Therapeutic inhibitory compounds

Abstract

Provided herein are heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds that are useful for inhibiting plasma kallikrein. Furthermore, the subject compounds and compositions are useful for the treatment of diseases wherein the inhibition of plasma kallikrein inhibition has been implicated, such as angioedema and the like.

Description

THERAPEUTIC INHIBITORY COMPOUNDSCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. Patent Application No. 63 / 624,203, filed on January 23, 2024; which is hereby incorporated by reference in its entirety.BACKGROUND

[0002] A need exists in the medicinal arts for the effective treatment of diseases and disorders related to the vascular system. Such diseases and disorders include, but are not limited to, angioedema, macular edema and brain edema.BRIEF SUMMARY OF THE INVENTION

[0003] Provided herein are heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibiting plasma kallikrein.

[0004] One embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (I):wherein,Ring A is 1,3-disubstituted pyridine or 1,3-disubstituted, 5-membered heteroaryl;R1is hydrogen, halo, cyano, or optionally substituted C1-C5 alkyl;R2is hydrogen, cyano, optionally substituted C1-C5 alkyl, or C1-C3 optionally substituted alkoxy;R3is hydrogen, cyano, C1-C3 optionally substituted alkoxy, or optionally substituted C1-C5 alkyl;R4and R5are independently hydrogen, cyano, halo, hydroxy, C1-C3 optionally substituted alkoxy, or optionally substituted C1-C5 alkyl;R6and R7are independently hydrogen, or optionally substituted C1-C5 alkyl;XI is G, or *J-CH2-K, wherein the * denotes attachment to -C(R4)(R5)-Ring A;G is optionally substituted bicyclic heteroaryl ring;W is independently N, C-H, or C-F;X is independently N, C-H, or C-F;Y is independently N, C-H, or C-F;Z is independently N, C-H, or C-F; andK is selected from optionally substituted oxopyrimidinyl, or optionally substituted oxopyridinyl.

[0005] One embodiment provides a compound of Formula (I), or pharmaceutically acceptable salt thereof, having the structure of Formula (la):wherein,Ring A is 1,3-disubstituted pyridine or 1,3-disubstituted, 5-membered heteroaryl;R1is hydrogen, halogen, cyano, or optionally substituted C1-C5 alkyl;R2is hydrogen, cyano, optionally substituted C1-C5 alkyl, or C1-C3 optionally substituted alkoxy;R3is hydrogen, cyano, C1-C3 optionally substituted alkoxy, or optionally substituted C1-C5 alkyl;R4and R5are independently hydrogen, cyano, halo, hydroxy, C1-C3 optionally substituted alkoxy, or optionally substituted C1-C5 alkyl;XI is G, or *J-CH2-K, wherein the * denotes attachment to -C(R4)(R5)-Ring A;G is optionally substituted bicyclic heteroaryl ring;W is independently N, C-H, or C-F;X is independently N, C-H, or C-F;Y is independently N, C-H, or C-F;Z is independently N, C-H, or C-F; andK is selected from optionally substituted oxopyrimidinyl, or optionally substituted oxopyridinyl.

[0006] One embodiment provides a method of treating angioedema, including hereditary and non- hereditary, or macular edema, including diabetic macular edema, in a patient in need thereof, comprising administering to the patient a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof.

[0007] One embodiment provides a method of prophylaxis to prevent attacks of angioedema in a patient in need thereof, the method comprising administering to the patient a compound as described in Formula (I) or (la), or a pharmaceutically acceptable salt thereof.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 those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and sub-combinations 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 -NH2 radical.

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

[0013] "Nitro" refers to the -NO2 radical.

[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-OH radical.

[0019] "Hydrazino" refers to the =N-NH2 radical.

[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- Cs alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., Cs-Cs alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl (zz-propyl), 1 -methylethyl (z.w-propyl), 1 -butyl (zz-butyl), 1 -methylpropyl ( ec-butyl), 2-methylpropyl (z.w-butyl), 1,1 -dimethylethyl (tert-butyl), 1 -pentyl (zz-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, -SIU, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, oxo or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, oxo or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). In certain embodiments, an optionally substituted alkyl is a haloalkyl. In otherembodiments, an optionally substituted alkyl is a fluoroalkyl. In other embodiments, an optionally substituted alkyl is a -CF3 group.

[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 (z.e., vinyl), prop-l-enyl (z.e., allyl), but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SIU, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[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, -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 or2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[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, ^-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., Ci-Cs alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., Cs-Cs alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, - SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, - N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[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-C8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (e.g., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., Cs-Cs alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C3-C5 alkenylene). Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SIU, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0026] " Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen,containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C2-C8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C2-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., Cs-Cs alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C3-C5 alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethyl silanyl, -ORa, -SIU, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or 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, z.e., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Huckel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl,halo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, - Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb- N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb- S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

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

[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, l-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

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

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

[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 heteroaryl alkyl 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 heteroaryl alkoxy 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 (R)- or (5 -. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term “geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[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. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in, for example, U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can, in some instances, 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, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,nC,13C,14C,15C,12N,13N,15N,16N,16O, 17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35C1,37C1,79Br,81Br,125I are all contemplated. In some embodiments, isotopic substitution with18F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

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

[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-ds (CD3I), are readily available and may be employed to transfer a deuteriumsubstituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD3I is illustrated, by way of example only, in the reaction schemes below.

[0057] Deuterium-transfer reagents, such as lithium aluminum deuteride (Li AID4), are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD4 is illustrated, by way of example only, in the reaction schemes below.

[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 kallikrein 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, 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 base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N- dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine,ethylenedianiline, 7V-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.

[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.Kallikrein Protein and FunctionKallikrein-Kinin System

[0066] Modulation of vascular permeability is important in regulating the passage of small molecules or blood cells between blood vessels and surrounding tissues. Vascular permeability depends upon the physiological states of tissues such as during inflammation, changes in blood pressure, and fluctuations in ion and nutrient gradients. The junctions between the endothelial cells that line blood vessels are the immediate controllers of vascular permeability. The strength of these junctions is tightly regulated by the kinin-kallikrein system of polypeptides and enzymes. Abnormalities in the kinin-kallikrein system lead to a range of pathologies including angioedema, macular edema and brain edema. Angioedema is a potentially fatal blood disorder characterized by swelling that may occur in the face, gastrointestinal tract, extremities, genitalsand upper airways. Genetic hereditary angioedema attacks result from the unregulated activation of the kallikrein system with uncontrolled increases in vascular permeability. Currently there is a need for agents that are useful for the treatment of angioedema and for agents that inhibit plasma kallikrein.

[0067] The kallikrein-kinin system represents a metabolic cascade that, when activated, triggers the release of vasoactive kinins. The kinin-kallikrein system (KKS) consists of serine proteases involved in the production of kinins, principally bradykinin and Lys-bradykinin (kallidin). The KKS contributes to a variety of physiological processes including inflammation, blood pressure control and coagulation. The activation of this system is particularly important in blood pressure regulation and in inflammatory reactions, due to the ability of bradykinin to elevate vascular permeability and to cause vasodilatation of arteries and veins of the gut, aorta, uterus and urethra. The kinin-kallikrein system, also referred to as the contact system, consists of three serine proenzymes (factor XII (FXII) or Hageman factor, factor IX (FIX), and prekallikrein), and the kinin precursor high molecular weight kinin (HK). Contact activation is triggered by the binding of FXII to a negatively charged surface and involves the formation of a-FXIIa via autocatalysis. Bound a-FXIIa converts prekallikrein into kallikrein. Kallikrein can further convert a-FXIIa to P-FXIIa by an additional cleavage at R334-N335, a positive feedback mechanism that leads to sufficient kallikrein production to drive downstream processes. a-FXIIa consists of a heavy and light chain that are disulphide linked, whereas P-FXIIa lacks the heavy chain and loses its capacity to bind to negatively charged surfaces (Stavrou E, Schmaier AH., Thrombosis Research, 2010, 125(3) pp. 210-215). The N-terminal region of FXII (a-FXIIa heavy chain) shows strong homology with tissue-type plasminogen activator (tPA), with the presence of fibronectin type I, epidermal growth factor, and Kringle domains (Ny et al., Proc Natl Acad Sci USA, 1984, 81(17) pp. 5355-5359; Cool DE, MacGillivray RT, The Journal of Biological Chemistry, 1987, 262(28) pp. 13662-13673). Kallikrein is a trypsin-like serine protease enzyme that cleaves high molecular weight kinin (HK) to produce bradykinin. Bradykinin then binds to the bradykinin 2R receptors (BK2R) on endothelial cells to trigger an increase in vascular permeability.

[0068] Protease inhibitors regulate the activation of the contact system. Several known serpins of plasma are Cl-inhibitor (CHNH), antithrombin III, a2 -macroglobulin, al-protease inhibitor, and a2-antiplasmin (Kaplan et al., Advances in Immunology, 1997 (66) pp.225-72; Pixley et al., The Journal of Biological Chemistry, 1985, 260(3) pp. 1723-9). However, CHNH is the major regulator of the intrinsic system, interfering with the activities of factor Xlla and of kallikrein (Cugno et al., The Journal of Laboratory and Clinical Medicine, 1993, 121(1) pp. 38-43). Both CHNH and a2 -macroglobulin account for more than 90% of the kallikrein inhibitory activity ofplasma. Thus, the FXII-dependent kallikrein-kinin system is tightly regulated by the CINH and when regulation of the FXII-dependent kallikrein-kinin system fails, in a subject, the subject is believed to suffer from hereditary angioedema (HAE) that is characterized by invalidating edema attacks.

[0069] Angioedema is a potentially fatal blood disorder characterized by swelling that may occur in the face, gastrointestinal tract, extremities, genitals and upper airways. Angioedema attacks begin in the deeper layers of the skin and mucous membranes with localized blood vessel dilatation and increased permeability. Symptoms of the disease result from the leakage of plasma from blood vessels into surrounding tissues. Genetic hereditary angioedema attacks result from unregulated activation of the kallikrein system with consequent overproduction of bradykinin and uncontrolled increases in vascular permeability. As vascular permeability rises beyond normal, plasma leaks out of the vasculature into surrounding tissue, causing swelling (Mehta D and Malik AB, Physiol. Rev., 86 (1), 279-367, 2006; Sandoval R et al., J. Physiol., 533(pt 2), 433-45, 2001; Kaplan AP and Greaves MW, Angioedema. J. Am. Acad. Dermatol., 2005).

[0070] HAE results from mutations in the genes that code for elements of the coagulation and inflammation pathways. The three forms of HAE are distinguished by their underlying causes and levels of the Cl -esterase inhibitor (Cl INH, serpin peptidase inhibitor, clade G, member 1) protein in the blood, which inhibits the activity of plasma kallikrein. In type I, patients have insufficient levels of functional CHNH, while type II patients have dysfunctional CHNH. While type I and II affect men and women at equal rates, type III, which primarily affects women, results from a mutation in coagulation factor XII (Hageman factor; HAE-FXII). The underlying causes of type I and II HAE are autosomal dominant mutations in CHNH gene (SERPING1 gene) on chromosome 11 (1 Iql2-ql3.1).

[0071] CHNH accounts for 90% of inhibition of FXIIa and 50% of inhibition of plasma kallikrein (Pixley RA et al., J. Biol. Chem., 260, 1723-9, 1985; Schapira M et al., Biochemistry, 20, 2738- 43, 1981). In addition, CHNH also inactivates prekallikrein (Colman RW et al, Blood, 65, 311- 8, 1985). When CHNH levels are normal, its activity blocks FXIIa from converting prekallikrein to kallikrein and blocks kallikrein's conversion to HK, thus preventing the production of bradykinin and the edemic episodes. When CHNH levels are low, or levels of dysfunctional CHNH are high, this inhibition fails and the pathogenic process ensues.

[0072] In addition to HAE, plasma kallikrein also contributes to non-hereditary angioedema, high altitude cerebral edema, cytotoxic cerebral edema, osmotic cerebral edema, diabetic macular edema (DME), clinically significant macular edema, cystoid macular edema (CME, Gao BB, Nat Med., 13(2), 181-8, 2007), retinal edema, radiation induced edema, lymph edema, glioma- associated edema, allergic edema e.g. airflow obstruction in chronic allergic sinusitis orperennial rhinitis. Other disorders of the plasma kallikrein system include retinopathy and diabetic retinopathy (Liu J and Feener EP, Biol. Chem. 394(3), 319-28, 2013), proliferative and non-proliferative retinopathy (Liu J et al, Invest. Ophthalmol. Vis. Sci., 54(2), 2013), CME following cataract extraction, CME induced by cryotherapy, CME induced by uveitis, CME following vascular occlusion (e.g., central retinal vein occlusion, branch retinal vein occlusion or hemiretinal vein occlusion), complications related to cataract surgery in diabetic retinopathy, hypertensive retinopathy (JA Phillips et al., Hypertension, 53, 175-181, 2009), retinal trauma, dry and wet age-related macular degeneration (AMD), ischemic reperfusion injuries (C Storoni et al., JPET, 381, 849-954, 2006), e.g., in a variety of contexts associated with tissue and / or organ transplantation.

[0073] Current treatments for angioedema, and those under development, target different elements in the HAE pathway. Three classes of therapies are currently available: (a) replacement therapy with C1INH concentrates (e.g., Cinryze, Berinert), (b) administration of selective kallikrein inhibitors (e.g., Ecallantide) and (c) bradykinin receptors antagonists (e.g., Firazyr). Replacement therapies have proven useful for both acute attacks, including emergency situations, such as laryngeal edema (Bork K et al., Transfusion, 45, 1774-1784, 2005; Bork K and Barnstedt S E, Arch. Intern. Med., 161, 714-718, 2001) and prophylaxis. Selective C1INH inhibitors inactivate both a-FXIIa and P-FXIIa molecules active early in the HAE pathway that catalyze the production of kallikrein (Muller F and Renne T, Curr. Opin. Hematol., 15, 516-21, 2008; Cugno M et al., Trends Mol. Med. 15(2):69-78, 2009). In addition to HAE, plasma kallikrein inhibitors are considered to be useful in the treatment of other edemas such as macular edema and brain edema, and retinopathy, e.g., retinopathy associated with diabetes and / or hypertension. There is evidence that plasma kallikrein inhibitors are also effective in the treatment of edema formation in diseases, e.g., edema formation related to ischemic reperfusion injuries. The bradykinin receptors antagonists prevent bradykinin from activating the vascular permeability pathway and stop the initiation of swelling.Novel Kallikrein Inhibitors

[0074] Provided herein are heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibiting plasma kallikrein.

[0075] One embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (I):wherein,Ring A is 1,3-disubstituted pyridine or 1,3-disubstituted, 5-membered heteroaryl;R1is hydrogen, halo, cyano, or optionally substituted C1-C5 alkyl;R2is hydrogen, cyano, optionally substituted C1-C5 alkyl, or C1-C3 optionally substituted alkoxy;R3is hydrogen, cyano, C1-C3 optionally substituted alkoxy, or optionally substituted C1-C5 alkyl;R4and R5are independently hydrogen, cyano, halo, hydroxy, C1-C3 optionally substituted alkoxy, or optionally substituted C1-C5 alkyl;R6and R7are independently hydrogen, or optionally substituted C1-C5 alkyl;XI is G, or *J-CH2-K, wherein the * denotes attachment to -C(R4)(R5)-Ring A;G is optionally substituted bicyclic heteroaryl ring;W is independently N, C-H, or C-F;X is independently N, C-H, or C-F;Y is independently N, C-H, or C-F;Z is independently N, C-H, or C-F; andK is selected from optionally substituted oxopyrimidinyl, or optionally substituted oxopyridinyl.

[0076] One embodiment provides a compound of Formula (I), or pharmaceutically acceptable salt thereof, having the structure of Formula (la):wherein,Ring A is 1,3-disubstituted pyridine or 1,3-disubstituted, 5-membered heteroaryl;R1is hydrogen, halo, cyano, or optionally substituted C1-C5 alkyl;R2is hydrogen, cyano, optionally substituted C1-C5 alkyl, or C1-C3 optionally substituted alkoxy;R3is hydrogen, cyano, C1-C3 optionally substituted alkoxy, or optionally substituted C1-C5 alkyl;R4and R5are independently hydrogen, cyano, halo, hydroxy, C1-C3 optionally substituted alkoxy, or optionally substituted C1-C5 alkyl;XI is G, or *J-CH2-K, wherein the * denotes attachment to -C(R4)(R5)-Ring A;G is optionally substituted bicyclic heteroaryl ring;W is independently N, C-H, or C-F;X is independently N, C-H, or C-F;Y is independently N, C-H, or C-F;Z is independently N, C-H, or C-F; andK is selected from optionally substituted oxopyrimidinyl, or optionally substituted oxopyridinyl.

[0077] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R6and R7are independently selected from hydrogen, fluoromethyl, hydroxymethyl, and methyl. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R6is hydrogen, and R7is hydrogen, hydroxymethyl, or methyl. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R6is hydrogen, and R7is hydrogen.

[0078] Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein XI is G.

[0079] Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein G is selected from optionally substituted quinolyl, optionally substituted indolyl, optionally substituted indazolyl, optionally substituted benzimidazolyl, optionally substituted isoquinolyl, optionally substituted cinnolinyl, optionally substituted phthalazinyl, optionally substituted quinazolinyl, optionally substituted naphthyridinyl, or optionally substituted benzoisoxazolyl.

[0080] Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein G is selected from optionally substituted quinolin-3-yl, or optionally substituted quinolin-6-yl. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted quinolin-6-yl, oroptionally substituted quinolin-3-yl is substituted with at least one substituent selected from optionally substituted C1-C3 alkyl, halogen, -CN, -SChMe, -SO2NH2, -CONH2, -CH2NHAC, - CChMe, -CO2H, -CH2OH, -CH2NH2, -NH2, -OH, or -OMe. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted quinolin-6-yl is substituted at least at the 3-position. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein the quinolin-6-yl is selected from 3-chloroquinolin-6-yl, 3-methylquinolin-6-yl, 3-trifluoromethylquinolin-6-yl, 3- fluoroquinolin-6-yl, or 3-cyanoquinolin-6-yl. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted quinolin-3-yl is substituted at least at the 6-position or the 7-position. Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein G is 3- chloroquinolin-6-yl.

[0081] Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein XI is *J-CH2-K, wherein the * denotes attachment to - C(R4)(R5)-Ring A.

[0082] Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein J is

[0083] Another embodiment provides the compound of Formula (I) or (la), or a pharmaceuticallyacceptable salt thereof, wherein J is W=XW is independently C-H, or C-F;X is independently C-H, or C-F;Y is independently C-H, or C-F; andZ is independently C-H, or C-F.

[0084] Another embodiment provides the compound of Formula (I) or (la), or a pharmaceuticallyacceptable salt thereof, wherein J is W=X Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein:W is independently C-H, or C-F;X is independently C-H, or C-F; andY is independently C-H, or C-F.

[0085] Another embodiment provides the compound of Formula (I) or (la), or a pharmaceuticallyacceptable salt thereof, wherein J is W-X Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein:W is independently C-H, or C-F;X is independently C-H, or C-F; andZ is independently C-H, or C-F.

[0086] Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein J isAnother embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein:W is independently C-H, or C-F;Y is independently C-H, or C-F; andZ is independently C-H, or C-F.

[0087] Another embodiment provides the compound of Formula (I) or (la), or a pharmaceuticallyacceptable salt thereof, wherein J is N—X Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein:X is independently C-H, or C-F;Y is independently C-H, or C-F; and Z is independently C-H, or C-F.

[0088] Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein K is optionally substituted oxopyrimidinyl. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted oxopyrimidinyl is optionally substituted with at least one fluoro. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted oxopyrimidinyl is optionally substituted 2-oxopyrimidin-l-yl. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted oxopyrimidinyl is optionally substituted 6-oxopyrimidin-l-yl.

[0089] Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein K is optionally substituted oxopyridinyl. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted oxopyridinyl is optionally substituted 2-oxopyridin-l-yl. Another embodimentprovides the compound, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 2-oxopyridin-l-yl is optionally substituted with at least one fluoro.

[0090] Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein Ring A is a 1,3 -di substituted pyridine having the structure:

[0091] Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein Ring A is a 1,3 -di substituted, 5-membered heteroaryl. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein the 1,3 -di substituted, 5-membered heteroaryl is selected from optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted triazole, optionally substituted oxazole, or optionally substituted oxadiazole. Another embodiment provides the compound or a pharmaceutically acceptable salt thereof, wherein the 1,3 -di substituted, 5-membered heteroaryl is selected from optionally substituted triazole, optionally substituted oxazole, or optionally substituted oxadi azole.

[0092] Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein Ring A is:

[0093] Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein Ring A is:

[0094] Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein Ring A is:

[0095] Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein Ring A is:

[0096] Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein Ring A is:

[0097] Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein Ring A is:

[0098] Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein R1is fluoro.

[0099] Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein R2is C1-C3 optionally substituted alkoxy. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein R2is -OCH3, - OCF3, -OCHF2, or -OCH2F. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein R2is -OCH3.

[0100] Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen.

[0101] Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein R4and R5are hydrogen.

[0102] One embodiment provides a kallikrein inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 1.Table 1Preparation of Compounds

[0103] The compounds used in the synthetic chemistry reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and / or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0104] 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 forexample, 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.

[0105] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (contact the American Chemical Society, Washington, D.C. for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference useful for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.Pharmaceutical Compositions

[0106] In certain embodiments, the kallikrein inhibitory compound described herein is administered as a pure chemical. In other embodiments, the kallikrein 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)).

