AKT1 modulators

Abstract

Provided herein are inhibitors of AKT1, pharmaceutical compositions comprising the inhibitory compounds, and methods for using the AKT1 inhibitory compounds for the treatment of disease.

Description

AKT1 MODULATORSCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of US Provisional Application No. 63 / 570,610, filed on March 27, 2024, US Provisional Application No. 63 / 667,630, filed on July 3, 2024, US Provisional Application No. 63 / 715,372, filed on November 1, 2024, and US Provisional Application No. 63 / 767,446, filed on March 5, 2025, all of which are hereby incorporated by reference in their entirety.BACKGROUND

[0002] AKT is a protein kinase and mediates cell survival and proliferation by inhibiting pathways which promotes apoptosis. AKT signaling cascade dysfunction is observed in several cancer types and may be associated with tumor aggressiveness. Additionally, malfunction of AKT typically lead to enhanced proliferation, growth, survival, and resistance to apoptosis. Pharmaceutical agents with the ability to modulate AKT1 activity would be useful in the treatment of disease, such as cancer.BRIEF SUMMARY OF THE INVENTION

[0003] Provided herein are inhibitors of AKT1, pharmaceutical compositions comprising said inhibitory compounds, and methods for using said inhibitory compounds for the treatment of disease.

[0004] One embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereofwherein,Ring A is an optionally substituted monocyclic, bicyclic, or tricyclic heteroaryl; w, x, y, and z are each independently N or C-R1; each R1is independently selected from H, D, halogen, or -CN;R2and R3are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R2and R3together form an oxo; or R2and R3join together to form a carbocycle or heterocycle;L is selected from -N(R4)-, -O-, or a divalent radical selected from:wherein the asterisk (*) indicates the bond towards the LCG;each R4is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl; each R25are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R25together form an oxo; or two independently selected R25join together to form a carbocycle or heterocycle; al is 0, 1, 2, 3, or 4; bl is 0, 1, 2, 3, or 4; cl is 1, 2, 3, or 4; dl is 1, 2, 3, or 4; el is 0, 1, 2, 3, or 4; fl is 0, 1, 2, 3, or 4; provided that e and f are not both 0; gl is 0, 1, 2, 3, or 4; provided that e and g are not both 0; hl is 0, 1, 2, 3, or 4; provided that gl and hl are not both 0; and provided that fl and hl are not both 0; p is 1, 2, 3, or 4; q is 0, 1, or 2; n is 0 or 1;LCG is a group selected from the group consisting of:Q2is O or S;Q3is a bond, O, S, N-R9a;R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R9is absent and Q3and L join together to form a heterocycle; andR9ais selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R9and R9ajoin together to form a heterocycle;T1is N or C-R10;T2is N or C-R10;T3is N or C-R10;T4is N or C-R10;T5is O, S, or N-R11; each R10is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R11is hydrogen, or optionally substituted C1-C6 alkyl;T7is N or C-R12;T8is N or C-R12; each R12is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted Cl- C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substitutedwherein each R13, R14, R15, and R16is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C=N .

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

[0006] One embodiment provides a method of treating a disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I), or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof. Another embodiment provides the method wherein the disease or disorder is cancer.INCORPORATION BY REFERENCE

[0007] 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

[0008] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not 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

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

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

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

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

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

[0014] " Oxo" refers to the =0 radical.

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

[0016] " Imino" refers to the =N-H radical.

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

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

[0019] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., Ci-C is alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., Ci-C 13 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 ( / / -propyl), 1 -methylethyl ( / .w-propyl), 1 -butyl ( / / -butyl), 1- methylpropyl (sec-butyl), 2-methylpropyl ( / .w-butyl), 1,1 -dimethylethyl (tert-butyl), 1 -pentyl (n- 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, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl). In certain embodiments, an optionally substituted alkyl is a haloalkyl. In other embodiments, an optionally substituted alkyl is a fluoroalkyl. In other embodiments, an optionally substituted alkyl is a -CF3 group.

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

[0021] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having 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 tri fluoromethyl).

[0022] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, 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 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] "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-Cs 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).

[0024] "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, ortrifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0025] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C2-C8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C2-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., Cs-Cs alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C3-C5 alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -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] "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, i.e., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance withthe Hiickel 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.

[0027] "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.

[0028] "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.

[0029] "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.

[0030] "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.

[0031] "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), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, oxo, thioxo, cyano, nitro, -Rb- 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 adirect 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.

[0032] "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.

[0033] "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.

[0034] "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.

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

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

[0037] "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 quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionallysubstituted 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.

[0038] 'W-heterocyclyl" or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An A-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.

[0039] " 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.

[0040] "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.

[0041] "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.

[0042] "Heteroaryl" refers to a radical derived from a 3 - to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, z.e., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Hiickel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally 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- 177-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.

[0043] " / f-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.

[0044] " 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.

[0045] "Heteroarylalkyl" refers to a radical of the formula -Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroaryl alkyl radical is optionally substituted as defined above for a heteroaryl group.

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

[0047] 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.

[0048] 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:

[0049] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,nC,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0050] 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.

[0051] 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.

[0052] In certain embodiments, the compounds disclosed herein have some or all of theJH atoms replaced with2H atoms. The methods of synthesis for deuterium-containing compoundsare known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAlD4), are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD4 is illustrated, by way of example only, in the reaction schemes below.

[0057] 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.

[0058] 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.

[0059] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the AKT1 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.

[0060] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates,oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenyl acetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared 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.

[0061] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropyl amine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N- dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, 7V-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0062] "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.

[0063] 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.

[0064] 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” means 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.AKT1 Protein and Function

[0065] AKT, also known as protein kinase B (PKB), is a serine / threonine protein kinase with three isoforms, AKT1, AKT2, and AKT3. While the isoforms are encoded by different genes, they are highly homologous at the protein level and share a conserved domain structure comprising an N-terminal pleckstrin homology (PH) domain, a kinase domain, and a C-terminal regulatory domain comprising a hydrophobic moiety, which includes the regulatory serine residue (Nitulescu, G. M. et al., Int J Oncol., 2018; 53(6): 2319-2331).

[0066] AKT proteins play a crucial role in major cellular functions including cell cycle progression, cell size, regulation of glucose metabolism, transcription, protein synthesis, genome stability, and neovascularization. AKT proteins can block apoptosis by inactivation of pro- apoptotic proteins, and mediate cellular growth factors, promoting cell survival. AKT is a major downstream effector of nuclear factor-kappaB (NtkB), which may link AKT signaling to the nucleus of a cell.

[0067] AKT1 is ubiquitously expressed, whereas AKT2 is primarily expressed in insulin- responsive tissues, and AKT3 is primarily expressed in brain and testes. A shared phosphorylation site of AKT in the catalytic domain corresponds to a threonine residue; specifically, Thr308 in AKT1, Thr309 in AKT2, and Thr305 in AKT3. A shared phosphorylation site in the C-terminus of the protein cis a serine residue; specifically, Ser473 in AKT1, Ser474 in AKT2, and Ser472 in AKT3.

[0068] AKT is a key downstream mediator of the phosphoinositide-3 -kinase (PI3K) signaling pathway. PI3Ks are activated by different compounds. For example, PI3Ka, PI3KP, and PI3K5, are activated by extracellular ligands binding to a transmembrane glycoprotein with enzymaticactivity, receptor tyrosine kinases (RTKs). In contrast, PI3Ky is activated by G-protein- compound receptors (GPCRs) and by RAS family of GTPases.

[0069] The AKT cascade can be activated by RTKs and G-protein-compound receptors (GPCRs), along with other signals including integrins, B cell receptors, T cell receptors, and cytokine receptors.AKT1 Mechanism

[0070] AKT is activated by a second phosphorylation at the regulatory serine residue, Ser473. Known phosphorylating agents of AKT at Ser473 include, but are not limited to PDK-1, integrin-linked kinase (ILK), members of the PI3K-related kinase (PIKK) family, and mammalian target of rapamycin (mTOR) (Nitulescu, G. M. et al., Int J Oncol., 2018; 53(6): 2319-2331).

[0071] mTOR is a key component in the AKT signaling pathway, which is a downstream member of AKT and an important regulator for cell metabolism and growth. mTOR is also an activator which can directly phosphorylate AKT’s regulatory serine residue, Ser473. mTOR forms a complex with rapamycin-insensitive companion of mTOR (RICTOR) (and other proteins) to form mTOR complex 2 (mT0RC2), which can directly phosphorylate AKT Ser473. AKT can affect cell survival and growth because it can influence the tuberous sclerosis complex (TSC) 1 / 2 along the mTORC signaling pathway and inhibit pro-apoptotic proteins or signals.

[0072] AKT is known as a survival kinase and mediates cell survival and proliferation by inhibiting pathways including, but not limited to Bcl2 and MDM2, which promotes apoptosis. Studies have shown that the AKT signaling cascade has frequent malfunctions in various cancers, and may be associated with tumor aggressiveness (Nitulescu, G. M. et al., Int J Oncol., 2018; 53(6): 2319-2331). Malfunctions of AKT typically lead to enhanced proliferation, growth, survival, and resistance to apoptosis (Alwhaibi, A. et al., Pharmacol Res., 2019, 145: 104270). Malfunction and mis-regulation of AKT may lead to cancers such as but not limited to breast cancer, gastric carcinoma, glioblastoma, gliosarcomas, head and neck squamous cell carcinoma, ovarian cancer, pancreatic cancer, and prostate cancer.

[0073] Additionally, AKT1 has been found to be involved in invasion and migration of cancerous cells (Alwhaibi, A. et al., Pharmacol Res., 2019, 145: 104270). Researchers found that silencing the AKT1 isoform can abrogate specific types of cancer cell migration. However, there have been other studies which have demonstrated that activated AKT1 resulted in less metastatic propensity for lung metastatic lesion cells and breast cancer cells. AKT1 has also been identified as a key protein involved in angiogenesis, lung cancer, and tumorigenesis.

[0074] Furthermore, overexpression of AKT has been correlated to resistance to chemotherapeutic agents such as cisplatin, methotrexate, and paclitaxel. Thus, there remains a need to find AKT inhibitors given its role in cell survival and cancer proliferation.

[0075] Recently, it has been found that the AKT1 gene mutation E17K can affect cell growth, proliferation, survival, and migration of breast cancer cells, colorectal cancer cells, and ovarian cancer cells (Chen, Y. et al., Front Cell Dev Biol., 2020; 8: 573599). These mutations in the PH structural domain increase the binding of AKT1 to Phosphatidylinositol-3,4,5-triphosphate (PIP3) lipid ligand, which accelerates transfer of AKT from the cytoplasm to the cell membrane through formation of hydrogen bonds. Transfer of AKT into the cell membrane allows it to be further phosphorylated. Once fully activated, AKT can return to the cytoplasm, or go to the nucleus or other intracellular sites, and phosphorylate other substrate proteins to regulate cell function.

[0076] The E17K mutation enhances migration of breast cancer cells, and also enhances resistance to chemotherapeutic drugs. However, the E17K mutation can also selectively destroy chemo-resistant tumor-promoting AKT1 quiescent cancer cells, suggesting that the AKT1(E17K) mutation is crucial in the oncogenic / anti-tumor mechanism.

[0077] A major pathway that activates PI3K-AKT signaling pathway is somatic cell mutations, with the E17K mutation being the highest frequency of AKT1 mutations. It is nearly exclusively present in AKT1. The AKT1(E17K) is a recurrent somatic cell mutation predominantly in breast cancer, ovarian cancer, meningioma, and Proteus syndrome.

[0078] AKT1(E17K) mutations mediate the PI3K-AKT signaling cascade by expanding PIP lipid specificity, which causes conformational changes. This also enhances subcellular localization to accelerate localization of the PH structural domain to the plasma membrane. The E17K mutation increases PIP3 binding specificity by 7-fold and phosphatidylinositol-(4,5)- bisphosphate (PIP2) by 100-fold.

[0079] The AKT1(E17K) mutation also causes rapid conformational changes in the AKT1 PH structural domain. The conformational changes to this domain result in a 4.5-fold increase in its membrane localization, which can result in excessive phosphorylation. The AKT1(E17K) mutation can also result in enhanced subcellular localization by increasing the transient expression.

[0080] Given the conformational and signaling effects of the AKT1(E17K) mutation, this target may be useful for targeted treatment of cancers.Prior Art AKT1 Inhibitors

[0081] Most AKT inhibitors targeting the ATP binding site are non-selective against the three isoforms, as well as having poor to no selectivity against other structurally similar kinases. Thus, there remains a need to develop new and novel AKT inhibitors. These ATP targeting inhibitors are classified as aminofurazans, azepane derivatives, isoquinoline-5-sulfonamides, phenylpyrazole derivatives, thiophene carboxamide derivatives, and thiazole carboxamide derivatives.

[0082] There are also ATP non-competitive AKT inhibitors which are allosteric modulators which have greater specificity than the ATP targeting inhibitors. Many of these allosteric modulator inhibitors are classified as purine derivatives, thiourea derivatives, alkylphospholipids, sulfonamides, 2,3-diphenylquinoxaline analogs, and indole-3 -carbinol derivatives.Novel AKT1 Inhibitory Compounds

[0083] In one aspect, provided herein is an AKT1 inhibitory compound.

