]+, 406.14 found 406.15. !HNMR (400 MHz, DMSO-t / 6) 88.60 (d, J = 2.4 Hz, 1H), 8.57 - 8.51 (m, 1H), 7.82 - 7.72 (m, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.64 - 7.58 (m, 1H), 7.58 - 7.51 (m, 2H), 7.51 - 7.44 (m, 1H), 7.42 - 7.35 (m, 1H), 7.29 (d, J = 1.9 Hz, 1H), 5.81 - 5.73 (m, 1H), 3.28 - 3.05 (m, 3H), 2.65 - 2.53 (m, 1H), 1.72 (s, 3H), 1.69 (s, 3H).19F NMR (377 MHz, DMSO-t / e) 8 -105.75, -105.76.

[0156] Example 12: (2-fluoro-4-(l-phenyl-3,4-dihydro-lH-benzo[4,5]imidazo[l,2- c][l,3]thiazin-8-yl)phenyl)dimethylphosphine oxidePreparation 12 A: 2-(6-bromo-lH-benzo[d]imidazol-2-yl)ethane-l -thiolTo a stirred solution of 4-bromobenzene-l,2-diamine (8.00 g, 42.772 mmol) and 3- mercaptopropionic acid (5.45 g, 51.326 mmol) in H2O (40 mL) was added HC1 (36%, 20 mL) at room temperature. The resulting mixture was stirred at 100 °C for 16 h under nitrogen atmosphere. The resulting mixture was diluted with H2O (150 mL) and neutralized to pH 7 withWSGR Ref: 53699-726.601NaOH (4 M). The precipitated solids were collected by filtration and washed with water (3 x 10 mL). The crude residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (0.1% FA), 0% to 15% gradient in 20 min; detector, 254 nm to afford 2-(5-bromo-3H-l,3-benzodiazol-2-yl)ethanethiol (2.01 g, 18%) as dark blue oil. MS ESI calculated for C9H9BrN2S [M + H]+, 256.97 258.97 found 257. 10 259.10. 'HNMR (400 MHz, DMSO-t / 6) 8 12.46 (s, 1H), 7.67 (d, J = 16.4 Hz, 1H), 7.44 (s, 1H), 7.32 - 7.21 (m, 1H), 3.22 (t, J = 3.4 Hz, 1H), 3.11 (t, J = 7.1 Hz, 2H), 2.94 (q, J = 7.3 Hz, 2H).Preparation 12B: 8-bromo-l-phenyl-3,4-dihydro-lH-benzo[4,5]imidazo[l,2-c][l,3]thiazine To a stirred solution of 2-(6-bromo-lH-benzo[d]imidazol-2-yl)ethane-l-thiol (2.00 g, 7.778 mmol) and K2CO3 (2.15 g, 15.556 mmol) in DMF (20 mL) was added (dibromomethyl)benzene (3.89 g, 15.556 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The reaction was quenched with water at room temperature followed by extraction with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (30:1) to afford 8- bromo-l-phenyl-3,4-dihydro-lH-benzo[4,5]imidazo[l,2-c][l,3]thiazine (600 mg, mixture) as a red solid. MS ESI calculated for Ci6Hi3BrN2S [M + H]+, 345.00 347.00 found 344.90 346.90. Example 12: (2-fluoro-4-(l-phenyl-3,4-dihydro-lH-benzo[4,5]imidazo[l,2-c][l,3]thiazin-8- yl)phenyl)dimethylphosphine oxideTo a stirred solution of 8-bromo-l-phenyl-3,4-dihydro-lH-benzo[4,5]imidazo[l,2- c][l,3]thiazine (200 mg, 0.579 mmol) and 2-[4-(dimethylphosphoryl)-3-fluorophenyl]-4,4,5,5- tetramethyl-l,3,2-dioxaborolane (207 mg, 0.695 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) were added K2CO3(240 mg, 1.737 mmol) and Pd(dppf)Cl2(42 mg, 0.058 mmol) at room temperature. The resulting mixture was stirred at 90 °C for 16 h under nitrogen atmosphere. The reaction was diluted with water at room temperature followed by extraction with EtOAc (3 x 15 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (0.1% FA), 23% to 35% gradient in 20 min; detector, 254 nm to afford (2-fluoro-4-(l-phenyl-3,4-dihydro-lH-benzo[4,5]imidazo[l,2-c][l,3]thiazin-8- yl)phenyl)dimethylphosphine oxide (21 mg, 8%) as a white solid. MS ESI calculated for C24H22FN2OPS [M + H]+, 437.12 found 437.20. TI NMR (400 MHz, Chloroform -d) 6 7.99 - 7.86 (m, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.50 - 7.44 (m, 1H), 7.39 - 7.31 (m, 4H), 7.19 - 7. 12 (m, 1H), 7. 12 - 7.07 (m, 2H), 6.96 (d, J = 1 .7 Hz, 1H), 6.52 (s, 1H), 3.71 - 3.51 (m, 2H), 3. 12 - 2.91 (m, 2H), 1.81 (s, 3H), 1.78 (s, 3H).19F NMR (377 MHz, Chloroform -t / ) 6 -105.96, -105.97.31PWSGR Ref: 53699-726.601NMR (162 MHz, Chloroform -d) 6 30.51.

[0157] Example 13 : 8-(4-(dimethylphosphoryl)-3-fluorophenyl)-l-phenyl-3,4-dihydro-lH- benzo[4,5]imidazo[l,2-c][l,3]thiazine 2-oxideTo a stirred solution of (2-fluoro-4-(l-phenyl-3,4-dihydro-lH-benzo[4,5]imidazo[l,2- c][l,3]thiazin-8-yl)phenyl)dimethylphosphineoxide(50 mg, 0.115 mmol) andNa2HPO4 (35 mg 0.253 mmol) in DCM (5 mL) was added m-CPBA (25 mg, 0.127 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 5 h. The resulting mixture was concentrated under reduced pressure. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart Cl 8 ExRS, 30* 150 mm, 5pm; Mobile Phase A: Water (10 mmol / L NH4HCO3 + 0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 13% B to 28% B in 60 min; Wave Length: 254 nm; RTl(min): 16.06) to afford 8-(4- (dimethylphosphoryl)-3-fluorophenyl)-l-phenyl-3,4-dihydro-lH-benzo[4,5]imidazo[l,2- c][l,3]thiazine 2-oxide (32 mg, 62%) as a white solid. MS ESI calculated for C24H22FN2O2PS [M + H]+, 453.11 found 453.20. !HNMR(400 MHz, Chloroform -d) 88.01 - 7.91 (m, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.58 - 7.51 (m, 1H), 7.47 - 7.35 (m, 4H), 7.26 - 7.20 (m, 1H), 7.17 (d, J = 1.1 Hz, 1H), 7.04 - 6.96 (m, 2H), 6.64 (s, 1H), 4.05 - 3.91 (m, 1H), 3.63 - 3.52 (m, 1H), 3.28 - 3.18 (m, 1H), 3.03 - 2.91 (m, 1H), 1.81 (s, 3H), 1.78 (s, 3H).19F NMR (377 MHz, Chloroform- d) 8 -105.80, -105.81.31P NMR (162 MHz, Chloroform -d) 8 30.44.

[0158] Example 14: (2-fluoro-4-((lR)-3-methoxy-l-phenyl-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazol-7-yl)phenyl)dimethylphosphine oxideWSGR Ref: 53699-726.601Preparation 14A: (S,E)-N-benzylidene-2-methylpropane-2-sulfinamideTo a stirred solution of benzaldehyde (50.00 g, 471.147 mmol) and (S)-2-methylpropane-2- sulfinamide (68.52 g, 565.376 mmol) in DCM (600 mL) was added CS2CO3 (168.00 g, 518.262 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (500 mL) followed by extraction with CH2Q2 (3 x 600 mL). The combined organic layers were washed with brine (2 x 500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10 / 1) to afford (S,E)-N-benzylidene-2-methylpropane-2-sulfinamide (96.01 g, 97%) as yellow green oil. MS ESI calculated for CnHi5NOS [M + H]+, 210.09 found 210.20. 'H NMR (400 MHz, Chloroform -6 68.65 - 8.50 (m, 1H), 7.91 - 7.73 (m, 2H), 7.57 - 7.34 (m, 3H), 1.28 (s, 9H). Preparation 14B: tert-butyl (R)-3-(((S)-tert-butylsulfinyl)amino)-3-phenylpropanoate Into a 3 L 4-necked round-bottom flask were added active Zinc (196.79 g, 3.010 mol), CuCI (63.85 g, 644.976 mmol) and THF (900 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. To the above mixture was added tert -butyl 2- bromoacetate (157 mL, 1.075 mol) dropwise at room temperature. The resulting mixture was stirred at 60 °C for additional 2 h. The mixture was allowed to cool down to 5 °C followed by addition of (S,E)-N-benzylidene-2-methylpropane-2-sulfinamide (90.00 g, 429.984 mmol) dropwise at 5 ~ 10 °C. The resulting mixture was stirred at room temperature for additional 16 h. The resulting mixture was filtered, the filter cake was washed with EtOAc (3 x 700 mL). The filtrate was quenched by 5% citric acid solution. The resulting mixture was extracted with EtOAc (3 x IL). The combined organic layers were washed with saturated NaHCO3(aq.)WSGR Ref: 53699-726.601 followed by brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by trituration with n- heptane / EA (10 / 1) (600 mL). This resulted in tert-butyl (R)-3-(((S)-tert-butylsulfinyl)amino)-3- phenylpropanoate (110.01 g, 78%) as a white solid. MS ESI calculated for C17H27NO3S [M + H]+, 326.17 found 326.15. 'H NMR (400 MHz, Chloroform -d) 8 7.37 - 7.23 (m, 5H), 4.80 - 4.70 (m, 1H), 4.67 - 4.58 (m, 1H), 2.82 - 2.70 (m, 2H), 1.38 (s, 9H), 1.22 (s, 9H).Preparation 14C: tert-butyl (R)-3-amino-3-phenylpropanoateTo a stirred solution of tert-butyl (R)-3-(((S)-tert-butylsulfinyl)amino)-3-phenylpropanoate (110.00 g, 337.973 mmol) in THF (600 mL) and H2O (120 mL) was added Iodine (21.45 g, 84.493 mmol) at room temperature. The resulting mixture was stirred at 50 °C overnight. The reaction was quenched with sat. NaHCO3(aq.) at room temperature followed by extraction with EtOAc (3 x 1 L). The combined organic layers were washed with water and brine. The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in MTBE (500 mL) followed by addition of L- Mailcacid (50.00 g) at room temperature. The resulting mixture was stirred at room temperature for additional 1 h. The precipitated solids were collected by filtration and washed with MTBE (3 x 100 mL). The residue was dissolved in EtOAc (1 L). The mixture was basified to pH 9 with saturated NaHCO3(aq.) followed by extraction with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (1 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl (R)-3-amino-3- phenylpropanoate (40.01 g, 53%) as a white solid. MS ESI calculated for CI3HI9NO2[M + H]+, 222.14 found 222.10. !HNMR(400 MHz, Chloroform -d) 6 8.71 (s, 2H), 7.55 - 7.45 (m, 2H), 7.40 - 7.30 (m, 3H), 4.65 - 4.52 (m, 1H), 3.18 - 3.06 (m, 1H), 3.03 - 2.91 (m, 1H), 1.29 (s, 9H). Preparation 14D: tert-butyl (R)-3-((5-chloro-2-nitrophenyl)amino)-3-phenylpropanoateTo a stirred solution of tert-butyl (R)-3-amino-3-phenylpropanoate (40.01 g, 180.750 mmol) and 4-chloro-2 -fluoro- 1 -nitrobenzene (33.32g, 189.787 mmol) in N,N-dimethylacetamide(200 mL) was added DIEA (47 mL, 271.125 mmol) at room temperature. The resulting mixture was stirred at 80 °C overnight. The resulting mixture was diluted with water (1 L) followed by extraction with EtOAc (1 L). The combined organic layers were washed with 3 x 500 mL of brine. The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2C12 / PE (1 / 3) to afford tert-butyl (R)-3-((5-chloro-2- nitrophenyl)amino)-3-phenylpropanoate (59.00 g, 86%) as a yellow solid. MS ESI calculated for CI9H2IC1N2O4[M + H]+, 377.12 found 377.05. !HNMR (400 MHz, Chloroform -d) 6 8.78 (d, J = 6.7 Hz, 1H), 8.19 - 8.03 (m, 1H), 7.40 - 7.27 (m, 5H), 6.69 (d, J = 2.1 Hz, 1H), 6.62 - 6.54WSGR Ref: 53699-726.601(m, 1H), 5.06 - 4.80 (m, 1H), 2.93 - 2.73 (m, 2H), 1.39 (s, 9H).Preparation 14E: (R)-3-((5-chloro-2-nitrophenyl)amino)-3-phenylpropanalTo a stirred solution of tert-butyl (R)-3-((5-chloro-2-nitrophenyl)amino)-3-phenylpropanoate (57.00 g, 151.258 mmol) in DCM (900 mL) was added Diisobutylaluminum hydride(l .0 M in DCM) (182 mL, 181.510 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 3 h. The reaction was quenched with IN HC1 (aq.) at -78 °C followed by extraction with CH2C12(3 x 500 mL). The combined organic layers were washed with brine (1 x 1 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PEZEA (4 / 1) to afford (R)-3-((5-chloro-2-nitrophenyl)amino)-3- phenylpropanal (36.01 g, 78%) as yellow oil. MS ESI calculated for CI5HI3C1N2O3[M - H]’, 303.06 found 303.00. TI NMR (400 MHz, Chloroform -d) 8 9.79 (s, 1H), 8.57 (d, J = 6.9 Hz, 1H), 8.10 (d, J = 9.1 Hz, 1H), 7.42 - 7.27 (m, 5H), 6.76 - 6.57 (m, 2H), 5.18 - 5.07 (m, 1H), 3.27 - 2.95 (m, 2H).Preparation 14F: (4R)-4-((5-chloro-2-nitrophenyl)amino)-4-phenyl-2- ((trim ethy 1 sily l)oxy )b utan enitril eTo a stirred solution of (R)-3-((5-chloro-2-nitrophenyl)amino)-3-phenylpropanal (35.00 g, 114.856 mmol) and TMSCN (22.79 g, 229.712 mmol) in DCM (350 mL) were added Et3N (1.16 g, 11 .486 mmol) and Znl2(3.67 g, 11 .486 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with sat. NH4C1 (aq.) at room temperature followed by extraction with CH2C12(3 x 300 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford (4R)-4-((5-chloro-2- nitrophenyl)amino)-4-phenyl-2-((trimethylsilyl)oxy)butanenitrile (41.00 g, 88%) as a yellow solid. The crude product was used in the next step directly without further purification. MS ESI calculated for Ci9H22ClN3O3Si [M + H]+, 404. 11 found 404.05 .Preparation 14G: (lR)-7-chloro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-3-ol To a stirred solution of (4R)-4-((5-chloro-2-nitrophenyl)amino)-4-phenyl-2- ((trimethylsilyl)oxy)butanenitrile (40.00 g, 99.025 mmol) in EtOH (400 mL) was added Titanium(III) chloride, 15-20% in 2N Hydrochloric acid) (610.86 g, 792.200 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. The resulting mixture was concentrated under vacuum. The residue was basified to pH 8 with saturated NaHCO3(aq.). The resulting mixture was filtered, the filter cake was washed with EtO Ac (3 x 1 L). The filtrate was extracted with EtO Ac (1 L) and washed with brine (1 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified byWSGR Ref: 53699-726.601 silica gel column chromatography, eluted with CH2Cl2 / MeOH (12 / 1) to afford (lR)-7-chloro-l- phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-3-ol (21.01 g, 74%) as a yellow solid. MS ESI calculated for CI6HI3C1N2O [M + H]+, 285.07 found 285.05. 'H NMR (400 MHz, Chloroform -6 67.71 - 7.63 (m, IH), 7.49 - 7.29 (m, 5H), 7.22 - 7.14 (m, 2H), 6.80 (s, IH), 5.74 - 5.27 (m, 2H), 3.60 - 3.12 (m, IH), 2.97 - 2.63 (m, IH).Preparation 14H: (1 R)-7-chloro-3 -methoxy- l-phenyl-2, 3 -dihydro- 1 H-benzo[d]pyrrolo[ 1,2- a]imidazoleTo a stirred solution of (lR)-7-chloro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol- 3-ol (100 mg, 0.351 mmol) in DMF (2 mL) was added NaH (21 mg, 0.526 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 15 min under nitrogen atmosphere. To the above mixture was added CH3I (100 mg, 0.702 mmol) at room temperature. The resulting mixture was stirred at room temperature for additional 2 h. The reaction was quenched with water at room temperature followed by extraction with EtOAc (50 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (12 / 1) to afford (1R)- 7-chloro-3-methoxy-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole (100 mg, 95%) as a yellow solid. MS ESI calculated for CI7HI5C1N2O [M + H]+, 299.09 found 299.05. >HNMR (400 MHz, Chloroform-; / ) 87.74 - 7.68 (m, IH), 7.49 - 7.27 (m, 5H), 7.23 - 7.15 (m, 2H), 5.65 - 5.27 (m, IH), 4.95 - 4.89 (m, IH), 3.74 - 3.61 (m, 3H), 3.53 - 3.05 (m, IH), 2.85 - 2.55 (m, IH).Example 14: (2-fluoro-4-((lR)-3-methoxy-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazol-7 -yl)pheny l)dimethy Iphosphine oxideTo a stirred solution of (lR)-7-chloro-3-methoxy-l-phenyl-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazole (100 mg, 0.335 mmol) and (2-fluoro-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl)dimethylphosphine oxide(150mg, 0.503 mmol) in 1,4-dioxane (0.8 mL) and H2O (0.2 mL) were added K3PO4(213 mg, 1.005 mmol), Sphos Pd G3 (26 mg, 0.034 mmol) and Sphos (27 mg, 0.067 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 30% to 50% gradient in 20 min; detector, 254 nm to afford (2 -fluoro-4-((lR)-3 -methoxy- 1- phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-7-yl)phenyl)dimethylphosphine oxide (78 mg, 53%) as a white solid. MS ESI calculated for C25H24FN2O2P [M + H]+, 435.16 foundWSGR Ref: 53699-726.601435.15. !H NMR (400 MHz, Chloroform-t ) 6 8.07 - 7.80 (m, 2H), 7.51 (d, J= 7.9 Hz, 1H), 7.43 - 7.37 (m, 3H), 7.37 - 7.29 (m, 2H), 7.25 - 6.89 (m, 3H), 5.81 - 5.33 (m, 1H), 5.01 (d, J = 7.1 Hz, 1H), 3.84 - 3.64 (m, 3H), 3.60 - 3.12 (m, 1H), 2.94- 2.62 (m, 1H), 1.81 (s, 3H), 1.78 (s, 3H).19F NMR (377 MHz, Chloroform -d) 6 -105.86.31P NMR (162 MHz, Chloroform -d) 6 30.39.