[0107] Provided herein is a pharmaceutical composition comprising at least one kallikrein inhibitory compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, orsolvate thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or the patient) of the composition.

[0108] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof.

[0109] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0110] In certain embodiments, the kallikrein inhibitory compound as described by Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0111] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0112] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0113] In certain embodiments, the kallikrein inhibitory compound as described by Table 1, or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0114] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0115] In some embodiments, the kallikrein inhibitory compound as described by Formula (I) or (la), or Table 1, or pharmaceutically acceptable salt or solvate thereof, is formulated for administrationby 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.

[0116] The dose of the composition comprising at least one kallikrein inhibitory compound as described herein differs depending upon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors.

[0117] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0118] Oral doses typically range from about 0.01 mg to about 1000 mg, one to four times, or more, per day.Methods of Treatment

[0119] One embodiment provides a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0120] Disclosed herein are methods of treating diseases or disorders wherein the inhibition of plasma kallikrein is indicated. One embodiment provides a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating angioedema, including hereditary and non-hereditary, or macular edema, including diabetic macular edema.

[0121] One embodiment provides a method of treating angioedema, including hereditary and non- hereditary, or macular edema, including diabetic macular edema, in a patient in need thereof, comprising administering to the patient a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof.

[0122] One embodiment provides a method of treating angioedema, including hereditary and non- hereditary, or macular edema, including diabetic macular edema, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0123] One embodiment provides a method of prophylaxis to prevent attacks of angioedema in a patient in need thereof, the method comprising administering to the patient a compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof.

[0124] One embodiment provides a method of prophylaxis to prevent attacks of angioedema in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0125] One embodiment provides a method of prophylaxis to prevent attacks of angioedema in a patient in need thereof, the method comprising administering to the patient a compound as described in Table 1, or a pharmaceutically acceptable salt thereof.

[0126] One embodiment provides a method of prophylaxis to prevent attacks of angioedema in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition comprising a compound as described in Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0127] Another embodiment provides the method wherein the angioedema is hereditary angioedema. Another embodiment provides the method wherein the angioedema is acute angioedema.

[0128] 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.

[0129] One embodiment provides a method of inhibiting kallikrein protein activity comprising contacting the kallikrein protein with a compound of Formula (I) or (la), or Table 1. Another embodiment provides the method of inhibiting kallikrein protein activity, wherein the kallikrein protein is contacted in an in vivo setting. Another embodiment provides the method of inhibiting kallikrein protein activity, wherein the kallikrein protein is contacted in an in vitro setting.

[0130] 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

[0131] In some embodiments, the kallikrein inhibitory compounds disclosed herein are synthesized according to the following examples. As used below, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: ACN acetonitrile°C degrees Celsius5H chemical shift in parts per million downfield from tetramethylsilaneDCM dichloromethane (CH2CI2)DIAD 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 u micro m multiplet (spectral); meter(s); milliM molarM+parent molecular ionMe methylMsCl methanesulfonyl chlorideMHz megahertz min minute(s) mol mole(s); molecular (as in mol wt) mL milliliterMS mass spectrometry nm nanometer(s)NMR nuclear magnetic resonance pH potential of hydrogen; a measure of the acidity or basicity of an aqueous solutionPE petroleum etherRT room temperature s singlet (spectral)t triplet (spectral)SFC Supercritical fluid chromatographyT temperatureTFA trifluoroacetic acidTHF tetrahydrofuranTPP Triphenylphosphine

[0132] Example 1: Preparation of N-((5-aminopyri din-2 -yl)methyl)-2-((3 -chi oroquinolin-6- yl)methyl)isonicotinamide

[0133] To a solution of 5-aminopicolinonitrile (1.0 g, 5.02 mmol, 1.0 eq) in THF (15 mL) was added LiAlH4 (IM in THF, 6 mL, 6.0 mmol, 1.2 eq) at -40 °C under N2. The mixture was stirred at 0 °C for 1 h, followed by addition of saturated NH4CI solution (80 mL), and extracted with EA (50 mLx 3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 2 / 1, v / v) to yield 6-(aminomethyl)pyri din-3 -amine (700 mg, 68%) as a yellow solid.

[0134] A mixture of 2-((3-chloroquinolin-6-yl)methyl)isonicotinic acid (100 mg, 0.33 mmol, 1.0 eq), 6- (aminomethyl)pyri din-3 -amine (42 mg, 0.33 mmol, 1.0 eq), HATU (191 mg, 0.50 mmol, 1.5 eq) and TEA (102 mg, 1.01 mmol, 3.0 eq) in DMF (5 mL) was stirred at rt for 1 h. The mixture was concentrated, and the resulting residue was purified by prep-HPLC to yield N-((5-aminopyridin- 2-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide (14 mg, 10%) as a white solid. LRMS (M+H+) m / z calculated 404.12, found 404.0. 'HNMR (DMS0 , 400 MHz) 5 9.18-9.15 (t, J= 6.0, 5.2 Hz, 1H), 8.83 (d, J= 2.4 Hz, 1H), 8.64 (d, J= 5.2 Hz, 1H), 8.53 (d, J= 2.4 Hz,1H), 7.99 (d, J =8.8 Hz, 1H), 7.86 (d, J= 2.8 Hz, 2H), 7.78 (s, 1H), 7.75 (dd, J= 8.8, 2.0 Hz, 1H), 7.65 (dd, J= 4.8, 1.2 Hz, 1H), 6.99 (d, J= 8.0 Hz, 1H), 6.87 (dd, J =8.4, 2.8 Hz, 1H), 5.19 (s, 2H), 4.39 (s, 2H), 4.37 (s, 2H).

[0135] Example 2: Preparation of N-((5-amino-3-methylpyridin-2-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)isonicotinamide7V-((5-amino-3-methylpyridin-2-yl)methyl)-2-((3- chloroqumolm-6-yl)methyl)isonicotinainide

[0136] To a solution of 3-methyl-5-nitropicolinonitrile (1.6 g, 9.81 mmol, 1.0 eq) in MeOH (20 mL) was added Pd / C (200 mg). The mixture was stirred under H2 (50 psi) at 30 °C overnight. The mixture was cooled to rt and filtered. The filtrate was concentrated to yield 5-amino-3- methylpicolinonitrile (1.3 g, quant.), which was used in the next step without further purification.

[0137] To a solution of 5-amino-3-methylpicolinonitrile (1.3 g, 9.76 mmol, 1.0 eq) in THF (20 mL) was added LiAlHq (1 M in THF, 12 mL, 12.0 mmol, 1.2 eq) at - 40 °C under N2. The mixture was stirred at 0 °C for 1 h, followed by the addition of saturated NH4CI solution (30 mL), and extracted with EA (50 mLx 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to yield 6-(aminomethyl)-5-methylpyridin-3-amine (700 mg, 52%) which was used in the next step without further purification.

[0138] A mixture of 2-((3-chloroquinolin-6-yl)methyl)isonicotinic acid (100 mg, 0.33 mmol, 1.0 eq), 6- (aminomethyl)pyri din-3 -amine (42 mg, 0.33 mmol, 1.0 eq), HATU (191 mg, 0.50 mmol, 1.5 eq) and TEA (102 mg, 1.01 mmol, 3.0 eq) in DMF (5 mL) was stirred at rt for 1 h. The mixture was concentrated, and the resulting residue was purified by prep-HPLC to yield N-((5-aminopyridin- 2-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide (14 mg, 10%) as a white solid. LRMS (M+H+) m / z calculated 418.14, found 418.1.1HNMR (DMSO , 400 MHz) 5 8.91 (t, J = 5.6, 5.2 Hz, 1H), 8.83 (d, J= 2.4 Hz, 1H), 8.62 (d, J = 5.2 Hz, 1H), 8.52 (d, J= 1.6 Hz, 1H), 7.99 (d, J= 8.8 Hz, 1H), 7.85 (s, 1H), 7.78 (s, 1H), 7.75 (dd, J= 8.4, 1.6 Hz,lH), 7.70 (d, J= 2.8 Hz, 1H), 7.64 (dd, J= 5.2, 2.0 Hz,lH), 6.72 (d, J= 2.4 Hz, 1H), 5.14 (s, 2H), 4.42 (d, J= 5.2 Hz, 2H), 4.36 (s, 2H), 2.17 (s, 3H).

[0139] Example 3: Preparation of N-((5-amino-3-fluoropyridin-2-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)isonicotinamideJV-((5 -amino-3 -fluoropyridin-2-yl)methyl)-2-((3 - chloroqumolm-6-yl)methyl)isonicotinamide

[0140] A mixture of 3-fluoropicolinonitrile (5.0 g, 41.0 mmol, 1.0 eq), KNO3 (8.3 g, 82.0 mmol, 2.0 eq) and trifluoroacetic anhydride (8.6 g, 41.0 mmol, 1.0 eq) in TFA (9.4 g, 82.0 mmol, 2.0 eq) was stirred at rt for 21 h under N2. The mixture was poured into saturated NaHCCL solution (400 mL), and extracted with ethyl acetate (200 mL x 3). The combined organic layers were dried, filtered and concentrated to afford 3-fluoro-5-nitropicolinonitrile (1.7 g, 25%) as a yellow solid.

[0141] To a solution of 3-fluoro-5-nitropicolinonitrile (300 mg, 1.8 mmol, 1.0 eq) in EtOAc (2 mL) were added Fe (503 mg, 9.0 mmol, 5.0 eq) and acetic acid (2 mL). The reaction mixture was stirred at 65 °C overnight. Saturated NaHCCh solution was added, and the mixture was extractedwith EA (200 mL x 3). The combined organic layers were dried, filtered and concentrated to get 5-amino-3-fluoropicolinonitrile (203 mg, 82%) as a yellow solid.

[0142] To a solution of 5-amino-3-fhioropicolinonitrile (200 mg, 1.5 mmol, 1.0 eq) in THF (10 mL) was added LiAlEL (3 mL, 3.0 mmol, 2.0 eq) at 0 °C under N2. The reaction mixture was stirred at rt for 3 h. The reaction mixture was then diluted with EtOAc (2 mL), and water (0.1 mL), NaOH (aq., 15 wt. %, 0.1 mL) and water (0.1 mL) were added sequentially. The reaction mixture was then dried over MgSO4, filtered and concentrated to afford 6-(aminomethyl)-5- fluoropyri din-3 -amine (107 mg, 52%) as a yellow solid.

[0143] To a solution of 6-(aminomethyl)-5-fluoropyridin-3-amine (107 mg, 0.76 mmol, 1.0 eq) in DMF (40 mL) were added PyBOP (474 mg, 0.91 mmol, 1.2 eq), 2-((3-chloroquinolin-6- yl)methyl)isonicotinic acid (219 mg, 0.76 mmol, 1.0 eq) and TEA (231 mg, 2.3 mmol, 3.0 eq). The reaction mixture was stirred at rt overnight and concentrated. The resulting residue was purified by prep-HPLC to afford N-((5-amino-3-fluoropyridin-2-yl)methyl)-2-((3- chloroquinolin-6-yl)methyl)isonicotinamide (23 mg, 7%) as a white solid. LRMS (M+H+) m / z calculated 422.11, found 422.0. 'HNMR (DMSO-tL, 400 MHz) 5 9.03 (t, J= 5.6, 5.6 Hz, 1H), 8.82 (d, J= 2.4 Hz, 1H), 8.62 (d, J= 5.2 Hz, 1H), 8.52 (d, J= 2.4 Hz, 1H), 7.98(d, J= 8.8 Hz, 1H), 7.85 (s, 1H), 7.76 (s, 1H), 7.74-7.72 (m, 2H), 7.64 (dd, J= 5.2, 1.2 Hz, 1H), 6.73 (dd, J= 4.4, 2.4 Hz, 1H), 5.59 (s, 2 H), 4.45 (d, J= 4.4 Hz, 2H), 4.35 (s, 2H).

[0144] Example 4: Preparation of N-((5-amino-3 -fluoro-4-m ethoxypyri din-2 -yl)methyl)-2-((3 - chloroquinolin-6-yl)methyl)isonicotinamide

[0145] To a solution of 5 -bromo-2-chl oro-3 -fluoropyridine (20.0 g, 95.2 mmol, 1.0 eq) in dioxane (300 mL) were added NH2B0C (12.2 g, 104.8 mmol, 1.1 eq), Xantphos (2.2 g, 3.8 mmol, 0.04 eq), CS2CO3 (62.1 g, 190.5 mmol, 2.0 eq) and Pd2(dba)s (1.1 g, 1.9 mmol, 0.02 eq) at rt. The mixture was stirred at 85 °C for 16 h under N2, then cooled to rt. After filtration, the solid was washed with DCM. The combined filtrates were washed with water, dried over ISfeSCU, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (PE / EA = 10 / 1, v / v) to yield tert-butyl (6-chloro-5-fluoropyridin-3-yl)carbamate (16.0 g, 68%) as a white solid.

[0146] To a solution of tert-butyl (6-chloro-5-fluoropyridin-3-yl)carbamate (8.0 g, 32.5 mmol, 1.0 eq) and TMEDA (11.3 g, 97.6 mmol, 3.0 eq) in THF (80 mL) was added n-BuLi (61 mL, 1.6 M in THF, 97.6 mmol, 3.0 eq) at -78 °C under N2 protection. The mixture was stirred at -20 °C for 1.5 h, and then NFSI (30.7 g, 97.6 mmol, 3.0 eq) was added at -78 °C. To this mixture was added HC1 (1 N, 80 mL) and it was extracted with EA (50 mL x 3). The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (PE / EA = 20 / 1, v / v) to yield tert-butyl (6- chloro-4,5-difluoropyridin-3-yl)carbamate (6.5 g, 76%) as a white solid.

[0147] To a solution of tert-butyl (6-chloro-4,5-difluoropyridin-3-yl)carbamate (4.4 g, 1.67 mmol, 1.0 eq) in MeOH (80 mL) was added NaOMe (1.0 g, 20.0 mmol, 1.2 eq) at rt under N2. The mixture was stirred 30 °C for 1 h, and then cooled to rt. H2O (40 mL) was added, and the mixture was extracted with EA (40 mL x 3). The combined organic layers were dried over ISfeSCL, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 20 / 1, v / v) to yield tert-butyl (6-chloro-5-fluoro-4-methoxypyridin-3-yl)carbamate (4.1 g, 89%) as a white solid.butyldi-1 -adamantylphosphinePd(OAc)2 / Cs2CO3,Dioxane / H2O

[0148] To a solution of tert-butyl (6-chloro-5-fluoro-4-methoxypyridin-3-yl)carbamate (6.9 g, 24.9 mmol, 1.0 eq ) and potassium {[(tert butoxy carbonyl)amino]methyl {trifluoroborate (6.5 g, 27.4 mmol, 1.1 eq) in dioxane / FEO (85 mL / 15 mL) were added Pd(OAc)2 (558 mg, 2.49 mmol, 0.1 eq), butyldi-l-adamantylphosphine (1.8 g, 4.98 mmol, 0.2 eq ) and CS2CO3 (16.2 g, 49.8 mmol, 2 eq). The mixture was stirred at 110 °C overnight under N2, and then filtered. The filtrate was concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 2 / 1, v / v) to afford tert-butyl (6-(((tert-butoxycarbonyl)amino)methyl)-5-fluoro-4- methoxypyri din-3 -yl)carbamate (3.2 g, 35%) as a yellow solid.

[0149] To a solution of tert-butyl (6-(((tert-butoxycarbonyl)amino)methyl)-5-fluoro-4-methoxypyridin-3-yl)carbamate (3.2 g, 8.62 mmol, 1.0 eq) in DCM (30 mL) at 0 °C was added TFA (10 mL). The mixture was stirred at rt for 1 h, and concentrated to afford 6-(aminomethyl)-5-fluoro-4- methoxypyri din-3 -amine as trifluoroacetate which was used in the next step without further purification.

[0150] A mixture of 2-((3-chloroquinolin-6-yl)methyl)isonicotinic acid (336 mg, 1.13 mmol, 1.0 eq), 6- (aminomethyl)-5-fluoro-4-methoxypyridin-3-amine trifluoroacetate (450 mg, 1.13 mmol, 1.0 eq), HATU (643 mg, 1.69 mmol, 1.5 eq) and TEA (342 mg, 1.38 mmol, 3.0 eq) in DMF (10 mL) was stirred at rt for 1 h. Water (50 mL) was added, and the mixture was extracted with EA (50 mL x 3). The combined organic layers were washed with brine, dried over ISfeSCL, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 20 / 1, v / v) to afford N-((5-amino-3-fluoro-4-methoxypyridin-2-yl)methyl)-2- ((3-chloroquinolin-6-yl)methyl)isonicotinamide (350 mg, 69%) as a white solid. LRMS (M+H+)m / z calculated 452.12, found 452.0. 'H NMR (DMSO-t / 6, 400 MHz) 5 9.05 (t, J= 5.6, 4.8 Hz 1H), 8.83 (d, J= 2.4 Hz, 1H), 8.63 (d, J= 5.6 Hz, 1H), 8.52 (d, J= 2.4 Hz, 1H), 7.99 (d, J =8.4 Hz, 1H), 7.85 (s, 1H), 7.76-7.73 (m, 3H), 7.63 (d, J= 5.2 Hz, 1H), 5.29 (s, 2H), 4.45 (d, J= 3.6 Hz, 2H), 4.36 (s, 2H), 3.88 (d, J= 2.0 Hz, 3H).

[0151] Example 5: Preparation of N-((5-amino-3 -fluoro-4-m ethoxypyri din-2 -yl)methyl)-2-((3 -chi oro- 8-fiuoroquinolin-6-yl)methyl)oxazole-5-carboxamide

[0152] To a solution of 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)oxazole-5-carboxylic acid (200 mg, 0.65 mmol, 1.0 eq) in DMF (20 mL) was added CDI (127 mg, 0.78 mmol, 1.2 eq). The mixture was stirred at rt for 2 h. 6-(Aminomethyl)-5-fluoro-4-methoxypyridin-3-amine trifluoroacetate (259 mg, 0.65 mmol, 1.0 eq) was added and the reaction mixture was stirred at rt overnight. Water (100 mL) was added and the mixture was extracted with EA (50 mL x 3). The combined organic layers were washed with brine, dried over ISfeSCU, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 20 / 1, v / v) to afford N-((5-amino-3-fluoro-4-methoxypyridin-2-yl)methyl)-2-((3-chloro-8- fluoroquinolin-6-yl)methyl)oxazole-5-carboxamide (210 mg, 70%) as a white solid.LRMS (M+H+) m / z calculated 460.09, found 460.0.1H NMR (DMSO-t / 6, 400 MHz) 5 8.93 (d, J = 2.0 Hz, 1H), 8.82 (t, J= 5.6, 4.8 Hz, 1H), 8.65 (s, 1H), 7.75-7.73 (m, 3H), 7.68 (d, J=11.6 Hz, 1H), 5.30 (s, 2H), 4.44 (s, 2H), 4.41 (d, J= 4.0 Hz, 2H), 3.89 (d, J= 2.0 Hz, 3H).

[0153] Example 6: Preparation of N-((5-amino-4-(difluoromethoxy)-3-fluoropyri din-2 -yl)methyl)-2- ((3-chloroquinolin-6-yl)methyl)isonicotinamide

[0154] To a solution of tert-butyl (6-chloro-5-fluoropyridin-3-yl)carbamate (1.0 g, 4.1 mmol, 1.0 eq) inTHF (15 mL) was added n-BuLi (2.5 M in THF , 4.1mL, 10.1 mmol, 2.5 eq) at -78 °C under N2.The mixture was stirred at -78 °C for 1 h. Trimethyl borate (943 mg, 8.1 mmol, 2.0 eq) was added. The mixture was stirred at rt for 24 h. Saturated NaOH solution (1.2 mL) and 30% H2O2(1.4 mL) were added at 0 °C. The resulting mixture was stirred for 2 h. The mixture was adjusted to pH 5 with 1 N HC1 solution. The solid was collected to give tert-butyl (6-chloro-5- fluoro-4-hydroxypyridin-3-yl)carbamate (490 mg, 49%) as a white solid.

[0155] To a solution of tert-butyl (6-chloro-5-fluoro-4-hydroxypyridin-3-yl)carbamate (300 mg, 1.14 mmol, 1.0 eq) in DMF (10 mL) were added 2-chloro-2,2-difluoroacetate sodium (522 mg, 3.42 mmol, 3.0 eq) and CS2CO3 (1.16 g, 3.42 mmol, 3.0 eq) at rt. The mixture was stirred at 100 °C overnight under N2, and concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 2 / 1, v / v) to provide tert-butyl (6-chloro-4-(difluoromethoxy)-5- fluoropyri din-3 -yl)carbamate (119 mg, 33 %).Pd(OAc)2 / Butyldi-1-adamantylphosphineDioxane / H2O / Cs2CO3

[0156] A mixture of tert-butyl (6-chloro-4-(difluoromethoxy)-5-fluoropyridin-3-yl)carbamate (65 mg, 0.21 mmol, 1.0 eq), butyldi-l-adamantylphosphine (8 mg, 0.02 mmol, 0.1 eq), Pd(OAc)2 (3 mg, 0.02 mmol, 0.1 eq) and CS2CO3 (203 mg, 0.62 mmol, 3.0 eq) in dioxane (5 mL) and H2O (1 mL ) was stirred at 100 °C overnight under N2. The mixture was concentrated and the resulting residue was purified by chromatography on silica gel column (PEZEA = 10 / 1, v / v) to yield tertbutyl (6-(((tert-butoxycarbonyl)amino)methyl)-4-(difluoromethoxy)-5-fluoropyridin-3- yl)carbamate (47 mg, 73%) as a white solid.