[0084] One embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein,Ring A is an optionally substituted monocyclic, bicyclic, or tricyclic heteroaryl; w, x, y, and z are each independently N or C-R1; each R1is independently selected from H, D, halogen, or -CN;R2and R3are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R2and R3together form an oxo; or R2and R3join together to form a carbocycle or heterocycle;L is selected from -N(R4)-, -O-, or a divalent radical selected from:wherein the asterisk (*) indicates the bond towards the LCG; each R4is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl;each R25are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R25together form an oxo; or two independently selected R25join together to form a carbocycle or heterocycle; al is 0, 1, 2, 3, or 4; bl is 0, 1, 2, 3, or 4; cl is 1, 2, 3, or 4; dl is 1, 2, 3, or 4; el is 0, 1, 2, 3, or 4; fl is 0, 1, 2, 3, or 4; provided that e and f are not both 0; gl is 0, 1, 2, 3, or 4; provided that e and g are not both 0; hl is 0, 1, 2, 3, or 4; provided that gl and hl are not both 0; and provided that fl and hl are not both 0; p is 1, 2, 3, or 4; q is 0, 1, or 2; n is 0 or 1;LCG is a group selected from the group consisting of:Q2is O or S;Q3is a bond, O, S, N-R9a;R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R9is absent and Q3and L join together to form a heterocycle; andR9ais selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R9and R9ajoin together to form a heterocycle;(b)T1is N or C-R10;T2is N or C-R10;T3is N or C-R10;T4is N or C-R10;T5is O, S, or N-R11; each R10is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R11is hydrogen, or optionally substituted C1-C6 alkyl;T7is N or C-R12;T8is N or C-R12; each R12is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted Cl- C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substitutedwherein each R13, R14, R15, and R16is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C=N .

[0085] Another embodiment provides the compound of Formula (I), having the structure of Formula (II), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ring A is:wherein,R5is optionally substituted aryl, or optionally substituted heteroaryl;A1is selected from N, C-H, or C-R23;A2is selected from N, C-H, or C-R24;R21, R22, R23, and R24are independently selected from H, D, halogen, -OR26, -SR26, -N(R26)2, - CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -CO2R26, - CON(R26)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each R26is independently H or optionally substituted C1-C6 alkyl.

[0086] Another embodiment provides the compound, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (Ila),

[0087] Another embodiment provides the compound of Formula (Ila), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A1is N. Another embodiment provides the compound of Formula (Ila), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A2is C-H. Another embodiment provides the compound of Formula (Ila), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R21and R22are H.

[0088] Another embodiment provides the compound of Formula (I), having the structure of Formula (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ring A is:wherein,R5is optionally substituted aryl, or optionally substituted heteroaryl;A1is selected from N, C-H, or C-R23;A2is selected from N, C-H, or C-R24;R21, R22, R23, and R24are independently selected from H, D, halogen, -OR26, -SR26, -N(R26)2, - CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -CO2R26, - CON(R26)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each R26is independently H or optionally substituted C1-C6 alkyl.

[0089] Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (Illa),acceptable salt, solvate, or deuteroisotope thereof, wherein A1is N. Another embodiment provides the compound of Formula (Illa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A2is C-H. Another embodiment provides the compound of Formula (Illa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R21and R22are H.

[0091] Another embodiment provides the compound, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (IV-i), wherein Ring A is:wherein,R5is optionally substituted aryl, or optionally substituted heteroaryl;A5is selected from N, C-H, or C-R29;A6is selected from N, C-H, or C-R30; each R37is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclyl;R29and R30are independently selected from H, D, halogen, -OR26, -SR26, -N(R26)2, -CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -CO2R26, -CON(R26)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R30and R37join together to form a C1-C6 alkylene; each R26is independently H or optionally substituted C1-C6 alkyl.

[0092] Another embodiment provides the compound of Formula (IV-i), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A5is C-H. Another embodiment provides the compound of Formula (IV-i), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A6is C-H.

[0093] Another embodiment provides the compound, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (IVa-i), wherein Ring A is:wherein,R5is optionally substituted aryl, or optionally substituted heteroaryl;A5is selected from N, C-H, or C-R29;A6is selected from N, C-H, or C-R30;R37is H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclyl;R29and R30are independently selected from H, D, halogen, -OR26, -SR26, -N(R26)2, -CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -CO2R26, -CON(R26)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R30and R37join together to form a C1-C6 alkylene; each R26is independently H or optionally substituted C1-C6 alkyl.

[0094] Another embodiment provides the compound of Formula (IVa-i), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A5is C-H. Another embodiment provides the compound of Formula (IVa-i), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A6is C-H.

[0095] Another embodiment provides the compound of Formula (I), having the structure of Formula (IV), wherein Ring A is:wherein,R5is optionally substituted aryl, or optionally substituted heteroaryl;A5is selected from N, C-H, or C-R29;A6is selected from N, C-H, or C-R30; each R37is independently selected from H or optionally substituted C1-C6 alkyl;R29and R30are independently selected from H, D, halogen, -OR26, -SR26, -N(R26)2, -CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -CO2R26, -CON(R26)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R30and R37join together to form a C1-C6 alkylene; each R26is independently H or optionally substituted C1-C6 alkyl.

[0096] Another embodiment provides the compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (IVa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ring A is:wherein,R5is optionally substituted aryl, or optionally substituted heteroaryl;A5is selected from N, C-H, or C-R29;A6is selected from N, C-H, or C-R30;R37is H or optionally substituted C1-C6 alkyl;R29and R30are independently selected from H, D, halogen, -OR26, -SR26, -N(R26)2, -CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -CO2R26, -CON(R26)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R30and R37join together to form a C1-C6 alkylene; each R26is independently H or optionally substituted C1-C6 alkyl.

[0097] Another embodiment provides the compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (IVb),

[0098] Another embodiment provides the compound of Formula (IVb), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A5is C-H. Another embodiment provides the compound of Formula (IVa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A6is C-H.

[0099] Another embodiment provides the compound of Formula (I), having the structure of Formula (V), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ring A is:wherein,R5is optionally substituted aryl, or optionally substituted heteroaryl;A1is selected from N, C-H, or C-R23;A2is selected from N, C-H, or C-R24;A3is selected from N, C-H, or C-R27;A4is selected from N, C-H, or C-R28;J1-!2- J3is selected from: -N=CH-N(R26)-; -N(R26)-CH=N-; -N=CH-O-; or -O-CH=N-;R23, R24, R27, and R28are independently selected from H, D, halogen, -OR26, -SR26, -N(R26)2, - CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -CO2R26, - CON(R26)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each R26is independently H or optionally substituted C1-C6 alkyl.

[0100] Another embodiment provides the compound of Formula (Va), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof,

[0101] Another embodiment provides the compound of Formula (Va), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A1is N. Another embodiment provides the compound of Formula (Va), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A2is N. Another embodiment provides the compound of Formula (Va), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A3is C-H. Another embodiment provides the compound of Formula (Va), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A4is C-H.

[0102] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (Vl-i), wherein Ring A is:wherein,R5is optionally substituted aryl, or optionally substituted heteroaryl;A1is selected from N, C-H, or C-R23;A2is selected from N, C-H, or C-R24;A3is selected from N, C-H, or C-R27;A4is selected from N, C-H, or C-R28;A7is selected from N, C-H, or C-R31;A8is selected from N, C-H, or C-R32;R23, R24, R27, R28, R31, and R32are independently selected from H, D, halogen, -OR26, - SR26, -N(R26)2, -CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, - CO2R26, -CON(R26)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each R26is independently H, -OH, -©(optionally substituted C1-C6 alkyl), or optionally substituted C1-C6 alkyl.

[0103] Another embodiment provides the compound of Formula (I), having the structure of Formula (VI), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ring A is:wherein,R5is optionally substituted aryl, or optionally substituted heteroaryl;A1is selected from N, C-H, or C-R23;A2is selected from N, C-H, or C-R24;A3is selected from N, C-H, or C-R27;A4is selected from N, C-H, or C-R28;A7is selected from N, C-H, or C-R31;A8is selected from N, C-H, or C-R32;R23, R24, R27, R28, R31, and R32are independently selected from H, D, halogen, -OR26, -SR26, - N(R26)2, -CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -CO2R26, -CON(R26)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each R26is independently H or optionally substituted C1-C6 alkyl.

[0104] Another embodiment provides the compound of Formula (I), having the structure of Formula (VII), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ring A is:wherein,R5is optionally substituted aryl, or optionally substituted heteroaryl;A1is selected from N, C-H, or C-R23;A2is selected from N, C-H, or C-R24;A9is selected from N, C-H, or C-R33;A10is selected from N, C-H, or C-R34;R23, R24, R33and R34are independently selected from H, D, halogen, -OR26, -SR26, -N(R26)2, - CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -CO2R26, - CON(R26)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; orR33and R34together form -(C(R36)2)tl-NHCO-(C(R36)2)t2-; tl is 0, 1, or 2; t2 is 0, 1, or 2; provided that at least one of tl or t2 is not 0; each R26is independently H or optionally substituted C1-C6 alkyl; and each R36is independently H, halogen, or optionally substituted C1-C6 alkyl.

[0105] Another embodiment provides the compound of Formula (I), having the structure of Formula (VIII), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ring A is:wherein,R5is optionally substituted aryl, or optionally substituted heteroaryl;A5is selected from N, C-H, or C-R29;A6is selected from N, C-H, or C-R30;A11is selected from N, C-H, or C-R35;R29, R30and R35are independently selected from H, D, halogen, -OR26, -SR26, -N(R26)2, -CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -CO2R26, -CON(R26)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each R26is independently H or optionally substituted C1-C6 alkyl.

[0106] Another embodiment provides the compound of Formula (Villa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof,

[0107] Another embodiment provides the compound of Formula (Villa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A5is C-H. Another embodiment provides the compound of Formula (Villa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A6is C-H. Another embodiment provides the compound of Formula (Villa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A11is C-H.

[0108] Another embodiment provides the compound of Formula (I), having the structure of Formula (IX), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ring A iswherein,R5is optionally substituted aryl, or optionally substituted heteroaryl;A1is selected from N, C-H, or C-R23;A2is selected from N, C-H, or C-R24;A12is selected from N-H, or CR38R39;A13is selected from N-H, or CR40R41;A14is selected from N-H, or CR42R43;A15is selected from N-H, or CR44R45;R23, R24, R38, R39, R40, R41, R42, R43, R44, and R45are independently selected from H, D, halogen, -OR26, -SR26, -N(R26)2, -CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -CO2R26, -CON(R26)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;R38and R39join to form an oxo;R39and R40join to form a bond;R40and R41join to form an oxo;R41and R42join to form a bond;R42and R43join to form an oxo;R43and R44join to form a bond;R44and R45join to form an oxo; and each R26is independently H or optionally substituted C1-C6 alkyl.

[0109] Another embodiment provides the compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A12is C-H2. Another embodiment provides the compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A13is C-H2. Another embodiment provides the compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A14is C-H2. Another embodiment provides the compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A15is C-H2.Another embodiment provides the compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A12is N-H. Another embodiment provides the compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein A13is N-H. Another embodiment provides the compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A14is N-H. Another embodiment provides the compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A15is N-H. Another embodiment provides the compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R38and R39join to form an oxo. Another embodiment provides the compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R39and R40join to form a bond. Another embodiment provides the compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R40and R41join to form an oxo. Another embodiment provides the compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R41and R42join to form a bond. Another embodiment provides the compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R42and R43join to form an oxo. Another embodiment provides the compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R43and R44join to form a bond. Another embodiment provides the compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R44and R45join to form an oxo.

[0110] Another embodiment provides the compound, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (X), wherein Ring A is:wherein,R5is optionally substituted aryl, or optionally substituted heteroaryl;A1is selected from N, C-H, or C-R23;A2is selected from N, C-H, or C-R24; andR21, R22, R23, and R24are independently selected from H, D, halogen, -OR26, -SR26, - N(R26)2, -CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -CO2R26, -CON(R26)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0111] Another embodiment provides the compound, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (Xa),

[0112] Another embodiment provides the compound, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A1is N.

[0113] Another embodiment provides the compound, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A2is C-H.

[0114] Another embodiment provides the compound, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R21and R22are H.

[0115] Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R5is optionally substituted aryl. Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R5is optionally substituted phenyl.

[0116] Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R5is optionally substituted heteroaryl. Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa),or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R5is optionally substituted pyridine.

[0117] Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R2and R3are H.

[0118] Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein n is 0.

[0119] Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein n is 1.

[0120] Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is selected from:

[0121] Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is:

[0122] Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is selected from:

[0123] Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is:

[0124] Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is -N(R4)-.

[0125] Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is selected from:

[0126] Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is:Q1is O or S;Q2is O or S;Q3is a bond, O, S, N-R9a;R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R9is absent and Q3and L join together to form a heterocycle; andR9ais selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R9and R9ajoin together to form a heterocycle.

[0127] Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is:T1is N or C-R10;T2is N or C-R10;T3is N or C-R10;T4is N or C-R10;T5is O, S, or N-R11; each R10is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; and each R11is hydrogen, or optionally substituted C1-C6 alkyl.

[0128] Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is:

[0129] Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III),(Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is:

[0130] Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is:

[0131] Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is:OH;T6is N or C-R12;T7is N or C-R12;T8is N or C-R12; each R12is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted Cl- C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl.

[0132] Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is:wherein each R13, R14, R15, and R16is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy.

[0133] Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is -C=N.

[0134] Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III),(Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is:

[0135] Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a-^-N N- - pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is: f

[0136] One embodiment provides an AKT1 inhibitory compound, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having a structure presented in Table 1.Table 1

[0137] Another embodiment provides an AKT1 inhibitory compound, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having a structure presented in Table 2.Table 2Preparation of Compounds

[0138] 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).

[0139] Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press,New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3527- 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) "Modem 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.

[0140] 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

[0141] In certain embodiments, the AKT1 inhibitory compound described herein is administered as a pure chemical. In other embodiments, the AKT1 inhibitory compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referredto 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)).

[0142] Provided herein is a pharmaceutical composition comprising at least one AKT1 inhibitory compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate 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.

[0143] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof.

[0144] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable carrier.

[0145] In certain embodiments, the AKT1 inhibitory compound as described by Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope 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.

[0146] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof.

[0147] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable carrier.

[0148] In certain embodiments, the AKT1 inhibitory compound as described by Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, is substantially pure, in thatit 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.

[0149] 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)).

[0150] In some embodiments, the AKT1 inhibitory compound as described by Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or Table 1, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, is formulated for administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a non-aqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like.