[0159] Example 15: (2-fluoro-4-((l S,2S)-2-hydroxy-l-phenyl-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazol-7-yl)phenyl)dimethylphosphine oxidePreparation 15 A: methyl 4-phenylbut-3 -enoateA solution of 4-phenylbut-3-enoic acid (48.00 g, 295.953 mmol) and cone. H2SO4 (1.6 mL, 29.595 mmol) in methanol (119 mL) was stirred at 70 °C overnight. The reaction was quenched with ice water followed by extraction with EtOAc (3 x 300 mL). The combined organic layers were washed with water (3 x 300 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in methyl 4-phenylbut-3 -enoate (55.00 g, 95%) as yellow oil. MS ESI calculated for CnHi2O2[M + H]+, 177.09 found 177.05.JH NMR (400 MHz, Chloroform -d) 57.37 (d, J= 7.2 Hz, 2H), 7.31 (t, J= 7.5 Hz, 2H), 7.23 (t, J = 7.2 Hz, 1H), 6.49 (d, J= 15.9 Hz, 1H), 6.35 - 6.24 (m, 1H), 3.72 (s, 3H), 3.28 - 3.22 (m, 2H). Preparation 15B: methyl 2-((2R,3R)-3-phenyloxiran-2-yl)acetateTo a stirred mixture of methyl 4 -phenylbut-3 -enoate (55.00 g, 312.119 mmol) and NaHCO3(131.01 g, 1.561 mol) in acetone (1 L) was added potassium peroxymonosulfate (162.00 g, 468.179 mmol) in H2O (250 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was filtered, the filter cake was washed with EtOAc (3 x 30 mL) followed by extraction with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration,WSGR Ref: 53699-726.601 the filtrate was concentrated under reduced pressure to afford methyl 2-((2R,3R)-3- phenyloxiran-2-yl)acetate (58.01 g, 88%) as light yellow oil. MS ESI calculated for C11H12O3 [M + H]+, 193.09 found 193.05. 'HNMR (400 MHz, Chloroform -tZ) 67.37 - 7.27 (m, 5H), 3.74 (s, 3H), 3.73 - 3.62 (m, 1), 3.38 - 3.30 (m, 1H), 2.80 - 2.66 (m, 2H).Preparation 15C: methyl (3R,4S)-4-bromo-3-hydroxy-4-phenylbutanoateTo a stirred solution of methyl 2-((2R,3R)-3-phenyloxiran-2-yl)acetate (30.00 g, 156.076 mmol) in CH3CN (600 mL) was added lithium bromide (40.00 g, 468.228 mmol) and Mg(C104)2(104.00 g, 468.228 mmol) at 0 °C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was filtered and the filter cake was washed with EtOAc (3 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / PE (10:l)to afford methyl (3R,4S)-4-bromo-3- hydroxy-4-phenylbutanoate (35.00 g, 82%) as yellow oil. MS ESI calculated for CiiHi3BrO3[M + H]+, 273.01 275.01 found 273.00 275.00.XH NMR (400 MHz, Chloroform -d) 8 7.48 - 7.44 (m, 2H), 7.38 - 7.35 (m, 1H), 7.35 - 7.31 (m, 2H), 4.98 (d, = 6.9 Hz, 1H), 4.54 - 4.48 (m, 1H), 3.71 (s, 3H), 3.66 (s, 1H), 2.91 - 2.85 (m, 1H), 2.67 - 2.59 (m, 1H).Preparation 15D: methyl (3R,4R)-4-azido-3-hydroxy-4-phenylbutanoateA mixture of methyl (3R,4S)-4-bromo-3-hydroxy-4-phenylbutanoate (35.00 g, 128.146 mmol) and NaN3(24 g, 384.438 mmol) in DMF (500 mL) was stirred at room temperature overnight. The reaction was quenched with water at 0 °C followed by extraction with CH2C12(3 x 500 mL). The combined organic layers were washed with brine (3 x 500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford methyl (3R,4R)-4-azido-3-hydroxy-4-phenylbutanoate (30.10 g, crude) as yellow oil. MS ESI calculated for CnHi3N3O3[M + H]+, 276.10 found N / A.Preparation 15E: (4S,5S)-4-hydroxy-5-phenylpyrrolidin-2-oneA mixture of methyl (3R,4R)-4-azido-3-hydroxy-4-phenylbutanoate (30.00 g, 127.528 mmol) and Pd / C (1.30 g) in methanol (500 mL) was stirred at room temperature overnight under hydrogen atmosphere. The resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:l) to afford (4S, 5 S)-4-hydroxy-5-phenylpyrrolidin-2 -one (18.01 g, 80%) as yellow oil. MS ESI calculated for CioHnN02[M + H]+, 178.09 found 178.05.XH NMR (400 MHz, DMSO-tZ6) 6 7.99 (s, 1H), 7.35 - 7.22 (m, 5H), 4.80 (d, J= 5.2 Hz, 1H), 4.68 (d, J= 5.3 Hz, 1H), 4.44 - 4.34 (m, 1H), 2.54 (d, J= 6.2 Hz, 1H), 2.12 - 2.04 (m, 1H).Preparation 15F: (4S,5S)-4-[(tert-butyldimethylsilyl)oxy]-5-phenylpyrrolidin-2-oneTo a stirred mixture of (4S,5S)-4-hydroxy-5-phenylpyrrolidin-2-one (17.00g, 95.935 mmol) and imidazole (19.59 g, 287.805 mmol) in DCE (540 mL) was added tert-WSGR Ref: 53699-726.601 butyl(chloro)dimethylsilane (28.92 g, 191.870 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 3 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PEZEA (1 :1) to afford (4S,5S)-4-[(tert-butyldimethylsilyl)oxy]-5-phenylpyrrolidin-2-one (7.60 g, 27%) as a white solid. MS ESI calculated for Ci6H25NO2Si [M + H]+, 292.17 found 292.15.1H NMR (400 MHz, DMSO-t / 6) 8 8.05 (s, 1H), 7.36 - 7.29 (m, 2H), 7.28 - 7.21 (m, 3 H), 4.77 (d, J = 4.8 Hz, 1H), 4.57 - 4.47 (m, 1H), 2.70 - 2.60 (m, 1H), 2.11 - 1.98 (m, 1H), 0.62 (s, 9H), -0.21 (s, 3H), -0.41 (s, 3H).Preparation 15G: (4S,5S)-4-[(tert-butyldimethylsilyl)oxy]-l-(5-chloro-2-nitrophenyl)-5- phenylpyrrolidin -2-oneTo a stirred mixture of (4S,5S)-4-[(tert-butyldimethylsilyl)oxy]-5-phenylpyrrolidin-2-one (2.00 g, 6.862 mmol) and 2 -brom o-4-chloro-l -nitrobenzene (1.78 g, 7.548 mmol) in toluene (40 mL) were added Cs2CO3(4.47 g, 13.724 mmol), Xantphos (397 mg, 0.686 mmol) andPd2(dba)3(628 mg, 0.686 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:l) to afford (4S,5S)-4-[(tert-butyldimethylsilyl)oxy]-l-(5-chloro-2-nitrophenyl)- 5-phenylpyrrolidin-2-one (1.37 g, 45%) as a yellow solid. MS ESI calculated for C22H27ClN2O4Si [M + H]+, 447.14 found 447.00. !HNMR(400 MHz, Chloroform -d) 6 7.85 (d, J = 8.7 Hz, 1H), 7.34 - 7.26 (m, 5H), 7.24 - 7.19 (m, 1H), 7.07 (d, J = 2.2 Hz, 1H), 5.20 (d, J = 5.0 Hz, 1H), 4.70 - 4.61 (m, 1H), 2.95 - 2.82(m, 1H), 2.72 - 2.63 (m, 1H), 0.74 (s, 9H), -0.15 (s, 3H), -0.39 (s, 3H).Preparation 15H: (1 S,2S)-7-chloro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-2- olTo a stirred solution of (4S,5S)-4-[(tert-butyldimethylsilyl)oxy]-l-(5-chloro-2-nitrophenyl)-5- phenylpyrrolidin-2-one (1.37 g, 3.065 mmol) in EtOH (14 mL) was added Titanium(III) chloride, 15-20% in 2N Hydrochloric acid (19.01 g, 24.520 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h. The resulting mixture was concentrated under vacuum. The residue was basified to pH 8 with saturated NaHCO3(aq.). The aqueous layer was extracted with EtOAc (3 x 100 mL). The organic layer was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford (l S,2S)-7-chloro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-2-ol (730 mg 84%) as a white solid. MS ESI calculated for CI6HI3C1N2O [M + H]+, 285.07 found 284.95. TI NMR (400 MHz, DMSO-t / 6) 8 7.60 (d, J = 8.6 Hz, 1H), 7.40 - 7.33 (m, 3H), 7.17 - 7.12 (m, 1H), 7.08 - 7.04 (m, 2H), 6.82 (d, J = 2.1 Hz, 1H), 5.62 (d, J = 6.1 Hz, 1H), 5.56 (d, J = 5.8 Hz,WSGR Ref: 53699-726.6011H), 5.13 - 5.00 (m, 1H), 3.41 - 3.34 (m, 1H), 2.97 - 2.89 (m, 1H).Example 15: (2-fluoro-4-((l S,2S)-2-hydroxy-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazol-7 -yl)pheny l)dimethy Iphosphine oxideTo a stirred mixture of (l S,2S)-7-chloro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazol-2-ol (60 mg, 0.211 mmol) and 2-[4-(dimethylphosphoryl)-3-fluorophenyl]-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane (75 mg, 0.253 mmol) in 1 ,4-dioxane (1.5 mL) and H2O (0.3 mL) were added K3PO4 (134 mg, 0.633 mmol), S-Phos (17 mg, 0.042 mmol) and SPhos Pd G3 (16 mg, 0.021 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 3 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 20% to 50% gradient in 25 min; detector, 254 nm. This resulted in (2-fluoro-4-((l S,2S)-2-hydroxy-l-phenyl-2,3-dihydro- lH-benzo[d]pyrrolo[l,2-a]imidazol-7-yl)phenyl)dimethylphosphine oxide (52 mg, 59%) as a white solid. MS ESI calculated for C24H22FN2O2P [M + H]+, 421.14 found 421.10. E NMR (400 MHz, DMSO-t / e) 8 7.80 - 7.74 (m, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.55 - 7.50 (m, 2H), 7.48 - 7.43 (m, 1H), 7.36 - 7.29 (m, 3H), 7. 19 (d, J = 1 .8 Hz, 1H), 7.11 - 7.03 (m, 2H), 5.69 (d, J = 6.2 Hz, 1H), 5.63 - 5.55 (m, 1H), 5.18 - 5.08 (m, 1H), 3.44 - 3.36 (m, 1H), 3.03 - 2.91 (m, 1H), 1.71 (s, 3H), 1.68 (s, 3H).19F NMR (377 MHz, DMSO-t / 6) 6 -105.76, -105.77.31P NMR (162 MHz, DMSC 8 28.25.

[0160] Example 16: (R)-(2,3-difluoro-4-(l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazol-7 -yl)pheny l)dimethy Iphosphine oxideTo a stirred solution of (R)-7-chloro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole (60 mg, 0.223 mmol) and 2-[4-(dimethylphosphoryl)-2,3-difluorophenyl]-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (105 mg, 0.335 mmol) in H2O (0.1 mL) and 1,4-dioxane (1 mL) were added Sphos (9 mg, 0.022 mmol), Sphos Pd G3 (8 mg, 0.011 mmol) and K3PO4 (94 mg, 0.446 mmol) at room temperature. The resulting mixture was stirred at 80 °C for2 h under nitrogen atmosphere. The resulting mixture was concentrated under reducedWSGR Ref: 53699-726.601 pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) followed by Prep-HPLC with the following conditions (Column:XBridge Prep OBD Cl 8 Column, 30*150 mm, 5 u m; Mobile Phase A: Water (10 mmol / LNH4HCO3 + 0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 32% B to 62% B in 10 min; Wave Length: 254 nm; RTl(min): 5.28) to afford (R)-(2,3-difluoro-4-(l- phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-7-yl)phenyl)dimethylphosphine oxide (59 mg, 63%) as a white solid. MS ESI calculated for C24H2iF2N2OP [M + H]+, 423.14 found 423.15.1HNMR(400 MHz, Chloroform-; / ) 67.84 (d, J = 8.5 Hz, 1H), 7.74 - 7.58 (m, 1H), 7.46 - 7.31 (m, 4H), 7.26 - 7.13 (m, 3H), 7.01 (s, 1H), 5.54 (t, J = 6.7 Hz, 1H), 3.39 - 3.12 (m, 3H), 2.76 - 2.53 (m, 1H), 1.84 (s, 3H), 1.80 (s, 3H).19FNMR(377 MHz, Chloroform-; / ) 8 -131.41, - 131.47, -143.14, -143.16, -143.20, -143.22.31P NMR (162 MHz, Chloroform-; / ) 6 29.94.

[0161] Example 17: 7-(4-(dimethylphosphoryl)-3-fluorophenyl)-l-phenyl-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazole-2-carbonitrilePreparation 17A: methyl l-(2,4-dimethoxybenzyl)-5-oxo-2-phenylpyrrolidine-3-carboxylate A solution of benzaldehyde (20.00 g, 188.459 mmol) and 1 -(2,4-dimethoxyphenyl)methanamine (31.51 g, 188.459 mmol) in toluene (100 mL) was stirred at 100 °C for 3 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature followed by addition of oxolane-2, 5-dione (18.86 g, 188.459 mmol). The resulting mixture was stirred at 100 °C for additional 16 h. The mixture was concentrated under reduced pressure. The residue was dissolved in acetone (100 mL). To the above mixture was added K2CO3(78.14 g, 565.377 mmol) and CH3I (80.25 g, 565.377 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 16 h under nitrogen atmosphere. The resulting mixture was concentrated underWSGR Ref: 53699-726.601 reduced pressure. The residue was dissolved in ethyl acetate (300 mL). The resulting mixture was washed with 2 x 300 mL of water. The combined organic layers was dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4: 1) to afford methyl methyl l-(2,4-dimethoxybenzyl)-5-oxo-2-phenylpyrrolidine-3-carboxylate (20.01 g, 29%) as a light yellow solid. MS ESI calculated for C2IH23NO5[M + H]+, 370.16 found 370.25.JH NMR (400 MHz, Chloroform -d) 87.40 - 7.29 (m, 3H), 7.17 - 7.10 (m, 2H), 6.92 (d, J= 8.0 Hz, 1H), 6.41 - 6.33 (m, 2H), 4.89 (d, = 14.7 Hz, 1H), 4.64 (d, J= 5.5 Hz, 1H), 3.79 (s, 3H), 3.73 - 3.69 (m, 1H), 3.66 (s, 3H), 3.63 (s, 3H), 3.05 - 2.95 (m, 1H), 2.91 - 2.72 (m, 2H).Preparation 17B: methyl 5 -oxo-2-phenylpyrrolidine-3 -carboxylateA solution of methyl l-(2,4-dimethoxybenzyl)-5-oxo-2-phenylpyrrolidine-3-carboxylate (20.01 g, 54.139 mmol) in trifluoroacetic acid (10 mL) was stirred at 100 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 20 min; detector, 254 nm to affordmethyl 5 -ox o-2-phenylpyrrolidine-3 -carboxylate (7.70 g, 65%) as a white solid. MS ESI calculated for CI2HI3NO3[M + H]+, 220.09 found 220.15. 'H NMR (400 MHz, Chloroform-t / ) 67.45 - 7.29 (m, 5H), 6.40 (s, 1H), 5.00 (d, J= 6.5 Hz, 1H), 3.74 (s, 3H), 3.23 - 3.08 (m, 1H), 2.74 (d, J= 9.0 Hz, 2H).Preparation 17C: methyl 1 -(5 -chloro-2-nitrophenyl)-5-oxo-2-phenylpyrrolidine-3 -carboxylate A solution of methyl 5 -ox o-2-phenylpyrrolidine-3 -carboxylate (7.70 g, 35.121 mmol), Cs2CO3(22.88 g, 70.242 mmol) and 4 -chloro-2 -fluoro- 1 -nitrobenzene (9.24 g, 52.681 mmol) in DMF (60 mL) was stirred at room temperature for 16 h. The resulting mixture was washed with 2 x 200 mL of water followed by extraction with EtOAc (300 mL). The combined organic layers was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / A (1 :1) to afford methyl l-(5-chloro-2-nitrophenyl)-5-oxo-2-phenylpyrrolidine-3-carboxylate (2.60 g, 20%) as a light yellow solid. MS ESI calculated for CISHI5C1N2O5 [M + H]+, 375.07 found 375.10.JH NMR (400 MHz, Chloroform-t ) 6 7.87 (d, J= 8.8 Hz, IH), 7.47 - 7.40 (m, 2H), 7.39 - 7.29 (m, 3H), 7.25 - 7.21 (m, IH), 7.04 (d, = 2.2 Hz, IH), 5.46 (d, = 7.9 Hz, IH), 3.75 (s, 3H), 3.47 - 3.34 (m, IH), 3.11 - 2.86 (m, 2H).Preparation 17D: 7-chloro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole-2- carboxylic acidA solution of methyl l-(5-chloro-2-nitrophenyl)-5-oxo-2-phenylpyrrolidine-3-carboxylate (2.60 g, 6.937 mmol) and Titanium(III) chloride, 15-20% in 2N Hydrochloric acid (57.06 g, 55.494WSGR Ref: 53699-726.601 mmol) in EtOH (46 mL) was stirred at 80 °C for 3 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10: 1) to afford the crude product. A mixture of product and LiOH (700 mg) in THF (5 mL) and H2O (5 mL) was stirred at room temperature for 2 h. The resulting mixture was adjusted to PH~2 by adding 1 M HC1 aq. followed by extraction with EtOAc. The combined organic layers was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed -phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (0.1% FA), 10% to 50% gradient in 20 min; detector, 254 nm to afford 7- chloro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole-2 -carboxylic acid (1.52 g, 70%) as a white solid. MS ESI calculated for CI7HI3C1N2O2[M + H]+, 313.07 found 313.05.JH NMR (400 MHz, DMSO-t / 6) 8 12.98 (s, 1H), 7.58 (d, J= 8.6 Hz, 1H), 7.45 - 7.37 (m, 3H), 7.34 - 7.27 (m, 2H), 7.17 - 7.11 (m, 1H), 6.77 (d, J = 2.1 Hz, 1H), 5.80 (d, J= 5.8 Hz, 1H),3.9O - 3.79 (m, 1H), 3.55 - 3.46 (m, 1H), 3.30 - 3.27 (m, 1H).Preparation 17E: 7-chloro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole-2- carboxamideA solution of 7-chloro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole-2-carboxylic acid (1.20 g, 3.837 mmol) and CDI (747 mg, 4.604 mmol) in DMF (12 mL) was stirred at 50 °C for 1 h under nitrogen atmosphere. To the above mixture was added ammonium carbonate (442 mg, 4.604 mmol) at room temperature. The resulting mixture was stirred at 50 °C for additional 1 h. The residue was diluted with water (3 x 20 mL) followed by extraction with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (15:l) to afford 7-chloro-l-phenyl-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazole-2-carboxamide (800 mg, 67%) as a white solid. MS ESI calculated for CI7HI4C1N3O [M + H]+, 312.08 found 312.20.XH NMR (400 MHz, DMSO-t / 6) 6 7.64 (s, 1H), 7.58 (d, J= 8.6 Hz, 1H), 7.49 - 7.37 (m, 3H), 7.36 - 7.21 (m, 3H), 7.17 - 7.11 (m, 1H), 6.78 (d, J= 2.1 Hz, 1H), 5.69 (d, J= 5.5 Hz, 1H), 3.73 - 3.60 (m, 1H), 3.59 - 3.44 (m, 1H), 3.20 - 3.08 (m, 1H).Preparation 17F: 7-chloro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole-2- carbonitrileTo a stirred solution of 7-chloro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole-2- carboxamide (500 mg, 1.604 mmol) and DMF (6 mg, 0.080 mmol) in DCE (10 mL) was added SOC12(0.42 mL, 5.774 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 16 h under nitrogen atmosphere. The reaction was quenchedWSGR Ref: 53699-726.601 with water at 0 °C and then extracted with EtOAc (30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3 :2) to afford 7-chloro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole-2- carbonitrile (200 mg, 42%) as a light yellow solid. MS ESI calculated for C17H12CIN3 [M + H]+, 294.07 found 294.20.XH NMR (400 MHz, DMSO-t / 6) 6 7.64 (d, J = 8.7 Hz, 1H), 7.53 - 7.47 (m, 3H), 7.43 - 7.38 (m, 2H), 7.22 - 7.16 (m, 1H), 6.64 (d, J=2.1 Hz, 1H), 5.90 (d, J= 7.4 Hz, 1H), 4.31 - 4.22 (m,lH), 3.69 - 3.61 (m, 1H), 3.54 - 3.46 (m, 1H).Example 17: 7 -(4-(dimethylphosphoryl)-3 -fluorophenyl)- 1 -phenyl-2,3 -dihydro-1 H- benzo[d]pyrrolo[l,2-a]imidazole-2-carbonitrileTo a stirred solution of 7-chloro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole-2- carbonitrile (100 mg, 0.340 mmol) and 2-[4-(dimethylphosphoryl)-3-fluorophenyl]-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane (152 mg, 0.510 mmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL) were added Sphos Pd G3 (27 mg, 0.034 mmol), Sphos (28 mg, 0.068 mmol) and K3PO4 (217 mg, 1.020 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 10% to 35% gradient in 20 min; detector, 254 nm to afford 7-(4-(dimethylphosphoryl)-3-fluorophenyl)-l-phenyl-2,3- dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole-2-carbonitrile (95 mg, 65%) as a white solid. MS ESI calculated for C25H2IFN3OP [M + H]+, 430.14 found 430.15. TI NMR (400 MHz, DMSO- tZ6) 6 7.80 - 7.72 (m, 2H), 7.57 - 7.52 (m, 1H), 7.52 - 7.36 (m, 7H), 7.00 (d, J = 1.8 Hz, 1H), 5.96 (d, J= 7.0 Hz, 1H), 4.33 - 4.23 (m, 1H), 3.73 - 3.47 (m, 2H), 1.72 (s, 3H), 1.68 (s, 3H).19F NMR (377 MHz, DMSO-t / 6) 6 -105.62.31P NMR (162 MHz, DMSO-t / 6) 6 28.26.