[0157] To a solution of tert-butyl (6-(((tert-butoxycarbonyl)amino)methyl)-4-(difluoromethoxy)-5- fluoropyri din-3 -yl)carbamate (80 mg, 0.20 mmol, 1.0 eq) in DCM (10 mL) was added TFA (3 mL) at rt. The mixture was stirred at rt for 2 h. The mixture was concentrated to yield tert-butyl (6-(aminomethyl)-4-(difluoromethoxy)-5-fluoropyridin-3-yl)carbamate trifluoroacetate (50 mg, quant.), which was used in the next step without further purification.

[0158] A mixture of 6-(aminomethyl)-5-fluoro-4-(fluoromethoxy)pyridin-3-amine trifluoroacetate (50 mg, 0.11 mmol, 1.0 eq), 2-((3-chloroquinolin-6-yl)methyl)isonicotinic acid (33 mg, 0.11 mmol, 1.0 eq), PyBOP (68 mg, 0.13 mmol, 1.5 eq) and TEA (55 mg, 0.55 mmol, 5.0 eq) in DMF (10 mL) was stirred at rt for 1 h. The reaction mixture was concentrated, and the resulting residue was purified by prep-HPLC to yield N-((5-amino-4-(difluoromethoxy)-3-fluoropyridin-2- yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide (20 mg, 37%) as a white solid. LRMS (M+H+) m / z calculated 488.10, found 488.1.1HNMR (DMS0 , 400 MHz) 5 9.10 (s, 1H), 8.83 (s, 1H), 8.64 (d, J= 4.0 Hz, 1H), 8.52 (s 1H), 7.99 (d, J= 8.4 Hz, 1H), 7.90 (s, 1H), 7.88 (1, 1H), 7.77-7.73 (m, 2H), 7.64 (d, J= 4.0 Hz, 1H), 7.29-6.92 (m, 1H), 5.68 (s, 2H), 4.48 (s, 2H), 4.37(s,2H).

[0159] Example 7: Preparation of N-((5-amino-3 -fluoro-4-methoxypyri din-2 -yl)methyl)-2-((6-((2- oxopyridin-l(2H)-yl)methyl)pyridin-3-yl)methyl)oxazole-5-carboxamide

[0160] To a solution of methyl 6-(hydroxymethyl)nicotinate (50 g, 0.3 mol, 1.0 eq) in DCM (500 mL) was added SOCh (53.4 g, 0.45 mol, 1.5 eq) at 0 °C. The mixture was stirred at rt for 1 h, and then concentrated to afford methyl 6-(chloromethyl)nicotinate as hydrochloride salt, which was used without further purification.

[0161] A mixture of methyl 6-(chloromethyl)nicotinate hydrochloride salt (66 g, 0.29 mol, 1.0 eq), pyridin-2(lH)-one (47.3 g, 0.43 mol, 1.5 eq), and K2CO3 (152 g, 1.1 mol, 3.8 eq) in acetone (1000 mL) was stirred at 50 °C for 48 h. The mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 15 / 1, v / v) to afford methyl 6-((2-oxopyridin-l(2H)-yl)methyl)nicotinate (50.6 g, 69%) as a yellow solid.

[0162] To a solution of methyl 6-((2-oxopyridin-l(2H)-yl)methyl)nicotinate (50.6 g, 0.2 mol, 1.0 eq) in THF (500 mL) was added LiAlLL QN, 208 mL, 208 mmol, 1.0 eq) at - 40 °C. The mixture was stirred at -40 °C for 3 h. To this reaction mixture was added H2O (8.67 mL), 15% NaOH (8.67 mL) and H2O (25.3 mL), and then MgSC The mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by column chromatography on silica gel (DCM / MeOH = 10 / 1, v / v) to afford l-((5-(hydroxymethyl)pyridin-2-yl)methyl)pyridin-2(lH)- one (38 g, 85%) as a yellow solid.

[0163] To a solution of l-((5-(hydroxymethyl)pyridin-2-yl)methyl)pyridin-2(lH)-one (38.0 g, 0.17 mol, 1.0 eq) in DCM (500 mL) was added SOCh (99 mL, 1.36 mol, 8.0 eq) at rt. The mixture was stirred at rt for 3 h, and concentrated to afford l-((5-(chloromethyl)pyridin-2- yl)methyl)pyridin-2(lH)-one as hydrochloride salt which was used without further purification.

[0164] A mixture of l-((5-(chloromethyl)pyridin-2-yl)methyl)pyridin-2(lH)-one hydrochloride salt (45.0 g, 177 mmol, 1.0 eq), K2CO3 (48.9 g, 354 mmol, 2.0 eq) and Pd(dppf)C12 (25.8 g, 35.4 mmol, 0.1 eq) in MeOH (150 mL) and THF (300 mL) was stirred at 40 °C overnight under the atmosphere of CO. The mixture was concentrated, and the resulting residue was purified by chromatography on silica gel column (PEZEA = 1 / 4, v / v) to afford methyl 2-(6-((2-oxopyridin- l(2H)-yl)methyl)pyri din-3 -yl)acetate (25 g, 54%).

[0165] To a solution of methyl 2-(6-((2-oxopyri din- l(2H)-yl)methyl)pyri din-3 -yl)acetate (9.4 g, 36.4 mmol, 1.0 eq) in DMF (450 mL) was added LiHMDS (1.0 M in THF, 55 mL, 55 mmol, 1.5 eq) at -50 °C. The mixture was stirred for 1 h, and ethyl 2-chlorooxazole-5-carboxylate (17.1 g, 97 mmol, 1.3 eq) in DMF (50 mL) was added. The reaction mixture was stirred at 0 °C for 3 h, quenched with saturated NH4CI solution (600 mL), and extracted with EA (200 mL- 2). The combined organic layers were washed with brine (300 mL), dried and concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 1 / 2, v / v) to afford ethyl 2-(2-methoxy-2-oxo-l-(6-((2-oxopyridin-l(2H)-yl)methyl)pyridin-3- yl)ethyl)oxazole-5-carboxylate (9.3 g, 64%).

[0166] To a solution of ethyl 2-(2-methoxy-2-oxo- l-(6-((2-oxopyri din- l(2H)-yl)methyl)pyri din-3 - yl)ethyl)oxazole-5-carboxylate (19.3 g, 48.6 mmol, 1.0 eq) in THF / MeOH (200 mL / 100 mL) was added LiOH.H2O (8.16 g, 194 mmol, 4.0 eq.) in H2O (300 mL) at 0 °C. The reaction mixture was stirred at rt for 4 h. Water was added, and the mixture was acidified to pH 5 with 1 N HC1 and concentrated. The resulting residue was purified by prep-HPLC to afford 2-((6-((2-oxopyridin-l(2H)-yl)methyl)pyridin-3-yl)methyl)oxazole-5-carboxylic acid (12.1 g, 80%) as an off-white solid.

[0167] To a solution of 2-((6-((2-oxopyri din- l(2H)-yl)methyl)pyri din-3 -yl)methyl)oxazole-5- carboxylic acid (322 mg, 1.03 mmol, 1.0 eq) in DMF (40 mL) were added 6-(aminomethyl)-5- fluoro-4-methoxypyri din-3 -amine trifluoroacetate (410 mg, 1.03 mmol, 1.0 eq), PyBOP (643 mg, 1.24 mmol, 1.2 eq) and TEA (313 mg, 3.1 mmol, 3.0 eq). The reaction mixture was stirred at rt for 3 h and concentrated. The resulting residue was purified by prep-HPLC to afford N-((5- amino-3-fluoro-4-methoxypyri din-2 -yl)methyl)-2-((6-((2-oxopyri din- l(2H)-yl)methyl)pyridin- 3-yl)methyl)oxazole-5-carboxamide (112 mg, 23%) as a white solid. LRMS (M+H+) m / z calculated 465.16, found 465.2. 'HNMR (DMSO-tL, 400 MHz) 5 8.77 (t, J= 5.2, 5.6 Hz, 1H), 8.48 (d, J= 2.0 Hz, 1H), 7.77-7.70 (m, 2H), 7.74 (s, 1H), 7.67 (s, 1H), 7.46-7.41 (m, 1H), 7.20 (d, J= 8.4 Hz, 1H), 6.39 (d, J= 92 Hz, 1H), 6.25-6.22 (m, 1H), 5.29 (s, 2H), 5.15 (s, 2H), 4.39 (dd, J= 4.0, 1.6 Hz, 2 H), 4.22 (s, 2H) , 3.88 (d, J= 2.4 Hz, 3H).

[0168] Example 8: Preparation of N-((5-amino-3 -fluoro-4-(fluorom ethoxy )pyri din-2-yl)methyl)-2-((3 - chloroquinolin-6-yl)methyl)isonicotinamide

[0169] To a solution of tert-butyl (6-chloro-5-fluoro-4-hydroxypyridin-3-yl)carbamate (400 mg, 1.52 mmol, 1.0 eq) in MeCN (30 mL) were added FCH2I (733 mg, 4.57 mmol, 3.0 eq) and K2CO3 (316 mg, 2.29 mmol, 2.3 eq) at rt. The mixture was stirred at 100 °C for 1 h under N2, then cooled to rt. After filtration, the solid was washed with EA (30 mL x 3). The combined filtrate was washed with water, dried over Na2SO4, filtered and concentrated. The resulting residue waspurified by chromatography on silica gel column (PEZEA = 10 / 1, v / v) to yield tert-butyl (6- chloro-5-fluoro-4-(fluoromethoxy)pyridin-3-yl)carbamate (230 mg, 52 %) as a yellow solid.Pd(OAc)2 / Butyldi-1- adamantylphosphineDioxane / H2O / Cs2CO3

[0170] A mixture of tert-butyl (6-chloro-5-fluoro-4-(fluoromethoxy)pyridin-3-yl)carbamate (220 mg, 0.75 mmol, 1.0 eq), butyldi-l-adamantylphosphine (27 mg, 0.07 mmol, 0.1 eq), Pd(OAc)2 (17 mg, 0.07 mmol, 0.1 eq) and Cs2COs(729 mg, 2.24 mmol, 3.0 eq) in dioxane (20 mL) and H2O(4 mL ) was stirred at 100 °C for 16 h under N2 protection. LCMS showed the reaction was completed. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel column (PEZEA = 10 / 1, v / v) to yield tertbutyl (6-(((tert-butoxycarbonyl)amino)methyl)-5-fluoro-4-(fluoromethoxy)pyridin-3- yl)carbamate (220 mg, 76%) as a white solid.

[0171] To a solution of tert-butyl (6-(((tert-butoxycarbonyl)amino)methyl)-5-fluoro-4- (fluoromethoxy)pyridin-3-yl)carbamate (200 mg, 0.51 mmol, 1.0 eq) in DCM (10 mL) was added TFA (3 mL) at rt. The mixture was stirred at rt for 1 h. Water was added (10 mL) and the mixture was extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to yield 6-(aminomethyl)-5-fluoro-4- (fluorom ethoxy )pyri din-3 -amine trifluoroacetate (288 mg, quant.), which was used in the next step without further purification.

[0172] A mixture of 6-(aminomethyl)-5-fluoro-4-(fluoromethoxy)pyridin-3-amine trifluoroacetate (450 mg, 1.16 mmol, 1.0 eq), 2-((3-chloroquinolin-6-yl)methyl)isonicotinic acid (337 mg, 1.16 mmol, 1.0 eq), HATU (644 mg, 1.75 mmol, 1.5 eq) and TEA (571 mg, 5.84 mmol, 5.0 eq) in DMF (45 mL) was stirred at rt for 1 h. The mixture was concentrated, and the resulting residue was purified by prep-HPLC to yield N-(4-amino-2-fluoro-3 -(fluorom ethoxy )benzyl)-2-((3- chloroquinolin-6-yl)methyl)isonicotinamide (360 mg, 66%) as a white solid.LRMS (M+H+) m / z calculated 469.12, found 469.1.1HNMR (DMSO-tL, 400 MHz) 5 9.07 (t, J= 5.2, 5.2 Hz,l H), 8.82 (d, J= 2.4 Hz 1 H), 8.63 (d, J = 4.8 Hz, 1H), 8.52 (d, J = 2.4 Hz, 1H), 7.98 (d, J= 8.8 Hz, 1H), 7.84 (d, J= 2.8 Hz, 2 H), 7.76 (s, 1H), 7.75-7.72 (m, 1H), 7.63 (dd, J= 4.8, 1.2 Hz, 1 H), 5.73 (s, 1H), 5.60 (s, 1 H), 5.53 (s, 2H), 4.46 (d, J= 4.0 Hz, 2 H), 4.35 (s,2H).

[0173] Example 9: Preparation of N-((5-amino-3-fluoro-4-methoxypyridin-2-yl)methyl)-2-(4-((5- fluoro-2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5-carboxamide

[0174] To a solution of methyl 2-(4-(bromomethyl)phenyl)acetate (12.0 g, 49.0 mmol, 1.0 eq) and 5- fluoropyridin-2(lH)-one (5.0 g, 44.0 mmol, 0.9 eq) in acetone (50 mL) was added K2CO3 (12.1 g, 88.0 mmol, 2.0 eq) at rt. The mixture was stirred at 50 °C overnight. After filtration, the filtrate was concentrated. The resulting residue was purified by chromatography on silica gel column (PE / EA = 3 / 1, v / v) to afford methyl 2-(4-((5-fluoro-2-oxopyridin-l(2H)- yl)methyl)phenyl)acetate (10.0 g, 82%) as a white solid.

[0175] To a mixture of methyl methyl 2-(4-((5-fluoro-2-oxopyridin-l(2H)-yl)methyl)phenyl)acetate (2.75 g, 10.0 mmol, 1.0 eq) and ethyl 2-chlorooxazole-5-carboxylate (1.75 g, 10.0 mmol, 1.0 eq) in DMF (20 mL) was added NaH (600 mg, 60% dispersion in paraffin liquid, 15.0 mmol, 1.5 eq) at 0 °C. The mixture was stirred at rt for 2 h. Water was added, and the mixture was extracted with EA (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried, andconcentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 3 / 1 , v / v) to afford ethyl 2-(l-(4-((5-fluoro-2-oxopyridin-l(2H)-yl)methyl)phenyl)-2- methoxy-2-oxoethyl)oxazole-5-carboxylate (2.0 g, 48%).

[0176] To a solution of ethyl 2-(l-(4-((5-fluoro-2-oxopyridin-l(2H)-yl)methyl)phenyl)-2-methoxy-2- oxoethyl)oxazole-5-carboxylate (2.0 g, 4.8 mmol, 1.0 eq) in THF / MeOH (10 mL / 5 mL) was added LiOH.EEO (811 mg, 19.3 mmol, 4.0 eq) in H2O (15 mL) at rt. The mixture was stirred at rt for 2 h and acidified to pH 5 with 1 N HC1 solution. The mixture was concentrated to give 2- (4-((5-fluoro-2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5 -carboxylic acid which was used in the next step without further purification.

[0177] A mixture of tert-butyl (6-chloro-5-fluoro-4-methoxypyridin-3-yl)carbamate (2.0 g, 7.2 mmol, 1.0 eq), Zn (CN)2 (930 mg, 7.9 mmol, 1.1 eq) Pd2(dba)s (660 mg, 0.7 mmol, 0.1 eq), Zn (24 mg, 0.18 mmol, 0.05 eq) and DPPF (400 mg, 0.7 mmol, 0.1 eq) in DMA (40 mL) was heated at 100 °C under N2 for 1.5 h. The mixture was cooled to rt, filtered and the filtrate was concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 20 / 1, v / v) to yield tert-butyl (6-cyano-5-fluoro-4-methoxypyridin-3-yl)carbamate (1.5 g, 78.9%) as a white solid.

[0178] To a solution of tert-butyl (6-cyano-5-fluoro-4-methoxypyridin-3-yl)carbamate (800 mg, 3.0 mmol, 1.0 eq) in MeOH (50 mL) were added NH3 H2O (5mL) and Raney Ni (80 mg). The mixture was stirred under H2 (0.5 MPa) at 30 °C for 16 h, cooled to rt and filtered. The filtrate was concentrated under reduced pressure to yield tert-butyl (6-(aminomethyl)-5-fluoro-4- methoxypyri din-3 -yl)carbamate (780 mg, 88.0%), which was used in the next step without further purification.

[0179] To a solution of 2-(4-((5-fluoro-2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5-carboxylic acid (100 mg, crude) in DMF (5 mL) were added tert-butyl (6-(aminomethyl)-5-fluoro-4- methoxypyri din-3 -yl)carbamate (83 mg, 0.30 mmol, 1.0 eq), PyBOP (187 mg, 0.36 mmol, 1.2 eq) and TEA (61 mg, 0.6 mmol, 2.0 eq). The mixture was stirred at rt for 2 h and concentrated. The resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 10 / 1, v / v) to afford tert-butyl (5-fluoro-6-((2-(4-((5-fluoro-2-oxopyridin-l(2H)- yl)methyl)benzyl)oxazole-5-carboxamido)methyl)-4-methoxypyridin-3-yl)carbamate (150 mg, 86%).

[0180] To a solution of tert-butyl (5-fluoro-6-((2-(4-((5-fluoro-2-oxopyridin-l(2H)- yl)methyl)benzyl)oxazole-5-carboxamido)methyl)-4-methoxypyridin-3-yl)carbamate (150 mg, 0.25 mmol, 1.0 eq) in DCM (1 mL) was added TFA (0.3 mL) at 0 °C. The mixture was stirred at rt for 2 h, diluted with DCM (30 mL). The organic layer was washed with saturated NaHCCL solution, dried, and concentrated. The resulting residue was purified by prep-HPLC to afford N- ((5-amino-3-fluoro-4-methoxypyridin-2-yl)methyl)-2-(4-((5-fluoro-2-oxopyridin-l(2H)- yl)methyl)benzyl)oxazole-5-carboxamide (55 mg, 45%) as a white solid. LRMS (M+H+) m / z calculated 482.16, found 482.0. 'H NMR (DMSO-tL, 400 MHz) 5 8.76 (t, J= 5.6, 5.2 Hz, 1H), 8.03 (t, J= 4.4, 4.0 Hz, 1H), 7.74 (s, 1H), 7.68 (s, 1H), 7.59-7.54 (m, 1H), 7.29 (s, 4H), 6.46- 6.42 (m, 1H), 5.29 (s, 2H), 5.01 (s, 2H), 4.39 (t, J= 3.6, 2.0 Hz, 2H), 4.16 (s, 2H), 3.88 (d, J= 2.4 Hz, 3H).

[0181] Example 10: Preparation of N-((5-amino-3-fluoro-4-methoxypyridin-2-yl)methyl)-2-((6-((3- fluoro-2-oxopyri din- l(2H)-yl)methyl)pyri din-3 -yl)methyl)oxazole-5 -carboxamide

[0182] A mixture of methyl 6-(chloromethyl)nicotinate as hydrochloride salt (20.0 g, 90.0 mmo1, 1.0 eq), 3-fluoropyridin-2(lH)-one (15.3 g, 135 mmol, 1.5 eq), and K2CO3 (45.9 g, 333 mmol, 3.7 eq) in acetone (300 mL) was stirred at 50 °C for 48 h. The mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 15 / 1, v / v) to afford methyl 6-((3-fluoro-2-oxopyridin-l(2H)- yl)methyl)nicotinate (14.0 g, 59%).

[0183] To a solution of methyl 6-((3-fluoro-2-oxopyridin-l(2H)-yl)methyl)nicotinate (14.0 g, 53.4 mmol, 1.0 eq) in THF (200 mL) was added LiAILL Q M in THF, 53 mL, 53 mmol, 1.0 eq) at - 40 °C. The mixture was stirred at -40 °C for 3 h. To this reaction mixture was added H2O (8.67 mL), 15% NaOH (8.67 mL) and H2O (25.3 mL), and then MgSC The reaction mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 10 / 1, v / v) to afford 3 -fluoro- 1 -((5- (hydroxymethyl)pyridin-2-yl)methyl)pyridin-2(lH)-one (3.9 g, 31%).

[0184] To a solution of 3-fluoro-l-((5-(hydroxymethyl)pyridin-2-yl)methyl)pyridin-2(lH)-one (3.9 g, 16.7 mmol, 1.0 eq) in DCM (80 mL) was added SOC12 (9.9 mL, 133.6 mmol, 8.0 eq) at rt. The mixture was stirred at rt for 3 h. The reaction solution was concentrated to afford l-((5- (chloromethyl)pyridin-2-yl)methyl)-3-fluoropyridin-2(lH)-one as hydrochloride salt which was used in next step without further purification.

[0185] A mixture of l-((5-(chloromethyl)pyridin-2-yl)methyl)-3-fluoropyridin-2(lH)-one hydrochloride salt (4.1 g, 14.2 mmol, 1.0 eq), K2CO3 (3.9 g, 28.4 mmol, 2.0 eq) and Pd(dppf)C12 (1.0 g, 1.4 mmol, 0.1 eq) in MeOH (50 mL) and THF (100 mL) was stirred at 40 °C overnight under the atmosphere of CO. The mixture was concentrated, and the resulting residue was purified by chromatography on a silica gel column (PEZEA = 1 / 4, v / v) to afford methyl 2-(6-((3- fluoro-2-oxopyri din- 1 (2H)-yl)methyl)pyri din-3 -yl)acetate (1.6 g, 41%).