[0151] The dose of the composition comprising at least one AKT1 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.

[0152] 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.

[0153] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.Methods of Treatment

[0154] One embodiment provides a compound of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treatment of the human or animal body.

[0155] One embodiment provides a compound of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treatment of cancer or neoplastic disease.

[0156] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or neoplastic disease.

[0157] One embodiment provides a use of a compound of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

[0158] In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a compound of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient.

[0159] One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treatment of the human or animal body.

[0160] One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treatment of cancer or neoplastic disease.

[0161] One embodiment provides a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and apharmaceutically acceptable excipient for use in a method of treatment of cancer or neoplastic disease.

[0162] One embodiment provides a use of a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

[0163] In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient.

[0164] One embodiment provides a method of treating a cancer in a patient in need thereof, comprising administering to the patient:(a) a composition comprising a compound of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof; and(b) at least one oncology therapeutic selected from an endocrine therapy, a hormonal therapy, an aromatase inhibitor, a selective estrogen receptor modulator (SERM) therapy, a selective estrogen receptor degrader (SERD) therapy, an anti-androgen, an androgen deprivation therapy, a taxane, a platinum agent, an anthracycline, an anti-metabolite, an alkylating agent, a microtubule affecting agent, an immune checkpoint inhibitor, a kinase inhibitor, a phosphatidylinositol 3 -kinase (PI3K) inhibitor, a human epidermal growth factor receptor 2 (HER2) inhibitor, an antibody, a poly-ADP ribose polymerase (PARP) inhibitor, an antibody drug conjugate (ADC), a radiopharmaceutical, a neurotrophic tyrosine receptor kinase (NTRK) inhibitor, a rearranged during transfection (RET) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor, a rapidly accelerated fibrosarcoma (RAF) inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, or a cyclin dependent kinase (CDK) inhibitor.

[0165] One embodiment provides a method of treating a cancer in a patient in need thereof, comprising administering to the patient:(a) a composition comprising a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof; and(b) at least one oncology therapeutic selected from an endocrine therapy, a hormonal therapy, an aromatase inhibitor, a selective estrogen receptor modulator (SERM) therapy, a selectiveestrogen receptor degrader (SERD) therapy, an anti-androgen, an androgen deprivation therapy, a taxane, a platinum agent, an anthracycline, an anti-metabolite, an alkylating agent, a microtubule affecting agent, an immune checkpoint inhibitor, a kinase inhibitor, a phosphatidylinositol 3 -kinase (PI3K) inhibitor, a human epidermal growth factor receptor 2 (HER2) inhibitor, an antibody, a poly-ADP ribose polymerase (PARP) inhibitor, an antibody drug conjugate (ADC), a radiopharmaceutical, a neurotrophic tyrosine receptor kinase (NTRK) inhibitor, a rearranged during transfection (RET) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor, a rapidly accelerated fibrosarcoma (RAF) inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, or a cyclin dependent kinase (CDK) inhibitor.

[0166] One embodiment provides the method wherein at least one oncology therapeutic is selected from an endocrine therapy, a hormonal therapy, a SERM therapy, a SERD therapy, an aromatase inhibitor, or an androgen deprivation therapy. Another embodiment provides the method wherein the endocrine therapy, a hormonal therapy, a SERM therapy, a SERD therapy, an aromatase inhibitor, or an androgen deprivation therapy is selected from megestrol, exemestane, anastrozole, letrozole, tamoxifen, torimifene, raloxifene, fulvestrant, camizestrant, elacestrant, amcenestrant, giredestrant, imlunestrant, rintodestrant, SHR9549, ZN-c5, D0502, vepdegrestrant, palazestrant, AC682, DT2216, apalutamide, bicalutamide, darolutamide, enzalutamide, flutamide, nilutamide, abiraterone, buserelin, goserelin, leuprorelin, triptorelin, degarelix, or relugolix,.

[0167] One embodiment provides the method wherein at least one oncology therapeutic is a taxane. Another embodiment provides the method wherein the taxane is selected from paclitaxel, docetaxel, cabazitaxel, or abraxane.

[0168] One embodiment provides the method wherein at least one oncology therapeutic is a platinum agent. Another embodiment provides the method wherein the platinum agent is selected from cisplatin, carboplatin, or oxaliplatin.

[0169] One embodiment provides the method wherein at least one oncology therapeutic is an anthracycline. Another embodiment provides the method wherein the anthracycline is selected from doxorubicin or epirubicin.

[0170] One embodiment provides the method wherein at least one oncology therapeutic is an anti-metabolite. Another embodiment provides the method wherein the anti-metabolite is selected from methotrexate, fluorouracil, pemetrexed, irinotecan, topotecan, capecitabine or gemcitabine.

[0171] One embodiment provides the method wherein at least one oncology therapeutic is an alkylating agent. Another embodiment provides the method wherein the alkylating agent is selected from ifosfamide, trabectedin, cyclophosphamide, melphalan, or dacarbazine.

[0172] One embodiment provides the method wherein at least one oncology therapeutic is a microtubule affecting agent. Another embodiment provides the method wherein the microtubule affecting agent is selected from ixabepilone, viborelbine, or eribulin.

[0173] One embodiment provides the method wherein at least one oncology therapeutic is an immune checkpoint inhibitor. Another embodiment provides the method wherein the immune checkpoint inhibitor is selected from a CTLA-4 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a LAG-3 inhibitor, a TIGIT inhibitor, or a bi-specific PD-1 / CTLA4 inhibitor.

[0174] One embodiment provides the method wherein the CTLA-4 inhibitor is selected from ipilimumab or tremelimumab. Another embodiment provides the method wherein the PD-1 inhibitor is selected from spartalizumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, durvalumab, dostarlimab, retifanlimab, or toripalimab. Another embodiment provides the method wherein the bi-specific PD-1 / CTLA4 inhibitor is selected from AK104, MGD019, XmAb20717, or MEDI5752.

[0175] One embodiment provides the method wherein at least one oncology therapeutic is a kinase inhibitor. Another embodiment provides the method wherein the kinase inhibitor is selected from lenvatinib, pazopanib, imatinib, sorafenib, or avutometinib.

[0176] One embodiment provides the method wherein at least one oncology therapeutic is a PI3K inhibitor. Another embodiment provides the method wherein the PI3K inhibitor is selected from copanlisib, alpelisib, idelalisib, duvelisib, or umbralisib.

[0177] One embodiment provides the method wherein at least one oncology therapeutic is a HER2 inhibitor. Another embodiment provides the method wherein the HER2 inhibitor is selected from lapatinib, neratinib, tucatinib, pyrotinib, or afatinib.

[0178] One embodiment provides the method wherein at least one oncology therapeutic is an antibody. Another embodiment provides the method wherein the antibody is selected from trastuzumab, pertuzumab, margetuxumab, bevacizumab, or rituximab.

[0179] One embodiment provides the method wherein at least one oncology therapeutic is a PARP inhibitor. Another embodiment provides the method wherein the PARP inhibitor is selected from olaparib, rucaparib, talazoparib, or niraparib.

[0180] One embodiment provides the method wherein at least one oncology therapeutic is an ADC. Another embodiment provides the method wherein the antibody drug conjugate is selected from ado-trastuzumab emtansine, fam-trastuzumab deruxtecan-nxki, sacituzumab govitecan,disitamab vedotin, tisotumab vedotin, raludotatug deruxtecan, ARX-788, datopotamab deruxtecan, patritumab deruxtecan, ladiratuzumab vedotin, HS-20089, pertuzumab, or margetuximab.

[0181] One embodiment provides the method wherein at least one oncology therapeutic is a radiopharmaceutical. Another embodiment provides the method wherein the radiopharmaceutical is [l l lIn] / [89Zr]-trastuzumab.

[0182] One embodiment provides the method wherein at least one oncology therapeutic is a NTRK inhibitor. Another embodiment provides the method wherein the NTRK inhibitor is selected from entrectinib or larotrectinib.

[0183] One embodiment provides the method wherein at least one oncology therapeutic is a RET inhibitor. Another embodiment provides the method wherein the RET inhibitor is selpercatinib or pralsetinib.

[0184] One embodiment provides the method wherein at least one oncology therapeutic is an EGFR inhibitor. Another embodiment provides the method wherein the EGFR inhibitor is erlotinib, osimertinib, neratinib, cetuximab, gefitinib, panitumumab, dacomitinib, afatinib, lapatinib, necitumumab, mobocertinib, or vandetanib.

[0185] One embodiment provides the method wherein at least one oncology therapeutic is a mTOR inhibitor. Another embodiment provides the method wherein the mTOR inhibitor is deforolimus, everolimus, sirolimus, or temsirolimus.

[0186] One embodiment provides the method wherein at least one oncology therapeutic is a RAF inhibitor. Another embodiment provides the method wherein the RAF inhibitor is vemurafenib, dabrafenib, encorafenib, tovorafenib, naporafenib, belvarafenib, or exarafenib.

[0187] One embodiment provides the method wherein at least one oncology therapeutic is a MEK inhibitor. Another embodiment provides the method wherein the MEK inhibitor is binimetinib, cobimetinib, trametinib, selumetinib, pimasertib, avutometinib, IMM-1-104, or NST-628.

[0188] One embodiment provides the method wherein at least one oncology therapeutic is a CDK inhibitor. Another embodiment provides the method wherein the CDK inhibitor is selected from palbociclib, abemaciclib, riboci clib, tagtociclib, ebvaciclib, lerociclib, PF-07220060, BLU- 222, INX-315, or AVZO-021.

[0189] One embodiment provides a method of treating a cancer in a patient in need thereof, comprising administering to the patient:(a) a composition comprising a compound of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof; and(b) at least one oncology therapeutic selected from CAR-T therapy, tumor-infiltrating lymphocytes (TIL) or a neoantigen vaccine.

[0190] One embodiment provides the method wherein the cancer is breast cancer. Another embodiment provides the method wherein the cancer is a hormone receptor positive (HR+) breast cancer. Another embodiment provides the method wherein the cancer is a human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Another embodiment provides the method wherein the cancer is a HR+ / HER2- breast cancer. Another embodiment provides the method wherein the cancer is a HR+ / HER2-low breast cancer. Another embodiment provides the method wherein the cancer is a HR+ / HER2+ breast cancer.

[0191] Another embodiment provides the method wherein the cancer is a triple negative breast cancer (TNBC). Another embodiment provides the method wherein the cancer is an invasive breast cancer. Another embodiment provides the method wherein the patient has shown progression on at least one CDK4 / 6 inhibitor. Another embodiment provides the method wherein the patient has shown progression on at least one endocrine-based regimen.

[0192] One embodiment provides the method wherein the cancer is uterine cancer. Another embodiment provides the method wherein the cancer is uterine sarcoma. Another embodiment provides the method wherein the cancer is endometrial cancer. Another embodiment provides the method wherein the cancer is Type I endometrial cancer.

[0193] One embodiment provides the method wherein the cancer is Type II endometrial cancer.

[0194] Another embodiment provides the method wherein the cancer is Type II endometrial papillary serous carcinoma. Another embodiment provides the method wherein the cancer is Type II endometrial clear cell carcinoma. Another embodiment provides the method wherein the cancer is Type II endometrial undifferentiated carcinoma. Another embodiment provides the method wherein the cancer is Type II endometrioid carcinoma. Another embodiment provides the method wherein the cancer is microsatellite instability (MSI) high and / or DNA mismatch repair (MMR) deficient. Another embodiment provides the method wherein the cancer is tumor mutational burden (TMB) high. Another embodiment provides the method wherein the cancer is HER2-.

[0195] One embodiment provides the method wherein the cancer is cervical cancer. Another embodiment provides the method wherein the cancer is a cervical squamous cell carcinoma.

[0196] Another embodiment provides the method wherein the cancer is a cervical adenocarcinoma.

[0197] One embodiment provides the method wherein the cancer is prostate cancer. Another embodiment provides the method wherein the cancer is prostate adenocarcinoma.

[0198] Another embodiment provides the method wherein the cancer is prostate neuroendocrine cancer. Another embodiment provides the method wherein the cancer is prostate small cell neuroendocrine cancer. Another embodiment provides the method wherein the cancer is prostate large cell carcinoma. Another embodiment provides the method wherein the cancer is prostate transitional cell carcinoma. Another embodiment provides the method wherein the cancer is prostate sarcoma.

[0199] One embodiment provides the method wherein the cancer is bladder cancer. Another embodiment provides the method wherein the cancer is urothelial cancer. Another embodiment provides the method wherein the cancer is squamous cell cancer of the bladder. Another embodiment provides the method wherein the cancer is small cell cancer of the bladder. Another embodiment provides the method wherein the cancer is adenocarcinoma of the bladder.

[0200] One embodiment provides the method wherein the cancer is lung cancer.

[0201] One embodiment provides the method wherein the cancer is non-small cell lung cancer.

[0202] One embodiment provides the method wherein the cancer is non-squamous non-small cell lung cancer.

[0203] One embodiment provides the method wherein the cancer is squamous non-small cell lung cancer.

[0204] One embodiment provides the method wherein the cancer is colon cancer.

[0205] One embodiment provides the method wherein the cancer is anal cancer.

[0206] One embodiment provides the method wherein the cancer is a meningioma.

[0207] One embodiment provides the method wherein the cancer is a glioma.

[0208] One embodiment provides the method wherein the cancer is pancreatic cancer. Another embodiment provides the method wherein the cancer is exocrine pancreatic cancer. Another embodiment provides the method wherein the cancer is neuroendocrine pancreatic cancer.

[0209] One embodiment provides the method wherein the cancer is thyroid cancer.

[0210] One embodiment provides the method wherein the cancer is myxofibrosarcoma.

[0211] One embodiment provides the method wherein the cancer is parotid gland cancer.

[0212] One embodiment provides the method wherein the cancer is esophageal cancer.