[0162] Example 18: 7-(4-(dimethylphosphoryl)-3-fluorophenyl)-l-methyl-4-phenyl-3,4- dihydrobenzo[4,5]imidazo[l,2-a]pyrimidin-2(lH)-oneWSGR Ref: 53699-726.601Preparation 18 A: 7-bromo-4-phenyl-3,4-dihydrobenzo[4,5]imidazo[l,2-a]pyrimidin-2(lH)-one and 8-bromo-4-phenyl-3,4-dihydrobenzo[4,5]imidazo[l,2-a]pyrimidin-2(lH)-oneA solution of 5-bromo-3H-l,3-benzodiazol-2-amine (3.00 g, 14.148 mmol) and methyl cinnamate (2.29 g, 14.119 mmol) in DMF (15 mL) was stirred at 153 °C for 16 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with H2O (20mL) and then the precipitated solids were collected by filtration and washed with EtOH (2 x 5 mL). The solid was concentrated under reduced pressure. The residue was purified by trituration with MeOH (20 mL) to afford the mixed isomers (1.10 g) as a light brown solid. The mixture (1.10 g) was purified by Prep-HPLC with the following conditions (Column: DAICEL DCpak P4VP 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MeOH(l% 2M NH3-MeOH); Flow rate: 90 mL / min; Gradient: isocratic 30% B; Wave Length: 254 nm; RTl(min): 6.16; RT2(min): 7.39).The first peak afforded 7-bromo-4-phenyl-3,4-dihydrobenzo[4,5]imidazo[l,2-a]pyrimidin- 2(lH)-one (300 mg, 6%) as a light yellow solid. MS ESI calculated for Ci6H|2BrN3O [M + H]+, 342.02 344.02 found 341.95 343.95.1HNMR(400 MHz, DMSO-t / 6) 8 11.80 (s, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.40 - 7.30 (m, 4H), 7.28 - 7.22 (m, 1H), 7.09 (d, J = 1.8 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 6.06 - 5.94 (m, 1H), 3.60 - 3.47 (m, 1H), 3.06 - 2.89 (m, 1H).The second peak afforded 8-bromo-4-phenyl-3,4-dihydrobenzo[4,5]imidazo[l,2-a]pyrimidin- 2(lH)-one (270 mg, 6%) as a light yellow solid. MS ESI calculated for Ci6Hi2BrN3O [M + H]+, 342.02 344.02 found 341.95 343.95.1HNMR(400 MHz, DMSO-t / 6) 6 11.79 (s, 1H), 7.64 (d, J = 1.9 Hz, 1H), 7.40 - 7.29 (m, 3H), 7.20 - 7.13 (m, 1H), 7.08 (t, J = 2.0 Hz, 1H), 7.07 (t, J = 1.5 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.02 - 5.92 (m, 1H), 3.60- 3.47 (m, 1H), 3.00 - 2.88 (m, 1H). Preparation 18B: 7-bromo-l-methyl-4-phenyl-3,4-dihydrobenzo[4,5]imidazo[l,2-a]pyrimidin- 2(lH)-oneTo a stirred solution of 7-bromo-4-phenyl-3,4-dihydrobenzo[4,5]imidazo[l,2-a]pyrimidin- 2(lH)-one (100 mg, 0.292 mmol) in DMF (2 mL) was added Z-BuOK (42 mg, 0.380 mmol) atWSGR Ref: 53699-726.6010 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 15 min. To the above mixture was added CH3I (124 mg, 0.876 mmol) atO °C. The resulting mixture was stirred at room temperature overnight. The mixture was purified by reversed -phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 5% to 95% gradient in 25 min; detector, 254 nm to afford 7- bromo-l-methyl-4-phenyl-3,4-dihydrobenzo[4,5]imidazo[l,2-a]pyrimidin-2(lH)-one (85 mg, 81%) as a light yellow solid. MS ESI calculated for Ci7Hi4BrN3O [M + H]+, 356.03 358.03 found 356.05 358.05. 'HNMR (400 MHz, Chloroform-; / ) 87.51 (d, J = 8.5 Hz, 1H), 7.40 - 7.33 (m, 3H), 7.33 - 7.28 (m, 1H), 7.06- 7.00 (m, 2H), 6.93 (d, J = 1.8 Hz, 1H), 5.58 - 5.50 (m, 1H), 3.59 (s, 3H), 3.45 - 3.34 (m, 1H), 3.23 - 3.12 (m, 1H).Example 18: 7-(4-(dimethylphosphoryl)-3-fluorophenyl)-l-methyl-4-phenyl-3,4- dihydrobenzo[4,5]imidazo[l,2-a]pyrimidin-2(lH)-oneTo a solution of 7-bromo-l-methyl-4-phenyl-3,4-dihydrobenzo[4,5]imidazo[l,2-a]pyrimidin- 2(lH)-one (80 mg, 0.225 mmol) and 2-[4-(dimethylphosphoryl)-3-fluorophenyl]-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane (80 mg, 0.270mmol) in 1,4-dioxane (1 mL) and H2O (0.2 mL) were added K2CO3(93 mg, 0.675 mmol) and Pd(dppf)Cl2(18 mg, 0.023 mmol). After stirring for 3 h at 80 °C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH(0% to 10%) followed by Prep-HPLC with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 5% to 95% gradient in 25 min; detector, 254 nm to afford 7 -(4-(dimethylphosphory l)-3-fluoropheny 1)- l-methyl-4-phenyl- 3,4-dihydrobenzo[4,5]imidazo[l,2-a]pyrimidin-2(lH)-one (45 mg, 44%) as a white solid. MS ESI calculated for C25H23FN3O2P [M + H]+, 448.15 found 448.10. 'H NMR (400 MHz, Chloroform-6068.03 - 7.88 (m, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.50 - 7.43 (m, 1H), 7.43 - 7.32 (m, 4H), 7.22 - 7.15 (m, 1H), 7.15 - 7.08 (m, 2H), 6.89 (d, J = 1.7 Hz, 1H), 5.66 (t, J = 5.9 Hz, 1H), 3.65 (s, 3H), 3.51 - 3.37 (m, 1H), 3.32 - 3.17 (m, 1H), 1.82 (s, 3H), 1.79 (s, 3H).19FNMR (377 MHz, Chloroform -d) 8 -105.92, -105.93.31P NMR (162 MHz, Chloroform-^ 8 30.42.

[0163] Example 19: 7-(4-(dimethylphosphoryl)-3-fluorophenyl)-l-phenyl-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazole-2-carboxamideWSGR Ref: 53699-726.601To a stirred mixture of 7-chloro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole-2- carboxamide (50 mg, 0.160 mmol) and 2-[4-(dimethylphosphoryl)-3-fluorophenyl]-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane (71 mg, 0.240mmol) in 1,4-dioxane (1 mL) and H2O (0.1 mL) were added Sphos (13 mg, 0.032 mmol), Sphos Pd G3 (12 mg, 0.016 mmol) and K3PO4(136 mg, 0.640 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 30% to 50% gradient in 20 min; detector, 254 nm. This resulted in 7-(4-(dimethylphosphoryl)-3- fluorophenyl)-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole-2-carboxamide (34 mg, 47%) as a white solid. MS ESI calculated for C25H23FN3O2P [M + H]+, 448.15 found 448.15. 'HNMR (400 MHz, DMSO-t / 6) 87.82 - 7.71 (m, 1H), 7.70- 7.64 (m, 2H), 7.58 - 7.21 (m, 9H), 7.15 (d, J= 1.9 Hz, 1H), 5.76 (d, J = 5.0 Hz, 1H), 3.75 - 3.64 (m, 1H), 3.60 - 3.48 (m, 1H), 3.22 - 3.05 (m, 1H), 1.72 (s, 3H), 1.68 (s, 3H).19F NMR (377 MHz, DMSO-t / 6) 8 -105.72.31P NMR (162 MHz, DMSO-t / 6) 828.24.

[0164] Example 20: (lR)-7-(4-(dimethylphosphoryl)-3-fluorophenyl)-l-phenyl-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazole-3 -carbonitrilePreparation 20 A: (lR)-7-chloro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole-3- carbonitrileTo a stirred mixture of (lR)-3,7-dichloro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazole (500 mg, 1.649 mmol), K2CO3(684 mg, 4.947 mmol) and Nal (370 mg, 2.474 mmol) in ACN (5 mL) was added TMSCN (245 mg, 2.474 mmol) at room temperature. TheWSGR Ref: 53699-726.601 resulting mixture was stirred at 80 °C for 12 h under nitrogen atmosphere. The resulting mixture was diluted with water followed by extraction with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford (lR)-7-chloro-l-phenyl- 2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole-3-carbonitrile (100 mg, 21%) as an off- white solid. MS ESI calculated for CI7HI2C1N3[M + H]+, 294.07 found 294.10. iJI NMR (400 MHz, Chloroform -t / ) 87.94 - 7.67 (m, IH), 7.52 - 7.36 (m, 3H), 7.28 - 7.16 (m, 2H), 7.14 - 7.03 (m, IH), 6.89 - 6.72 (m, IH), 5.70 - 5.36 (m, IH), 4.54 - 4.37 (m, IH), 3.62 - 3.38 (m, IH), 3.07 - 2.85 (m, IH).Example 20 : ( 1 R)-7 -(4-(dimethy Iphosphory l)-3 -fluorophenyl)- 1 -phenyl-2, 3 -dihydro- 1 H- benzo[d]pyrrolo[l,2-a]imidazole-3 -carbonitrileTo a stirred mixture of (lR)-7-chloro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazole-3 -carbonitrile (100 mg, 0.340 mmol) and 2-[4-(dimethylphosphoryl)-3- fluorophenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (121 mg, 0.408 mmol) in 1,4-dioxane (3 mL) and H2O (0.3 mL) were added K3PC>4 (216 mg, 1.020 mmol), Sphos (28 mg, 0.068 mmol) and Sphos Pd G3 (26 mg, 0.034 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) followed by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in water (0.1% NH3.H2O), 40% to 50% gradient in 20 min; detector, 254 nm to afford (lR)-7-(4-(dimethylphosphoryl)-3- fluorophenyl)-l -phenyl-2, 3 -dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole-3-carbonitrile (46 mg, 31%) as a white solid. MS ESI calculated for C25H2IFN3OP [M + H]+, 430.14 found 430.15. ^ NMR (400 MHz, Chloroform -d) 6 8.02 - 7.83 (m, 2H), 7.61 - 7.28 (m, 6H), 7.24 - 6.93 (m, 3H), 5.80 - 5.52 (m, IH), 4.58 - 4.44 (m, IH), 3.74 - 3.45 (m, IH), 3.14 - 2.92 (m, IH), 1.82 (s, 3H), 1.78 (s, 3H).19F NMR (377 MHz, Chloroform-tZ) 6 -105.78, -105.79.31P NMR (162 MHz, Chloroform -d) 8 30.68, 30.70.

[0165] Example 21 : (2-fluoro-4-((lR)-3-methyl-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazol-7 -yl)pheny l)dimethy Iphosphine oxideWSGR Ref: 53699-726.601Preparation 21 A: (lR)-3,7-dichloro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole To a stirred solution of (lR)-7-chloro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol- 3-ol (3.00 g, 10.536 mmol) and DIEA (2.72 g, 21.072 mmol) in ACN (60 mL) was added phosphoryl trichloride (9.69 g, 63.216 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 1 h. The resulting mixture was poured into ice water at 0 °C followed by extraction with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (12 / 1) to afford (lR)-3,7-dichloro-l-phenyl-2,3- dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole (2.60 g, 81%) as a black solid. MS ESI calculated for CI6HI2C12N2[M + H]+, 303.04 found 303.05.1HNMR(400 MHz, Chloroform -t / ) 8 7.71 (d, = 8.7 Hz, 1H), 7.47 - 7.33 (m, 3H), 7.29 - 7.15 (m, 3H), 6.94 - 6.65 (m, 1H), 5.68 - 5.37 (m, 2H), 3.85 - 2.85 (m, 2H).Preparation 2 IB: (lR)-7-chloro-3-methyl-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazoleTo a stirred solution of (lR)-3,7-dichloro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazole (1.00 g, 3.298 mmol) in THF (15 mL) was added CH3MgBr (11 mL, 32.980 mmol, 3 M in THF) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with sat. NH4C1 (aq.) at 0 °C followed by extraction with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed -phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (0.1% FA), 30% to 50% gradient in 20 min; detector, 254 nm to afford (lR)-7-chloro-3-methyl-l-phenyl-2,3- dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole (95 mg, 10%) as a yellow solid. MS ESI calculated for CI7HI5C1N2[M + H]+, 283.09 found 283.05. 'H NMR (400 MHz, Chloroform-; / ) 6 7.70 - 7.60 (m, 1H), 7.46 - 7.30 (m, 3H), 7.25 - 7.02 (m, 3H), 6.95 - 6.62 (m, 1H), 5.60 - 5.21 (m, 1H), 3.64 - 3.21 (m, 2H), 2.85 - 2.72 (m, 1H), 1.62 - 1.47 (m, 3H).Example 21 : (2-fluoro-4-((lR)-3-methyl-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazol-7 -yl)pheny l)dimethy Iphosphine oxideTo a stirred solution of (lR)-7-chloro-3-methyl-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazole (90 mg, 0.318 mmol) and (2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)dimethylphosphine oxide (142 mg, 0.477 mmol) in 1,4-dioxane (0.8 mL) and H2O (0.2 mL) were added K3PO4(203 mg, 0.954 mmol), Sphos Pd G3 (25 mg, 0.032 mmol) and Sphos (26 mg, 0.064 mmol) at room temperature. The resulting mixture was stirred at 80 °C forWSGR Ref: 53699-726.6012 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 30% to 50% gradient in 20 min; detector, 254 nm to afford (2-fluoro-4-((lR)-3-methyl-l-phenyl-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazol-7-yl)phenyl)dimethylphosphine oxide (86 mg, 65%) as a white solid. MS ESI calculated for C25H24FN2OP [M + H]+, 419.16 found 419.15.JH NMR (400 MHz, Methanol-t / 4) 87.84 - 7.66 (m, 2H), 7.59- 7.25 (m, 7H), 7.22 - 6.83 (m, 2H), 5.80 - 5.49 (m, 1H), 3.67 - 3.47 (m, 1H), 3.45 - 3.32 (m, 1H), 2.93 - 2.78 (m, 1H), 1.84 (s, 3H), 1.81 (s, 3H), 1.59 - 1.48 (m, 3H).19F NMR (377 MHz, Methanol-^) 6 -106.81, -106.85.31P NMR (162 MHz, Methanol-t / 4) 6 36.76.

[0166] Example 22: (2-fluoro-4-((l S,2S)-2-methoxy-l-phenyl-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazol-7-yl)phenyl)dimethylphosphine oxidePreparation 22A: (1 S,2S)-7-chloro-2-methoxy-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazoleTo a stirred mixture of (lS,2S)-7-chloro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazol-2-ol (110 mg, 0.386 mmol) in THF (2 mL) was added NaH (19 mg, 0.463 mmol, 60%) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 30 min under nitrogen atmosphere. To the above mixture was added CH3I (71mg, 0.502 mmol) at 0 °C. The resulting mixture was stirred at room temperature for additional 1 h. The reaction was quenched with water at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (20:1) to afford (lS,2S)-7-chloro-2-methoxy-l-phenyl-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazole (110 mg, 95%) as a white solid. MS ESI calculated for CI7HI5C1N2O [M + H]+, 299.09 found 298.95. !HNMR(400 MHz, Chloroform -d) 67.64 (d, J = 8.6 Hz, 1H), 7.42 - 7.36 (m, 3H), 7.21 - 7.16 (m, 1H), 7.14- 7.10 (m, 2H), 6.83 (d, J = 2.1 Hz, 1H), 5.56 (d, J = 6.3 Hz, 1H), 4.80 - 4.68 (m, 1H), 3.52 - 3.41 (m, 1H), 3.29 - 3.20 (m, 1H), 3.18 (s, 3H).Example 22: (2-fluoro-4-((lS,2S)-2-methoxy-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazol-7 -yl)pheny l)dimethy Iphosphine oxideWSGR Ref: 53699-726.601To a stirred mixture of (1 S,2S)-7-chloro-2-methoxy-l-phenyl-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazole (50 mg, 0.167 mmol) and 2-[4-(dimethylphosphoryl)-3- fluorophenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (60 mg, 0.200 mmol) in 1,4-dioxane (1.5 mL) and H2O (0.2 mL) were added K3PO4 (107 mg, 0.501 mmol), Sphos Pd G3 (13 mg, 0.017 mmol) and Sphos (14 mg, 0.033 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 25% to 55% gradient in 25 min; detector, 254 nm. This resulted in (2-fluoro-4-((l S,2S)-2-methoxy-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-7- yl)phenyl)dimethylphosphine oxide (9 mg, 12%) as a white solid. MS ESI calculated for C25H24FN2O2P [M + H]+, 435.16 found 435.20. 'H NMR (400 MHz, Chloroform -d) 6 7.99 - 7.88 (m, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.42 - 7.35 (m, 4H), 7.23 - 7.13 (m, 3H), 7.02 (s, 1H), 5.70 - 5.65 (m, 1H), 4.82 - 4.77 (m, 1H), 3.56 (d, J = 17.3 Hz, 1H), 3.32 (d, J = 16.3 Hz, 1H), 3.21 (s, 3H), 1.81 (s, 3H), 1.78 (s, 3H).19F NMR (377 MHz, Chloroform- d) 6 -105.92.31P NMR (162 MHz, Chloroform -d) 6 30.61.

[0167] Example 23 : 8-(4-(dimethylphosphoryl)-3-fluorophenyl)-l-phenyl-3,4-dihydro-lH- benzo[4,5]imidazo[l,2-c][l,3]thiazine 2,2-dioxideTo a stirred solution of (2-fluoro-4-(l-phenyl-3,4-dihydro-lH-benzo[4,5]imidazo[l,2- c][l,3]thiazin-8-yl)phenyl)dimethylphosphineoxide(80 mg, 0.183 mmol) in methanol (10 mL) was added Oxone (254 mg, 0.732 mmol) in H2O (2 mL) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was filtered, the filter cake was washed with methanol (3 mL). The filtrate was concentrated under reduced pressure. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep C18, 30* 150mm 5pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: isocratic 14% to 34% B in 14 min; Wave Length: 254 nm; RTl(min): 13.33 min) to afford 8 -(4-(dimethylphosphoryl)-3 -fluorophenyl)- l-phenyl-3, 4- dihydro-lH-benzo[4,5]imidazo[l,2-c][l,3]thiazine 2,2-dioxide (33 mg, 38%) as a white solid.WSGR Ref: 53699-726.601MS ESI calculated for C24H22FN2O3PS [M + H]+, 469.11 found 469.15.JH NMR (400 MHz, Chloroform -6 67.99 - 7.88 (m, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.57 - 7.42 (m, 4H), 7.32 - 7.27 (m, 2H), 7.26 - 7.24 (m, 1H), 7.15 - 7.06 (m, 1H), 6.84 (s, 1H), 6.37 (s, 1H), 4.00 - 3.89 (m, 2H), 3.70 - 3.55 (m, 1H), 3.50- 3.36 (m, 1H), 1.82 (s, 3H), 1.78 (s, 3H).19F NMR (377 MHz, Chloroform -t / ) 6 -105.69, -105.70.31P NMR (162 MHz, Chloroform-; / ) 6 30.63.