[0186] To a solution of methyl 2-(6-((3-fluoro-2-oxopyri din- l(2H)-yl)methyl)pyri din-3 -yl)acetate (1.6 g, 5.8 mmol, 1.0 eq) in DMF (30 mL) was added LiHMDS (1 M in THF, 9 mL, 9.0 mmol, 1.5 eq) at -50 °C. The mixture was stirred for 1 h and ethyl 2-chlorooxazole-5-carboxylate (1.3 g, 7.5 mmol, 1.3 eq) in DMF (10 mL) was added. The reaction mixture was stirred at 0 °C for 3 h, quenched with saturated NH4CI solution (60 mL), and extracted with EA (20 mL- 2). The combined organic layers were washed with brine (30 mL), dried, and concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 1 / 2, v / v) to afford ethyl 2-(l -(6-((3 -fluoro-2-oxopyridin- 1 (2H)-yl)methyl)pyri din-3 -yl)-2-methoxy-2- oxoethyl)oxazole-5-carboxylate (1.5 g, 62%).

[0187] To a solution of ethyl 2-(l-(6-((3-fluoro-2-oxopyridin-l(2H)-yl)methyl)pyridin-3-yl)-2- methoxy-2-oxoethyl)oxazole-5-carboxylate (1.5 g, 3.6 mmol, 1.0 eq) in THF / MeOH (20 mL / 10 mL) was added LiOH.J O (0.6 g, 14.4 mmol, 4.0 eq) in H2O (30 mL) at 0 °C. The reaction mixture was stirred at rt for 4 h. Water was added and the mixture was acidified to pH 5 with IN HC1 and concentrated. The resulting residue was purified by prep-HPLC to afford 2-((6-((3- fluoro-2-oxopyri din- l(2H)-yl)methyl)pyri din-3 -yl)methyl)oxazole-5 -carboxylic acid (1.0 g, 83%) as an off-white solid.

[0188] To a solution of 2-((6-((3-fluoro-2-oxopyri din- l(2H)-yl)methyl)pyri din-3 -yl)m ethyl)oxazole-5- carboxylic acid (100 mg, 0.3 mmol, 1.0 eq) in DMF (4 mL) were added tert-butyl (6- (aminomethyl)-5-fluoro-4-methoxypyridin-3-yl)carbamate (183 mg, 0.3 mmol, 1.0 eq), PyBOP (187 mg, 0.36 mmol, 1.2 eq) and TEA (61 mg, 0.6 mmol, 2.0 eq). The reaction mixture was stirred at rt for 3 h, and then concentrated. The resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 10 / 1, v / v) to afford tert-butyl (5-fluoro-6-((2-((6-((3- fluoro-2-oxopyri din- 1 (2H)-yl)methyl)pyri din-3 -yl)m ethyl)oxazole-5 -carb oxami do)m ethyl)-4- methoxypyri din-3 -yl)carbamate (50 mg, 30%) as a white solid.

[0189] To a solution of tert-butyl (5-fluoro-6-((2-(4-((5-fluoro-2-oxopyridin-l(2H)- yl)methyl)benzyl)oxazole-5-carboxamido)methyl)-4-methoxypyridin-3-yl)carbamate (50 mg, 0.1 mmol, 1.0 eq) in DCM (1 mL) was added TFA (0.3 mL) at 0 °C. The mixture was stirred at rt for 2 h, and diluted with DCM (30 mL). The organic layer was washed with saturated NaHCCL solution, dried, and concentrated. The resulting residue was purified by prep-HPLC to afford N-((5-amino-3-fluoro-4-methoxypyridin-2-yl)methyl)-2-(4-((3-fluoro-2-oxopyridin- l(2H)-yl)methyl)benzyl)oxazole-5-carboxamide (55 mg, 45%) as a white solid. LRMS (M+H+) m / z calculated 483.15, found 483.0. 'H NMR (DMSO-t / e, 400 MHz) 5 8.79 (s, 1H), 8.48 (s, 1H), 7.74 (d, J= 6.0 Hz, 2H), 7.68-7.64 (m, 2H), 7.42 (t, J= 8.4, 7.6 Hz, 1H), 7.25 (d, J= 8.4 Hz,1H), 6.23 (d, J= 4.8 Hz, 1H), 5.30 (s, 2H), 5.25 (s, 2H), 4.39 (d, J= 3.6 Hz, 2H), 4.23 (s, 2H), 3.89 (s, 3H).

[0190] Example 11: Preparation of N-((5-amino-3-fluoro-4-methoxypyridin-2-yl)methyl)-2-(4-((3- fluoro-2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5-carboxamide

[0191] To a solution of methyl 2-(4-(bromomethyl)phenyl)acetate (12.0 g, 49 mmol, 1.0 eq) and 3- fluoropyridin-2(1H)-one (5.0 g, 44 mmol, 0.9 eq) in acetone (50 mL) was added K2CO3 (12.1 g, 88 mmol, 2.0 eq) at rt. The mixture was heated at 50 °C overnight, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 5 / 1, v / v) to afford methyl 2-(4-((3-fluoro-2-oxopyridin-l(2H)-yl)methyl)phenyl)acetate (10.0 g, 82%) as a white solid.

[0192] To a solution of methyl 2-(4-((3-fluoro-2-oxopyridin-l(2H)-yl)methyl)phenyl)acetate (1.6 g, 5.81 mmol, 1.0 eq) in DMF (20 mL) was added NaH (60% dispersion in paraffin liquid, 580 mg, 14.5 mmol, 2.5 eq) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min and ethyl 2- chlorooxazole-5-carboxylate (1.1 g, 6.39 mmol, 1.1 eq) was added. The mixture was stirred at rt for 2 h under N2, quenched with water (50 mL) and extracted with EA (100 mL><3). The combined organic layers were washed with brine (100 mL), dried over ISfeSCU, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 1 / 1, v / v) to afford ethyl 2-(l-(4-((3-fluoro-2-oxopyridin-l(2H)-yl)methyl)phenyl)-2- methoxy-2-oxoethyl)oxazole-5-carboxylate (1.0 g, 40%).

[0193] To a solution of ethyl 2-(l-(4-((3-fluoro-2-oxopyridin-l(2H)-yl)methyl)phenyl)-2-methoxy-2- oxoethyl)oxazole-5-carboxylate (800 mg, 1.6 mmol, 1.0 eq) in THF / MeOH / J O (8 mL / 4 mL / 12 mL) at 0 °C was added LiOH.LLO (324 mg, 7.72 mmol, 4.0 eq). The mixture was stirred at rt for 2 h and acidified to pH 3~4 with 1 N HC1 solution. The mixture was concentrated to afford 2-(4-((3-fluoro-2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5-carboxylic acid which was used in the next step without further purification.

[0194] To a solution of 2-(4-((3-fluoro-2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5-carboxylic acid (100 mg, 0.3 mmol, 1.0 eq) in DMF (5 mL) were added tert-butyl (6-(aminomethyl)-5-fluoro-4- methoxypyri din-3 -yl)carbamate (91 mg, 0.34 mmol, 1.1 eq), PyBOP (238 mg, 0.46 mmol, 1.5 eq) and EtsN (61.5 mg, 0.61 mmol, 2.0 eq). The mixture was stirred at rt for 3 h, concentrated and the resulting residua was purified by chromatography on silica gel column (DCM / MeOH = 30 / 1, v / v) to give tert-butyl (5-fluoro-6-((2-(4-((3-fluoro-2-oxopyridin-l(2H)- yl)methyl)benzyl)oxazole-5-carboxamido)methyl)-4-methoxypyridin-3-yl)carbamate (82 mg, 46%) as an off-white solid.

[0195] To a solution of tert-butyl (5-fluoro-6-((2-(4-((3-fluoro-2-oxopyridin-l(2H)- yl)methyl)benzyl)oxazole-5-carboxamido)methyl)-4-methoxypyridin-3-yl)carbamate ( 82 mg, 0.14 mmol, 1.0 eq ) in DCM (9 mL) at 0 °C was added TFA (3 mL). The mixture was stirred at rt for 1 h and adjusted to pH 7 with NaHCCh aqueous solution. The mixture was extracted with DCM (30 mL x 3) and the combined organic layers were washed with brine, dried over ISfeSCU, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 20 / 1, v / v) to give N-((5-amino-3-fluoro-4-methoxypyridin-2-yl)methyl)-2-(4-((3-fluoro-2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5 -carboxamide (44 mg, 65%) as a white solid. LRMS (M+H+) m / z calculated 482.2, found 482.0.1H NMR (DMSO-t / e, 400 MHz) 5 8.76 (t, J= 5.2, 5.2 Hz, 1H), 7.74 (s, 1H), 7.68 (s, 1H),7.65 (d, J= 6.8 Hz, 1H), 7.41-7.36 (m, 1H), 7.28 (dd, J= 10.4, J= 8.8 Hz, 4H), 6.24-6.19 (m, 1H), 5.29 (s, 2H), 5.14 (s, 2H), 4.39 (dd, J= 5.2 Hz, J= 1.6, 2H), 4.16 (s, 2H), 3.88 (d, J= 2.0 Hz, 3H).

[0196] Example 12: Preparation of N-((5-amino-3 -fluoro-4-methoxypyri din-2 -yl)methyl)-2-((6-((2- oxopyridin.l(2H)-yl)methyl)pyri din-3 -yl)methyl)isonicotinamide

[0197] To a solution of l-(5-hydroxymethyl-pyridin-2-ylmethyl)-lH-pyridin-2-one (700 mg, 3.24 mmol) in DCM (10 mL) was added PBr, (1.04 g, 3.88 mmol) at rt. The mixture was stirred at rt overnight. The mixture was washed with saturated NaHCOs solution (10 mL), dried over Na2SC>4 and concentrated to afford l-(5-bromomethyl-pyridin-2-ylmethyl)-lH-pyridin-2-one (500 mg, 56%).

[0198] To a mixture of 2-trimethylstannanyl-isonicotinic acid methyl ester (560 mg, crude,) and l-(5- bromomethyl-pyridin-2-ylmethyl)-lH-pyridin-2-one (400 mg, crude) in dioxane (15 mL) was added Pd(PPh3)2Cl2(100 mg, 118 mmol) at rt. The mixture was heated to 90 °C and stirred for 6 h with N2. The reaction mixture was concentrated, and the resulting residue was purified by prep-HPLC to afford 2-[6- (2-oxo-2H-pyridin-l-ylmethyl)-pyridin-3-ylmethyl]-isonicotinic acid methyl ester (50 mg, 9%).

[0199] To a solution of methyl 2-((6-((2-oxopyridin-l(2H)-yl)methyl)pyridin-3-yl)methyl)isonicotinate (2.0 g, 5.96 mmol, 1.0 eq) in THF / MeOH (20 mL / 10 mL) was added LiOH.H2O (1.0 g, 23.8 mmol, 4.0 eq.) in H2O (30 mL) at 0 °C. The mixture was stirred at rt overnight and adjusted to pH 5 with 2 N HC1 solution. The mixture was concentrated to give 2-((6-((2-oxopyridin-l(2H)- yl)methyl)pyridin-3-yl)methyl)isonicotinic acid, which was used in the next step without further purification.

[0200] To a mixture of 2-((6-((2-oxopyridin-l(2H)-yl)methyl)pyridin-3-yl)methyl)isonicotinic acid (100 mg, 0.37 mmol, 1.0 eq) and PyBOP (248 mg, 0.48 mmol, 1.3 eq) in DMF (10 mL) were added tert-butyl (6-(aminomethyl)-5-fluoro-4-methoxypyridin-3-yl)carbamate (118 mg, 0.37 mmol, 1.0 eq) and TEA (111 mg, 1.1 mmol, 3.0 eq). The mixture was stirred at rt for 1 h. Water (50 mL) was added and the mixture was extracted with EA (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 20 / 1, v / v) to afford tert-butyl (5-fluoro-4-methoxy-6-((2-((6-((2-oxopyridin-l(2H)-yl)methyl)pyridin-3- yl)methyl)isonicotinamido)methyl)pyridin-3-yl)carbamate (140 mg, 66%) as a white solid.

[0201] To a solution of tert-butyl (5-fluoro-4-methoxy-6-((2-((6-((2-oxopyridin-l(2H)- yl)methyl)pyridin-3-yl)methyl)isonicotinamido)methyl)pyridin-3-yl)carbamate (140 mg, 0.24 mmol, 1.0 eq) in DCM (10 mL) was added TFA (3 mL) at 0 °C. The mixture was stirred at rt for 2 h, and washed with saturated NaHCCh solution andbrine. The organic layer was dried over Na2SO4, filtered and concentrated. The resulting residue was purified by chromatography onsilica gel column (DCM / MeOH = 15 / 1, v / v) to afford N-((5-amino-3-fluoro-4-methoxypyridin- 2-yl)methyl)-2-((6-((2-oxopyridin-l(2H)-yl)methyl)pyridin-3-yl)methyl)isonicotinamide (96 mg, 83.5%) as a white solid. LRMS (M+H+) m / z calculated 475.18, found 475.0. 'H NMR (DMSO-t / e, 400 MHz) 5 9.05 (t, J= 5.6, 5.2 Hz, 1H), 8.59 (d, J= 5.2 Hz, 1H), 8.46 (d, J= 2.0 Hz, 1H), 7.76-7.75 (m, 3H), 7.72 (s, 1H), 7.65 (dd, J= 8.0, 2.0 Hz, 1H) 7.45-7.41 (m, 1H), 7.14 (d, J= 8.0 Hz, 1H), 6.38 (d, J= 92 Hz, 1H), 6.25-6.22 (m, 1H), 5.13 (s, 2H), 4.45 (dd, J = 3.6, 2.0 Hz,lH), 4.14 (s, 2H), 3.90 (s, 3H).

[0202] Example 13: Preparation of N-((5-amino-3 -fluoro-4-m ethoxypyri din-2 -yl)methyl)-2-(3 -fluoro- 4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5-carboxamide

[0203] To a solution of 3-fluoro-4-methylbenzoic acid (30.8 g, 0.2 mol) in CCh (600 mL) were added NBS (37 g, 0.21 mol) and AIBN (3.2 g, 0.02 mol). The mixture was stirred at 80 °C overnight. Water (500 mL) was added and the mixture was extracted with DCM (200 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 4-(bromomethyl)-3 -fluorobenzoic acid which was used to next step without further purification.

[0204] To a solution of 4-(bromomethyl)-3 -fluorobenzoic acid (30.0 g, 129 mmol) in THF (250 mL) was added BH3 THF (193 mL, 193 mmol, 1 mol / L in THF) slowly in an ice bath. The mixture was stirred at rt for 12 h, cooled to 0 °C, quenched with MeOH (100 mL) and concentrated. The resulting residue was dissolved in EA (500 mL), washed with 1 M HC1 (500 mL) and brine (500 mL), dried over Na2SO4 and filtered. The filtrate was concentrated to give (4-(bromomethyl)-3- fluorophenyl)methanol (25.5 g, 90%).

[0001] To a solution of (4-(bromomethyl)-3-fluorophenyl)methanol (25.5 g, 116 mmol, 1.0 eq) in MeCN (500 mL) was added pyridin-2(lH)-one (11.1 g, 116 mmol, 1.0 eq) and K2CO3 (48.1 g, 349 mmol, 3.0 eq). The mixture was stirred at 50 °C for 24 h. The reaction mixture was concentrated and the resulting residue was purified by chromatography on silica gel column (PEZEA = 1 / 1, v / v) to afford l-(2-fluoro-4-(hydroxymethyl)benzyl)pyridin-2(lH)-one (14.0 g, 51%) as a colorless oil.

[0205] To a solution of l-(2-fluoro-4-(hydroxymethyl)benzyl)pyridin-2(lH)-one (17.0 g, 73.0 mmol, 1.0 eq) in DCM (150 mL) at 0 °C was added thionyl chloride (34.7 g, 292 mmol, 4.0 eq). The mixture was stirred at rt for 2 h and concentrated to afford l-(4-(chloromethyl)-2- fluorobenzyl)pyridin-2(lH)-one (16.0 g), which was used in the next step without further purification.

[0206] To a solution of l-(4-(chloromethyl)-2-fluorobenzyl)pyridin-2(lH)-one (16.0 g, 63.70 mmol, 1.0 eq.) in MeOH (120 mL) were added Pd(dppf)C12 (4.6 g, 6.37 mmol, 0.1 eq) and TEA (25.7 g, 255 mmol, 4.0 eq). The mixture was stirred at 70 °C overnight under CO atmosphere, and then concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 3 / 1, v / v) to afford methyl 2-(3-fluoro-4-((2-oxopyridin-l(2H)- yl)methyl)phenyl)acetate (11.8 g, 67%).

[0207] To a mixture of methyl 2-(3-fluoro-4-((2-oxopyridin-l(2H)-yl)methyl)phenyl)acetate (6.0 g, 21.80 mmol, 1.0 eq) in DMF (50 mL) was added NaH (2.2 g, 60% dispersion in paraffin liquid, 54.4 mmol, 2.5 eq) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min and ethyl 2- chlorooxazole-5-carboxylate (4.2 g, 24.0 mmol, 1.1 eq) was added. The mixture was stirred at rt for 2 h under nitrogen, quenched with water (200 mL) and extracted with EA (200 mL><3). The combined organic layers were washed with brine (200 mL), dried over ISfeSCL, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 1 / 1, v / v) to give ethyl 2-(l-(3-fluoro-4-((2-oxopyridin-l(2H)-yl)methyl)phenyl)-2- methoxy-2-oxoethyl)oxazole-5-carboxylate (3.7 g, 41%).

[0208] To a solution of ethyl 2-(l-(3-fluoro-4-((2-oxopyridin-l(2H)-yl)methyl)phenyl)-2-methoxy-2- oxoethyl)oxazole-5-carboxylate (3.7 g, 8.94 mmol, 1.0 eq) in TElF / MeOEl / EEO (14 / 7 / 21 mL) at 0 °C was added LiOEl.EEO (1.1 g, 26.8 mmol, 3.0 eq). The mixture was stirred at rt for 2 h, acidified to pH 3~4 with 1 N HC1 solution and concentrated to afford 2-(3-fhioro-4-((2- oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5-carboxylic acid which was used in the next step without further purification.

[0209] To a solution of 2-(3-fluoro-4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5-carboxylic acid (1.6 g, 4.87 mmol, 1.0 eq) in DMF (20 mL) were added tert-butyl (6-(aminomethyl)-5-fluoro-4- methoxypyri din-3 -yl)carbamate (1.4 g, 5.36 mmol, 1.1 eq), HATU (2.78 g, 7.32 mmol, 1.5 eq) and EtsN (985 mg, 9.76 mmol, 2.0 eq). The mixture was stirred at rt for 3 h. Water (60 mL) was added, and the mixture was extracted with EA (80 mLx 3), The combined organic layers werewashed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 30 / 1, v / v) to give tert-butyl (5- fluoro-6-((2-(3-fluoro-4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5- carboxamido)methyl)-4-methoxypyridin-3-yl)carbamate (1.0 g, 35%) as a white solid.

[0210] To a solution of tert-butyl (5-fluoro-6-((2-(3-fluoro-4-((2-oxopyridin-l(2H)- yl)methyl)benzyl)oxazole-5-carboxamido)methyl)-4-methoxypyridin-3-yl)carbamate (1.0 g, 1.72 mmol ) in DCM (20 mL) at 0 °C was added TFA (7 mL). The mixture was stirred at rt for 1 h, and adjusted to pH 7 with NaHCCh aqueous solution. The mixture was extracted with DCM (30 mLx 3). The combined organic layers were washed with brine, dried over ISfeSCU and filtered. The filtrate was concentrated, and the resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 20 / 1, v / v) and triturated from 2-m ethyltetrahydrofuran to give N-((5-amino-3-fluoro-4-methoxypyri din-2 -yl)methyl)-2-(3-fluoro-4-((2-oxopyri din- 1(2H)- yl)methyl)benzyl)oxazole-5-carboxamide (500 mg, 60%) as a white solid. LRMS (M+H+) m / z calculated 482.5, found 482.2. 'HNMR (DMSO-t / 6, 400 MHz) 5 8.78 (t, J= 5.6, 5.2 Hz 1H), 8.59 (d, J= 1.6, 1H), 7.75 (s, 1H), 7.71 (dd, J= 6.8, 2.0 Hz, 1H), 7.69 (s, 1H), 7.46-7.41 (m, 1H), 7.21 (d, J= 11.6, 1H), 7.11 (d, J= 5.2, 1H), 6.40 (d, J= 9.6, 1H), 6.27-6.23 (m, 1H), 5.30 (s, 2H), 5.10 (s, 2H), 4.40 (dd, J= 5.6, 2.0 Hz, 2H), 4.21 (s, 2H), 3.89 (d, J= 2.4, 3H).