[0213] One embodiment provides the method wherein the cancer is stomach cancer.

[0214] One embodiment provides the method wherein the cancer is skin cancer. Another embodiment provides the method wherein the cancer is nonmelanoma skin cancer. Another embodiment provides the method wherein the cancer is squamous nonmelanoma skin cancer. Another embodiment provides the method wherein the cancer is non-squamous nonmelanoma skin cancer.

[0215] One embodiment provides the method wherein the cancer is ovarian cancer. Another embodiment provides the method wherein the cancer is epithelial ovarian cancer. Another embodiment provides the method wherein the cancer is serous epithelial ovarian cancer. Another embodiment provides the method wherein the cancer is endometrioid ovarian cancer. Another embodiment provides the method wherein the cancer is clear cell ovarian cancer. Another embodiment provides the method wherein the cancer is mucinous ovarian cancer.

[0216] One embodiment provides the method wherein the cancer is adenoid cystic carcinoma.

[0217] One embodiment provides the method wherein the cancer is renal cell cancer.

[0218] One embodiment provides the method wherein the cancer is appendix cancer.

[0219] One embodiment provides the method wherein the cancer is multiple myeloma.

[0220] One embodiment provides the method wherein the cancer is acute myeloid leukemia.

[0221] One embodiment provides the method wherein the cancer is cancer of unknown primary.

[0222] One embodiment provides the method wherein the cancer is locally advanced.

[0223] One embodiment provides the method wherein the cancer is metastatic.

[0224] One embodiment provides the method wherein the method is adjuvant therapy following surgical resection.

[0225] One embodiment provides the method wherein the method is neo-adjuvant therapy.

[0226] One embodiment provides the method wherein the method is first-line systemic therapy for locally advanced or metastatic disease.

[0227] One embodiment provides the method wherein the patient has relapsed after prior therapy.

[0228] One embodiment provides the method wherein the patient has acquired resistance to prior therapy.

[0229] One embodiment provides the method wherein the patient is refractory to therapy.

[0230] One embodiment provides the method wherein the patient has shown progression on cytotoxic chemotherapy.

[0231] One embodiment provides the method wherein the cancer is characterized by existence of AKT1-E17K mutation.

[0232] One embodiment provides the method wherein the cancer exhibits one or more cooccurring alterations selected from a PIK3CA alteration, a PIK3R1 alteration, an AKT1 alteration, and PTEN alteration.

[0233] One embodiment provides the method wherein the patient exhibits risk factors for hyperglycemia.

[0234] One embodiment provides the method wherein the patient exhibits risk factors selected from obesity, body mass index greater than or equal to 30, fasting blood glucose over 160 mg / dL, Elb Ale greater than 6.0.

[0235] One embodiment provides the method wherein the patient exhibits Type I diabetes, diabetes requiring insulin, diabetes requiring metformin or another oral hypoglycemic agent, or pre-diabetes treated with metformin or another oral hypoglycemic agent.

[0236] Provided herein is the method wherein the pharmaceutical composition is administered orally. Another embodiment provides the method, wherein the oral administration occurs every other day, once per day, twice per day, or three times per day.

[0237] Provided herein is the method wherein the pharmaceutical composition is administered by injection.

[0238] One embodiment provides a method of inhibiting an AKT1 enzyme comprising contacting the AKT1 enzyme with a compound of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or Table 1. Another embodiment provides the method of inhibiting an AKT1 enzyme, wherein the AKT1 enzyme is contacted in an in vivo setting. Another embodiment provides the method of inhibiting an AKT1 enzyme, wherein the AKT1 enzyme is contacted in an in vitro setting.

[0239] 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

[0240] In some embodiments, the AKT1 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 (CH2Q2)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 n micro m multiplet (spectral); meter(s); milliM molarM+parent molecular ionMe methylMsCl methanesulfonyl chlorideMHz megahertz min minute(s) mol mole(s); molecular (as in mol wt) mL milliliterMS mass spectrometry nm nanometer(s)NMR nuclear magnetic resonance pH potential of hydrogen; a measure of the acidity or basicity of an aqueous solution PE petroleum etherRT room temperature s singlet (spectral) t triplet (spectral)SFC Supercritical fluid chromatographyT temperatureTFA trifluoroacetic acidTHF tetrahydrofuranTPP triphenylphosphineExperimental Procedures

[0241] Intermediate 1 : 8-(4-(Chloromethyl)phenyl)-9-phenyl-[l,2,4]triazolo[3,4- f] [ 1 ,6]naphthyri din-3 (2H)-oneStep 1 : 4-(((tert-Butyldimethylsilyl)oxy)methyl)benzonitrileTo a solution of 4-(hydroxymethyl)benzonitrile (9.0 g, 67.6 mmol) in CH2CI2 (100 mL) were added DMAP (826 mg, 6.76 mmol), TBSC1 (12.2 g, 81.1 mmol) and TEA (20.5 g, 203 mmol). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was quenched with H2O (100 mL) at 25 °C and extracted with CH2Q2 (250 mL x 2). The combined organic layers were washed with brine (300 mL), dried over anhydrous , filtNerae2dS aOnd4 concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 5% EtOAc in petroleum ether), the title compound (16.3 g, yield: 96%) was obtained as a colorless oil. 'H NMR (400 MHz, Chloroform^ / ) 5 7.65 - 7.58 (m, 2H), 7.46 - 7.39 (m, 2H), 4.78 (s, 2H), 0.95 (s, 9H), 0.11 (s, 6H).Step 2: l-(4-((( / er / -Butyldimethylsilyl)oxy)methyl)phenyl)-2-phenylethan-l-oneTo a solution of 4-((( / er / -butyldimethylsilyl)oxy)methyl)benzonitrile (1 g, 4.04 mmol) in THF (10 mL) was added benzylmagnesium chloride (8.08 mL, 8.08 mmol, 1 M in THF) at 0 °C under N2 atmosphere. The mixture was stirred at 0 °C for 3 hr under N2 atmosphere. The reaction mixture was quenched with aqueous NH4CI (30 mL) at 0 °C and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 3% EtOAc in petroleum ether), the title compound (1.05 g, yield: 75%) wasobtained as a yellow solid. MS: m / z = 341.2 [M + H]+.JH NMR (400 MHz, Dimethyl sulfoxide- d / ) 5 8.12 - 7.95 (m, 2H), 7.50 - 7.41 (m, 2H), 7.34 - 7.19 (m, 5H), 4.79 (s, 2H), 4.36 (s, 2H), 0.91 (s, 9H), 0.09 (s, 6H).Step 3: 2-(4-((( / cz7-Butyldimethylsilyl)oxy)methyl)phenyl)-5-chl oro-3 -phenyl- 1,6-naphthyri dine To a solution of l-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-2-phenylethan-l-one (450 mg, 1.32 mmol) in z-PrOH (5 mL) were added K2CO3 (913 mg, 6.61 mmol) and 4-amino-2- chloronicotinaldehyde (228 mg, 1.45 mmol). The mixture was stirred at 80 °C for 40 hr. The reaction mixture was quenched with H2O (5 mL) at 25 °C and stirred at 25 °C for 1 hr. The mixture was filtered and washed with H2O (10 mL). The solid was collected and dried. The crude product was triturated with CH2CI2 : IP A = 1 : 1 (10 mL) at 25 °C for 10 min. The title compound (350 mg, yield: 55%) was obtained as a yellow solid. MS: m / z = 461.2, 463.1 [M + H]+.XH NMR (400 MHz, Dimethylsulfoxide-d2) 8 8.58 (d, J= 6.0 Hz, 1H), 8.48 (s, 1H), 8.01 (d, J= 6.0 Hz, 1H), 7.42 - 7.35 (m, 5H), 7.34 - 7.30 (m, 2H), 7.27 - 7.23 (m, 2H), 4.71 (s, 2H), 0.88 (s, 9H), 0.06 (s, 6H).Step 4: 8-(4-(Hydroxymethyl)phenyl)-9-phenyl-[l,2,4]triazolo[3,4-f][l,6]naphthyridin-3(2J7)- oneTo a solution of 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-5-chloro-3-phenyl-l,6- naphthyridine (50 mg, 108 pmol) in z-PrOH (1 mL) were added methyl hydrazinecarboxylate (29.3 mg, 325 pmol) and HC1 (7.91 mg, 217 pmol 5 M). The mixture was stirred at 70 °C for 16 hr. The reaction mixture was basified with aqueous KOH (adjusted pH ~ 10) at 25 °C, and stirred at 25 °C for 1 hr. Then the reaction was acidified with aqueous AcOH (adjusted pH ~ 5), and stirred at 25 °C for 2 hr. The mixture was extracted with CH2Q2 (25 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The title compound (30 mg) was obtained as a yellow solid. MS: m / z = 368.9 [M + H]+.XH NMR (400 MHz, Dimethylsulfoxide-d2) 6 12.67 (br s, 1H), 8.36 (s, 1H), 7.89 (d, J= 7.6 Hz, 1H), 7.37 - 7.21 (m, 9H), 6.97 (d, = 7.6 Hz, 1H), 5.31 - 5.13 (m, 1H), 4.53 - 4.46 (m, 2H).Step 5: 8-(4-(Chloromethyl)phenyl)-9-phenyl-[l,2,4]triazolo[3,4-f][l,6]naphthyridin-3(2J7)-one To a solution of 8-(4-(hydroxymethyl)phenyl)-9-phenyl-[l,2,4]triazolo[3,4-f][l,6]naphthyridin- 3(2J7)-one (30 mg, 81.4 pmol) in CH2CI2 (6 mL) was added SOCI2 (0.3 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction was concentrated under reduced pressure to give the title compound (Intermediate 1, 34.5 mg, HC1 salt) as a yellow solid. MS: m / z = 386.9, 388.9 [M + H]+.

[0242] Intermediate 2: 4-(Piperidin-4-ylamino)pyrimidine-2-carbonitrileStep 1 : tert-Butyl 4-((2-cyanopyrimidin-4-yl)amino)piperidine-l -carboxylateTo a solution of tert-butyl 4-aminopiperidine-l -carboxylate (600 mg, 3.0 mmol) and 2- chloropyrimidine-4-carbonitrile (418 mg, 3.0 mmol) in DMF (5 mL) were added K2CO3 (1.24 g, 8.99 mmol) and Nal (89.8 mg, 599 pmol). The mixture was stirred at 80 °C for Ihr. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over , filteredN, aan2dSO4 concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0 ~ 50% EtOAc in petroleum ether) to give the title compound (860 mg, yield: 92%) as a white solid.JH NMR (400 MHz, Dimethylsulfoxide-d6) 5 8.13 - 8.01 (m, 2H), 6.66 (d, J= 5.6 Hz, 1H), 4.05 - 3.95 (m, 1H), 3.87 - 3.84 (m, 2H), 2.99 - 2.86 (m, 2H), 1.86 - 1.83 (m, 2H), 1.40 (s, 9H), 1.34 - 1.26 (m, 2H).Step 2: 4-(Piperidin-4-ylamino)pyrimidine-2-carbonitrileTo a solution of tert-Butyl 4-((2-cyanopyrimidin-4-yl)amino)piperidine-l -carboxylate (110 mg, 362 pmol) in DCM (3 mL) was added TFA (767 mg, 6.73 mmol). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure. The title compound (Intermediate 2, 120 mg, yield: 100%, TFA salt) was used in the next step without further purification. MS: m / z = 204.0 [M + H]+.

[0243] Intermediate 3: 4-(Piperazin-l-yl)pyrimidine-2-carbonitrileStep 1 : tert-Butyl 4-(2-cyanopyrimidin-4-yl)piperazine-l -carboxylateTo a solution of tert-butyl piperazine- 1 -carboxylate (550 mg, 2.95 mmol) and 2- chloropyrimidine-4-carbonitrile (412 mg, 2.95 mmol) in DMF (5 mL) were added K2CO3 (1.22 g, 8.86 mmol) and Nal (88.5 mg, 590 pmol). The mixture was stirred at 80 °C for 1 hr. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0 ~ 10% EtOAc in petroleum ether) to give the title compound (780 mg, yield: 92%) as a white solid. MS: m / z = 290.0 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) 5 8.29 (d, J= 6.4 Hz, 1H), 7.10 (d, J= 6.4 Hz, 1H), 3.73 - 3.60 (m, 4H), 3.46 - 3.41 (m, 4H), 1.42 (s, 9H).Step 2: 4-(Piperazin-l-yl)pyrimidine-2-carbonitrileTo a solution of tert-butyl 4-(2-cyanopyrimidin-4-yl)piperazine-l -carboxylate (140 mg, 483 pmol) in CH2CI2 (3 mL) was added TFA (767 mg, 6.73 mmol). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure. The title compound (Intermediate 3, 146 mg TFA salt, yield: 100%) was used in the next step without further purification. MS: m / z = 190.0 [M + H]+.

[0244] Intermediate 4: 1H-benzo[d] imidazole-5,6-diamineStep 1 : 5,6-Dinitro- 1H-benzo[d]imidazoleA solution of 1H-benzo[d]imidazole (1 g, 8.46 mmol) in H2SO4 (3.5 mL) was cooled at 0 °C in an ice bath. Then HNO3 (10 g, 159 mmol) was added dropwise to the solution. The reaction was kept at 0 °C for 20 min. The mixture was stirred at 70 °C for 16 hr. The resulting reaction mixture was cooled at 0 °C and neutralized with a solution of NaOH (1 M, adjusted pH ~ 9), and then extracted with EtOAc (150 mL x 2). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 5% MeOH in CH2Q2), the title compound (1.0 g, yield: 54%) was obtained as a yellow solid. MS: m / z = 209.1 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d2) δ 13.66 (br s, 1H), 8.77 (s, 1H), 8.49 (s, 2H).Step 2: 1H-Benzo[ ]imidazole-5,6-diamineTo a solution of 5,6-dinitro- 1H-benzo[ ]imidazole (900 mg, 4.32 mmol) in EtOH (30 mL) and H2O (6 mL) were added Fe (1.21 g, 21.6 mmol) and NH4CI (1.16 g, 21.6 mmol). The mixture was stirred at 80 °C for 5 hr. The reaction mixture was filtered and concentrated under reduce pressure to give the title compound (668 mg) as a brown solid. MS: m / z = 149.2 [M + H]+.