[0168] Example 24: (2-fluoro-4-(2-hydroxy-l-phenyl-lH-benzo[d]pyrrolo[l,2-a]imidazol-7- yl)phenyl)dimethylphosphine oxidePreparation 24 A: ethyl 2-[(2-methoxy-2-oxo-l-phenylethyl)carbamoyl]acetateTo a stirred mixture of methyl 2-amino-2 -phenylacetate hydrochloride (9.40 g, 46.615 mmol) and ethyl hydrogen malonate (6.47 g, 48.946 mmol) in DCM (100 mL) were added DMAP (1.71 g, 13.985 mmol) andEt3N (12.96 mL, 93.230 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. To the above mixture was added (3- [[(ethylimino)methylidene]amino]propyl)dimethylamine hydrochloride (9.83 g, 51.277 mmol) at 0 °C. The resulting mixture was stirred at room temperature for additional 16 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (500 mL). The resulting mixture was washed with 2 x 200 mL of water. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (l :l)to afford ethyl 2-[(2-methoxy-2-oxo-l-phenylethyl)carbamoyl]acetate (10.00 g, 77%) as colorless oil. MS ESI calculated for C i4Hi7NO5[M + H]+, 280.11 found 280.10. 'H NMR (400 MHz, Chloroform -6?) 88.27 - 7.99 (m, 1H), 7.45 - 7.29 (m, 5H), 5.59 (d, J = 7.0 Hz, 1H), 4.26 - 4.17 (m, 2H), 3.73 (s, 3H), 3.42 - 3.30 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H).Preparation 24B: methyl 2,4-dioxo-5-phenylpyrrolidine-3-carboxylateTo a stirred solution of ethyl 2-[(2-methoxy-2-oxo-l-phenylethyl)carbamoyl]acetate (9.01 g, 32.224 mmol) in toluene (90 mL) was added sodium methoxide (30% in methanol) (6.38 g, 35.446 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. TheWSGR Ref: 53699-726.601 resulting mixture was diluted with EtOAc (200 mL). The resulting mixture was washed with 3 x 200 mL of NaOH (1 N). The aqueous layer was acidified to pH 2 with cone. HC1. The precipitated solids were collected by filtration and washed with ethanol (50 mL). This resulted in methyl 2,4-dioxo-5-phenylpyrrolidine-3-carboxylate (5.77 g, 77%) as a white solid. MS ESI calculated for Ci2HnNO4[M + H]+, 234.07 found 234.10.JH NMR (400 MHz, DMSO-t / 6) 8 8.40 (s, 1H), 7.43 - 7.21 (m, 6H), 5.05 (s, 1H), 3.67 (s, 3H).Preparation 24C: 5 -phenylpyrrolidine-2, 4-dione and 4-hydroxy-5-phenyl-l,5-dihydro-2H- pyrrol-2-oneA solution of methyl 2,4-dioxo-5-phenylpyrrolidine-3 -carboxylate (1.00 g, 4.288 mmol) in CH3CN (10 mL) and H2O (0.5 mL) was stirred at 80 °C for 30 min. The resulting mixture was concentrated under vacuum. The resulting mixture was used in the next step directly without further purification. This resulted in 5 -phenylpyrrolidine-2, 4-dione and 4-hydroxy-5-phenyl-l,5- dihydro-2H-pyrrol-2-one (620 mg, 83%, ratio=l :l) as a white solid. MS ESI calculated for CIOH9N02[M + H]+ 176.06 found 176.10.Preparation 24D: l-(5-chloro-2-nitrophenyl)-4-hydroxy-5-phenyl-5H-pyrrol-2-oneTo a stirred mixture of 5 -phenylpyrrolidine-2, 4-dione and 4-hydroxy-5-phenyl-l,5-dihydro-2H- pyrrol-2-one (620 mg, 3.539 mmol) and Cs2CO3(3.46g, 10.617 mmol) in DMF (10 mL) was added 4-chloro-2-fluoro-l-nitrobenzene (683 mg, 3.893 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was filtered, the filter cake was washed with MeOH (2 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCCE), 20% to 50% gradient in 20 min. This resulted in 1 -(5-chloro-2-nitrophenyl)-4-hydroxy-5- phenyl-5H-pyrrol-2-one (450 mg, 38%) as a yellow solid. MS ESI calculated for Ci6HnClN2O4 [M + H]+, 331.04 found 331.10. 'H NMR (400 MHz, DMSO-t / 6) 6 11.82 (s, 1H), 8.18 (s, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.65 - 7.56 (m, 2H), 7.44 - 7.32 (m, 5H), 5.10 (s, 1H).Preparation 24E: 7-chloro-l-phenyl-lH-benzo[d]pyrrolo[l,2-a]imidazol-2-olA mixture of l-(5-chloro-2-nitrophenyl)-4-hydroxy-5-phenyl-5H-pyrrol-2-one (340 mg, 1.028 mmol) and Titanium(III) chloride, 15-20% in 2N Hydrochloric acid) (8.46 g, 8.224 mmol) in EtOH (10 mL) was stirred at 80 °C for 3 h. The resulting mixture was diluted with water (100 mL) followed by extraction with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) to afford 7-chloro-l-phenyl-lH-benzo[d]pyrrolo[l,2-a]imidazol-2-ol (208 mg, 72%) as a yellow solid. MS ESI calculated for CI6HHC1N2O [M+H]+, 283.06 found 283.10. TI NMR (400WSGR Ref: 53699-726.601MHz, DMSO-t / 6) 6 12.09 (s, 1H), 8.26 (s, 1H), 7.64 (d, J = 2.1 Hz, 1H), 7.44 - 7.36 (m, 3H), 7.36 - 7.31 (m, 3H), 7.24 - 7.17 (m, 1H), 5.82 (s, 1H).Example 24: (2 -fluoro-4-(2 -hydroxy-1 -phenyl-lH-benzo[d]pyrrolo[l,2-a]imidazol-7- yl)phenyl)dimethylphosphine oxideTo a stirred mixture of 7-chloro-l-phenyl-lH-benzo[d]pyrrolo[l,2-a]imidazol-2-ol (60 mg, 0.212 mmol) and 2-[4-(dimethylphosphoryl)-3-fluorophenyl]-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (95 mg, 0.318 mmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL) were added Sphos (17 mg, 0.042 mmol), Sphos Pd G3 (17 mg, 0.021 mmol) and K3PO4 (135 mg, 0.636 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 20% to 40% gradient in 20 min. This resulted in (2-fluoro-4-(2-hydroxy-l-phenyl-lH-benzo[d]pyrrolo[l,2-a]imidazol-7- yl)phenyl)dimethylphosphine oxide (36 mg, 41%) as a white solid. MS ESI calculated for C24H20FN2O2P [M + H]+, 419.12 found 419.20.1HNMR(400 MHz, DMSO-t / 6) 8 12.06 (s, 1H), 8.24 (s, 1H), 8.04 - 8.00 (m, 1H), 7.88 - 7.78 (m, 1H), 7.77 - 7.72 (m, 1H), 7.71 - 7.64 (m, 1H), 7.62 - 7.56 (m, 1H), 7.55 - 7.49 (m, 1H), 7.43 - 7.31 (m, 5H), 5.84 (s, 1H), 1.76 (s, 3H), 1.73 (s, 3H).19F NMR (377 MHz, DMSO-t / 6) 6 -105.77.31P NMR (162 MHz, DMSO-t / 6) 6 28.27.

[0169] Example 25: (2,3-difluoro-4-((lR)-3-fluoro-l-phenyl-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazol-7-yl)phenyl)dimethylphosphine oxidePreparation 25 A: (lR)-7-chloro-3-fluoro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazoleTo a stirred solution of (lR)-7-chloro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol- 3-ol (200 mg, 0.702 mmol) in DCM (5 mL) was added diethylaminosulfur trifluoride (226 mg, 1.404 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 5 h under nitrogen atmosphere. The resulting mixture was quenched with water followed by extraction with EtOAc (3 x 15 mL). The combined organic layers were concentrated under reduced pressure. This resulted in (lR)-7-chloro-3-fluoro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazole (130 mg, crude) as yellow oil. MS ESI calculated for CI6HI2C1FN2[M + H]+,WSGR Ref: 53699-726.601287.07 found 287.00.Example 25: (2,3-difluoro-4-((lR)-3-fluoro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazol-7 -yl)pheny l)dimethy Iphosphine oxideTo a stirred solution of (lR)-7-chloro-3-fluoro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazole (60 mg, 0.209 mmol) and 2-[4-(dimethylphosphoryl)-2,3-difluorophenyl]-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane (79 mg, 0.251 mmol) in 1,4-dioxane (2.5 mL) and H2O (0.5 mL) were added Sphos (17 mg, 0.042 mmol), Sphos Pd G3 (16 mg, 0.021 mmol) and K3PO4(133 mg, 0.628 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The reaction was quenched with water at room temperature followed by extraction with EtOAc (3 x 15 mL). The combined organic layers were concentrated under reduced pressure. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Water (10 mmol / L NH4HCO3 + 0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 22%B to 52% B in 10 min; Wave Length: 254 nm; RTl(min): 8.33) to afford (2,3-difluoro-4-((lR)-3-fluoro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-7- yl)phenyl)dimethylphosphine oxide (46 mg, 50%) as a white solid. MS ESI calculated for C24H20F3N2OP [M + H]+, 441.13 found 441.00.1HNMR (400 MHz, Chloroform-; / ) 8 7.94 (d, J = 8.4 Hz, 1H), 7.74 - 7.64 (m, 1H), 7.49 - 7.34 (m, 4H), 7.26 - 7. 19 (m, 3H), 6.97 (s, 1H), 6.25 - 6.03 (m, 1H), 5.80 - 5.52 (m, 1H), 3.68 - 3.33 (m, 1H), 3.01 - 2.82 (m, 1H), 1.84 (s, 3H), 1.81 (s, 3H).19F NMR (377 MHz, Chloroform-; / ) 6 -131 .27, -131.33, -142.97, -142.99, -143.03, - 143.04, -143.09, -143.10, -166.23, -171.37.31P NMR (162 MHz, Chloroform-; / ) 6 30.01.

[0170] Example 26: (R)-(4-(3,3-difluoro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazol-7 -yl)-2, 3 -difluorophenyl)dimethy Iphosphine oxidePreparation 26A: (R)-7-chloro-3,3-difluoro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazoleA solution of (R)-7-chloro-l-phenyl-l,2-dihydro-3H-benzo[d]pyrrolo[l,2-a]imidazol-3-one (120 mg, 0.424 mmol) in DCM (10 mL) was treated at 0 °C for 10 min under nitrogen atmosphere followed by the addition of diethylaminosulfur trifluoride (587 mg, 1 .696 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 16 h under nitrogen atmosphere.WSGR Ref: 53699-726.601The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DGMMeOH (30:1) to afford (R)-7-chloro-3,3- difluoro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole (40 mg, 30%) as a yellow solid. MS ESI calculated for CI6HIIC1F2N2 [M + H]+, 305.06 found 305.00. 'H NMR (400 MHz, Chloroform -d) 87.81 (d, J = 8.8 Hz, IH), 7.48 - 7.40 (m, 3H), 7.31 - 7.27 (m, IH), 7.25 - 7.20 (m, 2H), 6.91 - 6.85 (m, IH), 5.64 - 5.56 (m, IH), 3.75 - 3.55 (m, IH), 3.24 - 3.01 (m, IH).19F NMR (377 MHz, Chloroform -d) 6 -92.79, -93.49, -93.94, -94.65.Example 26: (R)-(4-(3,3-difluoro-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-7- yl)-2,3-difluorophenyl)dimethylphosphine oxideTo a stirred solution of (R)-7-chloro-3,3-difluoro-l-phenyl-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazole (30 mg, 0.098 mmol) and 2-[4-(dimethylphosphoryl)-2,3- difluorophenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (37 mg, 0.118 mmol) in 1,4-dioxane (2 mL) and H2O (0.4 mL) were added K3PO4 (62 mg, 0.294 mmol), Sphos (8 mg, 0.020 mmol) and Sphos Pd G3 (7 mg, 0.010 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. The reaction was quenched with water at room temperature followed by extraction with EtOAc (3 x 15 mL). The combined organic layers were concentrated under reduced pressure. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Water (10 mmol / L NH4HCO3 + 0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 26% B to 56% B in 10 min; Wave Length: 254 nm; RTl(min): 8.55) to afford (R)-(4-(3,3-difluoro-l -phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-7- yl)-2,3-difluorophenyl)dimethylphosphine oxide (33 mg, 73%) as a white solid. MS ESI calculated for C24Hi9F4N2OP [M + H]+, 459.12 found 458.95. 'H NMR (400 MHz, Chloroformed 6 8.00 (d, J = 8.4 Hz, IH), 7.77 - 7.63 (m, IH), 7.54 - 7.48 (m, IH), 7.46 - 7.40 (m, 3H), 7.29 - 7.26 (m, IH), 7.26 - 7.23 (m, 2H), 7. 10 - 7.05 (m, IH), 5.78 - 5.64 (m, IH), 3.78 - 3.59 (m, IH), 3.27 - 3.06 (m, IH), 1.84 (s, 3H), 1.81 (s, 3H).19F NMR (377 MHz, Chloroform -t / ) 6 - 92.72, -93.43, -93.99, -94.70, -131.14, -131.15, -131.20, -131.21, -142.96, -142.98, -143.02, - 143.04.31P NMR (162 MHz, Chloroform -t / ) 6 29.87.

[0171] Example 27: (S)-(2,3-difluoro-4-(4-phenyl-3,4-dihydro-lH-benzo[4,5]imidazo[2,l - c][l,4]oxazin-7-yl)phenyl)dimethylphosphine oxideWSGR Ref: 53699-726.601Preparation 27 A: (5S)-4-(5-chloro-2-nitrophenyl)-5-phenylmorpholin-3-oneA mixture of (5S)-5-phenylmorpholin-3-one (300 mg, 1.693 mmol), 4-chloro-2-fluoro-l- nitrobenzene (445 mg, 2.540 mmol) and CS2CO3 (1.65 g, 5.079 mmol) in DMF (2.5 mL) was stirred at room temperature for 16 h under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL) followed by extraction with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (12:1) to afford (5S)-4-(5-chloro- 2-nitrophenyl)-5-phenylmorpholin-3-one (300 mg, 53%) as a yellow solid. MS ESI calculated for C16H13CIN2O4 [M + H]+, 333.06 found 333.00. 'HNMR (400 MHz, Chloroform -d) 58.01 (s, 1H), 7.47 - 7.31 (m, 7H), 6.86 - 6.72 (m, 1H), 4.47 - 4.35 (m, 2H), 4.19 - 4.01 (m, 2H). Preparation 27B: (S)-7-chloro-4-phenyl-3,4-dihydro-lH-benzo[4,5]imidazo[2,l-c][l,4]oxazine To a stirred solution of (5S)-4-(5-chloro-2-nitrophenyl)-5-phenylmorpholin-3-one (300 mg, 0.902 mmol) in EtOH (6 mL) was added Titanium(III) chloride, 15-20% in 2N Hydrochloric acid (5.00 g, 7.216 mmol) dropwise at room temperature. The resulting mixture was stirred at 80 °C for 3 h. The resulting mixture was basified to pH 8 with saturated Na2CC>3 (aq.). The resulting mixture was filtered, the filter cake was washed with EtOAc (3 x 200 mL). The resulting solution was extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with brine (2 x 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford (S)-7-chloro-4-phenyl-3,4-dihydro- lH-benzo[4,5]imidazo[2,l-c][l,4]oxazine (200 mg, 78%) as a yellow solid. MS ESI calculated for CI6HI3C1N2O [M + H]+, 285.07 found 285.00.1HNMR(400 MHz, Chloroform-t ) 6 7.64 (d, J= 8.6 Hz, 1H), 7.42 - 7.37 (m, 3H), 7.21 - 7.14 (m, 3H), 6.69 (d, = 2.0 Hz, 1H), 5.41 - 5.33 (m, 1H), 5.13 (s, 2H), 4.41 - 4.32 (m, 1H), 4.05 - 3.94 (m, 1H).Example 27: (S)-(2,3-difluoro-4-(4-phenyl-3,4-dihydro-lH-benzo[4,5]imidazo[2,l- c][l,4]oxazin-7-yl)phenyl)dimethylphosphine oxideA mixture of (S)-7-chloro-4-phenyl-3,4-dihydro-lH-benzo[4,5]imidazo[2,l-c][l,4]oxazine (50 mg, 0.176 mmol), 2-[4-(dimethylphosphoryl)-2,3-difluorophenyl]-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (83 mg, 0.264 mmol), Sphos Pd G3 (6 mg, 0.009 mmol), Sphos (7 mg, 0.018 mmol) and K3PO4 (74 mg, 0.352 mmol) in l,4-dioxane(l mL) and H2O (0.1 mL) was stirred at 80 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2C12 / MeOH (10:1) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3),WSGR Ref: 53699-726.60120% to 50% gradient in 20 min; detector, 254 nm. This resulted in (S)-(2,3-difluoro-4-(4- phenyl-3,4-dihydro-lH-benzo[4,5]imidazo[2,l-c][l,4]oxazin-7-yl)phenyl)dimethylphosphine oxide (22 mg, 29%) as a white solid. MS ESI calculated for C24H21F2N2O2P [M + H]+, 439.13 found 439.00.XH NMR (400 MHz, Chloroform -t / ) 6 7.84 (d, J= 8.4 Hz, 1H), 7.71 - 7.63 (m, 1H), 7.46 - 7.42 (m, 1H), 7.41 - 7.37 (m, 3H), 7.24 - 7.19 (m, 2H), 7.19 - 7.14 (m, 1H), 6.89 (d, J= 1.7 Hz, 1H), 5.51 - 5.44 (m, 1H), 5.21 (s, 2H), 4.46 - 4.37 (m, 1H), 4.10 - 3.99 (m, 1H), 1.83 (s, 3H), 1.80 (s, 3H).19F NMR (377 MHz, Chloroform -d) 6 -131.33, -131.34, -131.39, - 131.40, -143.22, -143.23, -143.28, -143.29.31P NMR (162 MHz, Chloroform-; / ) 6 29.86.

[0172] Example 28: (2-fluoro-4-(2-methoxy-l-phenyl-lH-benzo[d]pyrrolo[l,2-a]imidazol-7- yl)phenyl)dimethylphosphine oxideTo a stirred mixture of (2-fluoro-4-(2-hydroxy-l-phenyl-lH-benzo[d]pyrrolo[l,2-a]imidazol-7- yl)phenyl)dimethylphosphine oxide (80 mg, 0.191 mmol) and K2CO3 (79 mg, 0.573 mmol) in DMF (2 mL) was added CH3I (54 mg, 0.382 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was purified by reversed -phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 30% to 50% gradient in 20 min. This resulted in (2- fluoro-4-(2-methoxy-l-phenyl-lH-benzo[d]pyrrolo[l,2-a]imidazol-7- yl)phenyl)dimethylphosphine oxide (30 mg, 36%) as a white solid. MS ESI calculated for C25H22FN2O2P [M + H]+, 433.14 found 433.20. 'H NMR (400 MHz, DMSO-6?6) 6 8.30 - 8.24 (m, 1H), 8.08 - 8.03 (m, 1H), 7.89 - 7.80 (m, 1H), 7.80 - 7.75 (m, 1H), 7.74 - 7.61 (m, 3H), 7.44 - 7.30 (m, 5H), 5.91 (s, 1H), 3.51 (s, 3H), 1.77 (s, 3H), 1.73 (s, 3H).19F NMR (377 MHz, DMSC 8-105.73, -105.74.31P NMR (162 MHz, DMSO-^) 8 28.29, 28.27.

[0173] Example 29: (2-fluoro-4-(l-(2-fluorophenyl)-l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2- a]pyridin-8-yl)phenyl)dimethylphosphine oxideWSGR Ref: 53699-726.601Preparation 29A: 6-(2-fluorophenyl)piperidin-2-oneTo a stirred mixture of 2-(2-fluorophenyl)piperidine (900 mg, 5.021 mmol) and H2O (904 mg, 50.210 mmol) in DCE (10 mL) were added copper(I)trifluoromethanesulfonate (214 mg, 1.004 mmol), dtbbpy (270 mg, 1.004 mmo), ABNO (141 mg, 1.004 mmol) and DMAP (123 mg, 1.004 mmol) at room temperature. The resulting mixture was stirred at room temperature for 36 h under oxygen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 20% to 50% gradient in 30 min. This resulted in 6-(2-fluorophenyl)piperidin -2-one (180 mg, 19%) as a white solid. MS ESI calculated for CnHi2FNO [M + H]+, 194.09 found 194.10.JH NMR (400 MHz, DMSO-t / 6) 8 7.72 (s, 1H), 7.37 - 7.29 (m, 2H), 7.26 - 7.13 (m, 2H), 4.81 - 4.74 (m, 1H), 2.27 - 2.21 (m, 2H), 2.07 - 1.97 (m, 1H), 1.72 - 1.55 (m, 3H).19F NMR (377 MHz, DMSO-t / 6) 6 -120.22.Preparation 29B: l-(5-chloro-2-nitrophenyl)-6-(2-fluorophenyl)piperidin-2-oneTo a stirred mixture of 6-(2-fluorophenyl)piperidin-2-one (170 mg, 0.880 mmol) and Cs2CO3(860 mg, 2.640 mmol) in DMF (2 mL) was added 4 -chloro-2-fluoro-l -nitrobenzene (162 mg, 0.924 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with water (20 mL) and acidified to pH~3 with HC1(2 N) followed by extraction with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) to afford l-(5-chloro-2-nitrophenyl)-6-(2-fluorophenyl)piperidin-2- one (110 mg, 36%) as a yellow solid. MS ESI calculated for Ci7Hi4ClFN2O3[M + H]+, 349.07 found 348.90. 'H NMR (400 MHz, Chloroform-; / ) 6 7.97 (d, J = 8.8 Hz, 1H), 7.35 - 7.27 (m, 3H), 7.22 - 7.16 (m, 1H), 7.08 - 7.00 (m, 1H), 6.95 - 6.87 (m, 1H), 5.18 - 5.05 (m, 1H), 2.50 -WSGR Ref: 53699-726.6011.87 (m, 6H).Preparation 29C: 8-chloro-l-(2-fluorophenyl)-l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2- a]pyridineTo a stirred mixture of l-(5-chloro-2-nitrophenyl)-6-(2-fluorophenyl)piperidin-2-one (100 mg, 0.287 mmol) in EtOH (0.5 mL) was added Titanium(III) chloride, 15-20% in 2N Hydrochloric acid (2.35 g, 2.296 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 3 h. The resulting mixture was diluted with water (20 mL) followed by extraction with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) to afford 8-chloro-l-(2-fluorophenyl)- l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2-a]pyridine (50 mg, 58%) as a yellow solid. MS ESI calculated for C17H14CIFN2 [M + H]+, 301.08 found 301.10.Example 29: (2-fluoro-4-(l-(2-fluorophenyl)-l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2- a]pyridin-8-yl)phenyl)dimethylphosphine oxideTo a stirred mixture of 8-chloro-l-(2-fluorophenyl)-l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2- a]pyridine (50 mg, 0.166 mmol) and 2-[4-(dimethylphosphoryl)-3-fluorophenyl]-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane (99 mg, 0.332mmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL) were added Sphos Pd G3 (13 mg, 0.017 mmol) and K3PO4 (106 mg, 0.498 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 30% to 50% gradient in 20 min. This resulted in (2-fluoro-4-(l- (2-fluorophenyl)-l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2-a]pyridin-8- yl)phenyl)dimethylphosphine oxide (36 mg, 50%) as a white solid. MS ESI calculated for C25H23F2N2OP [M + H]+, 437.16 found 437.15. !H NMR (400 MHz, Chloroform-; / ) 8 7.97 -7.88 (m, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.48 - 7.42 (m, 1H), 7.37 - 7.28 (m, 2H), 7.21 - 7.12 (m, 2H), 7.04 - 6.97 (m, 1H), 6.97 - 6.92 (m, 1H), 6.58 - 6.52 (m, 1H), 5.89 (t, J = 5.3 Hz, 1H), 3.34 - 3.14 (m, 2H), 2.56 - 2.43 (m, 1H), 2.33 - 2.24 (m, 1H), 2.03 - 1.93 (m, 2H), 1.81 (s, 3H), 1.78 (s, 3H).19F NMR (377 MHz, Chloroform-; / ) 6 -106.03, -106.04, -119.11.31P NMR (162 MHz, Chloroform-; / ) 6 30.47, 30.45.