[0211] Example 14: Preparation of N-((5-amino-3-fluoro-4-methoxypyridin-2-yl)methyl)-5-((6-((2- oxopyri din- l(2H)-yl)methyl)pyri din-3 -yl)m ethyl)- 1, 3, 4-oxadiazole-2-carboxamide

[0212] To a solution of tert-butyl (6-(aminomethyl)-5-fluoro-4-methoxypyridin-3-yl)carbamate (300 mg, 1.11 mmol, 1.0 eq) and K2CO3 (459 mg, 3.33 mmol, 3 eq) in MeCN (10 mL) was added ethyl 2-chloro-2-oxoacetate (227 mg, 1.66 mmol, 1.5 eq) at rt. The mixture was stirred at rt overnight. Water was added, and the mixture was extracted with EA (15 mL x 3). The combined organic layers were washed with brine (50 mL), dried, and concentrated to afford ethyl 2-(((5- ((tert-butoxycarbonyl)amino)-3-fluoro-4-methoxypyridin-2-yl)methyl)amino)-2-oxoacetate,

[0213] To a solution of ethyl 2-(((5-((tert-butoxycarbonyl)amino)-3-fluoro-4-methoxypyridin-2- yl)methyl)amino)-2-oxoacetate (400 mg, 1.08 mmol, 1.0 eq) in THF (6 mL) was added LiOH.EEO (66 mg, 1.62 mmol, 1.5 eq) in H2O (6 mL) at rt. The mixture was stirred at rt for 2 h, concentrated and acidified to pH 5 with 1 N HC1 solution. The solid was collected to give 2-(((5- ((tert-butoxycarbonyl)amino)-3-fluoro-4-methoxypyridin-2-yl)methyl)amino)-2-oxoacetic acid (300 mg, 81%).

[0214] To a solution of 2-(6-((2-oxopyri din- l(2H)-yl)methyl)pyri din-3 -yl)acetohydrazide (203 mg, crude) in DMF (10 mL) were added 2-(((5-((tert-butoxycarbonyl)amino)-3-fluoro-4- methoxypyridin-2-yl)methyl)amino)-2-oxoacetic acid (270 mg, 0.79 mmol, 1.0 eq), PyBOP (491 mg, 0.94 mmol, 1.2 eq) and TEA (239 mg, 2.36 mmol, 3.0 eq). The mixture was stirred at rt for 2 h, and concentrated. The resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 10 / 1, v / v) to afford tert-butyl (5-fluoro-4-methoxy-6-((2-oxo-2-(2-(2- (6-((2-oxopyri din- l(2H)-yl)methyl)pyri din-3 -yl)acetyl)hydrazineyl)acetamido)methyl)pyridin- 3-yl)carbamate (220 mg, 43%) as a white solid.

[0215] To a solution of tert-butyl (5-fluoro-4-methoxy-6-((2-oxo-2-(2-(2-(6-((2-oxopyridin-l(2H)- yl)methyl)pyridin-3-yl)acetyl)hydrazineyl)acetamido)methyl)pyridin-3-yl)carbamate (170 mg, 0.29 mmol, 1.0 eq) in ACN (6 mL) were added TsCl (166 mg, 0.87 mmol, 3.0 eq) and TEA (88 mg, 0.87 mmol, 3.0 eq). The mixture was stirred at 50 °C for 16 h, and concentrated. The resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 12 / 1, v / v) to afford tert-butyl (5-fluoro-4-methoxy-6-((5-((6-((2-oxopyridin-l(2H)-yl)methyl)pyridin- 3-yl)methyl)-l,3,4-oxadiazole-2-carboxamido)methyl)pyridin-3-yl)carbamate (130 mg, 79%) as a white solid.

[0216] To a solution of tert-butyl (5-fluoro-4-methoxy-6-((5-((6-((2-oxopyridin-l(2H)- yl)methyl)pyri din-3 -yl)methyl)-l, 3, 4-oxadiazole-2-carboxamido)methyl)pyri din-3 -yl)carbamate (130 mg, 0.23 mmol, 1.0 eq) in DCM (1 mL) was added TFA (0.3 mL) at 0 °C. After stirring at rt for 2 h, the mixture was diluted with DCM (30 mL). The organic layer was washed with saturated NaHCCL solution, dried, and concentrated. The resulting residue was purified by prep- HPLC to afford N-((5-amino-3-fluoro-4-methoxypyridin-2-yl)methyl)-5-((6-((2-oxopyridin- l(2H)-yl)methyl)pyridin-3-yl)methyl)-l,3,4-oxadiazole-2-carboxamide (55 mg, 52%) as a white solid. LRMS (M+H+) m / z calculated 466.16, found 466.0. 'H NMR (DMSO-tL, 400 MHz) 5 9.44 (t, J= 5.6, 5.2 Hz, 1H), 8.51 (d, J= 1.6 Hz, 1H), 7.79-7.74 (m, 3H), 7.47-7.42 (m, 1H), 7.21 (d, J= 8.4 Hz, 1H), 6.39 (d, J= 92 Hz, 1H), 6.27-6.23 (m, 1H), 5.32 (s, 2H), 5.17 (s, 2H), 4.43 (dd, J= 5.6, 2.0 Hz, 2H), 4.39 (s, 2H), 3.89 (d, J= 2.0 Hz, 3H).

[0217] Example 15: Preparation of N-((5-amino-3 -fluoro-4-m ethoxypyri din-2 -yl)methyl)-2-(3 -fluoro- 4-((3-fluoro-2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5-carboxamide

[0218] To a solution of (4-(bromomethyl)-3-fluorophenyl)methanol (2.0 g, 9.13 mmol, 1.0 eq) in acetone (30 mL) were added 3-fluoro-2-hydroxypyridine (1.2 g, 11.0 mmol, 1.2 eq) and K2CO3 (3.8 g, 27.4 mmol, 3.0 eq). The mixture was stirred at rt overnight and filtered. The filtrate was concentrated, and the resulting residue was purified by chromatography on silica gel column (PEZEA = 2 / 1, v / v) to afford 3-fluoro-l-(2-fluoro-4-(hydroxymethyl)benzyl)pyridin-2(lH)-one (1.7 g, 74%) as a white solid.

[0219] To a solution of 3-fluoro-l-(2-fluoro-4-(hydroxymethyl)benzyl)pyridin-2(lH)-one (1.7 g, 6.77 mmol, 1.0 eq) in DCM (25 mL) at 0 °C was added thionyl chloride (3.2 g, 27.1 mmol, 4.0 eq). The mixture was stirred at rt for 2 h, and concentrated to afford l-(4-(chloromethyl)-2- fluorobenzyl)-3-fluoropyridin-2(lH)-one which was used in the next step without further purification.

[0220] To a solution of l-(4-(chloromethyl)-2-fluorobenzyl)-3-fluoropyridin-2(lH)-one (2.2 g, 8.16 mmol, 1.0 eq.) in MeOH (30 mL) were added Pd(dppf)C12 (597 mg, 0.82 mmol, 0.1 eq) and EtsN (3.3 g, 32.6 mmol, 4.0 eq). The mixture was stirred at 70 °C overnight under CO atmosphere, and filtered. The filtrate was concentrated and the resulting residue was purified bychromatography on silica gel column (PEZEA = 3 / 1, v / v) to afford methyl 2-(3-fluoro-4-((3- fluoro-2-oxopyridin-l(2H)-yl)methyl)phenyl)acetate (1.7 g, 71%).

[0221] To a solution of methyl 2-(3-fluoro-4-((3-fluoro-2-oxopyridin-l(2H)-yl)methyl)phenyl)acetate (1.7 g, 5.80 mmol, 1.0 eq) in DMF (25 mL) was added NaH (60% dispersion in paraffin liquid, 580 mg, 14.5 mmol, 2.5 eq) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min and ethyl 2-chlorooxazole-5-carboxylate (1.1 g, 6.38 mmol, 1.1 eq) was added. The mixture was stirred at rt for 2 h under nitrogen,, quenched with water (50 mL) and extracted with EA (100 mL><3). The combined organic layers were washed with brine (100 mL), dried over ISfeSCL and filtered. The filtrate was concentrated, and the resulting residue was purified by chromatography on silica gel column (PEZEA = 1 / 1, v / v) to give ethyl 2-(l-(3-fluoro-4-((3-fluoro-2-oxopyridin- l(2H)-yl)methyl)phenyl)-2-methoxy-2-oxoethyl)oxazole-5-carboxylate (1.1 g, 44%).

[0222] To a solution of ethyl 2-(l-(3-fluoro-4-((3-fluoro-2-oxopyridin-l(2H)-yl)methyl)phenyl)-2- methoxy-2-oxoethyl)oxazole-5-carboxylate (200 mg, 0.46 mmol, 1.0 eq) in TElF / MeOEl / EEO (4 mL / 2 mL / 6 mL) at 0 °C was added LiOEl.EEO (77.7 mg, 1.85 mmol, 4.0 eq). The mixture was stirred at rt for 2 h, and acidified to pH 3~4 with 1 N HC1 solution. The mixture was concentrated to afford 2-(3-fluoro-4-((3-fluoro-2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5- carboxylic acid (120 mg), which was used in the next step without further purification.

[0223] To a solution of 2-(3-fluoro-4-((3-fluoro-2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5- carboxylic acid (120 mg, 0.35 mmol, 1.0 eq) in DMF (2 mL) were added tert-butyl (6- (aminomethyl)-5-fluoro-4-methoxypyridin-3-yl)carbamate (103 mg, 0.38 mmol, 1.1 eq), PyBOP(270 mg, 0.52 mmol, 1.5 eq) and EtsN (70.0 mg, 0.69 mmol, 2.0 eq). The mixture was stirred at rt for 3 h. Water (10 mL) was added, and the mixture was extracted with EA (30 mL><3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 30 / 1, v / v) to give tert-butyl (5-fluoro-6-((2-(3-fluoro-4-((3-fluoro-2-oxopyridin-l(2H)- yl)methyl)benzyl)oxazole-5-carboxamido)methyl)-4-methoxypyridin-3-yl)carbamate (80 mg, 40%) as a white solid.

[0224] To a solution of tert-butyl (5-fluoro-6-((2-(3-fluoro-4-((3-fluoro-2-oxopyridin-l(2H)- yl)methyl)benzyl)oxazole-5-carboxamido)methyl)-4-methoxypyridin-3-yl)carbamate (80 mg, 0.13 mmol, 1.0 eq ) in DCM (9 mL) at 0 °C was added TFA (3 mL). The mixture was stirred at rt for 1 h and adjusted to pH 7 with NaHCCh aqueous solution. The mixture was extracted with DCM (15 mL><3), and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 20 / 1, v / v) to give N-((5-amino-3-fluoro-4-methoxypyridin-2- yl)methyl)-2-(3-fluoro-4-((3-fluoro-2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5- carboxamide (23 mg, 35%) as a white solid. LRMS (M+H+) m / z calculated 500.0, found 501.0. 'H NMR (DMSO-tL, 400 MHz) 5 8.74 (t, J= 5.6, 5.2 Hz, 1H), 7.75 (s, 1H), 7.69 (s, 1H), 7.60 (d, .7= 6.4 Hz, 1H), 7.46-7.39 (m, 1H), 7.22 (d, J= 10.8 Hz, 1H), 7.17-7.11 (m, 2H), 6.27-6.22 (m, 1H), 5.31 (s, 2H), 5.18 (s, 2H), 4.40 (d, J= 3.6 Hz, 2H), 4.21 (s, 2H), 3.89 (d, J= 2.4 Hz, 3H).

[0225] Example 16: Preparation of N-((5-amino-3 -fluoro-4-m ethoxypyri din-2 -yl)methyl)-2-(3 -fhioro- 4-((5-fluoro-2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5-carboxamide

[0226] To a solution of (4-(bromomethyl)-3-fluorophenyl)methanol (2.0 g, 9.13 mmol, 1.0 eq) in acetone (30 mL) were added 5-fluoropyridin-2(lH)-one (1.2 g, 11.0 mmol, 1.2 eq) and K2CO3 (3.8 g, 27.4 mmol, 3.0 eq). The mixture was stirred at rt overnight, and filtered. The filtrate was concentrated, and the resulting residue was purified by chromatography on silica gel column (PEZEA = 2 / 1, v / v) to afford 5-fluoro-l-(2-fluoro-4-(hydroxymethyl)benzyl)pyridin-2(lH)-one (1.2 g, 52%) as a white solid.

[0227] To a solution of 5-fluoro-l-(2-fluoro-4-(hydroxymethyl)benzyl)pyridin-2(lH)-one (1.2 g, 4.78 mmol, 1.0 eq) in DCM (25 mL) at 0 °C was added thionyl chloride (2.3 g, 19.1 mmol, 4.0 eq). The mixture was stirred at rt for 2 h, and concentrated to afford l-(4-(chloromethyl)-2- fluorobenzyl)-5-fluoropyridin-2(lH)-one, which was used in the next step without further purification.

[0228] To a solution of l-(4-(chloromethyl)-2-fluorobenzyl)-3-fluoropyridin-2(lH)-one (1.6 g, 5.93 mmol, 1.0 eq) in MeOH (30 mL) were added Pd(dppf)C12 (434 mg, 0.59 mmol, 0.1 eq) and EtsN (2.4 g, 23.7 mmol, 4.0 eq). The mixture was stirred at 70 °C overnight under CO atmosphere, and filtered. The filtrate was concentrated, and the resulting residue was purified by chromatography on silica gel column (PEZEA = 3 / 1, v / v) to afford methyl 2-(3-fluoro-4-((5- fluoro-2-oxopyridin-l(2H)-yl)methyl)phenyl)acetate (1.2 g, 69%).

[0229] To a solution of methyl 2-(3-fluoro-4-((5-fluoro-2-oxopyridin-l(2H)-yl)methyl)phenyl)acetate (1.2 g, 4.09 mmol, 1.0 eq) in DMF (20 mL) was added NaH (60% dispersion in paraffin liquid, 409 mg, 10.2 mmol, 2.5 eq) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min and ethyl 2-chlorooxazole-5-carboxylate (788 mg, 4.5 mmol, 1.1 eq) was added. The mixture was stirred at rt for 2 h under nitrogen,, quenched with water (50 mL) and extracted with EA (150 mL><3). The combined organic layers were washed with brine (100 mL), dried over ISfeSCL, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (PE / EA = 1 / 1, v / v) to give ethyl 2-(l-(3-fluoro-4-((5-fluoro-2-oxopyridin-l(2H)- yl)methyl)phenyl)-2-methoxy-2-oxoethyl)oxazole-5-carboxylate (910 mg, 51%).

[0230] To a solution ethyl 2-(l-(3-fluoro-4-((5-fluoro-2-oxopyridin-l(2H)-yl)methyl)phenyl)-2- methoxy-2-oxoethyl)oxazole-5-carboxylate of (200 mg, 0.46 mmol, 1.0 eq) in TElF / MeOEl / EEO (4 mL / 2 mL / 6 mL) at 0 °C was added LiOEl.EEO (77.7 mg, 1.85 mmol, 4.0 eq). The mixture was stirred at rt for 2 h, and acidified to pH 3~4 with 1 N HC1 solution. The mixture was concentrated to afford 2-(3-fluoro-4-((5-fluoro-2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5- carboxylic acid (120 mg), which was used in the next step without further purification.

[0231] To a solution of 2-(3-fluoro-4-((5-fluoro-2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5- carboxylic acid (120 mg, 0.35 mmol, 1.0 eq) in DMF (5 mL) were added tert-butyl (6- (aminomethyl)-5-fluoro-4-methoxypyridin-3-yl)carbamate (103 mg, 0.38 mmol, 1.1 eq), HATU (198 mg, 0.52 mmol, 1.5 eq) and EtsN (70.0 mg, 0.69 mmol, 2.0 eq). The mixture was stirred atrt for 3 h. Water (20 mL) was added and the mixture was extracted with EA (30 mL><3), The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 30 / 1, v / v) to give tert-butyl (5-fluoro-6-((2-(3-fluoro-4-((5-fluoro-2-oxopyridin-l(2H)- yl)methyl)benzyl)oxazole-5-carboxamido)methyl)-4-methoxypyridin-3-yl)carbamate (160 mg, 77%) as an off-white solid.

[0232] To a solution of tert-butyl (5-fluoro-6-((2-(3-fluoro-4-((5-fluoro-2-oxopyridin-l(2H)- yl)methyl)benzyl)oxazole-5-carboxamido)methyl)-4-methoxypyridin-3-yl)carbamate (160 mg, 0.27 mmol, 1.0 eq ) in DCM (9 mL) at 0 °C was added TFA (3 mL). The mixture was stirred at rt for 1 h and adjusted to pH 7 with NaHCCL aqueous solution and extracted with DCM (15 mL><3). The combined organic layers were washed with brine, dried over ISfeSCU, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 20 / 1, v / v) to give N-((5-amino-3-fluoro-4-methoxypyridin-2-yl)methyl)-2-(3- fluoro-4-((5-fluoro-2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5-carboxamide (32.6 mg, 25%) as a white solid. LRMS (M+H+) m / z calculated 500.0, found 500.9.1H NMR (DMSO-t / e, 400 MHz) 5 8.79 (t, J= 5.6 Hz, 5.2 Hz, 1H), 7.96 (t, J= 4.0, 3.6 Hz, 1H), 7.75 (s, 1H), 7.69 (s, 1H), 7.63-7.59 (m, 1H), 7.22 (d, J= 11.2 Hz, 1H), 7.12 (d, J= 3.6 Hz, 2H), 6.46-6.43 (m, 1H), 5.31 (s, 2H), 5.06 (s, 2H), 4.40 (d, J= 4.0 Hz, 2H), 4.21 (s, 2H), 3.89 (d, J= 1.6 Hz, 3H).

[0233] Example 17: Preparation of N-((5-amino-3 -fluoro-4-m ethoxypyri din-2 -yl)methyl)-2-(4-((2- oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5-carboxamide

[0234] A mixture of methyl 2-(4-(bromomethyl)phenyl)acetate (30.0 g, 123 mmol, 1.0 eq), pyridin- 2(lH)-one (13.9 g, 147 mmol, 1.2 eq) and K2CO3 (50.9 g, 369 mmol, 3.0 eq) in DMF (300 mL) was stirred at rt overnight. The reaction mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 1 / 5, v / v) to afford methyl 2-(4-((2-oxopyridin-l(2H)-yl)methyl)phenyl)acetate (22.4 g, 71%) as a white solid.

[0235] To a solution of methyl 2-(4-((2-oxopyridin-l(2H)-yl)methyl)phenyl)acetate (22.0 g, 86 mmol, 1.0 eq) in DMF (400 mL) was added LiHMDS (1 M in THF, 215 mL, 215 mmol, 1.2 eq) at - 40 °C under nitrogen. The mixture was stirred for 1 h, and ethyl 2-chlorooxazole-5 -carboxylate (18 g, 103 mmol, 1.2 eq) in DMF (50 mL) was added at -40 °C. The reaction mixture was stirred at 0 °C for 2 h, quenched with saturated NH4CI solution (500 mL), and extracted with EA (500 mLx 2). The combined organic layers were washed with brine (100 mL), dried with anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 1 / 4, v / v) to afford ethyl 2-(2-methoxy-2-oxo-l-(4-((2-oxopyridin- l(2H)-yl)methyl)phenyl)ethyl)oxazole-5-carboxylate (25.1 g, 74%).

[0236] To a solution of ethyl 2-(2-methoxy-2-oxo-l-(4-((2-oxopyridin-l(2H)- yl)methyl)phenyl)ethyl)oxazole-5-carboxylate (25.1 g, 63 mmol, 1.0 eq) in THF / MeOH (100 mL / 50 mL) was added LiOH.EEO (10.6 g, 253 mmol, 4.0 eq) in H2O (150 mL) at 0 °C. The aqueous layer was separated and acidified to pH 3~4 with IN HC1. The solid was collected, washed with water, and dried to afford 2-(4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5- carboxylic acid (16.0 g, 82%) as an off-white solid.

[0237] To a solution of 2-(4-((2-oxopyri din- l(2H)-yl)methyl)benzyl)oxazole-5 -carboxylic acid (10.0 g, 32 mmol, 1.0 eq) in DMF (200 mL) was added CDI (6.3 g, 38 mmol, 1.2 eq). The mixture was stirred at rt for 3 h. tert-Butyl (6-(aminomethyl)-5-fluoro-4-methoxypyridin-3-yl)carbamate (8.7 g, 32 mmol, 1.0 eq) was added. The reaction mixture was stirred at rt overnight. Water (600 mL) was added, and the mixture was extracted with EA (400 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 20 / 1, v / v) to afford tert-butyl (5-fluoro-4-methoxy-6-((2-(4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5- carboxamido)methyl)pyridin-3-yl)carbamate (16.5 g, 91%) of as a white solid.

[0238] To a solution of tert-butyl (5-fluoro-4-methoxy-6-((2-(4-((2-oxopyridin-l(2H)- yl)methyl)benzyl)oxazole-5-carboxamido)methyl)pyridin-3-yl)carbamate (19.0 g, 34 mmol, 1.0 eq) in DCM (200 mL) was added TFA (40 mL) at 0 °C. The reaction mixture was stirred at rt for 5 h, washed with saturated NaHCCL solution, brine and dried over MgSCU and concentrated. The resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 15 / 1, v / v) to afford N-((5-amino-3-fluoro-4-methoxypyridin-2-yl)methyl)-2-(4-((2-oxopyridin- l(2H)-yl)methyl)benzyl)oxazole-5-carboxamide (15.5 g, 99%) as a white solid. LRMS (M+H+) m / z calculated 464.17, found 464.4. 'H NMR (DMSO-tL, 400 MHz) 5 8.74 (t, J= 5.6, 5.2 Hz, 1H), 7.76-7.75 (m, 1H), 7.74 (s, 1H), 7.67 (s, 1H), 7.42-7.38 (m, 1H), 7.28-7.23 (m, 4H), 6.41 (d, J= 9.2 Hz, 1H), 6.23 (m, 1H), 5.28 (s, 2H), 5.06 (s, 2H), 4.38 (dd, J= 5.6, 2.0 Hz, 2H), 4.15 (s, 2H), 3.89 (d, J= 2.4 Hz, 3H).