[0245] Intermediate 5: 7-(4-(Chloromethyl)phenyl)-6-phenyl-lH-imidazo[4,5-g]quinoxalineStep 1 : Methyl 4-(phenylethynyl)benzoateA mixture of methyl 4-bromobenzoate (20 g, 93.0 mmol), ethynylbenzene (11.4 g, 112 mmol), NH3 H2O (186 mmol, 25.6 mL, 28% purity), Pd(PPh3)2C12 (6.53 g, 9.30 mmol) and Cui (3.54 g, 18.6 mmol) in THF (200 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 35 °C for 16 hr under N2 atmosphere. The mixture was filtered through Celite at 25 °C and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 4% EtOAc in petroleum ether), the title compound (8.0 g, yield: 36%) was obtained as a yellow solid. MS: m / z = 237.0 [M + H]+.JH NMR (400 MHz, Dimethysulfoxide-d6) 8 8.04 - 7.95 (m, 2H), 7.74 - 7.67 (m, 2H), 7.65 - 7.55 (m, 2H), 7.51 - 7.42 (m, 3H), 3.87 (s, 3H).Step 2: Methyl 4-(2-oxo-2-phenylacetyl)benzoateTo a solution of methyl 4-(phenylethynyl)benzoate (50 mg, 212 pmol) in DMSO (2 mL) were added Pd(OAc)2(13 mg, 57.9 pmol) and CuBr (13.0 mg, 90.6 pmol). The mixture was stirred at 125 °C for 2 hr. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 5% EtOAc in petroleum ether), the title compound (78 mg, yield: 68%) was obtained as a yellow solid. MS: m / z = 269.0 [M + H]+. 'H NMR (400 MHz, Dimethysulfoxide-d6) 6 8.22 - 8.13 (m, 2H), 8.11 - 8.05 (m, 2H), 8.00 - 7.92 (m, 2H), 7.86 - 7.77 (m, 1H), 7.68 - 7.61 (m, 2H), 3.91 (s, 3H).Step 3: Methyl 4-(6-phenyl-1H-imidazo[4,5-g]quinoxalin-7-yl)benzoateTo a solution of methyl 4-(2-oxo-2-phenylacetyl)benzoate (1.1 g, 4.1 mmol) in z-PrOH (10 mL) were added 1H-benzo[d]imidazole-5,6-diamine (668 mg, 4.51 mmol) and K2CO3 (2.83 g, 20.5 mmol). The mixture was stirred at 80 °C for 16 hr. The reaction mixture was poured into H2O (30 mL) and extracted with CH2Q2 (100 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduce pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 90% EtOAc in petroleum ether), the title compound (830 mg, yield: 53% for two steps) was obtained as a yellow solid. MS: m / z = 381.0 [M + H]+. 'HNMR (400 MHz, Dimethysulfoxide-d2) 6 13.12 - 12.75 (m, 1H), 8.69 (s, 1H), 8.46 - 8.19 (m, 2H), 7.98 - 7.89 (m, 2H), 7.70 - 7.59 (m, 2H), 7.52 - 7.45 (m, 2H), 7.42 - 7.34 (m, 3H), 3.87 (s, 3H).Step 4: (4-(6-Phenyl-1H-imidazo[4,5-g]quinoxalin-7-yl)phenyl)methanolA solution of methyl 4-(6-phenyl-1H-imidazo[4,5-g]quinoxalin-7-yl)benzoate (300 mg, 787 pmol) in THF (5 mL) was degassed and purged with N2 three times. To the mixture was added LiAlH4 (2.5 M in THF, 379 pL) at 0 °C under N2 atmosphere. The mixture was stirred at 25 °Cfor 1 hr under N2 atmosphere. The reaction mixture was quenched with Na2SO4' IOH2O (1.0 g) at 0 °C, filtered and concentrated under reduced pressure to give the title compound (260 mg) as a yellow solid. MS: m / z = 353.1 [M + H]+.Step 5 : 7-(4-(Chloromethyl)phenyl)-6-phenyl-1H-imidazo[4,5-g]quinoxalineTo a solution of (4-(6-phenyl-1H-imidazo[4,5-g]quinoxalin-7-yl)phenyl)methanol (260 mg, 738 pmol) in CH2CI2 (5 mL) was added SOCI2 (0.5 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (Intermediate 5, 280 mg, HC1 salt) as a yellow solid. MS: m / z = 371.0, 372.1 [M + H]+.

[0246] Intermediate 6: 2-(4-(Chloromethyl)phenyl)-3-phenyl-l,6-naphthyridin-5(6J7)-oneStep 1 : 2-(4-(((tert-butyl dimethylsilyl)oxy)methyl)phenyl)-3-phenyl- l ,6-naphthyridineTo a solution of l -(4-(((tertb- utyldimethylsilyl)oxy)methyl)phenyl)-2-phenylethan- l -one (450 mg, 1.32 mmol, refer to Intermediate 1 for detail procedures) in z-PrOH (5 mL) were added K2CO3 (913 mg, 6.61 mmol) and 4-aminonicotinaldehyde (178 mg, 1.45 mmol). The mixture was stirred at 80 °C for 40 hr. The reaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with CH2Q2 (25 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 20% EtOAc in petroleum ether), the title compound (230 mg, yield: 40%) was obtained as a yellow oil. MS: m / z = 427.1 [M + H]+. 'HNMR (400 MHz, Chloroformd6) 5 9.47 - 9.36 (m, 1H), 8.84 - 8.65 (m, 1H), 8.37 (d, J= 3.2 Hz, 1H), 8.26 - 8.11 (m, 1H), 7.49 - 7.42 (m, 2H), 7.38 - 7.31 (m, 3H), 7.26 - 7.19 (m, 4H), 4.79 - 4.69 (m, 2H), 0.94 - 0.91 (m, 9H), 0.11 - 0.06 (m, 6H).Step 2: 2-(4-((( / ez7-Butyldimethylsilyl)oxy)methyl)phenyl)-3-phenyl-l,6-naphthyridine 6-oxide A solution of 2-(4-((( / ez7-butyldimethylsilyl)oxy)methyl)phenyl)-3-phenyl-l ,6-naphthyridine (170 mg, 398 pmol) in CH2Q2 (30 mL) was degassed and purged with N2 three times. To the above solution was added zzz-CPBA (89.0 mg, 438 pmol, 85% purity) at 0 °C. The mixture was stirred at 25 °C for 2 hr under N2 atmosphere. The reaction mixture was quenched with H2O (10mL) at 25 °C and extracted with CH2Q2 (15 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 3% MeOH in CH2Q2), the title compound (120 mg, yield: 61%) was obtained as a yellow solid. MS: m / z = 443.3 [M + H]+. 'HNMR (400 MHz, Chloroform^ / ) 5 8.89 (s, 1H), 8.36 (d, J= 7.2 Hz, 1H), 8.08 - 7.98 (m, 2H), 7.44 - 7.38 (m, 2H), 7.36 - 7.29 (m, 3H), 7.26 - 7.20 (m, 4H), 4.74 (s, 2H), 0.93 (s, 9H), 0.08 (s, 6H).Step 3 : 2-(4-(Hydroxymethyl)phenyl)-3-phenyl-l,6-naphthyridin-5(6J7)-oneTo a solution of 2-(4-((( / er / -butyldimethylsilyl)oxy)methyl)phenyl)-3-phenyl-l,6-naphthyridine 6-oxide (110 mg, 249 pmol) in AC2O (5 mL) was degassed and purged with N2 three times. The mixture was stirred at 130 °C for 16 hr under N2 atmosphere. The reaction mixture was quenched with H2O (5 mL) at 100 °C and stirred at 100 °C for 0.5 hr. The reaction was quenched with aqueous Na2COs (adjusted pH~7) at 25 °C and extracted with CH2Q2 (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 6% MeOH in CH2Q2), the title compound (36 mg, yield: 44%) was obtained as a yellow solid. MS: m / z = 328.9 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) 511.58 (br d, J= 5.2 Hz, 1H), 8.37 (s, 1H), 7.52 - 7.46 (m, 1H), 7.35 - 7.30 (m, 5H), 7.27 - 7.21 (m, 4H), 6.69 (d, J= 7.2 Hz, 1H), 5.22 (br t, J= 5.6 Hz, 1H), 4.49 (d, J = 5.6 Hz, 2H).Step 4: 2-(4-(Chloromethyl)phenyl)-3-phenyl-l,6-naphthyridin-5(6J7)-oneA solution of 2-(4-(hydroxymethyl)phenyl)-3-phenyl-l,6-naphthyridin-5(6J7)-one (35 mg, 106.59 pmol) in CH2CI2 (8 mL) was degassed and purged with N2 three times. SOCI2 (0.3 mL) was added. The mixture was stirred at 25 °C for 0.5 hr under N2 atmosphere. The reaction was concentrated under reduced pressure to give the title compound (Intermediate 6, 40.9 mg, HC1 salt) as a yellow solid. MS: m / z = 347.0, 348.9 [M + H]+.

[0247] Intermediate 7: 2-(4-(Chloromethyl)phenyl)-3-phenylimidazo[l,2-b]pyridazine-6- carb oxami deStep 1 : 2-Bromo-l -(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-2-phenylethan-l -one To a solution of l -(4-((( / c / 7-butyldimethylsilyl)oxy)methyl)phenyl)-2-phenylethan- l -one (refer to Intermediate 1 for detail procedures, 4.0 g, 11.8 mmol) in THF (40 mL) was added monopyridin-l-ium tribromide (4.13 g, 12.9 mmol) at 0 °C under N2 atmosphere. The mixture was stirred at 25 °C for 2 hr under N2 atmosphere. The reaction mixture was quenched with H2O (100 mL) at 0 °C and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with aqueous Na2S2C>4 (100 mL x 2) and brine (100 mL), dried over , filtered andNa2SO4 concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 2% EtOAc in petroleum ether), the title compound (1.1 g, yield: 21%) was obtained as a yellow solid.JH NMR (400 MHz, Chloroform-t / ) 5 7.99 - 7.92 (m, 2H), 7.56 - 7.50 (m, 2H), 7.42 - 7.30 (m, 5H), 6.38 (s, 1H), 4.77 (s, 2H), 0.94 (s, 9H), 0.10 (s, 6H).Step 2: Methyl 2-(4-(((terLbutyldimethylsilyl)oxy)methyl)phenyl)-3-phenylimidazo[l,2- b]pyridazine-6-carboxylateTo a solution of 2-bromo-l-(4-(((terLbutyldimethylsilyl)oxy)methyl)phenyl)-2-phenylethan-l- one (700 mg, 1.67 mmol) in z-PrOH (10 mL) were added methyl 6-aminopyridazine-3- carboxylate (307 mg, 2.00 mmol) and DIEA (431 mg, 3.34 mmol). The mixture was stirred at 85 °C for 3 hr. The reaction mixture was quenched with H2O (30 mL) at 25 °C and extracted with CH2Q2 (25 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2,S fOilt4ered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 20% EtOAc in petroleum ether), the title compound (480 mg, yield: 58%) was obtained as a yellow solid. MS: m / z = 474.2 [M + H]+. 'H NMR (400 MHz, Chloroformd6) 5 8.10 (d, J= 9.6 Hz, 1H), 7.79 (d, J= 9.6 Hz, 1H), 7.71 - 7.63 (m, 4H), 7.52 - 7.45 (m, 3H), 7.31 (d, J= 8.4 Hz, 2H), 4.76 (s, 2H), 3.99 (s, 3H), 0.94 (s, 9H), 0.10 (s, 6H).Step 3 : 2-(4-(((tert-butyl dimethylsilyl)oxy)methyl)phenyl)-3-phenylimidazo[ l ,2-b]pyridazine-6- carboxamideA solution of methyl 2-(4-(((te / 7-butyldimethylsilyl)oxy)methyl)phenyl)-3-phenylimidazo[l,2- b]pyridazine-6-carboxylate (460 mg, 971 pmol) in 7 M NH3 in MeOH (30 mL) was stirred at 50 °C for 5 hr. The reaction was concentrated under reduced pressure to give the title compound (440 mg) as a yellow solid. MS: m / z = 459.3 [M + H]+.JH NMR (400 MHz, Chloroform-t / ) 5 8.13 (d, J= 9.6 Hz, 1H), 7.92 (d, J= 9.6 Hz, 1H), 7.68 (d, J= 8.0 Hz, 2H), 7.62 - 7.56 (m, 2H), 7.55 - 7.45 (m, 3H), 7.30 (d, J= 8.0 Hz, 2H), 7.16 - 7.08 (m, 1H), 5.60 - 5.53 (m, 1H), 4.76 (s, 2H), 0.94 (s, 9H), 0.10 (s, 6H).Step 4: 2-(4-(Hydroxymethyl)phenyl)-3-phenylimidazo[l,2-b]pyridazine-6-carboxamide To a solution of 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-3-phenylimidazo[l,2- b]pyridazine-6-carboxamide (459 mg, 1.00 mmol) in THF (5 mL) was added TBAF (1 M in THF, 3 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was quenched with H2O (25 mL) at 25 °C and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (100 mL x 5), dried over anhydrous , filteredN aan2dSO4 concentrated under reduced pressure. The title compound (360 mg) was obtained as a yellow solid. MS: m / z = 345.2 [M + H]+.XH NMR (400 MHz, Dimethylsulfoxide-d2) 8 8.12 (d, J= 9.6 Hz, 1H), 7.92 (d, J= 9.2 Hz, 1H), 7.70 (d, J= 8.4 Hz, 2H), 7.62 - 7.56 (m, 2H), 7.54 - 7.47 (m, 3H), 7.34 (d, J= 8.0 Hz, 2H), 7.16 - 7.09 (m, 1H), 5.62 - 5.49 (m, 1H), 4.72 (s, 2H).Step 5: 2-(4-(Chloromethyl)phenyl)-3-phenylimidazo[l,2-b]pyridazine-6-carboxamideTo a solution of 2-(4-(hydroxymethyl)phenyl)-3-phenylimidazo[l,2-b]pyridazine-6-carboxamide (200 mg, 581 pmol) in CH2Q2 (5 mL) was added SOCI2 (0.5 mL). The mixture was stirred at 40 °C for 2 hr. The reaction was concentrated under reduced pressure to give the title compound (Intermediate 7, 232 mg, HC1 salt) as a yellow solid. MS: m / z = 363.1, 365.1 [M + H]+.