[0174] Example 30: (4-((lR)-l-(2-(difluoromethoxy)phenyl)-3-fluoro-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazol-7-yl)-2-fluorophenyl)dimethylphosphine oxideWSGR Ref: 53699-726.601Preparation 30 A: (lR)-7-chloro-l-(2-(difluoromethoxy)phenyl)-3-fluoro-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazoleTo a stirred solution of (1 R)-7-chloro-l -(2 -(difluoromethoxy )phenyl)-2, 3 -dihydro- 1H- benzo[d]pyrrolo[l,2-a]imidazol-3-ol (350 mg, 0.998 mmol) in DCM (5 mL) was added diethylaminosulfur trifluoride (483 mg, 2.994 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water followed by extraction with CH2C12(3 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (12:1) to afford (lR)-7-chloro-l-(2- (difluoromethoxy)phenyl)-3-fluoro-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole (250 mg, 71%) as yellow oil. MS ESI calculated for CI7HI2C1F3N2O [M + H]+, 353.06 found 353.10.JH NMR (400 MHz, Chloroform -d) 8 7.82 - 7.64 (m, 1H), 7.49 - 7.31 (m, 1H), 7.32 - 7.06 (m, 3H), 7.00 - 6.80 (m, 2H), 6.77- 6.49 (m, 1H), 6.41 - 5.85 (m, 2H), 3.68 - 3.29 (m, 1H), 3.02 - 2.70 (m, 1H).19F NMR (377 MHz, Chloroform-; / ) 6 -80.13, -80.21, -80.57, -80.65, -80.86, - 81.06, -81.31, -81.50, -165.82, -170.88.Example 30: (4-((lR)-l-(2-(difluoromethoxy)phenyl)-3-fluoro-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazol-7-yl)-2-fluorophenyl)dimethylphosphine oxideTo a stirred solution of (1 R)-7-chloro-l-(2 -(difluorometh oxy)phenyl)-3-fluoro-2, 3 -dihydro- 1H- benzo[d]pyrrolo[l,2-a]imidazole (40 mg, 0.113 mmol) and 2-[4-(dimethylphosphoryl)-3- fluorophenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (50 mg, 0.170 mmol) in 1,4-dioxane (2 mL) and H2O (0.4 mL) were added K3PO4(72 mg, 0.339 mmol), Sphos (9 mg, 0.023 mmol) and Sphos Pd G3 (9 mg, 0.011 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The reaction was quenched with water followed by extraction with EtOAc (3 x 5 mL). The combined organic layers were concentrated under reduced pressure. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30* 150 mm, 5pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 25%B to 40%B in 17 min; Wave Length: 254 nm; RT1 : 12.96 min) to afford (4-((lR)-l-(2- (difluoromethoxy)phenyl)-3 -fluoro-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-7-yl)-2-WSGR Ref: 53699-726.601 fluorophenyl)dimethylphosphine oxide (24 mg, 44%) as a white solid. MS ESI calculated for C25H21F4N2O2P [M + H]+, 489.13 found 489.00.JH NMR (400 MHz, Chloroform-t ) 6 8.03 - 7.89 (m, 2H), 7.60 - 7.50 (m, 1H), 7.50 - 7.34 (m, 2H), 7.31 - 7.27 (m, 1H), 7.25 - 7.10 (m, 2H), 7.06 - 6.96 (m, 1H), 6.96- 6.34 (m, 2H), 6.26 - 5.96 (m, 2H), 3.70 - 3.36 (m, 1H), 3.04 - 2.79 (m, 1H), 1.82 (s, 3H), 1.79 (s, 3H).19F NMR (377 MHz, Chloroform -d) 6 -80.10, -80.18, - 80.54, -80.62, -81.00, -81.12, -81.44, -81.56, -105.80, -165.63, -170.89.31P NMR (162 MHz, Chloroform -d) 5 30.49.

[0175] Example 31 : (4-((lR)-l-(2-(difluoromethoxy)phenyl)-3-fluoro-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazol-7-yl)-2,3-difluorophenyl)dimethylphosphine oxideA mixture of (lR)-7-chloro-l-(2 -(difluoromethoxy )phenyl)-3-fluoro-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazole (40 mg, 0.113 mmol), Sphos Pd G3 (8 mg, 0.011 mmol), Sphos (9 mg, 0.023 mmol), K3PO4 (72 mg, 0.339 mmol) and 2-[4-(dimethylphosphoryl)-2,3- difluorophenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane(53 mg, 0.170mmol) in 1,4-dioxane (1 mL) and H2O (0.2 mL) was stirred at 80 °C for 4 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1) followed by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30* 150 mm, 5pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 25% B to 40% B in 17 min; Wave Length: 254 nm; RT1 : 13.72 min) to afford (4-((lR)-l-(2- (difluoromethoxy)phenyl)-3-fluoro-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-7-yl)-2,3- difluorophenyl)dimethylphosphine oxide (20 mg, 34%) as a white solid. MS ESI calculated for C25H2OF5N202P [M + H]+, 507.13 found 507.15.JH NMR (400 MHz, DMSO-t / 6) 8 7.97 - 7.84 (m, 1H), 7.63 - 7.37 (m, 5H), 7.36- 7.13 (m, 3H), 7.09 (s, 1H), 6.75 - 6.25 (m, 1H), 6.22- 5.97 (m, 1H), 3.77 - 3.28 (m, 1H), 3.18 - 2.60 (m, 1H), 1.77 (s, 3H), 1.73 (s, 3H).19F NMR (377 MHz, DMSC 8 -80.77, -81.22, -81.29, -81.60, -81.73, -81.82, -82.04, -82.27, -131.46, - 131.47, -131.52, -131.53, -131.57, -131.58, -131.63, -131.65, -143.89, -143.91, -143.95, - 143.97, -144.11, -144.12, -144.17, -144.18, -166.32, -170.51.31P NMR (162 MHz, DMSO-t / 6) 8 28.56.WSGR Ref: 53699-726.601

[0176] Example 32: (R)-(4-(l-(2 -(difluoromethoxy )phenyl)-2, 3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazol-7-yl)-2-fluorophenyl)dimethylphosphine oxidePreparation 32A: tert-butyl (3R)-3-amino-3-[2-(difluoromethoxy)phenyl]propanoateA mixture of (lR)-l-[2-bromo-6-(difluoromethoxy)phenyl]-3-(tert-butoxy)-3-oxopropan-l- aminium (S)-hydroxy(phenyl)acetate (15.00 g, 28.938 mmol) and Pd / C (1.50 g, 1.410 mmol, 10%) in methanol (150 mL) was stirred at room temperature for 2 h under hydrogen atmosphere (1 atm). The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. This resulted in tert-butyl (3R)-3-amino-3- [2-(difluoromethoxy)phenyl]propanoate (8.00 g, 96%) as a light yellow solid. MS ESI calculated for CI4HI9F2NO3 [M + H]+, 288.13 found 288.15. 'HNMR (400 MHz, Chloroform^ / ) 6 7.52 - 7.45 (m, 1H), 7.30- 7.23 (m, 1H), 7.23 - 7.17 (m, 1H), 7.12 - 7.06 (m, 1H), 6.58 (t, J= 73.9 Hz, 1H), 4.71 - 4.62 (m, 1H), 2.69 - 2.57 (m, 2H), 1.39 (s, 9H).19F NMR (377 MHz, Chloroform -d) 8 -79.76, -79.98, -79.99, -80.46.Preparation 32B: tert-butyl (3R)-3-[(5-chloro-2-nitrophenyl)amino]-3-[2- (difluoromethoxy)phenyl]propanoateTo a stirred solution of tert-butyl (3R)-3-amino-3-[2-(difluoromethoxy)phenyl]propanoate (8.00 g, 27.845 mmol) and 4-chloro-2-fluoro-l -nitrobenzene (4.89 g, 27.845 mmol) in N,N- Dimethylacetamide (100 mL) was added DIEA (7.28 mL, 41.767 mmol) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for additional 16 h. The resulting mixture was diluted with water (500 mL) followed by extraction with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reducedWSGR Ref: 53699-726.601 pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0~5%) to afford tert-butyl (3R)-3-[(5-chloro-2-nitrophenyl)amino]-3-[2-(difluoromethoxy)phenyl]propanoate (12.00 g, 97%) as a light yellow solid. MS ESI calculated for C20H21CIF2N2O5 [M + H]+, 443. 11 found 443. 10. 'HNMR (400 MHz, Chloroform -d) 8 8.86 (d, J = 7.3 Hz, lH), 8.12 (d, J= 9.1 Hz, 1H), 7.39 - 7.30 (m, 2H), 7.18 (t, J = 7.3 Hz, 2H), 6.70 - 6.68 (m, 1H), 6.63 - 6.50 (m, 1H), 5.29 (q, J = 6.9 Hz, 1H), 2.91 - 2.79 (m, 2H), 1.38 (s, 9H).19F NMR (377 MHz, Chloroform-; / ) 6 -79.48, -79.92, -80.75, -81.19.Preparation 32C: (3R)-3-[(5-chloro-2-nitrophenyl)amino]-3-[2- (difluoromethoxy)phenyl]propanalTo a stirred solution of tert-butyl (3R)-3-[(5-chloro-2-nitrophenyl)amino]-3-[2- (difluoromethoxy)phenyl]propanoate (10.50 g, 23.711 mmol) in DCM (150 mL) was added diisobutylaluminum hydride (26.1 mL, 26.082 mmol, 1.0 Min DCM) dropwise at -78 °C under nitrogen atmosphere. The mixture was stirred for 0.5 h at -78 °C. The reaction was poured into sat. NH4CI (aq.) 10 mL at -78 °C. The resulting mixture was filtered, the filter cake was washed with EtOAc (3 x 10 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5 :1) to afford (3 R)-3-[(5-chloro-2-nitrophenyl)amino]-3-[2 -(difluoromethoxy )phenyl]propanal (5.00 g, 57%) as a yellow solid. MS ESI calculated for C16H13CIF2N2O4 [M + H]+, 371.05 found 371.20.1HNMR (400 MHz, Chloroform -d) 69.80 (s, 1H), 8.60 (d, J = 7.5 Hz, 1H), 8.11 (d, J = 9.1 Hz, 1H), 7.43 - 7.38 (m, 1H), 7.37 - 7.28 (m, 1H), 7.24 - 7. 16 (m, 2H), 6.92 - 6.71 (m, 2H), 6.65 - 6.61 (m, 1H), 5.53 - 5.35 (m, 1H), 3.18 - 3.04 (m, 2H).19F NMR (377 MHz, Chloroform -d) 8 -79.74, -80.18, -80.80, -81.24.Preparation 32D: (4R)-4-[(5-chloro-2-nitrophenyl)amino]-4-[2-(difluoromethoxy)phenyl]-2- [(trimethylsilyl)oxy]butanenitrileTo a stirred solution of (3R)-3-[(5-chloro-2-nitrophenyl)amino]-3-[2- (difluoromethoxy)phenyl]propanal (5.00 g, 13.487 mmol) and TMSCN (2.68 g, 26.974 mmol) in DCM (5 mL) were added EtsN (136 mg, 1.349 mmol), Znf (430 mg, 1.349 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction was quenched with sat. NH4C1 (aq.) at room temperature followed by extraction with CH2C12(3 x 300 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford (4R)-4-[(5-chloro-2-nitrophenyl)amino]-4-[2- (difluoromethoxy)phenyl]-2-[(trimethylsilyl)oxy]butanenitrile (5.50 g, crude) as a yellow solid. The crude product was used in the next step directly without further purification. MS ESIWSGR Ref: 53699-726.601 calculated for C2oH22ClF2N304Si [M + H]+, 470.10 found 470.10.Preparation 32E: (lR)-7-chloro-l-(2-(difluoromethoxy)phenyl)-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazol-3-olTo a stirred solution of (4R)-4-[(5-chloro-2-nitrophenyl)amino]-4-[2-(difluoromethoxy)phenyl]- 2-[(trimethylsilyl)oxy]butanenitrile (5.50 g, 11.704 mmol) in EtOH (60 mL) was added Titanium(III) chloride, 15-20% in 2N Hydrochloric acid (72.20 g, 93.632 mmol) dropwise at room temperature. The resulting mixture was stirred at 80 °C for additional 3 h. The resulting mixture was basified to pH 8 with saturated Na2CO3(aq.). The resulting mixture was filtered, the filter cake was washed with EtOAc (3x200 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH ( 10 : 1 ) to afford (1 R)-7 -chloro- 1 -(2-(difluoromethoxy)phenyl)-2, 3 -dihydro- 1 H- benzo[d]pyrrolo[l,2-a]imidazol-3-ol (1.00 g, 24%) as yellow oil. MS ESI calculated for CI7HI3C1F2N2O2[M + H]+, 351.06 found 351.05. !H NMR (400 MHz, Chloroform -t / ) 8 7.71 - 7.65 (m, 1H), 7.44 - 7.35 (m, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.23 - 7.14 (m, 2H), 6.96 - 6.85 (m, 2H), 6.77 - 6.40 (m, 1H), 6.07- 5.82 (m, 1H), 5.65 - 5.48 (m, 1H), 3.68 - 3.54 (m, 1H), 3.31 - 3.18 (m, 1H).19F NMR (377 MHz, Chloroform -d) 6 -79.88, -80.01, -80.32, -80.45, -80.88, - 80.98, -81.32, -81.42.Preparation 32F: (lR)-3,7-dichloro-l-(2-(difluoromethoxy)phenyl)-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazoleTo a stirred solution of (1 R)-7-chloro-l -(2 -(difluoromethoxy )phenyl)-2, 3 -dihydro- 1H- benzo[d]pyrrolo[l,2-a]imidazol-3-ol (1.10 g, 3.136 mmol) in CH3CN (11 mL) were added phosphoryl trichloride (1.90 g, 12.544 mmol) and DIEA (810 mg, 6.272 mmol) dropwise at room temperature. The resulting mixture was stirred at 80 °C for 4 h. The resulting mixture was concentrated under reduced pressure. The residue was basified to pH 8 with saturated NaHCO3(aq.) followed by extraction with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (20:1) to afford (lR)-3,7-dichloro-l-(2- (difluoromethoxy)phenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole(780 mg, 67%) as a brown solid. MS ESI calculated for CI7HI2C12F2N2O [M + H]+, 369.03 found 369.00. TI NMR (400 MHz, Chloroform-; / ) 67.78 - 7.74 (m, IH), 7.48 - 7.38 (m, IH), 7.30 - 7.27 (m, IH), 7.25 - 7.22 (m, IH), 7.22 - 7.14 (m, IH), 6.99 - 6.94 (m, IH), 6.88 - 6.74 (m, IH), 6.70 - 6.39 (m, IH), 6.05 - 5.88 (m, IH), 5.58 - 5.46 (m, IH), 3.40 - 3.32 (m, IH), 3.21 - 3.07 (m, IH).WSGR Ref: 53699-726.601Preparation 32G: (R)-7-chloro-l-(2-(difluoromethoxy)phenyl)-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazoleTo a stirred solution of (lR)-3,7-dichloro-l -(2 -(difluoromethoxy )phenyl)-2, 3 -dihydro- 1H- benzo[d]pyrrolo[l,2-a]imidazole (780 mg, 2.113 mmol) in EtOH (8 mL) was added Raney -Ni (248 mg, 4.226 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for 24 h under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOH (8 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (12:1) to afford (R)-7-chloro- 1 -(2 -(difluoromethoxy )phenyl)-2, 3 -dihydro- 1H- benzo[d]pyrrolo[l,2-a]imidazole (600 mg, 85%) as a yellow solid. MS ESI calculated for CI7HI3C1F2N2O [M + H]+, 335.07 found 335.10. !HNMR(400 MHz, Chloroform-; / ) 87.67 (d, J = 8.7 Hz, 1H), 7.41 - 7.34 (m, 1H), 7.25 - 7.12 (m, 3H), 7.04 - 6.89 (m, 1H), 6.81 - 6.76 (m, 1H), 6.53 (d, = 73.2 Hz, 1H), 5.86 - 5.77 (m, 1H), 3.29 - 3.00 (m, 3H), 2.60 - 2.49 (m, 1H).19F NMR (377 MHz, Chloroform-; / ) 6 -80.00, -80.45, -80.67, -81.11.Example 32: (R)-(4-(l-(2-(difluoromethoxy)phenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazol-7-yl)-2-fluorophenyl)dimethylphosphine oxideA mixture of (R)-7-chloro-l-(2-(difluoromethoxy)phenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazole (50 mg, 0.149 mmol), 2-[4-(dimethylphosphoryl)-3-fluorophenyl]-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane (66 mg, 0.223 mmol), Sphos Pd G3 (5 mg, 0.007 mmol), Sphos (6 mg, 0.015 mmol) and K3PO4 (63 mg, 0.298 mmol) in 1,4-dioxane (1 mL) and H2O (0.1 mL) was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (12:1) to followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, 254 nm. This resulted in (R)-(4-(l-(2- (difluoromethoxy)phenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-7-yl)-2- fluorophenyl)dimethylphosphine oxide (44 mg, 63%) as a white solid. MS ESI calculated for C25H22F3N2O2P [M + H]+, 471.14 found 470.95. !H NMR (400 MHz, Chloroform-; / ) 6 7.99 - 7.90 (m, 1H), 7.84 (d, = 8.5 Hz, 1H), 7.51 - 7.46 (m, 1H), 7.45 - 7.34 (m, 2H), 7.26 - 7.19 (m, 2H), 7.17 - 7.08 (m, 2H), 6.86- 6.46 (m, 2H), 5.96 - 5.86 (m, 1H), 3.36 - 3.13 (m, 3H), 2.68 - 2.54 (m, 1H), 1.81 (s, 3H), 1.78 (s, 3H).19FNMR (377 MHz, Chloroform-; / ) 6 -80.02, -80.45, - 80.46, -80.79, -81.23, -105.94.31P NMR (162 MHz, Chloroform-; / ) 6 30.36.