[0239] Example 18: Preparation of N-((5-amino-3-fluoro-4-methoxypyridin-2-yl)methyl)-2-((6-((5- fluoro-2-oxopyri din- l(2H)-yl)methyl)pyri din-3 -yl)methyl)oxazole-5 -carboxamide

[0240] To a solution of (5-bromopyridin-2-yl)methanol (5.0 g, 26.6 mmol, 1.0 eq) in DMF (70 mL) were added 5-fluoropyridin-2(lH)-one (3.0 g, 26.6 mmol, 1.0 eq), DEAD (7.0 g, 40.0 mmol, 1.5 eq) and PF13P (10.5 g, 40.0 mmol, 1.5 eq) at 0 °C under nitrogen. The mixture was stirred at rt overnight, and concentrated. The resulting residue was purified by chromatography on silica gel column (PE / EA = 1 / 1, v / v) to afford l-((5-bromopyridin-2-yl)methyl)-5-fluoropyridin-2(lH)- one (6.2 g, 82%) as a white solid.X-phos / Allylpalladium chloride THF

[0241] To a solution of l-((5-bromopyridin-2-yl)methyl)-5-fluoropyridin-2(lH)-one (2.2 g, 7.8 mmol, 1.0 eq) in THF (75 mL) were added allylpalladium chloride (285 mg, 0.78 mmol, 0.1 eq.), X- phos (371 mg, 0.78 mmol, 0.1 eq.) and (2-ethoxy-2-oxoethyl)zinc(II) bromide (1 M in THF, 15 mL, 15 mmol, 1.9 eq) at 0 °C under nitrogen. The mixture was stirred at 50 °C overnight, and concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 1 / 1, v / v) to afford ethyl 2-(6-((5-fluoro-2-oxopyridin-l(2H)-yl)methyl)pyridin-3- yl)acetate (1.5 g, 66%).

[0242] To a solution of ethyl 2-(6-((5-fluoro-2-oxopyridin-l(2H)-yl)methyl)pyridin-3-yl)acetate (800 mg, 2.8 mmol, 1.0 eq) in DMF (40 mL) was added LiHMDS (1 M in THF, 7 mL, 7.0 mmol, 2.5 eq) at - 40 °C under nitrogen. The mixture was stirred at - 40 °C for 1 h and ethyl 2- chlorooxazole-5-carboxylate (595 mg, 3.4 mmol, 1.2 eq) in DMF (5 mL) was added. The reaction mixture was stirred at 0 °C for 2 h, quenched with water (80 mL), and extracted with EA (80 mLx 2). The combined organic layers were washed with brine (50 mL), dried, and concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 1 / 1, v / v) to afford ethyl 2-(2-ethoxy-l-(6-((5-fluoro-2-oxopyridin-l(2H)- yl)methyl)pyridin-3-yl)-2-oxoethyl)oxazole-5-carboxylate (540 mg, 45%).

[0243] To a solution of ethyl 2-(2-ethoxy-l-(6-((5-fluoro-2-oxopyridin-l(2H)-yl)methyl)pyridin-3-yl)- 2-oxoethyl)oxazole-5-carboxylate (440 mg, 1.0 mmol, 1.0 eq) in THF / MeOH (20 mL / 10 mL) was added LiOH.EhO (172 mg, 4.0 mmol, 4.0 eq) in H2O (30 mL) at 0 °C. The mixture was stirred at rt overnight and adjusted to pH 5 with 1 N HC1 solution. The solvent was removed to give 2-((6-((5-fluoro-2-oxopyridin-l(2H)-yl)methyl)pyridin-3-yl)methyl)oxazole-5-carboxylic acid, which was used in the next step without further purification.

[0244] To a solution of 2-((6-((5-fluoro-2-oxopyri din- l(2H)-yl)methyl)pyri din-3 -yl)m ethyl)oxazole-5- carboxylic acid (100 mg, crude) in DMF (10 mL) were added tert-butyl (6-(aminomethyl)-5- fluoro-4-methoxypyridin-3-yl)carbamate (82 mg, 0.3 mmol, 1.0 eq), PyBOP (187 mg, 0.36mmol, 1.2 eq) and TEA (91 mg, 0.9 mmol, 3.0 eq). The mixture was stirred at rt overnight, and concentrated. The resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 20 / 1, v / v) to afford tert-butyl (5-fluoro-6-((2-((6-((5-fluoro-2-oxopyridin-l(2H)- yl)methyl)pyridin-3-yl)methyl)oxazole-5-carboxamido)methyl)-4-methoxypyri din-3- yl)carbamate (100 mg, 56%).

[0245] To a solution of tert-butyl (5-fluoro-6-((2-((6-((5-fluoro-2-oxopyridin-l(2H)-yl)methyl)pyridin- 3-yl)methyl)oxazole-5-carboxamido)methyl)-4-methoxypyridin-3-yl)carbamate (200 mg, 0.34 mmol, 1.0 eq) in DCM (3 mL) was added TFA (1 mL) at 0 °C. After stirring at rt for 3 h, the mixture was diluted with DCM (30 mL). The organic layer was washed with saturated NaHCCL solution, dried, and concentrated. The resulting residue was purified by prep-HPLC to afford N- ((5-amino-3-fluoro-4-methoxypyri din-2 -yl)methyl)-2-((6-((5-fluoro-2-oxopyridin-l(2H)- yl)methyl)pyridin-3-yl)methyl)oxazole-5-carboxamide (34 mg, 21%) as a white solid. LRMS (M+H+) m / z calculated 483.15, found 483.0. 'H NMR (DMSO-cL, 400 MHz) 5 8.78 (t, J= 5.6, 5.2 Hz, 1H), 8.49 (d, J= 1.6 Hz, 1H), 8.00 (t, J= 4.4, 4.0 Hz, 1H), 7.74 (s, 1H), 7.73 (dd, J= 8.0, 2.0 Hz, 1H), 7.67 (s, 1H), 7.62-7.57 (m, 1H), 7.23 (d, J= 8.0 Hz, 1H), 6.42 (dd, J= 5.6, 4.4 Hz, 1H), 5.29 (s, 2H), 5.11 (s, 2H), 4.39 (dd, J= 5.2, 1.6 Hz, 2H), 4.22 (s, 2H), 3.89 (d, J= 2.0 Hz, 3H).

[0246] Example 19: Preparation of N-((5-amino-3-fluoro-4-methoxypyridin-2-yl)methyl)-5-((6-((2- oxopyri din- l(2H)-yl)methyl)pyri din-3 -yl)methyl)-4H-l, 2, 4-triazole-3 -carboxamide7V-((5-amino-3-fluoro-4-methoxypyridin-2-yl)methyl)-5-((6-((2-oxopyridin-l(2ZT)- yl)methyl)pyridin-3 -yl)methyl)-4 / / - 1 ,2,4-triazole-3 -carboxamide

[0247] To a solution of ethyl 2-(6-((2-oxopyri din- l(2H)-yl)methyl)pyri din-3 -yl)acetate (1.0 g, 3.7 mmol, 1.0 eq) in MeOH (10 mL) was added hydrazine hydrate (2 mL). The mixture was stirred at 80 °C overnight. After cooling, the white precipitate was collected to afford 2-(6-((2- oxopyri din- l(2H)-yl)methyl)pyri din-3 -yl)acetohydrazide which was used in the next step without further purification.

[0248] A mixture of 2-(6-((2-ox opyri din- l(2H)-yl)methyl)pyri din-3 -yl)acetohydrazide (500 mg, 1.9 mmol, 1.0 eq) and ethyl 2-ethoxy-2-iminoacetate (562 mg, 3.8 mmol, 2.0 eq) in EtOH (10 mL) was stirred at rt overnight. The mixture was concentrated to afford ethyl (E)-2-amino-3-(2-(2-(6- ((2-oxopyri din- l(2H)-yl)methyl)pyri din-3 -yl)acetyl)hydrazineylidene)propanoate, which was used in the next step without further purification.

[0249] Ethyl (E)-2-amino-3-(2-(2-(6-((2-oxopyri din- l(2H)-yl)m ethyl)pyri din-3 - yl)acetyl)hydrazineylidene)propanoate (300 mg, 0.84 mmol, 1.0 eq) and molecular sieve (4A, 100 mg) in xylene (10 mL) was stirred at 170 °C for 16 h. The mixture was concentrated and the resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 10 / 1, v / v) to afford ethyl 5-((6-((2-oxopyridin-l(2H)-yl)methyl)pyridin-3-yl)methyl)-4H-l,2,4- triazole-3 -carboxylate (200 mg, 70%).

[0250] To a solution of ethyl 5-((6-((2-oxopyridin-l(2H)-yl)methyl)pyridin-3-yl)methyl)-4H-l,2,4- triazole-3 -carboxylate (250 mg, 0.74 mmol, 1.0 eq) in THF (6 mL) was added was added LiOH.J O (62 mg, 1.47 mmol, 4.0 eq) in H2O (6 mL) at rt. The mixture was stirred at rt for 16 h, concentrated and acidified to pH 5 with 1 N HC1 solution. The solid was collected to give 5- ((6-((2-oxopyri din- l(2H)-yl)methyl)pyri din-3 -yl)methyl)-4H-l, 2, 4-triazole-3 -carboxylic acid, which was used in the next step without further purification.

[0251] To a solution of 5-((6-((2-oxopyridin-l(2H)-yl)methyl)pyridin-3-yl)methyl)-4H-l,2,4-triazole-3- carboxylic acid (200 mg, crude) in DMF (5 mL) were added tert-butyl (6-(aminomethyl)-5- fluoro-4-methoxypyridin-3-yl)carbamate (174 mg, 0.64 mmol, 1.0 eq), PyBOP (401 mg, 0.77 mmol, 1.2 eq) and TEA (194 mg, 1.92 mmol, 3.0 eq). The mixture was stirred at rt for 2 h, and concentrated. The resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 10 / 1, v / v) to afford tert-butyl (5-fluoro-4-methoxy-6-((5-((6-((2-oxopyridin-l(2H)- yl)methyl)pyri din-3 -yl)methyl)-4H- 1,2, 4-triazole-3-carboxamido)methyl)pyri din-3 - yl)carbamate (120 mg, 27%) as a white solid.

[0252] To a solution of tert-butyl (5-fluoro-4-methoxy-6-((5-((6-((2-oxopyridin-l(2H)- yl)methyl)pyri din-3 -yl)methyl)-4H- 1,2, 4-triazole-3-carboxamido)methyl)pyri din-3 - yl)carbamate (120 mg, 0.21 mmol, 1.0 eq) in DCM (1 mL) was added TFA (0.3 mL) at 0 °C. After stirring at rt for 2 h, the mixture was diluted with DCM (30 mL). The organic layer was washed with saturated NaHCCL solution, dried, and concentrated. The resulting residue waspurified by prep-HPLC to afford N-((5-amino-3-fluoro-4-methoxypyridin-2-yl)methyl)-5-((6- ((2-oxopyri din- l(2H)-yl)methyl)pyri din-3 -yl)methyl)-4H-l, 2, 4-triazole-3 -carboxamide (70 mg, 72%) as a white solid. LRMS (M+H+) m / z calculated 465.17, found 465.1.1H NMR (DMSO-t / e, 400 MHz) 5 14.54 (brs, 1H), 8.61 (s, 1H), 8.45 (s, 1H), 7.77-7.74 (m, 2H), 7.66 (d, J= 7.6 Hz,1H), 7.42-7.46 (m, 1H), 7.16 (d, J= 8.4 Hz, 1H), 6.38 (d, J= 8.8 Hz, 1H), 6.26-6.23 (m, 1H),5.29 (s, 2H), 5.14 (s, 2H), 4.42 (d, J= 4.0 Hz, 2H), 4.11 (s, 2H), 3.89 (d, J= 2.0 Hz, 3H).

[0253] Example 20: Preparation of N-((5-amino-3-fluoro-4-methoxypyridin-2-yl)methyl)-2-(2,3- difluoro-4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5 -carboxamide

[0254] A mixture of (2,3-difhiorophenyl)methanol (10.0 g, 69.39 mol, 1.0 eq) , imidazole(7.1 g, 104.1 mol, 1.5 eq) and TMSC1 (12.6 g, 83.26mol, 1.2 eq) in DCM (200 mL) was stirred at rt for 3 h. Water (60 mL) was added, and the mixture was extracted with EA (40 mL x 3). The combined organic layers were washed with brine, dried over ISfeSCU, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (PE / EA = 100 / 1, v / v) to afford tert-butyl((2,3-difluorobenzyl)oxy)dimethylsilane (14 g, 78%).

[0255] To a solution of tert-butyl((2,3-difluorobenzyl)oxy)dimethylsilane (70.0 g, 0.27 mol, 1.0 eq) in THF (600 mL) was added n-BuLi (2.5 M in THF, 164 mL, 0.41 mol, 1.5 eq) at -78 °C for 2 h under nitrogen. DMF (29.7 g, 0.41 mol, 1.5 eq) was added. The reaction mixture was stirred at rt for 2 h, quenched with saturated aqueous NH4CI (300 mL) and extracted with EA (300 mL x 3). The combined organic layers were dried over ISfeSCU, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 100 / 1, v / v) to afford 4- (((tert-butyldimethylsilyl)oxy)methyl)-2,3-difluorobenzaldehyde (71 g, 91%).

[0256] To a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-2,3-difluorobenzaldehyde (71 g, 0.25 mol, 1.0 eq) in THF (500 mL) and MeOH (50 mL) was added NaBEL (6.6 g, 0.17 mol, 0.7 eq). The mixture was stirred at ice-bath for 2 h, quenched with saturated brine (200 mL) and extracted with EA (300 mL x 3). The combined organic layers were dried over ISfeSCL, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 20 / 1, v / v) to afford (4-(((tert-butyldimethylsilyl)oxy)methyl)-2,3- difluorophenyl)methanol (62 g, 89%).

[0257] A mixture of (4-(((tert-butyldimethylsilyl)oxy)methyl)-2,3-difluorophenyl)methanol (62 g, 0.22 mol, 1.0 eq.), PPh3(67.7 g, 0.26 mol, 1.2 eq.) and NBS (45.9 g, 0.26 mol, 1.2 eq.) in DCM (1000 mL) was stirred at rt overnight. The reaction mixture was quenched with saturated brine (300 mL) and extracted with DCM (300 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 10 / 1, v / v) to afford ((4-(bromomethyl)-2,3-difluorobenzyl)oxy)(tert- butyl)dimethylsilane (67 g, 53%) as a colorless oil.

[0258] To a solution of ((4-(bromomethyl)-2,3-difluorobenzyl)oxy)(tert-butyl)dimethylsilane (40 g, 0.11 mol, 1.0 eq) in acetonitrile (600 mL) was added pyridin-2(lH)-one (10.8 g, 0.11 mol, 1 eq) and K2CO3 (39.3 g, 0.28 mol, 2.5 eq). The mixture was stirred at 80 °C for 5 h, cooled to rt and poured into H2O (300 mL), extracted with EA (300 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 5 / 1, v / v) to afford l-(4-(((tert- butyldimethylsilyl)oxy)methyl)-2,3-difluorobenzyl)pyridin-2(lH)-one (27.1 g, 65%) as a white solid.

[0259] To a solution of l-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,3-difluorobenzyl)pyridin-2(lH)- one (2.0 g, 5.47 mmol, 1.0 eq) in DCM (20 mL) was added SOCI2 (9.8 g, 82.07 mmol, 15 eq) at0 °C. The mixture was stirred at rt for 4 h and concentrated in vacuum to yield l-(4- (chloromethyl)-2,3-difluorobenzyl)pyridin-2(lH)-one (1.5 g), which was used in next step without further purification.

[0260] A mixture of l-(4-(chloromethyl)-2,3-difhiorobenzyl)pyridin-2(lH)-one (1.5 g, 5.56 mmol, 1.0 eq), Pd(dppf)C12 (400 mg, 0.56 mmol, 0.1 eq) and TEA(1.65 g, 16.5 mmol, 3 eq) in MeOH (15 mL) was stirred at 70 °C overnight under the atmosphere of CO. The reaction mixture was diluted with brine and extracted with EA (300 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 5 / 1, v / v) to afford methyl 2-(2,3-difluoro-4-((2-oxopyridin- l(2H)-yl)methyl)phenyl)acetate (1.4 mg, 68%).

[0261] To a solution of methyl 2-(2,3-difluoro-4-((2-oxopyridin-l(2H)-yl)methyl)phenyl)acetate (300 mg, 0.94 mmol, 1.0 eq) in DMF (10 mL) was added LiHMDS (1 M in THF, 2.4 mmol, 2.4 mmol,, 2.5 eq) at -40 °C. The reaction mixture was stirred for 1 h and ethyl 2-chlorooxazole-5- carboxylate (204 mg, 0.94 mol, 1.0 eq) was added and continued to stir at rt for 1 h. The reaction mixture was quenched with NH4CI (30 mL), and extracted with EA (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 1 / 1, v / v) to afford ethyl 2-(l-(2,3-difluoro-4-((2-oxopyridin-l(2H)-yl)methyl)phenyl)-2-methoxy-2- oxoethyl)oxazole-5-carboxylate (300 mg, 64%).

[0262] To a solution of ethyl 2-(l -(2,3 -difluoro-4-((2-oxopyri din- l(2H)-yl)methyl)phenyl)-2-m ethoxy - 2-oxoethyl)oxazole-5-carboxylate (300 mg, 0.69 mmol, 1.0 eq) in MeOH / THF / J O (2 mL / 4 mL / 6 mL) was added LiOH.J O (116 mg, 2.77 mmol, 4.0 eq) at 0 °C. The reaction mixture was stirred at rt for 4 h. EA (20 mL) was added, and the aqueous layer was separated and acidified to pH 3~4 with 1 N HC1. The solid was collected, washed with water and dried to afford 2-(4-((2- oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5-carboxylic acid (170 mg, 81%) as an off-white solid.

[0263] To a mixture of 2-(2,3-difluoro-4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5-carboxylic acid (150 mg, 0.43 mmol, 1.0 eq) and PyBOP (293 mg, 0.56 mmol, 1.3 eq) in DMF (5 mL) were added tert-butyl (6-(aminomethyl)-5-fluoro-4-methoxypyridin-3-yl)carbamate (118 mg, 0.43 mmol, 1.0 eq) and TEA (131 mg, 1.3 mmol, 3.0 eq). The reaction mixture was stirred at rt for 1 h, quenched with NH4CI aqueous (30 mL), extracted with EA (30 mL x 3). The combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 20 / 1, v / v) to afford tert-butyl (6-((2-(2,3-difluoro-4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole- 5-carboxamido)methyl)-5-fluoro-4-methoxypyridin-3-yl)carbamate (190 mg, 73%) as a white solid.

[0264] To a solution of tert-butyl (6-((2-(2,3-difluoro-4-((2-oxopyridin-l(2H)- yl)methyl)benzyl)oxazole-5-carboxamido)methyl)-5-fluoro-4-methoxypyridin-3-yl)carbamate (190 mg, 0.32 mmol, 1.0 eq) in DCM (5 mL) was added TFA (1.5 mL) at 0 °C. The reaction mixture was stirred at rt for 3 h, washed with saturated NaHCCL solution, brine, dried over MgSO4, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 15 / 1, v / v) to afford N-((5-amino-3-fluoro-4-methoxypyridin- 2-yl)methyl)-2-(2,3-difluoro-4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5-carboxamide (100 mg, 63%) as a white solid. LRMS (M+H+) m / z calculated 500.15, found 500.0. 'H NMR(DMSO-tL, 400 MHz) 5 8.79 (t, J= 5.2, 5.6 Hz, 1H), 7.77-7.75 (m, 2H), 7.68 (s, 1H), 7.45 (t, J = 7.6, 7.6 Hz, 1H), 7.18 (t, J = 7.2, 7.2 Hz, 1H), 6.92 (t, J= 7.2, 7.2 Hz, 1H), 6.42-6.40 (d, J= 9.2 Hz, 1H), 6.27 (t, J= 6.8, 6.8 Hz, 1H), 5.30 (s, 2H), 5.16 (s, 2H), 4.40-4.39 (d, J= 4.0 Hz, 2H), 4.27 (s, 2H), 3.88 (s, 3H).

[0265] Example 21: Preparation of N-((5-amino-3 -fluoro-4-m ethoxypyri din-2 -yl)methyl)-2-((2-((2- oxopyridin-l(2H)-yl)methyl)pyrimidin-5-yl)methyl)oxazole-5-carboxamideAf-((5-amino-3-fluoro-4-methoxypyridin-2-yl)methyl)-2-((2-((2-oxopyridin-l(2 / T)- yl)methyl)pyrimidin-5 -yl)methyl)oxazole-5 -carboxamide

[0266] To a solution of (5-bromopyrimidin-2-yl)methanol (2.0 g, 10.58 mmol, 1.0 eq) in DMF (20 mL) were added TBDMSC1 (2.39 g, 15.87 mmol, 1.5 eq) and TEA (2.14 g, 21.16 mmol, 2.0 eq). The mixture was stirred at rt for 16 h. Water (50 mL) was added and the mixture was extracted with EA (50 mL x 3). The combined organic layers were dried and concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 10 / 1, v / v) to afford 5- bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidine (2.8 g, 87%).