[0248] Intermediate 8: 2-(4-(Chloromethyl)phenyl)-3-phenylimidazo[l,2-b]pyridazineStep 1 : 2-(4-(((te / 7-Butyldimethylsilyl)oxy)methyl)phenyl)-3-phenylimidazo[l,2-b]pyridazineTo a solution of 2-bromo-l-(4-(((terLbutyldimethylsilyl)oxy)methyl)phenyl)-2-phenylethan-l- one (refer to Intermediate 7 for detail procedures, 350 mg, 834 pmol) in z-PrOH (10 mL) were added pyridazin-3 -amine (95.2 mg, 1.00 mmol) and DIEA (216 mg, 1.67 mmol). The mixturewas stirred at 85 °C for 1 hr. The reaction mixture was quenched with H2O (30 mL) at 25 °C and extracted with CH2Q2 (25 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 20% EtOAc in petroleum ether), the title compound (110 mg, yield: 29%) was obtained as a yellow solid. MS: m / z = 416.1 [M + H]+. 'HNMR (400 MHz, Chloroformd6) 5 8.30 (dd, J= 4.4, 1.6 Hz, 1H), 8.01 (dd, J= 9.2, 1.6 Hz, 1H), 7.69 - 7.65 (m, 2H), 7.62 - 7.57 (m, 2H), 7.52 - 7.45 (m, 3H), 7.30 - 7.27 (m, 2H), 7.09- 7.03 (m, 1H), 4.75 (s, 2H), 0.93 (s, 9H), 0.09 (s, 6H).Step 2: (4-(3-Phenylimidazo[l,2-b]pyridazin-2-yl)phenyl)methanolTo a solution of 2-(4-((( / er / -butyldimethylsilyl)oxy)methyl)phenyl)-3-phenylimidazo[l,2- b]pyridazine (110 mg, 265 pmol) in THF (5 mL) was added TBAF (1 M in THF, 794 pL). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was quenched with H2O (25 mL) at 25 °C and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (100 mL x 5), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The title compound (73 mg) was obtained as a yellow solid. MS: m / z = 302.2 [M + H]+. 'HNMR (400 MHz, Chloroformd6) 5 8.31 (dd, J= 4.4, 1.6 Hz, 1H), 8.02 (dd, J= 9.2, 1.6 Hz, 1H), 7.72 - 7.67 (m, 2H), 7.62 - 7.57 (m, 2H), 7.52 - 7.45 (m, 3H), 7.34 - 7.30 (m, 2H), 7.10- 7.04 (m, 1H), 4.71 (s, 2H).Step 3 : 2-(4-(Chloromethyl)phenyl)-3-phenylimidazo[l,2-b]pyridazineTo a solution of (4-(3-phenylimidazo[l,2-b]pyridazin-2-yl)phenyl)methanol (73 mg, 242 pmol) in CH2Q2 (5 mL) was added SOCI2 (0.1 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction was concentrated under reduced pressure to give the title compound (Intermediate 8, 86.3 mg, HC1 salt) as a yellow solid. MS: m / z = 320.1, 322.2 [M + H]+.

[0249] Intermediate 9: 2-(4-(Chloromethyl)phenyl)-3 -phenylquinoxalineStep 1 : Methyl 4-(3-phenylquinoxalin-2-yl)benzoateTo a solution of methyl 4-(2-oxo-2-phenylacetyl)benzoate (500 mg, 1.86 mmol, refer to Intermediate 5 for detail procedures) in z-PrOH (7 mL) were added benzene- 1,2-diamine (222 mg, 2.05 mmol) and K2CO3 (1.29 g, 9.32 mmol). The mixture was stirred at 80 °C for 2 hr. The mixture was diluted with H2O (50 mL) and extracted with CH2Q2 (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous , filteredN anad2SO4 concentrated. After purification by silica gel flash chromatography (Eluent of 0% ~ 3% EtOAcin Petroleum ether), the title compound (420 mg, yield: 66 %) was obtained as a yellow solid. MS: m / z = 341.1 [M + H]+. 'HNMR (400 MHz, Dimethylsulfoxide-de) 5 8.25 - 8.15 (m, 2H), 8.00 - 7.88 (m, 4H), 7.62 (d, J= 8.4 Hz, 2H), 7.52 - 7.45 (m, 2H), 7.44 - 7.33 (m, 3H), 3.86 (s, 3H).Step 2: (4-(3-Phenylquinoxalin-2-yl)phenyl)methanolTo a solution of methyl 4-(3-phenylquinoxalin-2-yl)benzoate (200 mg, 588 pmol) in THF (3 mL) was added LiAlH4 (2.5 M, 470 pL, 1.18 mmol) at 0 °C. The mixture was stirred at 20 °C for 1 hr under N2. The residue was quenched with ISfeSCH IOH2O in portions till no bubbles were formed. The resulting mixture was stirred at 20 °C for 20 mins and filtered. The filter cake was washed with THF (10 mL x 2), and the combined filtrate was concentrated to give the title compound (184 mg) as a light yellow solid, which was used into the next step directly. MS: m / z = 313.1 [M + H]+.Step 3: 2-(4-(Chloromethyl)phenyl)-3-phenylquinoxalineTo a solution of (4-(3-phenylquinoxalin-2-yl)phenyl)methanol (184 mg, 588 pmol) in CH2Q2 (3 mL) was added SOCI2 (210 mg, 1.76 mmol). Then the mixture was stirred at 20 °C for 1 hr. The mixture was concentrated to give the tile compound (Intermediate 9, 194 mg) as a yellow solid, which was used directly in the next step. MS: m / z = 331.0, 333.0 [M + H]+.

[0250] Intermediate 10: 2-Hydroxy-4-(piperazin-l-yl)benzaldehydeStep 1 : tert-Butyl 4-(4-formyl-3-hydroxyphenyl)piperazine-l -carboxylateTo a solution of 5-fluoro-2-hydroxy -benzaldehyde (200 mg, 1.43 mmol) and tert-butyl piperazine- 1 -carboxylate (266 mg, 1.43 mmol) in DMSO (2 mL) was added DIEA (746 pL, 4.28 mmol). The mixture was degassed and purged with N2 three times and stirred at 100 °C for 16 hr under N2. The reaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (25 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 1-25% EtOAc in petroleum ether) to give the title compuond (197 mg, yield: 45%) as a white solid. MS: m / z = 307.1 [M+H]+.1H NMR (400 MHz, Chloroformd6) 11.48 (s, 1H), 9.58 (s, 1H), 7.34 (d, J= 8.8 Hz, 1H), 6.44 (dd, J= 8.8, 2.4 Hz, 1H), 6.25 (d, J= 2.4 Hz, 1H), 3.60 - 3.53 (m, 4H), 3.44 - 3.37 (m, 4H), 1.48 (s, 9H).Step 2: 2-Hydroxy-4-(piperazin-l-yl)benzaldehydeTo a solution of tert-butyl 4-(3-formyl-4-hydroxy-phenyl)piperazine-l-carboxylate (190 mg, 621 pmol) in 1,4-di oxane (1 mL) was added HC1 in 1,4-di oxane (4M, 2 mL). The mixture was degassed and purged with N2 three times and stirred at 25 °C for 2 hr under N2. The reaction mixture was concentrated under reduced pressure to give the title compound (Intermediate 10, 146 mg HC1 salt, yield: 98%) as a gray solid, which was used directly to the next step. MS: m / z = 207.0 [M+H]+.

[0251] Intermediate 11 : 6-Bromo-7-phenyl-3,4-dihydro-l,5-naphthyridin-2(U7)-oneStep 1 : 7-Phenyl-3,4-dihydro-l,5-naphthyridin-2(U7)-oneTo a solution of 7-bromo-3,4-dihydro-l,5-naphthyridin-2(U7)-one (1.9 g, 8.37 mmol) in a mixed solvent of 1,4-dioxane (50 mL) and H2O (10 mL) were added phenylboronic acid (1.12 g, 9.20 mmol), CS2CO3 (8.18 g, 25.1 mmol) and Pd(dppf)C12 (612 mg, 837 pmol) under N2. The mixture was stirred at 100 °C for 2 hr under N2. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. After purification by silica gel flash chromatography (Eluent of 6 ~ 10% MeOH in CH2Q2), the title compound (1.52 g, yield: 81%) was obtained as a brown solid.JH NMR (400 MHz, Dimethylsulfoxide- e) 5 10.22 (s, 1H), 8.40 - 8.35 (m, 1H), 7.64 - 7.58 (m, 2H), 7.50 (t, J= 7.6 Hz, 2H), 7.45 - 7.37 (m, 2H), 3.06 (t, J= 7.2 Hz, 2H), 2.63 (t, J= 7.2 Hz, 2H).Step 2: 6-Bromo-7-phenyl-3,4-dihydro-l,5-naphthyridin-2(U7)-oneTo a solution of 7-phenyl-3,4-dihydro-l,5-naphthyridin-2(U7)-one (200 mg, 892 pmol) in DMF (6 mL) was added NBS (317 mg, 1.78 mmol). The reaction mixture was stirred at 80 °C for 1 hr. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated. The title compound (Intermediate 11, 250 mg) was obtained as a brown solid, which was used directly in the next step.1H NMR (400 MHz, Dimethylsulfoxide- tZ6) 8 10.29 (s, 1H), 7.51 - 7.43 (m, 3H), 7.42 - 7.37 (m, 2H), 7.12 (s, 1H), 3.07 (t, J= 7.6 Hz, 2H), 2.68 - 2.61 (m, 2H).

[0252] Intermediate 12: 4-((l-(4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileStep 1 : l-Bromo-4-(chloromethyl)benzeneTo a solution of (4-bromophenyl)methanol (5 g, 26.7 mmol) in CH2C12(50 mL) was added SOCh (9.54 g, 80.2 mmol). The mixture was stirred at 25 °C for 1 hr. The reaction was concentrated under reduced pressure to give the title compound (6.47 g, HC1 salt) as a lightyellow oil.JH NMR (400 MHz, Dimethylsulfoxide-d6) 5 7.58 (d, J= 8.0 Hz, 2H), 7.40 (d, J= 8.4 Hz, 2H), 4.74 (s, 2H).Step 2: 4-((l-(4-Bromobenzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile To a solution of l-bromo-4-(chloromethyl)benzene (6.47 g, 26.7 mmol, HC1 salt) and Intermediate 2 (8.48 g, 26.7 mmol, TFA salt) in DMF (70 mL) were added K2CO3 (18.5 g, 134 mmol) and Nal (802 mg, 5.35 mmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was quenched with H2O (200 mL) at 25 °C and extracted with EtOAc (250 mL x 2). The combined organic layers were washed with brine (500 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0 ~ 5% MeOH in CH2Q2), the title compound (7.5 g, yield: 74% for two steps) was obtained as an off-white solid. MS: m / z = 371.6, 373.6 [M + H]+. 'HNMR (400 MHz, Dimethylsulfoxide-d6) 8 8.07 (d, J= 6.0 Hz, 1H), 8.01 (d, J= 7.2 Hz, 1H), 7.51 (d, J= 8.0 Hz, 2H), 7.26 (d, J= 8.0 Hz, 2H), 6.66 (d, J= 6.0 Hz, 1H), 3.86 - 3.70 (m, 1H), 3.44 (s, 2H), 2.81 - 2.69 (m, 2H), 2.17 - 2.04 (m, 2H), 1.90 - 1.76 (m, 2H), 1.53 - 1.39 (m, 2H).Step 3: 4-((l-(4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrileA mixture of 4-((l-(4-bromobenzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile (6.7 g, 18.0 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (9.14 g, 36.0 mmol), KO Ac (5.30 g, 54.0 mmol) and Pd(dppf)C12 (1.32 g, 1.80 mmol) in 1,4-dioxane (70 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 90 °C for 2 hr under N2 atmosphere. The reaction mixture was quenched with H2O (100 mL) at 25 °C and extracted with CH2Q2 (150 mL x 2). The combined organic layers were washed with brine (300 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0 ~ 5% MeOH in CH2CI2), the title compound (Intermediate 12, 7.55 g, yield: 90%) was obtained as a black solid. MS: m / z = 420.2 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d2) 68.08 (d, J= 6.0 Hz, 2H), 7.65 (d, J= 7.2 Hz, 2H),7.41 - 7.28 (m, 2H), 6.67 (d, J= 5.6 Hz, 1H), 3.87 - 3.72 (m, 1H), 3.65 - 3.42 (m, 2H), 2.93 - 2.65 (m, 2H), 2.32 - 1.98 (m, 2H), 1.93 - 1.79 (m, 2H), 1.57 - 1.38 (m, 2H), 1.28 (s, 12H).