[0177] Example 33 : (R)-(4-(l-(2 -(difluoromethoxy )phenyl)-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazol-7-yl)-2,3-difluorophenyl)dimethylphosphine oxideWSGR Ref: 53699-726.601A mixture of (R)-7-chloro-l-(2-(difluoromethoxy)phenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazole (50 mg, 0.149 mmol), 2-[4-(dimethylphosphoryl)-2,3-difluorophenyl]-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane (70 mg, 0.223 mmol), Sphos Pd G3 (5 mg, 0.007 mmol), Sphos (6 mg, 0.015 mmol) and K3PO4 (63 mg, 0.298 mmol) in 1,4-dioxane (1 mL) and H2O (0.1 mL) was stirred at 80 °C for 4 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH^Ch / MeOH (12:1) to followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, 254 nm. This resulted in (R)-(4-(l-(2- (difluoromethoxy)phenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-7-yl)-2,3- difluorophenyl)dimethylphosphine oxide (25 mg, 35%) as a white solid. MS ESI calculated for C25H21F4N2O2P [M + H]+, 489.13 found 489.10.JH NMR (400 MHz, Chloroform -d) 87.86 (d, J = 8.5 Hz, 1H), 7.75 - 7.65 (m, 1H), 7.46 - 7.41 (m, 1H), 7.40 - 7.34 (m, 1H), 7.33 - 7.27 (m, 1H), 7.25 - 7.21 (m, 1H), 7.17 - 7.11 (m, 1H), 7.08 (s, 1H), 6.88 - 6.84 (m, 1H), 6.63 (t, J = 73.2 Hz, 1H), 5.92 (t, J= 6.4 Hz, 1H), 3.37 - 3.20 (m, 3H), 2.71 - 2.54 (m, 1H), 1.84 (s, 3H), 1.80 (s, 3H).19F NMR (377 MHz, Chloroform -d) 6 -80.05, -80.49, -80.79, -81.24, -131.34, - 131.40, -143.16, -143.22.31P NMR (162 MHz, Chloroform -d) 629.80.

[0178] Example 34: (R)-(2,3-difluoro-4-(l-(3-fluorophenyl)-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazol-7-yl)phenyl)dimethylphosphine oxideWSGR Ref: 53699-726.601Preparation 34 A: (S)-N-[(3-fluorophenyl)methylidene]-2-methylpropane-2-sulfinamide To a stirred mixture of 3 -fluorobenzaldehyde (50.00 g, 402.855 mmol) and CS2CO3 (144.38 g, 443.129 mmol) in DCM (500 mL) was added (S)-2-methylpropane-2-sulfinamide (58.59 g, 483.426 mmol) at room temperature. The mixture was stirred for 16 h at room temperature. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0-20%) to afford (S)-N-[(3 -fluorophenyl)methylidene]- 2-methylpropane-2-sulfinamide (75.01 g, 82%) as yellow oil. MS ESI calculated for C11H14FNOS [M + H]+, 228.08 found 228.05.1HNMR(400 MHz, Chloroform-tZ) 88.57 (s, 1H), 7.65 - 7.55 (m, 2H), 7.51 - 7.42 (m, 1H), 7.26 - 7.18 (m, 1H), 1.28 (s, 9H).Preparation 34B: tert-butyl (R)-3-(((S)-tert-butylsulfinyl)amino)-3-(3-fluorophenyl)propanoate A mixture of CuCI (49.00 g, 494.940 mmol) and Zinc (151.01 g, 2309.720 mmol) in THF (I L) was stirred at 60 °C for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to 0 °C. To the above mixture was added tert-butyl 2-bromoacetate (120.26 mL, 824.900 mmol) dropwise over 30 min atO °C. The resulting mixture was stirred at 60 °C for additional 2 h. The mixture was allowed to cool down to 5 °C. To the above mixture was added (S)-N-[(3- fluorophenyl)methylidene]-2-methylpropane-2-sulfinamide (75.00 g, 329.960 mmol) dropwise at 5 °C. The resulting mixture was stirred at room temperature for additional 16 h. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with EtOAc (3 x 700 mL). The filtrate was quenched by 5% citric acid solution followed by extraction with EtOAc (3 x IL). The combined organic layers were washed with saturated NaHCO3(aq.) and brine and dried over anhydrous Na2SO4. After filtration, theWSGR Ref: 53699-726.601 filtrate was concentrated under reduced pressure. The crude product was purified by trituration with w-heptane / EA(10 / l) (600 mL). This resulted in tert -butyl (R)-3-(((S)-tert- butylsulfinyl)amino)-3-(3-fluorophenyl)propanoate (80.01 g, 71%) as a white solid. MS ESI calculated for C17H26FNO3S [M + H]+, 344.16 found 344.10. 'H NMR (400 MHz, Chloroform- d) 8 7.36 - 7.24 (m, 1H), 7.18 - 7.10 (m, 1H), 7.10 - 7.02 (m, 1H), 7.02 - 6.92 (m, 1H), 4.78 - 4.72 (m, 1H), 4.69 (d, J = 4.4 Hz, 1H), 2.78 (s, 1H), 2.77 -2.75 (m, 1H), 1.41 (s, 9H), 1.24 (s, 9H).Preparation 34C: tert-butyl (R)-3-amino-3-(3-fluorophenyl)propanoateTo a stirred solution of tert-butyl (R)-3-(((S)-tert-butylsulfinyl)amino)-3-(3- fluorophenyl)propanoate (55.00 g, 160.135 mmol) in THF (600 mL) and H2O (120 mL) was added iodine (10.16 g, 40.034 mmol) at room temperature. The resulting mixture was stirred at 50 °C overnight. The mixture was allowed to cool down to room temperature and diluted with EtOAc (2 L). The reaction was quenched with sat. NaHCCL (aq.) at room temperature. The organic layer was washed with water and brine. The combined organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in MTBE (500 mL) followed by addition of L-Mailcacid (50.00 g) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The precipitated solids were collected by filtration and washed with MTBE (3 x 100 mL). The residue was dissolved in EtOAc (1 L) and basified to pH 9 with saturated NaHCO3(aq.) followed by extraction with EtOAc (2 x 500 mL). The combined organic layers were washed with brine (1 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl (3R)-3-amino-3-(3-fluorophenyl)propanoate (32.10 g, 84%) as colorless oil. MS ESI calculated for C13H18FNO2 [M + H]+, 240.13 found240.15. 'H NMR (400 MHz, Chloroform -d) 6 7.32 - 7.24 (m, 1H), 7.16 - 7.05 (m, 2H), 6.98 - 6.90 (m, 1H), 4.43 - 4.31 (m, 1H), 2.63 - 2.51 (m, 2H), 1.42 (s, 9H).Preparation 34D: tert-butyl (R)-3-((5-chloro-2-nitrophenyl)amino)-3-(3- fluorophenyl)propanoateTo a stirred solution of tert-butyl (3R)-3-amino-3-(3-fluorophenyl)propanoate (20.00 g, 83.581 mmol) and 4-chloro-2-fluoro-l -nitrobenzene (14.67 g, 83.581 mmol) (14.67 g, 83.581 mmol) in N,N-dimethylacetamide (200 mL) was added DIEA (21.84 mL, 125.371 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h. The resulting mixture was diluted with EtOAc (1 L). The organic layer was washed with 3 x 500 mL of water and 3 x 500 mL of brine. The combined organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2C12 / PE (1 :3) to afford tert-butyl (R)-3-((5-chloro-2-WSGR Ref: 53699-726.601 nitrophenyl)amino)-3-(3-fluorophenyl)propanoate (27.02 g, 82%) as a yellow solid. MS ESI calculated for CI9H2OC1FN204 [M + H]+, 395.11 found 395.10.JH NMR (400 MHz, Chloroform-^ 88.76 (d, = 6.4 Hz, IH), 8.17 - 8.09 (m, IH), 7.39 - 7.31 (m, IH), 7.22 - 7.12 (m, IH), 7.11 - 7.04 (m, IH), 7.04 - 6.96 (m, IH), 6.67 - 6.60 (m, 2H), 5.01 - 4.89 (m, IH), 2.82 (d, J = 6.6 Hz, 2H), 1.40 (s, 9H).Preparation 34E: (R)-3 -((5 -chloro-2-nitrophenyl)amino)-3 -(3 -fluoropheny l)propanal To a stirred solution of tert-butyl tert-butyl (R)-3-((5-chloro-2-nitrophenyl)amino)-3-(3- fluorophenyl)propanoate (25.00 g, 63.318 mmol) in DCM (375 mL) was added diisobutylaluminum hydride (1.0 M in DCM) (82.31 mL, 82.313 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 3 h under nitrogen atmosphere. The reaction was quenched with 1NHC1 (aq.) at -78 °C followed by extraction with CH2C12(2 x 500 mL). The combined organic layers were washed with brine (300 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4:1) to afford (R)-3 -((5 -chloro-2-nitrophenyl)amino)-3 -(3 -fluoropheny l)propanal (13.01 g, 63%) as yellow oil. MS ESI calculated for CI5HI2C1FN2O3[M + H]+, 323.05 found 323.10. 'H NMR (400 MHz, Chloroform-t / ) 69.80 (d, J= 1.2 Hz, IH), 8.54 (d, J= 6.7 Hz, IH), 8.12 (d, J = 9.1 Hz, IH), 7.40 - 7.31 (m, IH), 7.20 - 7.15 (m, IH), 7.12 - 7.06 (m, IH), 7.04 - 6.97 (m, IH), 6.69 (d, J = 2.1 Hz, IH), 6.67 - 6.62 (m, IH), 5.21 - 5.05 (m, IH), 3.24 - 3.00 (m, 2H). Preparation 34F: (4R)-4-((5-chloro-2-nitrophenyl)amino)-4-(3 -fluoropheny l)-2- ((trim ethy 1 sily l)oxy )b utan enitril eTo a stirred solution of (R)-3 -((5 -chloro-2-nitrophenyl)amino)-3 -(3 -fluoropheny l)propanal (13.00 g, 40.283 mmol) and Et3N (5.60 mL, 40.283 mmol) in DCM (130 mL) were added Znl2(12.86 g, 40.283 mmol) and TMSCN (7.99 g, 80.566 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction was quenched with sat. NH4C1 (aq.) at room temperature followed by extraction with CH2C12(3 x 200 mL). The combined organic layers were washed with brine (1 x 200 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to afford (4R)-4-((5-chloro-2-nitrophenyl)amino)-4-(3 -fluoropheny l)-2- ((trimethylsilyl)oxy)butanenitrile (15.01 g, crude) as a yellow solid. The crude product was used in the next step directly without further purification. MS ESI calculated for Ci9H2iQFN3O3Si [M + H]+, 422.10 found 422.10.Preparation 34G: (lR)-7-chloro-l-(3-fluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazol-3-olTo a stirred solution of (4R)-4-((5-chloro-2-nitrophenyl)amino)-4-(3-fluorophenyl)-2-WSGR Ref: 53699-726.601((trimethylsilyl)oxy)butanenitrile (1.00 g, 2.370 mmol) in EtOH (10 mL) was added Titanium(III) chloride, 15-20% in 2N Hydrochloric acid (19.49 g, 18.960 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 3 h. The resulting mixture was concentrated under vacuum. The residue was basified to pH 8 with saturated NaHCO3(aq.). The resulting mixture was filtered, the filter cake was washed with EtO Ac (10 mL). The filtrate was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (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, eluted with CH2C12 / MeOH (12:1) to afford (lR)-7-chloro-l-(3-fluorophenyl)-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazol-3-ol (400 mg, 56%) as a light yellow solid. MS ESI calculated for CI6HI2C1FN2O [M + H]+, 303.06 found 303.00. !HNMR (400 MHz, Chloroform-t ) 67.71 - 7.61 (m, 1H), 7.44 - 7.34 (m, 1H), 7.25 - 7.19 (m, 1H), 7.18 - 6.84 (m, 4H), 5.71 - 5.31 (m, 2H), 3.60 - 2.63 (m, 2H).Preparation 34H: (R)-7-chloro-l-(3-fluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazoleA solution of (lR)-7-chloro-l-(3-fluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazol-3-ol (380 mg, 1.255 mmol), DIEA (324 mg, 2.510 mmol) and phosphoryl trichloride (1.15 g, 7.530 mmol) was stirred at 60 °C for 1 h under nitrogen atmosphere. The reaction was quenched with ice water at 0 °C. The mixture was basified to pH 9 with saturated NaHCO3(aq.) followed by extraction with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the crude product. The residue was dissolved in EtOH (5 mL) followed by addition of Raney-Ni (37 mg, 0.627 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h under hydrogen atmosphere. The mixture was filtered, the filter cake was washed with ethanol (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed -phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 min; detector, 254 nm to afford (R)-7-chloro-l-(3- fluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole (280 mg, 78%) as a white solid. MS ESI calculated for CI6HI2C1FN2[M + H]+, 287.07 found 287.05. 'H NMR (400 MHz, DMSO-t / 6) 67.59 (d, J= 8.6 Hz, 1H), 7.51 - 7.38 (m, 1H), 7.25 - 7.09 (m, 3H), 7.10 - 7.03 (m, 1H), 6.91 (d, J = 2.1 Hz, 1H), 5.70 - 5.60 (m, 1H), 3.26 - 2.98 (m, 3H), 2.58 - 2.52 (m, 1H). Example 34: (R)-(2,3-difluoro-4-(l-(3-fluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazol-7 -yl)pheny l)dimethy Iphosphine oxideWSGR Ref: 53699-726.601To a stirred solution of (R)-7-chloro-l-(3-fluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazole (100 mg, 0.349 mmol) and2-[4-(dimethylphosphoryl)-2,3-difluorophenyl]-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane (165 mg, 0.523 mmol) in 1,4-dioxane (5 mL) and H2O (0.5 mL) were added Sphos Pd G3 (27 mg, 0.035 mmol), Sphos (29 mg, 0.070 mmol) and K3PO4 (222 mg, 1.047 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (15 :1) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, 254 nm to afford (R)-(2,3-difluoro-4-(l-(3-fluorophenyl)-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazol-7-yl)phenyl)dimethylphosphine oxide (67 mg, 44%) as a white solid. MS ESI calculated for C24H20F3N2OP [M + H]+, 441 .13 found 441 .10.JH NMR (400 MHz, DMSO-t / 6) 8 7.72 (d, J = 8.4 Hz, 1H), 7.60 - 7.51 (m, 1H), 7.47 - 7.34 (m, 3H), 7.21 - 7.13 (m, 2H), 7.12 - 7.06 (m, 2H), 5.76 - 5.64 (m, 1H), 3.31 - 3.04 (m, 3H), 2.60 - 2.52 (m, 1H), 1.76 (s, 3H), 1.73 (s, 3H).19F NMR (377 MHz, DMSO-tZ6) 8 -112.35, -131.69, -144.31.31P NMR (162 MHz, DMSO-t / 6) 8 28.43.