[0267] To a solution of 5-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidine (2.8 g, 9.23 mmol, 1.0 eq) in dioxane (40 mL) were added CS2CO3 (9.03 g, 27.69 mmol, 3.0 eq), X-phos (881 mg, 1.85 mmol, 0.2 eq) and Pd(OAc)2 (208 mg, 0.92 mmol, 0.1 eq). The reaction mixture was stirred at 100 °C for 16 h. After filtration, the filtrate was concentrated and the resulting residue was purified by chromatography on silica gel column (PEZEA = 3 / 1, v / v) to afford diethyl 2-(2-(((tert- butyldimethylsilyl)oxy)methyl)pyrimidin-5-yl)malonate (2.3 g, 65%).

[0268] To a solution of diethyl 2-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidin-5-yl)malonate (1.70 g, 4.44 mmol, 1.0 eq) in DMSO (20 mL) was added NaCl (259 mg, 4.44 mmol, 1.0 eq). The reaction mixture was stirred at 100 °C for 16 h. Water (70 mL) was added and the mixture was extracted with EA (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried, and concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 3 / 1, v / v) to afford ethyl 2-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidin-5- yl)acetate (1.4 g), which was used in the next step without further purification.

[0269] To a solution of ethyl 2-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidin-5-yl)acetate (1.4 g, 4.52 mmol, 1.0 eq) in THF (15 mL) was added H2O (5 mL ) and AcOH (5 mL). The mixture was stirred at rtfor 16 h, and concentrated to afford ethyl 2-(2-(hydroxymethyl)pyrimidin-5- yl)acetate, which was used in the next step without further purification.

[0270] To a solution of ethyl 2-(2-(hydroxymethyl)pyrimidin-5-yl)acetate (1.0 g, 4.52 mmol, 1.0 eq) in DCM (20 mL) was added SOCh (1 mL). The mixture was stirred at rtfor 16 h, and concentrated to afford ethyl 2-(2-(chloromethyl)pyrimidin-5-yl)acetate, which was used in the next step without further purification.

[0271] To a solution of ethyl 2-(2-(chloromethyl)pyrimidin-5-yl)acetate (900 mg, 4.19 mmol, 1.0 eq) inMeCN (15 mL) was added K2CO3 (2.31 g, 16.76 mmol, 4.0 eq) and pyridin-2(lH)-one (438 mg,4.61 mmol, 1.1 eq). The mixture was stirred at rt for 16 h. After filtration, the filtrate was concentrated in vacuum and the resulting residue was purified by chromatography on silica gel column (PEZEA = 2 / 1, v / v) to afford ethyl 2-(2-((2-oxopyridin-l(2H)-yl)methyl)pyrimidin-5- yl)acetate (300 mg, 26%).

[0272] To a solution of ethyl 2-(2-((2-oxopyridin-l(2H)-yl)methyl)pyrimidin-5-yl)acetate (250 mg, 0.92 mmol, 1.0 eq) in DMF (5 mL) was added LiHMDS (1 M in THF, 2.3 mL, 2.3 mmol, 2.5 eq) at -40 °C. The mixture was stirred at 40 °C for 1 h and ethyl 2-chlorooxazole-5 -carboxylatemethane (272 mg, 1.43 mmol, 1.5 eq) was added. The reaction mixture was stirred at rt for 2 h, quenched with saturated NEUC1 solution and extracted with EA (5 mL x 3). The combined organic layers were dried over MgSO4, filtrated and concentrated in vacuum. The resulting residue was purified by chromatography on silica gel column (PEZEA = 2 / 1, v / v) to afford ethyl 2-(2-ethoxy -2-oxo- 1 -(2-((2-oxopyridin- 1 (2H)-yl)methyl)pyrimidin-5-yl)ethyl)oxazole-5 - carboxylate (100 mg, 26%).

[0273] To a solution of ethyl 2-(2-ethoxy-2-oxo-l-(2-((2-oxopyridin-l(2H)-yl)methyl)pyrimidin-5- yl)ethyl)oxazole-5-carboxylate (100 mg, 0.24 mmol, 1.0 eq.) in THF / MeOH (2 mL / 1 mL) was added LiOEl.EEO (40 mg, 0.96 mmol, 4.0 eq). The mixture was stirred at rt for 3 h, acidified to pH 5 with 1 N HC1 solution, and concentrated to provide 2-((2-((2-oxopyridin-l(2H)- yl)methyl)pyrimidin-5-yl)methyl)oxazole-5-carboxylic acid, which was used in the next step without further purification.

[0274] To a solution of 2-((2-((2-oxopyridin-l(2H)-yl)methyl)pyrimidin-5-yl)methyl)oxazole-5- carboxylic acid (100 mg, crude) in DMF (3 mL) were added PyBOP (151 mg, 0.29 mmol, 1.2 eq), tert-butyl (6-(aminomethyl)-5-fluoro-4-methoxypyridin-3-yl)carbamate (65 mg, 0.24 mmol, 1.0 eq) and TEA (73 mg, 0.72 mmol, 1.0 eq). The mixture was stirred at rt for 2 h, and concentrated. The resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 10 / 1, v / v) to afford tert-butyl (5-fluoro-4-methoxy-6-((2-((2-((2-oxopyridin-l(2H)- yl)methyl)pyrimidin-5-yl)methyl)oxazole-5-carboxamido)methyl)pyridin-3-yl)carbamate (70 mg, 52%) as a white solid.

[0275] To a solution of tert-butyl (5-fluoro-4-methoxy-6-((2-((2-((2-oxopyridin-l(2H)- yl)methyl)pyrimidin-5-yl)methyl)oxazole-5-carboxamido)methyl)pyridin-3-yl)carbamate (70 mg, 0.12 mmol, 1.0 eq) in DCM (1 mL) was added TFA (0.3 mL) at 0 °C. After stirring at rt for 2 h, the mixture was diluted with DCM (30 mL), washed with saturated NaHCCL solution, dried, and concentrated. The resulting residue was purified by prep-HPLC to afford N-((5-amino-3- fluoro-4-methoxypyridin-2-yl)methyl)-2-((2-((2-oxopyridin-l(2H)-yl)methyl)pyrimidin-5- yl)methyl)oxazole-5-carboxamide (5 mg, 9%) as a white solid. LRMS (M+H+) m / z calculated 466.16, found 466.0. 'H NMR (DMSO-t / 6400 MHz) 5 8.82 (t, J= 5.6, 5.2 Hz, 1H), 8.76 (s, 2 H), 7.77 (dd, J= 6.8, 2.0 Hz, 1H), 7.75 (s, 1H), 7.67 (s, 1H), 7.48-7.44 (m, 1H), 6.28 (d, J= 92 Hz, 1H), 6.28-6.24 (m, 1H), 5.29 (s, 2H), 5.28 (s, 2H), 4.40 (dd, J= 5.6, 2.0 Hz, 2H), 4.27 (s, 2H), 3.89 (d, J = 2.4 Hz, 3H).

[0276] Example 22: Preparation of N-((5-amino-3 -fluoro-4-methoxypyri din-2 -yl)methyl)-2-((6-((2- oxopyridin-l(2H)-yl)methyl)pyridazin-3-yl)methyl)oxazole-5-carboxamideJV-((5-ammo-3-fluoro-4-methoxypyridin-2-yl)methyl)-2-((6-((2-oxopyridin- l(277)-yl)methyl)pyridazm-3-yl)methyl)oxazole-5-carboxamideTrichloroisocyanuric acidCHCI3ClCl

[0277] To a solution of 3-chloro-6-methylpyridazine (6.0 g, 46.7 mmol, 1.0 eq) in CHCh (200 mL) was added tri chloroisocyanuric acid (4.3 g, 18.7 mmol, 0.4 eq). The mixture was stirred at 60 °C overnight, cooled to rt, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 10 / 1, v / v) to give 3-chloro-6- (chloromethyl)pyridazine (2.5 g, 33%) as a yellow solid.

[0278] A mixture of 3-chloro-6-(chloromethyl)pyridazine (2.5 g, 15.3 mmol, 1.0 eq), pyridin-2(lH)-one (1.8 g, 18.4 mmol, 1.2 eq) and K2CO3 (6.3 g, 46.0 mmol, 3.0 eq) in MeCN (40 mL) was stirred at rt overnight. The mixture was filtered and the filtrate was concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 3 / 1, v / v) to afford l-((6- chloropyridazin-3-yl)methyl)pyridin-2(lH)-one (2.1 g, 62%) as a yellow solid.

[0279] To a solution of l-((6-chloropyridazin-3-yl)methyl)pyridin-2(lH)-one (2.1 g, 9.5 mmol, 1.0 eq) in DMSO (15 mL) were added CS2CO3 (9.3 g, 28.4 mmol, 3.0 eq) and diethyl malonate (1.8 g, 11.4 mmol, 1.2 eq). The reaction mixture was stirred at 110 °C overnight. Water (50 mL) was added, and the mixture was extracted with EA (100 mLx 3). The combined organic layers were washed with brine (100 mL), dried and concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 1 / 1, v / v) to give diethyl 2-(6-((2-oxopyridin- l(2H)-yl)methyl)pyridazin-3-yl)mal onate (1.6 g, 48%) as a yellow solid.

[0280] To a mixture of diethyl 2-(6-((2-oxopyri din- l(2H)-yl)methyl)pyridazin-3-yl)mal onate (1.6 g, 4.63 mmol, 1.0 eq) in DMSO (10 mL) was added NaCl (0.3 g, 5.10 mmol, 1.1 eq). The reaction mixture was stirred at 140 °C for 4 h. Water (30 mL) was added and the mixture was extracted with EA (500 mL x 3). The combined organic layers were washed with brine (50 mL), dried and concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 2 / 1, v / v) to give ethyl 2-(6-((2-oxopyridin-l(2H)-yl)methyl)pyridazin-3-yl)acetate (0.68 g, 52%).

[0281] To a solution of ethyl 2-(6-((2-oxopyridin-l(2H)-yl)methyl)pyridazin-3-yl)acetate (680 mg, 2.49 mmol, 1.0 eq) in DMF (10 mL) was added NaH (60% dispersion in paraffin liquid, 249 mg, 6.22 mmol, 2.5 eq) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min, and ethyl 2- chlorooxazole-5-carboxylate (479 mg, 2.74 mmol, 1.1 eq) was added. The mixture was stirred at rt for 2 h under nitrogen. Water (40 mL) was added, and the mixture was extracted with EA (50 mLx 3). The combined organic layers were washed with brine (50 mL), dried and concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 1 / 1, v / v) to give ethyl 2-(2-ethoxy-2-oxo-l-(6-((2-oxopyridin-l(2H)-yl)methyl)pyridazin-3- yl)ethyl)oxazole-5-carboxylate (670 mg, 65%).

[0282] To a solution of ethyl 2-(2-ethoxy-2-oxo-l-(6-((2-oxopyridin-l(2H)-yl)methyl)pyridazin-3- yl)ethyl)oxazole-5-carboxylate (670 mg, 1.62 mmol, 1.0 eq ) in TElF / MeOEl / EEO (10 mL / 5 mL / 15 mL) at 0 °C was added LiOEl.EEO (205 mg, 4.87 mmol, 3.0 eq ). The mixture was stirred at rt for 2 h and acidified to pH 3~4 with 1 N HC1 solution. The mixture was concentrated to afford 2-((6-((2-oxopyridin-l(2H)-yl)methyl)pyridazin-3-yl)methyl)oxazole-5-carboxylic acid, which was used in the next step without further purification.

[0283] To a solution of 2-((6-((2-oxopyridin-l(2H)-yl)methyl)pyridazin-3-yl)methyl)oxazole-5- carboxylic acid (120 mg, crude) in DMF (10 mL) were added tert-butyl (6-(aminomethyl)-5- fluoro-4-methoxypyridin-3-yl)carbamate (104 mg, 0.38 mmol, 1.0 eq), HATU (175 mg, 0.46 mmol, 1.2 eq) and TEA (115 mg, 1.14 mmol, 3.0 eq). The mixture was stirred at rt for 2 h, and concentrated. The resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 20 / 1, v / v) to afford tert-butyl (5-fluoro-4-methoxy-6-((2-((6-((2-oxopyridin-l(2H)- yl)methyl)pyridazin-3-yl)methyl)oxazole-5-carboxamido)methyl)pyridin-3-yl)carbamate (110 mg, 51%) as an off-white solid.

[0284] To a solution of tert-butyl (5-fluoro-4-methoxy-6-((2-((6-((2-oxopyridin-l(2H)- yl)methyl)pyridazin-3-yl)methyl)oxazole-5-carboxamido)methyl)pyridin-3-yl)carbamate (110 mg, 0.19 mmol, 1.0 eq) in DCM (10 mL) was added TFA (2 mL) at 0 °C. The mixture was stirred at rt for 3 h, diluted with DCM (30 mL) and washed with saturated NaHCCL solution, dried, and concentrated. The resulting residue was purified by prep-HPLC to afford N-((5- amino-3-fluoro-4-methoxypyri din-2 -yl)methyl)-2-((6-((2-oxopyri din- 1(2H)- yl)methyl)pyridazin-3-yl)methyl)oxazole-5-carboxamide (40 mg, 45%) as a white solid. LRMS (M+H+) m / z calculated 466.16, found 466.1. 'H NMR (DMSO-tL, 400 MHz) 5 8.78 (t, J= 5.6, 5.6 Hz, 1H), 7.85 (dd, J= 6.4, 1.6 Hz, 1H), 7.74 (s, 1H), 7.70 (s, 1H), 7.72 (d, J= 8.4 Hz, 1H), 7.57 (d, J= 8.8 Hz, 1H), 7.47 (m, 1H), 6.41 (d, J= 9.2 Hz, 1H), 6.30-6.26 (m, 1H), 5.34 (s, 2H), 5.29 (s, 2H), 4.55 (s, 2H), 4.39 (dd, J= 7.6, 2.0 Hz, 2H), 3.89 (d, J= 2.0 Hz, 3H).

[0285] Example 23: Preparation of N-((5-amino-3 -fluoro-4-m ethoxypyri din-2 -yl)methyl)-2-(4-((2- oxopyrimidin-l(2H)-yl)methyl)benzyl)oxazole-5-carboxamideN-((5-ammo-3-fluoro-4-methoxypyridm-2-yl)methyl)-2-(4-((2-oxopyrimidm- l(2 / / )-yl)methyl)benzyl)oxazole-5-carboxamide

[0286] A mixture of methyl 2-(4-(bromomethyl)phenyl)acetate (10.0 g, 41.1 mol, 1.0 eq), pyrimidin- 2(lH)-one (4.7 g, 49.4 mol, 1.2 eq) and K2CO3 (17.0 g, 123 mol, 3.0 eq) in DMF (200 mL) was stirred at rt overnight. The reaction mixture was filtered and the filtrate was concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 1 / 1, v / v) to methyl 2-(4-((2-oxopyrimidin-l(2H)-yl)methyl)phenyl)acetate (7.5 g, 71%) as a white solid.

[0287] To a solution of methyl 2-(4-((2-oxopyrimidin-l(2H)-yl)methyl)phenyl)acetate (2.0 g, 7.7 mmol, 1.0 eq) in DMF (40 mL) was added LiHMDS (1 M in THF, 19 mL, 19.0 mmol, 2.5 eq) at -40 °C under nitrogen. The mixture was stirred for 1 h and ethyl 2-chlorooxazole-5-carboxylate (16 g, 9.3 mmol, 1.2 eq) in DMF (5 mL) was added. The reaction mixture was stirred at 0 °C for 2 h, quenched with water (80 mL), and extracted with EA (50 mLx 2). The combined organic layers were washed with brine (50 mL), dried, and concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 1 / 1, v / v) to afford ethyl 2-(2- methoxy-2-oxo-l-(4-((2-oxopyrimidin-l(2H)-yl)methyl)phenyl)ethyl)oxazole-5-carboxylate (150 mg, 5%).

[0288] To a solution of ethyl 2-(2-methoxy-2-oxo-l-(4-((2-oxopyrimidin-l(2H)- yl)methyl)phenyl)ethyl)oxazole-5-carboxylate (150 mg, 0.38 mmol, 1.0 eq) in THF / MeOH (4 mL / 2 mL) was added LiOH.J O (60 mg, 1.4 mmol, 3.7 eq) in H2O (6 mL) at 0 °C. The reaction mixture was stirred at rt for 2 h, and acidified to pH 5 with 1 N HC1 solution. The mixture was concentrated to give 2-(4-((2-oxopyrimidin-l(2H)-yl)methyl)benzyl)oxazole-5-carboxylic acid, which was used in the next step without further purification.

[0289] To a solution of 2-(4-((2-oxopyrimidin-l(2H)-yl)methyl)benzyl)oxazole-5 -carboxylic acid (150 mg, crude) in DMF (10 mL) were added tert-butyl (6-(aminomethyl)-5-fluoro-4- methoxypyri din-3 -yl)carbamate (130 mg, 0.48 mmol, 1.0 eq), HATU (220 mg, 0.58 mmol, 1.2 eq) and DIEA (186 mg, 1.4 mmol, 3.0 eq). The mixture was stirred at rt for 2 h and concentrated. The resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 15 / 1, v / v) to afford tert-butyl (5-fluoro-4-methoxy-6-((2-(4-((2-oxopyrimidin-l(2H)- yl)methyl)benzyl)oxazole-5-carboxamido)methyl)pyridin-3-yl)carbamate (75 mg, 28%).

[0290] To a solution of tert-butyl (5-fluoro-4-methoxy-6-((2-(4-((2-oxopyrimidin-l(2H)- yl)methyl)benzyl)oxazole-5-carboxamido)methyl)pyridin-3-yl)carbamate (75 mg, 0.13 mmol, 1.0 eq) in DCM (1 mL) was added TFA (0.3 mL) at 0 °C. The reaction mixture was stirred at rt for 3 h, diluted with DCM (20 mL). The organic layer was washed with saturated NaHCCL solution, dried, and concentrated. The resulting residue was purified by prep-HPLC to afford N- ((5-amino-3-fluoro-4-methoxypyridin-2-yl)methyl)-2-(4-((2-oxopyrimidin-l(2H)- yl)methyl)benzyl)oxazole-5-carboxamide (8.9 mg, 15%) as a white solid. LRMS (M+H+) m / z calculated 465.16, found 465.1. 'H NMR (DMSO-tL, 400 MHz) 5 8.76 (t, J= 5.6, 5.2 Hz, 1H), 8.54 (dd, J= 4.0, 2.4 Hz, 1H), 8.31 (dd, J= 6.4, 2.8 Hz, 1H), 7.74 (s, 1H), 7.67 (s, 1H), 7.29 (s, 4H), 6.39 (dd, J= 6.8, 4.4 Hz, 1H), 5.29 (s, 2H), 5.02 (s, 2H), 4.39 (dd, J= 5.6, 2.4 Hz, 2H), 4.17 (s, 2H), 3.89 (d, J= 2.0 Hz, 3H).

[0291] Example 24: Preparation of N-((5-amino-3 -fluoro-4-m ethoxypyri din-2 -yl)methyl)-2-((6-((2- oxopyrimidin-l(2H)-yl)methyl)pyridin-3-yl)methyl)oxazole-5-carboxamideJV-((5-amino-3-fluoro-4-methoxypyridin-2-yl)methyl)-2-((6-((2-oxopyrimidin-1 (277)-yl)methyl)pyridm-3 -yl)methyl)oxazole-5 -carboxamide

[0292] To a solution of (5-bromopyridin-2-yl)methanol (25.0 g, 133 mmol, 1.0 eq) in DMF (300 mL) were added TBDMSCI (19.9 g, 133 mmol, 1.0 eq) and TEA (40.3 g, 399 mmol, 3.0 eq). The mixture was stirred at rt overnight. Water (50 mL) was added. The mixture was extracted with EA (300 mL x 3). The combined organic layers were dried and concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 30 / 1, v / v) to afford 5- bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)pyridine (40.0 g, 83%) as a colorless oil. Diethyl malonate Pd(OAc)2, X-phosCs2CO3 / Dioxane

[0293] To a solution of 5-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)pyridine (15.0 g, 49.5 mmol,1.0 eq) in dioxane (250 mL) were added CS2CO3 (9.03 g, 27.7 mmol, 3.0 eq), X-phos (2.4 g, 5.0 mmol, 0.1 eq) and Pd(OAc)2 (1.1 g, 5.0 mmol, 0.1 eq). The mixture was stirred at 100 °C overnight under nitrogen, and concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 3 / 1, v / v) to afford diethyl 2-(6-(((tert- butyldimethylsilyl)oxy)methyl)pyridin-3-yl)malonate (15.0 g, 80%).

[0294] To a solution of diethyl 2-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)malonate (2.0 g,5.2 mmol, 1.0 eq) in DMSO (20 mL) was added NaCl (303 mg, 5.2 mmol, 1.0 eq). The mixture was stirred at 120 °C overnight. Water (50 mL) was added, and the mixture was extracted withEA (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried, and concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 10 / 1, v / v) to afford ethyl 2-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3- yl)acetate (1.2 g, 75%).

[0295] To a solution of ethyl 2-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)acetate (1.2 g, 3.9 mmol, 1.0 eq) in DCM (15 mL) was added SOCh (4.6 g, 39.0 mmol, 10.0 eq). The mixture was stirred at rt for 3 h, and concentrated to afford ethyl 2-(6-(chl oromethyl)pyri din-3 -yl)acetate as hydrochloride salt, which was used in the next step without further purification.

[0296] A mixture of ethyl 2-(6-(chloromethyl)pyridin-3-yl)acetate hydrochloride salt (700 mg, 2.8 mol, 1.0 eq), pyrimidin-2(lH)-one (326 mg, 3.4 mol, 1.0 eq) and K2CO3 (1.5 g, 11.2 mol, 4.0 eq) in DMF (10 mL) was stirred at rt overnight. The reaction mixture was filtered and the filtrate was concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 1 / 10, v / v) to ethyl 2-(4-((2-oxopyrimidin-l(2H)-yl)methyl)phenyl)acetate (650 mg, 85%).