[0253] Intermediate 13: 2-(4-(Chloromethyl)phenyl)-3-phenyl-7,8-dihydro-l,6-naphthyridin- 5(6J7)-oneStep 1 : (Z)- l -(4-(((tert-Butyldimethylsilyl)oxy)methyl)phenyl)-3-(dimethylamino)-2- phenylprop-2-en- 1 -oneA solution of l-(4-(((te / 7-butyldimethylsilyl)oxy)methyl)phenyl)-2-phenylethan-l-one (1 g, 2.94 mmol, refer to Intermediate 1 for detail procedures) in DMF-DMA (10 mL) was stirred at 80 °C for 16 hr. The reaction was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 30% EtOAc in petroleum ether), the title compound (500 mg, yield: 32%) was obtained as a yellow solid.1H NMR (400 MHz, Chloroform-t / ) 5 7.44 - 7.39 (m, 2H), 7.36 - 7.34 (m, 1H), 7.29 - 7.26 (m, 1H), 7.26 - 7.24 (m, 1H), 7.23 - 7.18 (m, 3H), 7.17 - 7.14 (m, 2H), 4.72 (s, 2H), 2.72 (s, 6H), 0.93 (s, 9H), 0.08 (s, 6H).Step 2: 4-(5-Oxo-3-phenyl-5,6,7,8-tetrahydro-l,6-naphthyridin-2-yl)benzyl acetateTo a solution of (Z)- l -(4-((( / c / 7-butyldimethylsilyl)oxy)methyl)phenyl)-3-(dimethylamino)-2- phenylprop-2-en-l-one (100 mg, 253 pmol) in AcOH (2 mL) were added 4A MS (20 mg), piperidine-2, 4-dione (42. 9 mg, 379 pmol), and NH4OAC (58.5 mg, 758 pmol). The mixture was stirred at 100 °C for 5 hr. The reaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with CH2Q2 (15 mL x 2). The combined organic layers were washed with aqueous NaHCCh (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (60 mg) as a yellow solid. MS: m / z = 373.1 [M + H]+. Step 3 : 2-(4-(Hydroxymethyl)phenyl)-3-phenyl-7,8-dihydro-l,6-naphthyridin-5(6J7)-one To a solution of 4-(5-oxo-3-phenyl-5,6,7,8-tetrahydro-l,6-naphthyridin-2-yl)benzyl acetate (60 mg, 161 pmol) in MeOH (1 mL), THF (1 mL) and H2O (1 mL) was added K2CO3 (66.8 mg, 483 pmol, 3 eq). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with CH2CI2 (15 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentratedunder reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 6% MeOH in CH2Q2), the title compound (35 mg, yield: 65% for two steps) was obtained as a yellow solid. MS: m / z = 331.2 [M + H]+. 'HNMR (400 MHz, Chloroform^ / ) 5 8.37 (s, 1H), 7.42 - 7.38 (m, 2H), 7.29 - 7.26 (m, 5H), 7.21 - 7.17 (m, 2H), 5.95 - 5.87 (m, 1H), 4.68 (s, 2H), 3.75 - 3.70 (m, 2H), 3.33 - 3.29 (m, 2H).Step 4: 2-(4-(Chloromethyl)phenyl)-3-phenyl-7,8-dihydro-l,6-naphthyridin-5(6J7)-oneTo a solution of 2-(4-(hydroxymethyl)phenyl)-3-phenyl-7,8-dihydro-l,6-naphthyridin-5(6J7)-one (35 mg, 106 pmol) in CH2Q2 (2 mL) was added SOCI2 (0.4 mL). The mixture was stirred at 25 °C for 0.5 hr under N2. The reaction was concentrated under reduced pressure to give the title compound (Intermediate 13, 37 mg) as a yellow solid. MS: m / z = 349.2, 351.0 [M + H]+.

[0254] Intermediate 14 & 15: (4-(l-Methyl-6-phenyl-1H-imidazo[4,5-g]quinoxalin-7- yl)phenyl)methanol & (4-(l-methyl-7-phenyl-1H-imidazo[4,5-g]quinoxalin-6- yl)phenyl)methanolStep 1 : Methyl 4-(l-methyl-6-phenyl-1H-imidazo[4,5-g]quinoxalin-7-yl)benzoate & methyl 4- (l-methyl-7-phenyl-1H-imidazo[4,5-g]quinoxalin-6-yl)benzoateTo a mixture of methyl 4-(6-phenyl-17 / -imidazo[4,5-g]quinoxalin-7-yl)benzoate (700 mg, 1.84 mmol, refer to Intermediate 5 for detail procedures) in DMF (7 mL) was added NaH (88.3 mg, 2.21 mmol, 60% purity) at 0 °C. The mixture was stirred at 0 °C for 20 min under N2. Mel (287 mg, 2.02 mmol) was added at 0 °C. The mixture was stirred at 20 °C for 30 min under N2. The mixture was quenched with NH4CI (20 mL) under N2 and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous IS^SCh, filtered and concentrated. After purification by silica gel flash chromatography (Eluent of 0 ~ 5% MeOH in CH2Q2), the title compounds (467 mg, yield: 64.34%) were obtained as yellow liquid. MS: m / z = 395.1 [M + H]+. 'HNMR (400 MHz, Dimethylsulfoxide-t / 6) 8 8.65 (s, 1H), 8.42 (d, J= 3.60 Hz, 1H), 8.39 (d, J= 8.00 Hz, 1H), 7.95 - 7.92 (m, 2H), 7.65 (d, J= 7.20 Hz, 2H), 7.53 - 7.48 (m, 2H), 7.42 - 7.37 (m, 3H), 4.01 (s, 3H), 3.87 (s, 3H).Step 2: (4-(l-Methyl-6-phenyl-1H-imidazo[4,5-g]quinoxalin-7-yl)phenyl)methanol & (4-(l- methyl-7-phenyl-1H-imidazo[4,5-g]quinoxalin-6-yl)phenyl)methanolTo a solution of methyl 4-(l-methyl-6-phenyl- 1H-imidazo[4,5-g]quinoxalin-7-yl)benzoate, and methyl 4-(l-methyl-7-phenyl- 1H-imidazo[4,5-g]quinoxalin-6-yl)benzoate, 467 mg, 1.18 mmol) in THF (5 mL) was added LiAIH4 (2.5 M in THF, 710.41 pL) at 0 °C. The mixture was stirred at 25 °C for 0.5 hr under N2. The residue was quenched withNa2SO4 IOH2O in portions till no bubbles were formed. The resulting mixture was stirred at 25 °C for 20 mins and filtered. The filter cake was washed with THF (10 mL x 3), and the combined filtrate was concentrated. After purification by prep-HPLC (column: Welch Xtimate C18 150 x 25mm x 5 pm; mobile phase: [water(NH3H2O + NH4HCO3)-ACN]; gradient: 29% - 39% B over 11 min), the title compound (Intermediate 14, 160 mg, yield 30%) & the other title compound (Intermediate 15, 110 mg, yield: 21%) were obtained as yellow solids. Spectra for Intermdiate 14: MS: m / z = 367.2 [M + H]+. 'HNMR (400 MHz, Dimethylsulfoxide-d6) 8 8.62 (s, 1H), 8.38 (s, 1H), 8.34 (s, 1H), 7.54 - 7.50 (m, 2H), 7.47 (d, J= 8.00 Hz, 2H), 7. 41 - 7. 37 (m, 3H), 7.30 (d, J= 8.40 Hz, 2H), 5.25 (t, J= 5.60 Hz,lH), 4.53 (d, J= 5.60 Hz, 2H), 4.01 (s, 3H). Spectra for Intermediate 15: MS: m / z = 367.1 [M + H]+. 'HNMR (400 MHz, Dimethyl sulfoxi de-d6) 6 8.62 (s, 1H), 8.36 (d, J= 16.4 Hz, 2H), 7.53 - 7.50 (m, 2H), 7.49 - 7.46 (m, 2H), 7. 41 - 7. 37 (m, 3H), 7.30 (d, J= 8.00 Hz, 2H), 5.25 (t, J= 5.60 Hz, 1H), 4.53 (d, J= 5.20 Hz, 2H), 4.01 (s, 3H).

[0255] Intermediate 16: 2-(4-(Chloromethyl)phenyl)-3-phenyl-l,6-naphthyridine-7- carb oxami deStep 1 : 2-(4-(((tert-Butyldimethylsilyl)oxy)methyl)phenyl)-7-chl oro-3 -phenyl- 1,6-naphthyri dine To a solution of l-(4-(((terLbutyldimethylsilyl)oxy)methyl)phenyl)-2-phenylethan-l-one (2 g, 5.87 mmol, refer to Intermediate 1 for detail procedures) in z-PrOH (20 mL) were added K2CO3 (4.06 g, 29.4 mmol) and 4-amino-6-chloronicotinaldehyde (920 mg, 5.87 mmol). The mixture was stirred at 80 °C for 16 hr. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrousNa2SO4, filtered, and concentrated under reduced pressure. Afterpurification by silica gel flash chromatography (Eluent of 0% ~ 5% EtOAc in petroleum ether), the title compound (1.15 g, yield: 41%) was obtained as a yellow oil. MS: m / z = 461.2, 463.1 [M + H]+. 'H NMR (400 MHz, Chloroformd6) 59.12 (s, 1H), 8.26 (s, 1H), 8.07 (s, 1H), 7.42 (d, J= 8.4 Hz, 2H), 7.34 - 7.31 (m, 3H), 7.26 - 7.21 (m, 4H), 4.74 (s, 2H), 0.93 (s, 9H), 0.08 (s, 6H). Step 2: Ethyl 2-(4-((( / er / -butyldimethylsilyl)oxy)methyl)phenyl)-3-phenyl-l,6-naphthyridine-7- carboxylateTo a solution of 2-(4-(((tertb- utyldimethylsilyl)oxy)methyl)phenyl)-7-chloro-3-phenyl- l ,6- naphthyridine (500 mg, 1.08 mmol) in EtOH (10 mL) were added Pd(dppf)C12 (159 mg, 217 pmol) and TEA (329 mg, 3.25 mmol) under N2. The suspension was degassed and purged with CO three times. The mixture was stirred under CO (50 psi) at 80 °C for 40 hr. The reaction was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 15% EtOAc in petroleum ether), the title compound (400 mg, yield: 71%) was obtained as a yellow oil. MS: m / z = 499.4 [M + H]+.1H NMR (400 MHz, DimethylsulfoxidesL) 5 9.55 (s, 1H), 8.72 (s, 1H), 8.58 (s, 1H), 7.42 - 7.24 (m, 9H), 4.72 (s, 2H), 4.48 - 4.37 (m, 2H), 1.44 - 1.33 (m, 3H), 0.89 (s, 9H), 0.06 (s, 6H).Step 3 : 2-(4-((( / <77-Butyldimethylsilyl)oxy)methyl)phenyl)-3-phenyl- l ,6-naphthyridine-7- carboxamideA solution of ethyl 2-(4-((( / er / -butyldimethylsilyl)oxy)methyl)phenyl)-3 -phenyl- 1,6- naphthyridine-7-carboxylate (400 mg, 802 pmol) in NH3 (20 mL, 7 M in MeOH) was stirred at 60 °C for 16 hr. The reaction was concentrated under reduced pressure to give the title compound (350 mg, yield: 93%) as a yellow solid. MS: m / z = 470.3 [M + H]+. 'H NMR (400 MHz, DimethylsulfoxidesL) 8 9.51 (s, 1H), 8.71 (s, 1H), 8.52 (s, 1H), 8.38 - 8.34 (m, 1H), 7.91 - 7.81 (m, 1H), 7.44 - 7.25 (m, 9H), 4.72 (s, 2H), 0.89 (s, 9H), 0.07 (s, 6H).Step 4: 2-(4-(Hydroxymethyl)phenyl)-3-phenyl-l,6-naphthyridine-7-carboxamideTo a solution of 2-(4-((( / er / -butyldimethylsilyl)oxy)methyl)phenyl)-3-phenyl-l,6-naphthyridine- 7-carboxamide (350 mg, 745 pmol) in THF (5 mL) was added TBAF (2.24 mL, 1 M in THF). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL x 5), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The title compound (240 mg, yield: 91%) was obtained as a yellow solid. MS: m / z = 356.3 [M + H]+.XH NMR (400 MHz, DimethylsulfoxidesL) 6 9.51 (s, 1H), 8.72 - 8.69 (m, 1H), 8.52 (s, 1H), 8.37 - 8.34 (m, 1H), 7.91 - 7.77 (m, 1H), 7.42 - 7.25 (m, 9H), 5.27 - 5.22 (m, 1H), 4.51 (d, .7= 5.6 Hz, 2H).Step 5: 2-(4-(Chloromethyl)phenyl)-3-phenyl-l,6-naphthyridine-7-carboxamideTo a solution of 2-(4-(hydroxymethyl)phenyl)-3-phenyl-l,6-naphthyridine-7-carboxamide (100 mg, 281 pmol) in CH2Q2 (5 mL) was added SOCI2 (0.5 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction was concentrated under reduced pressure to give the title compound (Intermediate 16, 115 mg, HC1 salt) as a yellow solid. MS: m / z = 374.0, 376.0 [M + H]+.