[0179] Example 35 : (R)-(2,3-difluoro-4-(l-(4-fluorophenyl)-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazol-7-yl)phenyl)dimethylphosphine oxideWSGR Ref: 53699-726.601Preparation 35 A: (S)-N-[(4-fluorophenyl)methylidene]-2-methylpropane-2-sulfinamide To a stirred solution of 4-fluorobenzaldehyde (95.00 g, 765.425 mmol) and (S)-2- methylpropane-2-sulfinamide(l 11.00 g, 918.510 mmol) in DCM (500 mL) was added CS2CO3 (274.00 g, 841.967 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 80 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford (S)-N-[(4- fluorophenyl)methylidene]-2-methylpropane-2-sulfinamide (173.00 g, 99%) as yellow oil. MS ESI calculated for C11H14FNOS [M + H]+, 228.08 found 228.10. 'H NMR (400 MHz, Chloroform -d) 5 8.56 (s, 1H), 7.93 - 7.81 (m, 2H), 7.19 - 7.13 (m, 2H), 1.27 (s, 9H).Preparation 35B: tert-butyl (3R)-3-(4-fluorophenyl)-3-{[(S)-2-methylpropane-2- sulfinyl]amino}propanoateTo a stirred mixture of Zn (90.60 g, 1.386 mol) in THF (500 mL) was added CuCl (29.40 g, 296.964 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 2 h. To the above mixture was added tert-butyl 2-bromoacetate (72.10 mL, 494.940 mmol) dropwise over 10 min at 0 °C. The resulting mixture was stirred at 60 °C for additional 2 h. To the above mixture was added (S)-N-[(4-fluorophenyl)methylidene]-2- methylpropane-2-sulfinamide (45.00 g, 197.976 mmol) dropwise over 10 min at 0 °C. The resulting mixture was stirred at room temperature for additional 16 h. The resulting mixture was filtered, the filter cake was washed with EtOAc (3 x 500 mL). The filtrate was quenched by 5% citric acid solution followed by extraction with EtOAc (3 x 500 mL). The combined organic layers were washed with saturated NaHCO3(aq.) and brine and dried over anhydrous Na2SO4,WSGR Ref: 53699-726.601 filtered and concentratedunder reduced pressure. The crude product was purified by trituration with / / -heptane / EA( l 0 / 1) (600 mL). This resulted in tert-butyl (3R)-3-(4-fluorophenyl)-3-{[(S)- 2-methylpropane-2-sulfinyl]amino}propanoate (60 g, 88%) as a light yellow solid. MS ESI calculated for C17H26FNO3S [M + H]+, 344. 16 found 344.10. 'H NMR (400 MHz, Chloroformed 8 7.33 - 7.29 (m, 2H), 7.04 - 7.00 (m, 2H), 4.77 - 4.72 (m, 1H), 2.75 (d, J = 1 .5 Hz, 2H), 1.40 (s, 9H), 1.22 (s, 9H).Preparation 35C: tert-butyl (3R)-3-amino-3-(4-fluorophenyl)propanoateTo a stirred solution of tert-butyl (3R)-3-(4-fluorophenyl)-3-{[(S)-2-methylpropane-2- sulfinyl]amino}propanoate (74.80 g, 217.784 mmol) in THF (500 mL) and H2O (100 mL) was added I2(13.80 g, 54.446 mmol) at room temperature. The resulting mixture was stirred at 50 °C for 16 h. The reaction was quenched by the addition of NaHCO3(aq.) (500 mL) at 0 °C followed by extraction with EtOAc (5 x 300 mL). The combined organic layers were washed with brine (3 x 300 mL) and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product in tert-Butyl methyl ether (500 mL) was added Di-p- toluoyl-L-tartaric acid (100.00 g, 261.341 mmol) at room temperature. The precipitate was collected through filtration after 1 h. The solid was dissolved in EA (500 mL) and adjusted PH~9 with NaHCO3(aq.) (500 mL) at 0 °C. The organic layer was washed with brine (3 x 300 mL) and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. This resulted in tert-butyl (3R)-3-amino-3-(4-fluorophenyl)propanoate (49.90 g, 95%) as yellow oil. MS ESI calculated for CI3HI8FNO2[M + H]+, 240.13 found 240.10. 'H NMR (400 MHz, Chloroform -d) 67.49 - 7.31 (m, 2H), 7.08 - 6.83 (m, 2H), 4.43 - 4.29 (m, 1H), 2.58 - 2.51 (m, 2H), 1.41 (s, 9H).Preparation 35D: tert-butyl (3R)-3-[(5-chloro-2-nitrophenyl)amino]-3-(4- fluorophenyl)propanoateTo a stirred solution of tert-butyl (3R)-3-amino-3-(4-fluorophenyl)propanoate (49.90 g, 208.534 mmol) and 4-chloro-2 -fluoro- 1 -nitrobenzene (38.40 g, 218.961 mmol) in N,N- dimethylacetamide (500 mL) was added DIEA (54.4 mL, 312.801 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 3 h. The resulting mixture was diluted with water (300 mL) at 0 °C followed by extraction with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (5 x 200 mL) and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford tert-butyl (3R)-3-[(5- chloro-2-nitrophenyl)amino]-3-(4-fluorophenyl)propanoate (60.00 g, 72%) as yellow oil. MS ESI calculated for CI9H20C1FN2O4[M + H]+, 395.11 found 395.10. >H NMR (400 MHz, Chloroform-d) 68.77 (d, J = 6.5 Hz, IH), 8. 12 (d, J = 9. 1 Hz, IH), 7.39 - 7.30 (m, 2H), 7. 11 -WSGR Ref: 53699-726.6017.01 (m, 2H), 6.67 - 6.58 (m, 2H), 4.94 (q, J = 6.6 Hz, 1H), 2.89 - 2.75 (m, 2H), 1.39 (s, 9H). Preparation 35E: (3R)-3-[(5-chloro-2-nitrophenyl)amino]-3-(4-fluorophenyl)propanalA solution of tert-butyl (3R)-3-[(5-chloro-2-nitrophenyl)amino]-3-(4-fluorophenyl)propanoate (30.00 g, 75.982 mmol) in DCM (450 mL) was stirred at room temperature for5 min under nitrogen atmosphere. To the above mixture was added Diisobutylaluminum hydride (1.0 M in DCM) (14.01 g, 98.777 mmol) dropwise over 3 h at -78 °C. The resulting mixture was stirred at -78 °C for additional 30 min. The reaction was quenched by the addition of IN HC1 (100 mL) at -78 °C followed by extraction with CH2CI2 (3 x 300 mL). The combined organic layers were washed with brine (300 mL) and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5 : 1 ) to afford (3R)-3-[(5-chloro-2-nitrophenyl)amino]-3- (4-fluorophenyl)propanal (13.20 g, 53%) as yellow oil. MS ESI calculated for C15H12CIFN2O3 [M + H]+, 323.05 found 323.25.1HNMR(400 MHz, Chloroform-t ) 6 9.79 (s, 1H), 8.55 (d, J = 6.8 Hz, 1H), 8.11 (d, J = 9.1 Hz, 1H), 7.40 - 7.33 (m, 2H), 7.11 - 7.02 (m, 2H), 6.69 (d, J = 2.1 Hz, 1H), 6.65 - 6.61 (m, 1H), 4.18 - 4.07 (m, 1H), 3.19 - 3.12 (m, 1H), 3.09 - 3.01 (m, 1H). Preparation 35F: (4R)-4-[(5-chloro-2-nitrophenyl)amino]-4-(4-fluorophenyl)-2- [(trimethylsilyl)oxy]butanenitrileTo a stirred solution of (3R)-3-[(5-chloro-2-nitrophenyl)amino]-3-(4-fluorophenyl)propanal (12.20 g, 37.804 mmol) in DCM (120 mL) were added Znl2(1.21 g, 3.780 mmol), TMSCN (7.50 g, 75.608 mmol) and Et4N (382 mg, 3.780 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched by the addition of water (50 mL) at 0 °C followed by extraction with CH2CI2 (3 x 200 mL). The combined organic layers were washed with brine (2 x 100 mL) and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford (4R)-4-[(5-chloro-2-nitrophenyl)amino]-4-(4- fluorophenyl)-2-[(trimethylsilyl)oxy]butanenitrile (15.50 g, 97%) as a yellow solid. MS ESI calculated for Ci^iClFNsChSi [M + H]+, 422.10 found 422.10. !H NMR (400 MHz, Chloroform-d) 68.52 (d, J = 6.5 Hz, 1H), 7.95 - 7.91 (m, 1H), 7.16- 7.11 (m, 2H), 6.93 - 6.88 (m, 2H), 6.47 - 6.43 (m, 1H), 6.38 (d, J = 2.1 Hz, 1H), 4.70 - 4.60 (m, 1H), 4.31 - 4.26 (m, 1H), 2.35 - 2.22 (m, 1H), 2.20 - 2.08 (m, 1H), 0.06 (s, 9H).Preparation 35G: (lR)-7-chloro-l-(4-fluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazol-3-olTo a stirred solution of (4R)-4-[(5-chloro-2-nitrophenyl)amino]-4-(4-fluorophenyl)-2- [(trimethylsilyl)oxy]butanenitrile (14.50 g, 34.366 mmol) in EtOH (150 mL) was added Titanium(III) chloride, 15-20% in 2N Hydrochloric acid (42.40 g, 274.928 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 1 h. The resulting mixture wasWSGR Ref: 53699-726.601 concentrated under reduced pressure. The residue was diluted with water (100 mL) at 0 °C and basified to pH 8 with saturated NaHC03(aq.). The precipitate was removed by filtration, the filter cake was washed with EtO Ac (100 mL). The aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2C12 / MeOH (10: l) to afford (lR)-7-chloro- l-(4-fluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-3-ol (6.10 g, 58%) as a brown solid. MS ESI calculated for CI6HI2C1FN2O [M + H]+, 303.06 found 303.00. E NMR (400 MHz, Chloroform-; / ) 87.69 - 7.64 (m, IH), 7.39 - 7.32 (m, 2H), 7.23 - 7.15 (m, 2H), 7.13 - 7.06 (m, 2H), 5.68 (t, J = 6.9 Hz, IH), 5.60 - 5.55 (m, IH), 5.54 - 5.48 (m, IH), 2.92 - 2.80 (m, IH), 2.71 - 2.62 (m, IH).Preparation 35H: (R)-7-chloro-l-(4-fluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazoleA solution of (lR)-7-chloro-l-(4-fluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazol-3-ol (500 mg, 1 .652 mmol), DIEA (426 mg, 3.304 mmol) and phosphoryl trichloride (1.15 g, 7.530 mmol) was stirred at 60 °C for 1 h. The reaction was quenched with ice water at 0 °C and basified to pH~9 with saturated NaHCO3(aq.) followed by extraction with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in EtOH (2 mL) was added Raney -Ni (484 mg, 8.260 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for16 h under hydrogen atmosphere. The mixture was filtered, the filter cake was washed with ethanol (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (12:1) to afford (R)-7- chloro-l-(4-fluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole (145 mg, 30%) as yellow oil. MS ESI calculated for CI6HI2C1FN2[M + H]+, 287.07 found 287.00. >H NMR (400 MHz, Chloroform -<7) 67.63 (d, J = 8.6 Hz, IH), 7.21 - 7.04 (m, 5H), 6.79 (s, IH), 5.41 (t, J = 6.7 Hz, IH), 3.27 - 3.09 (m, 3H), 2.60 - 2.52 (m, IH).Example 35: (R)-(2,3-difluoro-4-(l-(4-fluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazol-7 -yl)pheny l)dimethy Iphosphine oxideTo a stirred solution of (R)-7-chloro-l-(4-fluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazole (70 mg, 0.244 mmol) and 2-[4-(dimethylphosphoryl)-2,3-difluorophenyl]-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane (92 mg, 0.293 mmol) in 1,4-dioxane (1 mL) and H2O (0.1 mL) were added Sphos (20 mg, 0.049 mmol), Sphos Pd G3(19 mg, 0.024 mmol) and K3PO4(155 mg, 0.732 mmol) at room temperature. The resulting mixture was stirred at 80 °C forWSGR Ref: 53699-726.6012 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2C12 / MeOH (12: 1) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 10% to 48% gradient in 10 min; detector, 254 nm to afford (R)-(2,3-difluoro-4-(l-(4- fluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-7-yl)phenyl)dimethylphosphine oxide (59 mg, 55%) as a white solid. MS ESI calculated for C24H20F3N2OP [M + H]+, 441.13 found 441.15.JH NMR (400 MHz, Chloroform-t ) 8 7.83 (d, J = 8.6 Hz, 1H), 7.74 - 7.66 (m, 1H), 7.43 - 7.38 (m, 1H), 7.33 - 7.27 (m, 1H), 7.21 - 7.14 (m, 2H), 7.07 (t, J = 8.6 Hz, 2H), 6.99 (d, J = 1.7 Hz, 1H), 5.52 (t, J = 6.6 Hz, 1H), 3.39 - 3.14 (m, 3H), 2.66 - 2.53 (m, 1H), 1.84 (s, 3H), 1.81 (s, 3H).19F NMR (377 MHz, Chloroform -tZ) 6 -112.92, -131.36, -131.37, -131.42, - 131.43, -143.22, -143.23, -143.28, -143.29.31P NMR (162 MHz, Chloroform-; / ) 6 29.93.

[0180] Example 36 and 37: (R,E)-(2-fhioro-4-(3 -(meth oxyimino)- l-phenyl-2, 3 -dihydro- info enzo[d]pyrrolo[l,2-a]imidazol-7-yl)phenyl)dimethylphosphine oxide and (R,Z)-(2-fluoro-4-(3- (methoxyimino)-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-7- yl)phenyl)dimethylphosphine oxidePreparation 36 A: (R)-7-chloro-l-phenyl-l,2-dihydro-3H-benzo[d]pyrrolo[l,2-a]imidazol-3-one To a stirred solution of (1 R)-7-chloro-l-phenyl-2, 3 -dihydro- 1 H-benzo[d]pyrrolo[ l,2-a]imidazol- 3-ol (500 mg, 1.756 mmol) in CHCI3 (30 mL) was added MnC>2 (1.53 g, 17.560 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 16 h. The resulting mixture was filtered, the filter cake was washed with CH2C12(3 x 30 mL). The filtrate was diluted with water followed by extraction with CH2Q2 (2 x 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. The organic layer was concentratedWSGR Ref: 53699-726.601 under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (12:1) to afford (R)-7-chloro-l-phenyl-l,2-dihydro-3H- benzo[d]pyrrolo[l,2-a]imidazol-3-one (300 mg, 60%) as a brown solid. MS ESI calculated for CI6HHC1N2O [M + H]+, 283.06 found 283.05. !HNMR(400 MHz, Chloroform -d) 87.90 (d, J = 8.9 Hz, 1H), 7.47 - 7.40 (m, 3H), 7.38 - 7.31 (m, 1H), 7.21 - 7.16 (m, 2H), 7.03 (d, J = 2.0 Hz, 1H), 5.86 - 5.77 (m, 1H), 3.89 - 3.71 (m, 1H), 3.25 - 3.13 (m, 1H).Preparation 36B: (R)-7-chloro-l-phenyl-l,2-dihydro-3H-benzo[d]pyrrolo[l,2-a]imidazol-3-one O-methyl oximeTo a stirred solution of (R)-7-chloro-l-phenyl-l,2-dihydro-3H-benzo[d]pyrrolo[l,2-a]imidazol- 3-one (150 mg, 0.531 mmol) and O-methylhydroxylamine hydrochloride (66 mg, 0.796 mmol) in EtOH (3 mL) was added pyridine (126 mg, 1.593 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (20:1) to afford (R)-7-chloro-l-phenyl-l,2-dihydro-3H-benzo[d]pyrrolo[l,2- a]imidazol-3-one O-methyl oxime (110 mg, 67%) as a white solid. MS ESI calculated for C17H14CIN3O [M + H]+, 312.08 found 312.10. 'HNMR (400 MHz, Chloroform -d) 67.76 (d, J = 8.8 Hz, 1H), 7.44 - 7.38 (m, 3H), 7.25 - 7.22 (m, 1H), 7.18 - 7.14 (m, 2H), 6.91 (d, J = 2.0 Hz, 1H), 5.63 - 5.56 (m, 1H), 4.11 (s, 3H), 3.98 - 3.90 (m, 1H), 3.34 - 3.25 (m, 1H).Example 36 and 37: (R,E)-(2-fluoro-4-(3-(methoxyimino)-l-phenyl-2,3-dihydro-lH- benzo [d]pyrrolo[l,2-a]imidazol-7-yl)phenyl)dimethylphosphine oxide and (R,Z)-(2-fluoro-4-(3-(methoxyimino)-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-7- yl)phenyl)dimethylphosphine oxideTo a stirred mixture of (R)-7-chloro-l-phenyl-l,2-dihydro-3H-benzo[d]pyrrolo[l,2-a]imidazol- 3 -one O-methyl oxime (70 mg, 0.225 mmol) and 2-[4-(dimethylphosphoryl)-3-fluorophenyl]- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane(80 mg, 0.270 mmol) in 1,4-dioxane (1.5 mL) and H2O (0.1 mL) were added Sphos Pd G3 (18 mg, 0.023 mmol), Sphos (18 mg, 0.045 mmol) and K3PO4 (143 mg, 0.675 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reducedWSGR Ref: 53699-726.601 pressure. The residue was purified by silica gel column chromatography, eluted withCH2Cl2 / MeOH (12:1) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 25% to 55% gradient in 25 min; detector, 254 nm. The first peak afforded (R,E)-(2-fluoro-4-(3- (methoxyimino)-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-7- yl)phenyl)dimethylphosphine oxide (18 mg, 18%) as a white solid. MS ESI calculated for C25H23FN3O2P [M + H]+, 448.15 found 448.15. !H NMR (400 MHz, Chloroform -d) 8 8.06 - 8.01 (m, 1H), 7.98 - 7.91 (m, 1H), 7.53 (d, J= 1.7 Hz, 1H), 7.44 - 7.36 (m, 4H), 7.23 - 7.16 (m, 3H), 7.08 (d, J= 1.7 Hz, 1H), 5.75 - 5.69 (m, 1H), 4.23 (s, 3H), 4.03 - 3.93 (m, 1H), 3.44 - 3.32 (m, 1H), 1.82 (s, 3H), 1.78 (s, 3H).19F NMR (377 MHz, Chloroform -t / ) 6 -105.78.31P NMR (162 MHz, Chloroform-t / ) 6 30.55. The second peak afforded (R,Z)-(2-fluoro-4-(3- (methoxyimino)-l-phenyl-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-7- yl)phenyl)dimethylphosphine oxide (60 mg, 60%) as a white solid. MS ESI calculated for C25H23FN3O2P [M + H]+, 448.15 found 448.15. !H NMR (400 MHz, Chloroform -d) 6 8.01 - 7.86 (m, 2H), 7.55 - 7.46 (m, 1H), 7.42- 7.33 (m, 4H), 7.22 - 7.15 (m, 3H), 7.08 (s, 1H), 5.71 - 5.63 (m, lH), 4.12 (s, 3H), 4.05 - 3.88 (m, 1H), 3.40 - 3.26 (m, 1H), 1.81 (s, 3H), 1.78 (s, 3H).19F NMR (377 MHz, Chloroform-; / ) 6 -105.85.31P NMR (162 MHz, Chloroform-; / ) 6 30.48.

[0181] Example 38: (R)-(2,3-difluoro-4-(l-(2-fluorophenyl)-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazol-7-yl)phenyl)dimethylphosphine oxidePreparation 38 A: (S,E)-N-(2-fluorobenzylidene)-2-methylpropane-2-sulfinamideTo a stirred mixture of 2-fluorobenzaldehyde (42.00 g, 338.399 mmol) and (S)-2- methylpropane-2-sulfinamide (49.2 g, 406.079 mmol) in DCM (420 mL) was added Cs2CO3(121 g, 372.239 mmol) at room temperature. The resulting mixture was stirred at roomWSGR Ref: 53699-726.601 temperature for 2 h. The resulting mixture was filtered, the filter cake was washed with DCM (4 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PEZEA (5 :1) to afford (S,E)-N-(2- fluorobenzylidene)-2-methylpropane-2-sulfinamide (75.01 g, 98%) as yellow oil. MS ESI calculated for CnHi4FNOS [M + H]+, 228.08 found 228.10. !HNMR (400 MHz, Chloroform-; / ) 8 8.91 (s, 1H), 8.04 - 7.97 (m, 1H), 7.54 - 7.46 (m, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.19 - 7.12 (m, 1H), 1.28 (s, 9H).Preparation 38B: tert-butyl (R)-3-(((S)-tert-butylsulfinyl)amino)-3-(2-fluorophenyl)propanoate To a stirred mixture of Zinc (74.50 g, 1.139 mol) in THF (50 mL) was added CuCl (24.10 g, 244. 170 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 2 h followed by addition of tert-butyl 2-bromoacetate (79.40 g, 406.950 mmol) dropwise over 40 min at 0 °C. The resulting mixture was stirred at 60 °C for additional 2 h. To the above mixture was added (S)-N-[(2-fluorophenyl)methylidene]-2-methylpropane-2- sulfinamide (37.00 g, 162.780 mmol) in THF (50 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature for additional 16 h. The resulting mixture was filtered, the filter cake was washed with ethyl acetate (6 x 70 mL). The filtrate was concentrated under reduced pressure. The residue was dissolvedin ethyl acetate (1 L). Then the solution was washed with 1 L of 20% Citric acid (aq.) followed by 1 L of sat. sodium hyposulfite (aq.) and 1 L of sat. NaCl (aq.). The organic layer was concentrated under reduced pressure. This resulted in tert -butyl (R)- 3-(((S)-tert-butylsulfinyl)amino)-3-(2-fluorophenyl)propanoate (48.01 g, 86%) as light yellow oil. MS ESI calculated for CI7H26FNO3S [M + H]+, 344.16 found 344.25. 'H NMR (400 MHz, Chloroform-6067.40 - 7.32 (m, 1H), 7.30 - 7.22 (m, 1H), 7.15 - 7.08 (m, 1H), 7.07 - 6.99 (m, 1H), 5.06 - 4.98 (m, 1H), 4.62 (d, J = 5.8 Hz, 1H), 2.94 - 2.81 (m, 2H), 1.37 (s, 9H), 1.21 (s, 9H).Preparation 38C: tert-butyl (R)-3-amino-3-(2-fluorophenyl)propanoateTo a stirred solution of tert-butyl (R)-3-(((S)-tert-butylsulfinyl)amino)-3-(2- fluorophenyl)propanoate (51.00 g, 148.489 mmol) in THF (500 mL) and H2O (100 mL) was added Iodine (9.42 g, 37. 122 mmol) at room temperature. The resulting mixture was stirred at 50 °C for 16 h. The reaction was quenched by the addition of sat. NaHCO3(aq.) (1 L) at 0 °C followed by extraction with EtOAc (3 x 400 mL). The combined organic layers were washed with brine (2 x 800 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue in MTBE (4 L) was added (2S)-2- hydroxybutanedioic acid (23.90 g, 178.187 mmol) in MTBE (1 L) dropwise at room temperature. The resulting mixture was stirred at 50 °C for 2 h. The precipitated solids were collected by filtration and washed with MTBE (6 x 300 mL). The precipitated solid wasWSGR Ref: 53699-726.601 dissolved in sat. NaHCO3(aq.) (1 L) followed by extraction with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (2 x 1 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert -butyl (R)-3- amino-3-(2-fluorophenyl)propanoate (24.50 g, 69%, ee>98%) as a yellow solid. MS ESI calculated for CI3HI8FNO2[M + H]+, 240.13 found 240.05. !HNMR (400 MHz, Chloroform-tZ) 8 7.46 - 7.38 (m, 1H), 7.27 - 7.19 (m, 1H), 7.15 - 7.09 (m, 1H), 7.06 - 6.98 (m, 1H), 4.65 - 4.58 (m, 1H), 2.71 - 2.58 (m, 2H), 1.41 (s, 9H).Preparation 38D: tert-butyl (R)-3-((5-chloro-2-nitrophenyl)amino)-3-(2- fluorophenyl)propanoateTo a stirred mixture of tert-butyl (R)-3-amino-3-(2-fluorophenyl)propanoate (44. 10 g, 183.877 mmol) and 4-chloro-2 -fluoro- 1 -nitrobenzene (33.90 g, 193.071 mmol) in N,N- dimethylacetamide (440 mL) was added DIEA (48 mL, 275.816 mmol) dropwise at room temperature. The resulting mixture was stirred at 80 °C for 16 h. The resulting mixture was diluted with water (500 mL) followed by extraction with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (5 x 500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PEZEA (10:1) to afford tert-butyl (R)-3-((5- chloro-2-nitrophenyl)amino)-3-(2-fluorophenyl)propanoate (68.01 g, 94%) as a yellow solid. MS ESI calculated for CI9H20C1FN2O4[M + H]+, 395.11 found 395.15. !H NMR (400 MHz, Chloroform-6068.82 (d, J = 7.4 Hz, IH), 8. 12 (d, J = 9. 1 Hz, IH), 7.34 - 7.27 (m, 2H), 7.16 - 7.08 (m, 2H), 6.73 - 6.69 (m, IH), 6.64 - 6.59 (m, IH), 5.28 - 5.20 (m, IH), 2.91 - 2.86 (m, 2H), 1.38 (s, 9H).Preparation 38E: (R)-3-((5-chloro-2-nitrophenyl)amino)-3-(2-fluorophenyl)propanal To a stirred solution of tert-butyl (R)-3-((5-chloro-2-nitrophenyl)amino)-3-(2- fluorophenyl)propanoate (10.00 g, 25.327 mmol) in DCM (150 mL) was added Diisobutylaluminum hydride (28 mL, 27.860 mmol, 1 M in DCM) dropwise at -78 °C under nitrogen atmosphere. The resulting solution was stirred for 0.5 h at -78 °C. The reaction was quenched with sat. NH4C1 (aq.) at -78 °C followed by extraction with DCM (3 x 50 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PEZEA (8:1) to afford (R)-3-((5-chloro-2- nitrophenyl)amino)-3-(2-fluorophenyl)propanal (4.10 g, 50%) as a yellow solid. MS ESI calculated for CI5HI2C1FN2O3[M + H]+, 323.05 found 323.10. TI NMR (400 MHz, Chloroform -6 69.80 (s, IH), 8.60 (d, J = 7.7 Hz, IH), 8.11 (d, J = 9. 1 Hz, IH), 7.40 - 7.28 (m, 2H), 7.19 - 7.09 (m, 2H), 6.81 - 6.76 (m, IH), 6.68 - 6.61 (m, IH), 5.46 - 5.36 (m, IH), 3.24 - 3.07 (m, 2H).WSGR Ref: 53699-726.601Preparation 38F: (4R)-4-((5-chloro-2-nitrophenyl)amino)-4-(2-fluorophenyl)-2- ((trim ethy 1 sily l)oxy )b utan enitril eTo a stirred solution of (R)-3-((5-chloro-2-nitrophenyl)amino)-3-(2-fluorophenyl)propanal (4.00 g, 12.395 mmol) and TMSCN (2.46 g, 24.790 mmol) in DCM(100 mL) were added Et3N (0.13 g, 1.240 mmol) and Znl2(400 mg, 1.240 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with water (100 mL) followed by extraction with CH2C12(3 x 50 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in (4R)-4-((5-chloro-2-nitrophenyl)amino)4- (2-fluorophenyl)-2-((trimethylsilyl)oxy)butanenitrile (4.50 g, 86%) as brown oil. The crude product was used to the next step without further purification. MS ESI calculated for Ci9H2iClFN3O3Si [M + H]+, 422.10 found 422.10.Preparation 38G: (lR)-7-chloro-l-(2-fluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazol-3-olTo a stirred solution of (4R)-4-[(5-chloro-2-nitrophenyl)amino]-4-(2-fluorophenyl)-2- [(trimethylsilyl)oxy]butanenitrile (3.50 g, 8.295 mmol) in EtOH (35 mL) was added Titanium(III) chloride, 15-20% in 2N Hydrochloric acid (68.20 g, 66.360 mmol) dropwise at room temperature. The resulting mixture was stirred at 80 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water (500 mL) and basified to pH 8 with saturated Na2CO3(aq.) followed by extraction with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:l) to afford (lR)-7-chloro- l-(2-fluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-3-ol (2.50 g, 99%) as a yellow solid. MS ESI calculated for CI6HI2C1FN2O [M + H]+, 303.06 found 303.05.JH NMR (400 MHz, Chloroform-; / ) 87.70 - 7.63 (m, IH), 7.40 - 7.31 (m, IH), 7.25 - 7.08 (m, 4H), 6.98 - 6.89 (m, IH), 5.99 - 5.73 (m, IH), 5.64 - 5.51 (m, IH), 3.66 - 3.19 (m, IH), 3.04 - 2.67 (m, IH).Preparation 38H: (R)-7-chloro-l-(2-fluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazoleTo a stirred mixture of (lR)-7-chloro-l-(2-fhiorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazol-3-ol (500 mg, 1.652 mmol) and phosphoryl trichloride (1.50 g, 9.912 mmol) in CH3CN (5 mL) was added DIEA (427 mg, 3.304 mmol) dropwise at room temperature. The resulting mixture was stirred at 80 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water (15 mL) and basified to pH 8 withWSGR Ref: 53699-726.601 saturated NaHCO3(aq.) followed by extraction with CH2C12(3 x 10 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOH (5 mL). To the above mixture was added Raney -Ni (485 mg, 8.260 mmol) at room temperature. The reaction was stirred at room temperature for additional 16 h under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOH (3 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford (R)-7-chloro-l-(2-fluorophenyl)- 2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazole (267 mg, 56%) as a yellow solid. MS ESI calculated for CI6HI2C1FN2[M + H]+, 287.07 found 287.00. !HNMR (400 MHz, Chloroform-; / ) 8 7.65 (d, J = 8.7 Hz, 1H), 7.39 - 7.32 (m, 1H), 7.22 - 7.18 (m, 1H), 7.17 - 7.07 (m, 2H), 6.94 - 6.90 (m, 1H), 6.88 - 6.82 (m, 1H), 5.78 - 5.73 (m, 1H), 3.32 - 3.10 (m, 3H), 2.70 - 2.59 (m, 1H).Example 38: (R)-(2,3-difluoro-4-(l-(2-fluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazol-7 -yl)pheny l)dimethy Iphosphine oxideTo a stirred solution of (R)-7-chloro-l-(2-fluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2- a]imidazole (100 mg, 0.349 mmol) and (2,3-difluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)phenyl)dimethylphosphine oxide (132 mg, 0.419 mmol) in 1,4-dioxane (2.5 mL) and H2O (0.5 mL) were added Sphos (29 mg, 0.070 mmol), Sphos Pd G3 (27 mg, 0.035 mmol) and K3PO4 (222 mg, 1.047 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 1 h under nitrogen atmosphere. The resulting mixture was filtered and concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (Column: XBridge Prep OBD C18 Column 30* 150 mm, 5pm; Mobile Phase A: Water(10 mmol / L NH4HCO3 + 0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 22% B to 40% B in 10 min; Wave Length: 220 nm; RT1 : 9.98 min) to afford (R)-(2,3-difluoro-4-(l-(2-fluorophenyl)-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-7- yl)phenyl)dimethylphosphine oxide (44 mg, 28%) as a white solid. MS ESI calculated for C24H2OF3N2OP [M + H]+, 441.13 found 441.15. 'HNMR (400 MHz, Chloroform -d) 6 7.82 (d, J = 8.5 Hz, 1H), 7.74 - 7.64 (m, 1H), 7.45 - 7.38 (m, 1H), 7.36 - 7.30 (m, 2H), 7.19 - 7.04 (m, 3H), 6.91 - 6.84 (m, 1H), 5.87 - 5.80 (m, 1H), 3.35 - 3.12 (m, 3H), 2.72 - 2.60 (m, 1H), 1.84 (s, 3H), 1.81 (s, 3H).19F NMR (377 MHz, Chloroform-; / ) 6 -118.85, -131.44, -131.45, -131.50, - 131.51, -143.12, -143.14, -143.18, -143.20.31P NMR (162 MHz, Chloroform-; / ) 6 30.04.