[0297] To a solution of ethyl 2-(6-((2-oxopyrimidin-l(2H)-yl)methyl)pyri din-3 -yl)acetate (650 mg, 2.4 mmol, 1.0 eq) in DMF (20 mL) was added LiHMDS (1 M in THF, 6 mL, 6.0 mmol, 2.5 eq) at - 40 °C under nitrogen. The mixture was stirred for 1 h, and ethyl 2-chlorooxazole-5 -carboxylate (504 mg, 2.9 mmol, 1.2 eq) in DMF (5 mL) was added. The reaction mixture was stirred at 0 °C for 2 h, quenched with water (100 mL), and extracted with EA (70 mLx 2). The combined organic layers were washed with brine (50 mL), dried, and concentrated. The resulting residue was purified by chromatography on silica gel column (PEZEA = 1 / 1, v / v) to afford ethyl 2-(2-ethoxy-2-oxo-l-(6-((2-oxopyrimidin-l(2H)-yl)methyl)pyridin-3-yl)ethyl)oxazole-5-carboxylate (250 mg, 25%).

[0298] To a solution of ethyl 2-(2-ethoxy-2-oxo-l-(6-((2-oxopyrimidin-l(2H)-yl)methyl)pyri din-3 - yl)ethyl)oxazole-5-carboxylate (250 mg, 0.61 mmol, 1.0 eq) in THF / MeOH (4 mL / 2 mL) was added LiOH.J O (102 mg, 2.4 mmol, 3.0 eq.) in H2O (6 mL) at 0 °C. The mixture was stirred at rt for 2 h, acidified to pH 5 with 1 N HC1 solution and concentrated to give 2-((6-((2- oxopyrimidin-l(2H)-yl)methyl)pyridin-3-yl)methyl)oxazole-5-carboxylic acid which was used in the next step without further purification.

[0299] To a solution of 2-((6-((2-oxopyrimidin-l(2H)-yl)methyl)pyridin-3-yl)methyl)oxazole-5- carboxylic acid (100 mg, crude) in DMF (5 mL) were added tert-butyl (6-(aminomethyl)-5- fluoro-4-methoxypyridin-3-yl)carbamate (87 mg, 0.32 mmol, 1.0 eq), HATU (144 mg, 0.38 mmol, 1.2 eq) and DIEA (124 mg, 0.96 mmol, 3.0 eq). The mixture was stirred at rt for 2 h, and concentrated. The resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 10 / 1, v / v) to afford tert-butyl (5-fluoro-4-methoxy-6-((2-((6-((2-oxopyrimidin-l(2H)- yl)methyl)pyridin-3-yl)methyl)oxazole-5-carboxamido)methyl)pyridin-3-yl)carbamate (80 mg, 44%).

[0300] To a solution of tert-butyl (5-fluoro-4-methoxy-6-((2-((6-((2-oxopyrimidin-l(2H)- yl)methyl)pyridin-3-yl)methyl)oxazole-5-carboxamido)methyl)pyridin-3-yl)carbamate (80 mg, 0.14 mmol, 1.0 eq) in DCM (1 mL) was added TFA (0.3 mL) at 0 °C. The mixture was stirred at rt for 2 h, diluted with DCM (30 mL), washed with saturated NaHCCL solution, dried, andconcentrated. The resulting residue was purified by prep-HPLC to afford N-((5-amino-3-fluoro- 4-methoxypyridin-2-yl)methyl)-2-((6-((2-oxopyrimidin-l(2H)-yl)methyl)pyri din-3 - yl)methyl)oxazole-5-carboxamide (5.4 mg, 8%) as a white solid. LRMS (M+H+) m / z calculated 466.16, found 466.1. 'H NMR (DMSO-tL, 400 MHz) 5 8.78 (t, J= 5.2, 4.8 Hz, 1H), 8.57 (dd, J = 4.0, 2.8 Hz, 1H), 8.48 (d, J= 2.0, 1H), 8.30 (dd, J= 6.4, 2.8 Hz, 1H), 7.74 (dd, J= 8.0, 2.0 Hz, 1H),7.74 (s, 1H), 7.67 (s, 1H), 7.3 (d, J= 7.4 Hz, 1H), 6.47 (dd, J= 6.4, 4.0 Hz, 1H), 5.29 (s, 2H), 5.13 (s, 2H), 4.39 (dd, J= 5.2, 1.6 Hz, 2H), 4.23 (s, 2H), 3.89 (d, J= 2.0 Hz, 3H).

[0301] Example 25: Preparation of N-((5-amino-3 -fluoro-4-m ethoxypyri din-2 -yl)methyl)-2-(4-((6- oxopyrimidin-l(6H)-yl)methyl)benzyl)oxazole-5-carboxamide

[0302] To a solution of methyl 2-(4-(bromomethyl)phenyl)acetate (5.0 g, 20.6 mmol, 1.0 eq) in DMF (70 mL) was added pyrimidin-4(3H)-one (2.4 g, 24.7 mmol, 1.2 eq) and K2CO3 (8.5 g, 61.7 mmol, 3.0 eq). The mixture was stirred at rt overnight, and filtered. The filtrate was concentrated and the resulting residue was purified by chromatography on silica gel column (PEZEA = 1 / 1, v / v) to afford methyl 2-(4-((6-oxopyrimidin-l(6H)-yl)methyl)phenyl)acetate (4.1 g, 77%) as a yellow solid.

[0303] To a solution of methyl 2-(4-((6-oxopyrimidin-l(6H)-yl)methyl)phenyl)acetate (700 mg, 2.71 mmol, 1.0 eq) in DMF (10 mL) was added NaH (60%, dispersion in paraffin liquid, 271 mg, 6.78 mmol, 2.5 eq) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min, and ethyl 2- chlorooxazole-5-carboxylate (522 mg, 2.98 mmol, 1.1 eq) was added. The reaction mixture wasstirred at rt for 2 h under nitrogen, quenched with water (30 mL) and extracted with EA (50 mL><3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (PE / EA = 1 / 1, v / v) to give ethyl 2-(2 -methoxy -2-oxo-l -(4-((6-oxopyrimidin-l(6H)- yl)methyl)phenyl)ethyl)oxazole-5-carboxylate (540 mg, 50%).

[0304] To a solution of ethyl 2-(2-methoxy-2-oxo-l-(4-((6-oxopyrimidin-l(6H)- yl)methyl)phenyl)ethyl)oxazole-5-carboxylate (540 mg, 1.36 mmol, 1.0 eq) in TElF / MeOEl / EEO (6 mL / 3 mL / 9 mL) at 0 °C was added LiOEl.EEO (228 mg, 5.44 mmol, 4.0 eq). The mixture was stirred at rt for 2 h and acidified to pH 3~4 with 1 N HC1 solution. The mixture was concentrated to afford 2-(4-((6-oxopyrimidin-l(6H)-yl)methyl)benzyl)oxazole-5-carboxylic acid which was used in the next step without further purification.

[0305] To a solution of 2-(4-((6-oxopyrimidin-l(6H)-yl)methyl)benzyl)oxazole-5 -carboxylic acid (392 mg, 1.25 mmol, 1.0 eq) in DMF (6 mL) were added tert-butyl (6-(aminomethyl)-5-fluoro-4- methoxypyri din-3 -yl)carbamate (373 mg, 1.38 mmol, 1.1 eq), HATU (714 mg, 1.88 mmol, 1.5 eq) and EtsN(253 mg, 2.5 mmol, 2.0 eq). The reaction mixture was stirred at rt for 3 h. Water (20 mL) was added and the mixture was extracted with EA (30 mL><3). The combined organic layers were washed with brine, dried over ISfeSCU, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 30 / 1, v / v) to give tert-butyl (5-fluoro-4-methoxy-6-((2-(4-((6-oxopyrimidin-l(6H)-yl)methyl)benzyl)oxazole-5 carboxamido)methyl)pyridin-3-yl)carbamate (78 mg, 11%) as an off-white solid.

[0306] To a solution of tert-butyl (5-fluoro-4-methoxy-6-((2-(4-((6-oxopyrimidin-l(6H)- yl)methyl)benzyl)oxazole-5 carboxamido)methyl)pyridin-3-yl)carbamate (78 mg, 0.14 mmol,I.0 eq ) in DCM (3 mL) at 0 °C was added TFA (1 mL). The mixture was stirred at rt for 1 h and adjusted to pH 7 with NaHCCL aqueous solution. The mixture was extracted with DCM (15 mL><3) and the combined organic layers were washed with brine, dried over ISfeSCU, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (DCM / MeOH = 20 / 1, v / v) to give N-((5-amino-3-fluoro-4-methoxypyridin-2-yl)methyl)-2-(4- ((6-oxopyrimidin-l(6H)-yl)methyl)benzyl)oxazole-5-carboxamide (53 mg, 82%) as a white solid. LRMS (M+H+) m / z calculated 465.2, found 465.1. 'H NMR (DMSO-tL, 400 MHz) 5 8.75 (t, J= 6.4, 6.4 Hz, 1H), 8.64 (s, 1H), 7.91 (d, J= 7.2 Hz, 1H), 7.74 (s, 1H), 7.68 (s, 1H), 7.29 (s, 4H),6.41 (dd, J= 6.4, 0.8 Hz, 1H), 5.29 (s, 2H), 5.07 (s, 2H), 4.39 (dd, J= 5.6, 2.4 Hz, 2H), 4.17 (s, 2H), 3.88 (d, J= 2.4 Hz, 3H).II. Biological EvaluationExample 1: In vitro enzyme inhibition

[0307] The ability of the compounds disclosed herein to inhibit human plasma kallikrein activity was quantified according to the procedures below.

[0308] A 10 mM solution of the test compound was made in DMSO. This solution was serially diluted 1 :5 in DMSO to yield 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256 and 0.00512 pM compound test solutions. A control tube containing only DMSO is included. 16 pL of each compound test solution was combined with 384 pL of assay buffer (50 mM Tris-HCl pH 7.5, 150 mM NaCl, 0.01% Triton X-100) to yield a “4X test compound buffer stock”.

[0309] Separately, a 40 nM solution of human Plasma Kallikrein (Abeam) and a 93.6 pM solution Pro- Phe-Arg-AMC (Bachem) were made using assay buffer. These solutions are hereby refered to as 4X hPK and 2X PFR-AMC, respectively.

[0310] 60 pL of each 4X test compound buffer stock was combined with 60pL of 4X hPK to yield 120 pL of “2X test compound buffer stock / 2X hPK”. 50 pL was removed from this mixture and placed into duplicate wells on a Microfluor IBlack U-bottom microtiter plate (Thermo Scientific). This plate was incubated for 5 minutes at 37 °C. To each well, 50 pL of prewarmed 2X PFR-AMC was added to start the enzymatic reaction. Cleavage of PFR-AMC was monitored in a Biotek Synergy H4 reader set at 37 °C. Readings are taken every 43 seconds for 1 hour. The highest mean velocity over 20 reads (~15 minutes) is used to calculate the IC50. The IC50 is calculated using the Gen5 (Biotek Instruments) and is provided in Table 2.Example 2: In vitro cellular assay

[0311] The ability of the compounds disclosed herein to inhibit cellular kallikrein activity was quantified and the respective EC50 value was determined.Materials:

[0312] Plasma kallikrein inhibitor C1NH (Athens Research & Technology, Cat#16-16-031509); DXS (Sigma, Cat#31395); FXIIa (Enzyme Research Laboratories, Cat#FXIIa 3850AL); Substrate Z- FR-2-AMC (GL Biochem, Cat#55352); Thermo Scientific™ Nunc™ 96-Well Polypropylene MicroWell Plates (Thermo Scientific, Cat#267342). Methods:

[0313] An assay buffer was prepared comprising 50 mM Tris-HCl pH 7.2, 150 mM NaCl, and 0.01% Triton X-100.

[0314] Two-fold serial dilutions in DMSO were prepared from a 4 mM test compound stock solution, to yield six solutions with concentrations between 400000 nM and 390 nM. The six solutions of the test compound, prepared by serial dilutions, were further diluted four-fold in the assay buffer.

[0315] Human plasma was thawed on ice and centrifuged for 15 min at 4 °C to remove platelets.

[0316] A 10 mg / mL stock solution of DXS was diluted to 1.25 mg / mL, lul of this DXS was mixed with 47ul of 100% human plasma in assay plate. The plate was incubated for 7 min at 4 °C. A 16000 nM stock solution of FXIIa was diluted to 500 nM, lul of this FXIIa was mixed with 47 pl of 100% human plasma in assay plate. The plate was incubated for 30 min at 4 °C.

[0317] The test compound at various concentrations, prepared by serial dilutions as described above, was added to the test wells. The volume of the test compound added to each test well was 1 pL, to yield final concentrations of 2000 nM, 500 nM, 125 nM, 31.25 nM, 7.81 nM and 1.95 nM. Each test compound concentration was tested in duplicate.

[0318] In addition to the inhibitor control and test wells, the 96-well assay plate included positive control wells which contain the mixture of human plasma and DXS / FXIIa without test compound, and background wells which contain neither the mixture of human plasma and DXS / FXIIa nor test compound. The total volume of liquid in positive control and background wells was brought up to 49 pL, using the assay buffer.

[0319] The assay plate containing test compound, mixed with human plasma and ellagic acid and appropriate controls, was incubated at 37 °C for 5 min.

[0320] A 10 mM stock solution of substrate Z-FR-2-AMC was diluted to 2000 pM in the assay buffer, and 1 pL of the diluted substrate was added to each well, to yield a final substrate concentration of 40 pM in each well. The reagents were mixed well by shaking the plate gently for 30 sec.

[0321] The enzyme reaction was quantified by immediate kinetic reading of the assay plate using excitation / emission wavelengths of 330 nm / 440 nm respectively. Fluorescence intensity was recorded for 60 min, using a time interval of 43 sec. The highest mean velocity for 10 reads within the first 30 minutes was used to calculate the ECso and EC90 values.

[0322] The inhibition activity of compounds was evaluated using the EC50 and EC90 values, calculated according to the dose-response curve of compounds, fitted using the “log (inhibitor)-response (variable slope)” equation in GraphPad Prism software (GraphPad Software, Inc.).The percentage inhibition was calculated using the following equation:Inhibition" / . = 100Mean (PC)- Mean (BG)Where, Mean(BG) is the average value of the fluorescence intensity of the background wells and Mean (PC) is the average value of the fluorescence intensity of the positive control wells.

[0323] The ability of the compounds disclosed herein to inhibit human plasma kallikrein activity was determined and summarized in Table 2.Table 2Note: Biochemical assay (hPK IC50) data are designated within the following ranges:A: < 0.10 pMB: > 0.10 pM to < 1.0 pMC: > 1.0 pM to < 10 pMNote: Celluar assay (plasma EC50) data are designated within the following ranges: A: < 0.20 pM C: > 1.0 pM to < 10 pMB: > 0.20 pM to < 1.0 pM D: > 10 pMIII. Preparation of Pharmaceutical Dosage Forms

[0324] Example 1 : Oral capsule

[0325] The active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof. A capsule for oral administration is prepared by mixing 1-1000 mg of active ingredient with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration.

[0326] Example 2: Solution for injection

[0327] The active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and is formulated as a solution in sesame oil at a concentration of 50 mg-eq / mL.

[0328] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

CLAIMSWe claim:

1. A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (I):wherein,Ring A is 1,3-disubstituted pyridine or 1,3-disubstituted, 5-membered heteroaryl;R1is hydrogen, halo, cyano, or optionally substituted C1-C5 alkyl;R2is hydrogen, cyano, optionally substituted C1-C5 alkyl, or C1-C3 optionally substituted alkoxy;R3is hydrogen, cyano, C1-C3 optionally substituted alkoxy, or optionally substituted C1-C5 alkyl;R4and R5are independently hydrogen, cyano, halo, hydroxy, C1-C3 optionally substituted alkoxy, or optionally substituted C1-C5 alkyl;R6and R7are independently hydrogen, or optionally substituted C1-C5 alkyl;XI is G, or *J-CH2-K, wherein the * denotes attachment to -C(R4)(R5)-Ring A;G is optionally substituted bicyclic heteroaryl ring;W is independently N, C-H, or C-F;X is independently N, C-H, or C-F;Y is independently N, C-H, or C-F;Z is independently N, C-H, or C-F; andK is selected from optionally substituted oxopyrimidinyl, or optionally substituted oxopyridinyl. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein XI is G.3 The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein G is selected from optionally substituted quinolyl, optionally substituted indolyl, optionally substituted indazolyl, optionally substituted benzimidazolyl, optionally substituted isoquinolyl, optionally substituted cinnolinyl, optionally substituted phthalazinyl, optionally substituted quinazolinyl, optionally substituted naphthyridinyl, or optionally substituted benzoisoxazolyl.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein G is selected from optionally substituted quinolin-3-yl, or optionally substituted quinolin-6-yl.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted quinolin-6-yl, or optionally substituted quinolin-3-yl is substituted with at least one substituent selected from optionally substituted C1-C3 alkyl, halogen, -CN, -SChMe, -SO2NH2, - CONH2, -CH2NHAC, -CO2Me, -CO2H, -CH2OH, -CH2NH2, -NH2, -OH, or -OMe.6 The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted quinolin-6-yl is substituted at least at the 3-position.7 The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein the quinolin-6- yl is selected from 3-chloroquinolin-6-yl, 3-methylquinolin-6-yl, 3-trifluoromethylquinolin-6-yl, 3-fluoroquinolin-6-yl, or 3-cyanoquinolin-6-yl.8 The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted quinolin-3-yl is substituted at least at the 6-position or the 7-position.9 The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein G is 3- chloroquinolin-6-yl.10 The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein XI is *J-CH2- K, wherein the * denotes attachment to -C(R4)(R5)-Ring A.11 The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein J is12 The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein J isW is independently C-H, or C-F;X is independently C-H, or C-F;Y is independently C-H, or C-F; andZ is independently C-H, or C-F.13 The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein J is14 The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein J is7-NW=X15. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein J is16. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein J is17. The compound of claim 13, 14, 15, or 16, or a pharmaceutically acceptable salt thereof, wherein W is independently C-H, or C-F;X is independently C-H, or C-F;Y is independently C-H, or C-F; andZ is independently C-H, or C-F.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein K is optionally substituted oxopyrimidinyl.

19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted oxopyrimidinyl is optionally substituted 2-oxopyrimidin-l-yl.

20. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted oxopyrimidinyl is optionally substituted 6-oxopyrimidin-l-yl.

21. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein K is 2-oxopyrimidin-l-yl, or 6-oxopyrimidin-l-yl.

22. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein K is optionally substituted oxopyridinyl.

23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted oxopyridinyl is optionally substituted 2-oxopyridin-l-yl.

24. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 2-oxopyridin-l-yl is optionally substituted with at least one fluoro.

25. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein K is 2-oxopyridin-l-yl.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 1,3-disubstituted pyridine having the structure:

27. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 1,3-disubstituted, 5-membered heteroaryl.

28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein the 1,3- disubstituted, 5-membered heteroaryl is selected from optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted triazole, optionally substituted oxazole, or optionally substituted oxadiazole.

29. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein the 1,3- disubstituted, 5-membered heteroaryl is selected from optionally substituted triazole, optionally substituted oxazole, or optionally substituted oxadiazole.

30. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein Ring A is:

31. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein Ring A is:

32. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein Ring A is:

33. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein Ring A is:

34. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein Ring A is:

35. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein Ring A is:

36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein R1is fluoro.

37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein R2is C1-C3 optionally substituted alkoxy.

38. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein R2is -OCH3, -OCF3, -OCHF2, or -OCH2F.

39. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein R2is -OCH3.

40. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein R6and R7are independently selected from hydrogen, fluoromethyl, hydroxymethyl, and methyl.

41. The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein R6is hydrogen, and R7is hydrogen, hydroxymethyl, or methyl.

42. The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein R6is hydrogen, and R7is hydrogen.

43. A compound, or a pharmaceutically acceptable salt thereof, as described in Table 1.

44. A pharmaceutical composition comprising a compound of Formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

45. A pharmaceutical composition comprising a compound as described in Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

46. A method of treating angioedema in a patient in need thereof, the method comprising administering to the patient a compound of Formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

47. A method of treating angioedema in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

48. A method of treating angioedema in a patient in need thereof, the method comprising administering to the patient a compound as described in Table 1, or a pharmaceutically acceptable salt thereof.

49. A method of treating angioedema in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition comprising a compound as described in Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

50. The method of any one of claims 46-49, wherein the angioedema is hereditary angioedema.

51. The method of any one of claims 46-49, wherein the angioedema is acute angioedema.

52. A method of prophylaxis to prevent attacks of angioedema in a patient in need thereof, the method comprising administering to the patient a compound of Formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

53. A method of prophylaxis to prevent attacks of angioedema in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

54. A method of prophylaxis to prevent attacks of angioedema in a patient in need thereof, the method comprising administering to the patient a compound as described in Table 1, or a pharmaceutically acceptable salt thereof.

55. A method of prophylaxis to prevent attacks of angioedema in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition comprising a compound as described in Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

56. The method of any one of claims 52-55, wherein the angioedema is hereditary angioedema.

57. The method of any one of claims 52-55, wherein the angioedema is acute angioedema.