[0182] Example 39: (R)-(2-fluoro-4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',l':2,3]imidazo[4,5- b]pyridin-2-yl)phenyl)dimethylphosphine oxideWSGR Ref: 53699-726.601Preparation 39 A: (R,Z)-N-(2,6-dichloropyridin-3-yl)-5-phenylpyrrolidin-2-imine A mixture of (R)-5-phenylpyrrolidin-2-one (500 mg, 3.102 mmol), 3 -amino-2,6- dichloropyridine (556 mg, 3.412 mmol) and phosphoryl trichloride (124 mg, 0.806 mmol) was stirred at 100 °C for 2 h under nitrogen atmosphere. The reaction was quenched with ice water at room temperature andbasified to pH 9 with saturated NaHCO3(aq.) followed by extraction with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2C12 / MeOH (20: 1) to afford (R,Z)-N-(2,6-dichloropyridin-3-yl)-5-phenylpyrrolidin-2-imine (280 mg, 29%) as a purple solid. MS ESI calculated for C15H13CI2N3 [M + H]+, 306.05 found 306.05. 'H NMR (300 MHz, Chloroform-; / ) 88.29 - 7.23 (m, 8H), 5.52 - 4.95 (m, 1H), 3.05 - 2.55 (m, 3H), 2.23 - 2.08 (m, 1H).Preparation 39B: (R)-2-chloro-8-phenyl-7,8-dihydro-6H-pyrrolo[2',l':2,3]imidazo[4,5- b]pyridineTo a stirred solution of 2,6-dichloro-N-[(2Z,5R)-5-phenylpyrrolidin-2-ylidene]pyridin-3-amine (280 mg, 0.914 mmol) and N1,N2 -dimethyl ethane- 1,2-diamine (16 mg, 0.183 mmol) in CH3CN (5 mL) were added Cui (17 mg, 0.091 mmol) and K2CO3(253 mg, 1.828 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (2 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (20:1) to afford (R)-2-chloro-8-phenyl-7,8-dihydro- 6H-pyrrolo[2',l':2,3]imidazo[4,5-b]pyridine (80 mg, 32%) as a white solid. MS ESI calculated for C15H12CIN3 [M + H]+, 270.07 found 270. 10.XH NMR (300 MHz, Chloroform-; / ) 6 8.00 (s, 1H), 7.36 - 7.30 (m, 3H), 7.26 - 7.14 (m, 1H), 7.09 - 7.00 (m, 2H), 5.91 - 5.62 (m, 1H), 3.37 - 2.88 (m, 3H), 2.78 - 2.49 (m, 1H).Example 39: (R)-(2-fluoro-4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2', T:2,3]imidazo[4,5-b]pyridin- 2-yl)phenyl)dimethylphosphine oxideTo a stirred solution of (R)-2-chloro-8-phenyl-7,8-dihydro-6H-pyrrolo[2',l':2,3]imidazo[4,5- b]pyridine (80 mg, 0.297 mmol) and (2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)dimethylphosphine oxide (133 mg, 0.446 mmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL) were added Sphos Pd G3 (23 mg, 0.030 mmol), Sphos (24 mg, 0.059 mmol) and K3PO4WSGR Ref: 53699-726.601(126 mg, 0.594 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (15 :1) followed by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 min; detector, 254 nm to afford (R)-(2-fluoro-4-(8-phenyl-7,8-dihydro-6H- pyrrolo[2',T:2,3]imidazo[4,5-b]pyridin-2-yl)phenyl)dimethylphosphine oxide (48 mg, 40%) as a white solid. MS ESI calculated for C23H2IFN3OP [M + H]+, 406.14 found 406.10. !HNMR (400 MHz, DMSO-tC) 6 8.37 - 7.59 (m, 5H), 7.61 - 6.84 (m, 5H), 5.90 - 5.68 (m, 1H), 3.32 - 2.99 (m, 3H), 2.66 - 2.54 (m, 1H),1.73 (s, 3H), 1.70 (s, 3H).19F NMR (377 MHz, DMSO-tL) 8 - 105.86.31P NMR (162 MHz, DMSO-t / 6) 6 28.44.

[0183] Example 40: (2-fluoro-4-(l-hydroxy-l-phenyl-2,3-dihydro-lH- cyclopenta[4,5]imidazo[l,2-a]pyridin-7-yl)phenyl)dimethylphosphine oxidePreparation 40 A: 3-((5-bromopyridin-2-yl)amino)cyclopent-3-en-l-oneTo a stirred solution of 1,3 -cyclopentanedione (2.00 g, 20.387 mmol) in HOAc (20 mL) was added 5-bromopyridin-2-amine (3.88 g, 22.426 mmol) at room temperature. The resulting mixture was stirred at 130 °C for 1 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with CH2C12(20 mL). This resulted in 3-((5-bromopyridin-2-yl)amino)cyclopent-3-en-l-one (3.30 g, 64%) as a light yellow solid. MS ESI calculated for Ci0H9BrN2O [M + H]+, 252.99 254.99 found 253.00 255.00. iH NMR (400 MHz, DMSO-t / 6) 6 10.21 (s, 1H), 8.42 (d, J = 2.5 Hz, 1H), 7.96 - 7.88 (m, 1H), 7.00 (d, J= 8.8 Hz, 1H), 6.32 (s, 1H), 2.80 - 2.73 (m, 2H), 2.25 - 2.17 (m, 2H). Preparation 40B: 7-bromo-2,3-dihydro-lH-cyclopenta[4,5]imidazo[l,2-a]pyridin-l-one To a stirred solution of 3-((5-bromopyridin-2-yl)amino)cyclopent-3-en-l-one (2.00 g, 7.902 mmol) and hydroxy phenyl 4-methylbenzene-l-sulfonoperoxoyl iodide (3.72 g, 9.482 mmol) in DCE (40 mL) was added Silver Hexafluoroantimonate(V) (3.26 g, 9.482 mmol) at roomWSGR Ref: 53699-726.601 temperature. The resulting mixture was stirred at 80 °C overnight under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed -phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN in Water (10 mmol / L NH4HCO3), 20% to 30% gradient in 10 min; detector, 254 nm. This resulted in 7-br...

Claims

WSGR Ref: 53699-726.601CLAIMSWe claim:1 . A compound of Formula (I), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer:wherein,A is N or C;B is N or C; wherein at least one of A or B is N;V is N or C-R9;W is N or C-R3;X is N or C-R4;Y is N or C-R5;Z is N or C-R6; provided that at least two of W, X, Y and Z are not N;R is an optionally substituted aryl or optionally substituted heteroaryl;R1is hydrogen, -OH, or an optionally substituted C1 -C6 alkyl; or R1is optionally substituted C1-C6 alkyl, and R and R1join to form an optionally substituted spirocyclic ring; each R2is independently optionally substituted C1 -C6 alkyl; or two R2join to form optionally substituted phosphorus-containing 3- to 8-membered ring;R3, R4, R5, and R6are each independently selected from hydrogen, deuterium, halogen, - CN, or optionally substituted C1 -C3 alkyl;R7, R8, and R9are each independently selected from hydrogen, deuterium, halogen, -CN, or optionally substituted C1 -C3 alkyl;J is -C(R10)2-, or -N(Rn)-;K is absent, -O-, or -C(R12)2-;L is -C(R13)2-, -S-, -SO-, or -SO2-; each R10is independently selected from hydrogen, deuterium, halogen, -CN, -OH, - CO(NR14)2, optionally substituted C1 -C6 alkyl, or optionally substituted C1 -C6 alkoxy; or two R10form an oxo; or two R10form an =N-O-(optionally substituted C1 -C6 alkyl);R11is selected from hydrogen, or optionally substituted C1 -C6 alkyl;WSGR Ref: 53699-726.601R12is selected from hydrogen, deuterium, halogen, -CN, -OH, optionally substituted Cl- C6 alkyl, or optionally substituted C1-C6 alkoxy; or two R12form an oxo;R13are independently selected from hydrogen, deuterium, halogen, -CN, -OH, - CO(NR14)2, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 alkoxy; or two R13form an oxo; andR14is selected from hydrogen, or optionally substituted C1-C6 alkyl.

2. The compound of claim 1, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein A is C.

3. The compound of claim 1, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein A is N.

4. The compound of claim 1 or 3, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein B is C.

5. The compound of claim 1 or 2, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein B is N.

6. The compound of any one of claims 1-5, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein R is an optionally substituted heteroaryl.

7. The compound of claim 6, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein the optionally substituted heteroaryl is an optionally substituted pyridinyl.

8. The compound of any one of claims 1-5, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein R is an optionally substituted aryl.

9. The compound of claim 8, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein the optionally substituted aryl is an optionally substituted phenyl.

10. The compound of claim 9, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein the optionally substituted phenyl is a structure provided in Formula (a):wherein,WSGR Ref: 53699-726.601R15is selected from hydrogen, halogen, -CN, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 alkoxy, or optionally substituted C1-C6 alkynyl;R16, R17, and R18is selected from hydrogen, or halogen; andR19is selected from hydrogen, halogen, -CN, optionally substituted C1-C6 alkoxy, or optionally substituted C1-C3 alkyl.

11. The compound of any one of claims 1 -9, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein R1is optionally substituted Cl -C6 alkyl, and R and R1join to form optionally substituted spirocyclic ring.

12. The compound of claim 11, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein the optionally substituted spirocyclic ring has the structure provided in Formula (b):wherein,G is an optionally substituted alkylene.

13. The compound of claim 12, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein Gis an optionally substituted C2-C7 alkylene.

14. The compound of claim 12, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein Gis an optionally substituted C2 alkylene.

15. The compound of claim 12, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein Gis an optionally substituted C3 alkylene.

16. The compound of claim 12, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein Gis an optionally substituted C4 alkylene.

17. The compound of claim 12, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein Gis an optionally substituted C5 alkylene.WSGR Ref: 53699-726.60118. The compound of any one of claims 1 -17, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein R15is hydrogen, halogen, or optionally substituted C1 -C6 alkoxy.

19. The compound of claim 18, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein R15is -OCHF2.

20. The compound of any one of claims 1 -19, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein J is -CH2-, - CF2-, -CHF-, -C(H)OCH3-, -CHCN-, or -C(H)CH3-.

21. The compound of any one of claims 1 -19, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein J is -NH-, or - NCH3-.

22. The compound of any one of claims 1 -21, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein K is absent.

23. The compound of any one of claims 1 -21, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein K is -O-.

24. The compound of any one of claims 1 -21, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein K is -C(R12)2-.

25. The compound of any one of claims 1 -21, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein K is -CH2-.

26. The compound of any one of claims 1 -25, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein L is -S-, -SO-, or -SO2-.

27. The compound of any one of claims 1 -25, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein L is -C(R13)2-.

28. The compound of any one of claims 1 -25, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein L is -CH2-, - C(H)OH-, -C(H)OCH3-, -CHCN-, or -C(H)CH3-.

29. A compound of Formula (II) or (III), or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer:WSGR Ref: 53699-726.601wherein,V is N or C-R9;W is N or C-R3;X is N or C-R4;Y is N or C-R5;Z is N or C-R6; provided that at least two of W, X, Y and Z are not N;R is an optionally substituted aryl or optionally substituted heteroaryl;R1is hydrogen, -OH, or optionally substituted C1 -C6 alkyl; or R1is optionally substituted C1-C6 alkyl, and R and R1join to form optionally substituted spirocyclic ring; each R2is independently optionally substituted C1 -C6 alkyl; or two R2join to form optionally substituted phosphorus-containing 3- to 8-membered ring;R3, R4, R5, and R6are each independently selected from hydrogen, deuterium, halogen, - CN, or optionally substituted C1 -C3 alkyl;R7, R8, and R9are each independently selected from hydrogen, deuterium, halogen, -CN, or optionally substituted C1 -C3 alkyl;R20is hydrogen, deuterium, optionally substituted C1 -C3 alkyl, or optionally substituted C1-C6 alkoxy;R21is hydrogen, deuterium, or optionally substituted C1 -C3 alkyl;R22is hydrogen;R23is hydrogen;R24is hydrogen, deuterium, optionally substituted C1-C3 alkyl, or optionally substituted C1-C6 alkoxy.

30. The compound of any one of claims 1 -29, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein each R2is independently optionally substituted C1 -C6 alkyl.31 . The compound of any one of claims 1 -29, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein each R2is CH3.WSGR Ref: 53699-726.60132. The compound of any one of claims 1 -31, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein W is N.

33. The compound of any one of claims 1 -32, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein X is N.

34. The compound of any one of claims 1 -33, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein Y is N.

35. The compound of any one of claims 1 -34, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein Z is N.

36. The compound of any one of claims 1 -31 or 33-35, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein W is C-R11.

37. The compound of any one of claims 1 -32 or 34-36, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein X is C-R12.

38. The compound of any one of claims 1 -33 or 35-37, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein Y is C-R13.

39. The compound of any one of claims 1 -34 or 36-38, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein Z is C-R14.

40. The compound of any one of claims 1 -39, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein each R11, R12, R13, and R14is independently selected from H, D, or halogen.41 . The compound of any one of claims 1 -40, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein V is C-H.

42. The compound of any one of claims 1 -41, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, wherein R7, R8, and R9are each independently selected from hydrogen, deuterium, or halogen.

43. A compound described in Table 1 , or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer.

44. A compound describedin Table 2, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer.

45. A pharmaceutical composition comprising the compound of any one of claims 1 -44, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, and a pharmaceutically acceptable excipient or carrier.WSGR Ref: 53699-726.60146. A method of preparing a pharmaceutical composition comprising mixing the compound of any one of claims 1-44, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, and a pharmaceutically acceptable excipient or carrier.

47. A compound of any one of claims 1-44, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, or the pharmaceutical composition of claim 45, for use in a method of treatment of the human or animal body.

48. A compound of any one of claims 1-44, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, or the pharmaceutical composition of claim 45, for use in a method of treatment of inflammatory or autoimmune disease or disorder.

49. Use of a compound of any one of claims 1-44, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, or the pharmaceutical composition of claim 45, in the manufacture of a medicament for the treatment of an inflammatory or autoimmune disease or disorder.

50. A pharmaceutical composition comprising the compound of any one of claims 1-44, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, for use in an inflammatory or autoimmune disease or disorder in a patient in need thereof.

51. A method of treating an inflammatory or autoimmune disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effectively amount of the compound of any one of claims 1-44, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, or the pharmaceutical composition of claim 45.

52. A method of inhibiting TNF-a activity comprising contacting the TNF-a protein with the compound of any one of claims 1-44, or tautomer thereof, or deuteroisotope of said compound or tautomer, wherein the TNF-a protein is contacted in an in vitro setting.

53. A method of inhibiting TNF-a activity comprising contacting the TNF-a protein with the compound of any one of claims 1-44, or tautomer thereof, or deuteroisotope of said compound or tautomer, or the pharmaceutical composition of claim 45, wherein the TNF-a protein is contacted in an in vivo setting.

54. A method of treating or preventing a condition conducive to treatment or prevention by inhibition of TNF-a in a patient comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1-44, or tautomer thereof, orWSGR Ref: 53699-726.601 pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, or the pharmaceutical composition of claim 45.

55. A pharmaceutical composition comprising the compound of any one of claims 1-44, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, for use in treating or preventing a condition conducive to treatment or prevention by inhibition of TNF-a in a patient.

56. The compound of any one of claims 1-44, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, or the pharmaceutical composition of claim 45, for use in treating or preventing a condition conducive to treatment or prevention by inhibition of TNF-a in a patient.

57. Use of the compound of any one of claims 1 -44, or tautomer thereof, or pharmaceutically acceptable salt, solvate, or deuteroisotope of said compound or tautomer, or the pharmaceutical composition of claim 45, in the preparation of a medicament for treating or preventing a condition conducive to treatment or prevention by inhibition of TNF-a in a patient.

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