[0256] Intermediate 17: 2-(4-(Chloromethyl)phenyl)-3-phenyl-l,7-naphthyridine-6- carb oxami deStep 1 : 2-(4-(((tert-Butyldimethylsilyl)oxy)methyl)phenyl)-6-chl oro-3 -phenyl- 1,7-naphthyri dine To a solution of l-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-2-phenylethan-l-one (500 mg, 1.47 mmol, refer to Intermediate 1 for detail procedures) in DMF (5 mL) were added K2CO3 (203 mg, 1.47 mmol) and tert-butyl (6-chloro-4-formylpyridin-3-yl)carbamate (377 mg, 1.47 mmol). The mixture was stirred at 80 °C for 16 hr. The mixture was diluted with H2O (50 mL) and extracted with EtOAc ( 50 mL x 2). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 5% EtOAc in Petroleum ether), the title compound (520 mg, yield: 73%) was obtained as a light yellow solid. MS: m / z = 461.1, 462.7 [M + H]+. 'HNMR (400 MHz, Dimethysulfoxide-d2) 8 9.31 (s, 1H), 8.44 (s, 1H), 8.17 (s, 1H), 7.39 - 7.35 (m, 5H), 7.30 - 7.27 (m, 2H), 7.24 (d, J= 8.0 Hz, 2H), 4.71 (s, 2H), 0.89 (s, 9H), 0.06 (s, 6H)Step 2: Ethyl 2-(4-(((tert-Butyldimethylsilyl)oxy)methyl)phenyl)-3-phenyl-l,7-naphthyridine-6- carb oxy lateTo a solution of 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-6-chloro-3-phenyl-l,7- naphthyridine (200 mg, 434 pmol) in EtOH (5 mL) were added Pd(dppf)C12 (63.5 mg, 86.8 pmol) and TEA (132 mg, 1.30 mmol) under N2. The suspension was degassed and purged with CO three times. The mixture was stirred under CO (50 psi) at 80 °C for 48 hr. The reaction mixture was quenched with H2O (20 mL) and extracted with EtOAc (20 mL x 2). The combinedorganic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 20% EtOAc in Petroleum ether), the title compound (190 mg, yield: 84%) was obtained as a yellow oil. MS: m / z = 499.4 [M + H]+.1H NMR (400 MHz, Dimethysulfoxide-d6) 5 9.50 (s, 1H), 8.78 (s, 1H), 8.69 (s, 1H), 7.40 (d, J= 8.0 Hz, 2H), 7.38 - 7.35 (m„ 3H), 7.32 - 7.29 (m, 2H), 7.25 (d, J= 8.0 Hz, 2H), 4.72 (s, 2H), 4.43 (q, J= 7.2 Hz, 2H), 1.39 (t, J= 7.2 Hz, 3H), 0.89 (s, 9H), 0.06 (s, 6H)Step 3 : 2-(4-(((tert-butyl dimethylsilyl)oxy)methyl)phenyl)-3-phenyl- l ,7-naphthyridine-6- carboxamideA solution of ethyl 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-3-phenyl-l,7- naphthyridine-6-carboxylate (190 mg, 381 pmol) in NH3 (10 mL, 7 M in MeOH) was stirred at 50 °C for 16 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (179 mg) as a light yellow solid. MS: m / z = 470.5 [M + H]+.1H NMR (400 MHz, Dimethysulfoxide-d6) 8 9.45 (s, 1H), 8.70 (s, 1H), 8.67 (s, 1H), 8.33 (br s, 1H), 7.81 (br s, 1H), 7.40 (d, J= 8.0 Hz, 2H), 7.37 - 7.35 (m, 3H), 7.32 - 7.30 (m, 2H), 7.25 (d, J= 8.4 Hz, 2H), 4.72 (s, 2H), 0.89 (s, 9H), 0.06 (s, 6H).Step 4: 2-(4-(Hydroxymethyl)phenyl)-3-phenyl-l,7-naphthyridine-6-carboxamideTo a solution of 2-(4-(((terLbutyldimethylsilyl)oxy)methyl)phenyl)-3-phenyl-l,7-naphthyridine- 6-carboxamide (179 mg, 381 pmol) in THF (3 mL) was added TBAF (2 mL, 1 M in THF). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was quenched with H2O (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL x 5), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The title compound (Intermediate 17, 120 mg) was obtained as a light yellow solid. MS: m / z = 356.2 [M + H]+.Step 5: 2-(4-(Chloromethyl)phenyl)-3-phenyl-l,7-naphthyridine-6-carboxamideTo a solution of 2-(4-(hydroxymethyl)phenyl)-3-phenyl-l,7-naphthyridine-6-carboxamide (120 mg, 338 pmol) in CH2Q2 (5 mL) was added SOCI2 (1 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give the title comopound (Intermediate 17, 126 mg, HC1 salt) as a yellow solid. MS: m / z = 374.1, 376.0 [M + H]+.

[0257] Intermediate 18: 6-Bromo-7-phenyl-l,5-naphthyridin-2(U7)-oneStep 1 : 3-Amino-5-phenylpicolinaldehydeTo a solution of 3-amino-5-bromopicolinaldehyde (1 g, 4.97 mmol), phenylboronic acid (667 mg, 5.47 mmol) in 1,4-di oxane (10 mL) and H2O (2 mL) were added Pd(dppf)C12 (364 mg, 497 mol) and CS2CO3 (4.86 g, 14.9 mmol). The mixture was degassed and purged with N2 three times and stirred at 80 °C for 2 hr under N2. The reaction mixture was quenched with H2O (100 mL) at 25 °C and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 20% EtOAc in petroleum ether), the title compound (800 mg, yield: 75%) was obtained as a yellow solid. MS: m / z = 199.0 [M + H]+. *H NMR (400 MHz, Chloroform^ / ) 5 10.10 (s, 1H), 8.36 (d, J= 1.6 Hz, 1H), 7.64 - 7.56 (m, 2H), 7.53 - 7.41 (m, 3H), 7.18 (d, J= 1.6 Hz, 1H), 6.12 (br s, 2H).Step 2: 3-Amino-6-bromo-5-phenylpicolinaldehydeTo a solution of 3-amino-5-phenylpicolinaldehyde (400 mg, 2.02 mmol) in DMF (3 mL) was added NBS (539 mg, 3.03 mmol). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 30% EtOAc in petroleum ether), the title compound (100 mg, yield: 17%) was obtained as a yellow solid. MS: m / z = 277.0, 279.0 [M+H]+. 'H NMR (400 MHz, Chloroformd6) 5 10.03 (s, 1H), 7.49 - 7.42 (m, 5H), 7.00 (s, 1H), 6.10 (br s, 2H).Step 3: Ethyl (£)-3-(3-amino-6-bromo-5-phenylpyridin-2-yl)acrylateTo a solution of ethyl 2-(diethoxyphosphoryl)acetate (97.1 mg, 433 pmol) in THF (5 mL) was added NaH (17.6 mg, 433 pmol, 60% purity) at 0 °C under N2. The mixture was stirred at 0 °C for 1 hr. 3-Amino-6-bromo-5-phenylpicolinaldehyde (100 mg, 361 pmol) was added at 25 °C. The mixture was stirred at 25°C for 2 hr under N2. The reaction mixture was quenched withaqueous NH4CI (10 mL) at 25 °C and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The title compound (120 mg) was obtained as a yellow solid. MS: m / z = 347.0, 349.0 [M + H]+. 'HNMR (400 MHz, Chloroformd6) 5 7.70 (d, J= 15.2 Hz, 1H), 7.45 - 7.40 (m, 5H), 7.00 (d, J= 15.2 Hz, 1H), 6.95 (s, 1H), 4.31 - 4.25 (m, 2H), 1.35 - 1.32 (m, 3H). Step 4: 6-Bromo-7-phenyl-l,5-naphthyridin-2(U7)-oneTo a solution of ethyl (E)-3-(3-amino-6-bromo-5-phenylpyridin-2-yl)acrylate (120 mg, 346 pmol) in AcOH (2 mL). The mixture was stirred at 80 °C for 48 hr. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (10 mL) and extracted with CH2Q2 (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 40% EtOAc in petroleum ether), the title compound (Intermediate 18, 40 mg, yield: 33% for two steps) was obtained as a yellow solid. MS: m / z = 301.0, 303.0 [M + H]+.

[0258] Intermediate 19: 4-(4-(4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)piperazin- 1 -yl)pyrimidine-2-carbonitrileStep 1 : 4-(4-(4-Bromobenzyl)piperazin-l-yl)pyrimidine-2-carbonitrileTo a solution of l-bromo-4-(chloromethyl)benzene (9.95 g, 48.4 mmol) and Intermediate 3 (7.34 g, 24.2 mmol, TFA salt) in DMF (100 mL) were added K2CO3 (16.7 g, 121 mmol) and Nal (363 mg, 2.42 mmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was quenched with H2O (200 mL) and extracted with EtOAc (250 mL x 2). The combined organic layers were washed with brine (500 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0 ~ 5% MeOH in CH2CI2), the title compound (8 g, yield: 74%) was obtained as an off white solid. MS: m / z = 358.0, 359.9 [M + H]+. 'H NMR (400 MHz, Chloroform^ / ) 5 8.17 (d, J= 6.4 Hz, 1H), 7.46 (d, J= 8.4 Hz, 2H), 7.21 (d, J= 8.4 Hz, 2H), 6.57 (d, J= 6.4 Hz, 1H), 3.78 - 3.59 (m, 4H), 3.50 (s, 2H), 2.55 - 2.43 (m, 4H).Step 2: 4-(4-(4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)piperazin-l-yl)pyrimidine- 2-carbonitrileA mixture of 4-(4-(4-bromobenzyl)piperazin-l-yl)pyrimidine-2-carbonitrile (8 g, 22.3 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (11.3 g, 44.7 mmol), KO Ac (6.57 g,67.0 mmol) and Pd(dppf)C12 (1.63 g, 2.23 mmol) in 1,4-dioxane (100 mL) was degassed, purged with N2 three times, and stirred at 80 °C for 2 hr under N2. The reaction mixture was quenched with H2O (100 mL) at 25 °C and extracted with CH2CI2 (150 mL x 2). The combined organic layers were washed with brine (300 mL x 3), dried over anhydrous , filteredN aan2dSO4 concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0 ~ 30% EtOAc in petroleum ether), the title compound (Intermeidate 19, 6.5 g, yield: 67%) was obtained as a yellow solid. MS: m / z = 406.1 [M + H]+.JH NMR (400 MHz, Chloroform-t / ) 58.17 (d, J= 6.4 Hz, 1H), 7.79 (d, J= 7.6 Hz, 2H), 7.34 (d, J= 8.0 Hz, 2H), 6.56 (d, J= 6.4 Hz, 1H), 3.80 - 3.61 (m, 4H), 3.57 (s, 2H), 2.55 - 2.47 (m, 4H), 1.35 (s, 12H).

[0259] Intermediate 20: 4-(l,4-Diazepan-l-yl)pyrimidine-2-carbonitrileStep 1 : / c / V-Butyl 4-(2-cyanopyrimidin-4-yl)-l,4-diazepane-l -carboxylateTo a solution of terLbutyl 1,4-diazepane-l -carboxylate (2 g, 9.99 mmol) and 4- chloropyrimidine-2-carbonitrile (1.46 g, 10.5 mmol) in MeCN (20 mL) were added K2CO3 (4.14 g, 30.0 mmol) and Nal (299 mg, 2.00 mmol). The mixture was degassed, purged with N2 three times, and stirred at 80 °C for 2 hr under N2. The reaction mixture was quenched with H2O (100 mL) at 25 °C and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 50% EtOAc in petroleum ether), the title compound (3 g, yield: 98%) was obtained as an off white solid. MS: m / z = 304.0 [M + H]+.XH NMR (400 MHz, Dimethylsulfoxide-d2) 8 8.24 (d, J= 6.0 Hz, 1H), 7.02 (d, J= 6.0 Hz, 1H), 3.89 - 3.69 (m, 3H), 3.65 - 3.48 (m, 3H), 3.32 - 3.21 (m, 2H), 1.80 - 1.63 (m, 2H), 1.30 - 1.21 (m, 9H).Step 2: 4-(l,4-Diazepan-l-yl)pyrimidine-2-carbonitrileTo a solution of terLbutyl 4-(2-cyanopyrimidin-4-yl)- 1,4-diazepane-l -carboxylate (170 mg, 560 pmol) in CH2CI2 (2 mL) was added TFA (0.5 mL). The mixture was degassed, purged with N2 three times, and stirred at 25 °C for 1 hr under N2. The reaction mixture was concentrated under reduced pressure to give the title compound (Intermediate 20, 178 mg, TFA salt) as a yellow oil, which was used directly in the next step. MS: m / z = 204.1 [M + H]+.

[0260] Intermediate 21 : 4-((Methyl-t / 3)(piperidin-4-yl)amino)pyrimidine-2-carbonitrileStep 1 : tert-Butyl 4-((2-cyanopyrimidin-4-yl)(methyl-t / 3)amino)piperidine-l -carboxylate To a solution of tert-butyl 4-((2-cyanopyrimidin-4-yl)amino)piperidine-l -carboxylate (1 g, 3.30 mmol, refer to Intermediate 2 for detail procedures) in THF (10 mL) was added NaH (264 mg, 6.59 mmol, 60% in oil) at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 hr under N2, and CD3I (956 mg, 6.59 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 16 hr under N2. The reaction mixture was quenched with H2O (50 mL) at 25 °C and extracted with CH2Q2 (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The title compound (1 g, yield: 90%) was obtained as a yellow solid. MS: m / z = 321.3 [M + H]+. D%: 3D% = 100%. 'HNMR (400 MHz, Dimethylsulfoxide-d2) 8 8.25 (d, J= 6.4 Hz, 1H), 7.30 - 6.72 (m, 1H), 4.11 - 4.05 (m, 1H), 2.96 - 2.76 (m, 2H), 2.50 - 2.48 (m, 2H), 1.68 - 1.56 (m, 4H), 1.41 (s, 9H).Step 2: 4-((Methyl-t / 3)(piperidin-4-yl)amino)pyrimidine-2-carbonitrileTo a solution of tert-butyl 4-((2-cyanopyrimidin-4-yl)(methyl-t / 3)amino)piperidine-l-carboxylate (90 mg, 281 pmol) in CH2Q2 (2 mL) was added TFA (96.1 mg, 843 pmol). The mixture was stirred at 25 °C for 0.5 hr. The reaction was concentrated under reduced pressure to give the title compound (Intermediate 21, 93.9 mg, TFA salt) as a yellow oil. MS: m / z = 221.2 [M + H]+.

[0261] Intermediate 22: l-(4-(6-Phenyl-1H-imidazo[4,5-g]quinoxalin-7-yl)benzyl)piperidin-4- amineStep 1 : tert-Butyl (l-(4-(6-phenyl-1H-imidazo[4,5-g]quinoxalin-7-yl)benzyl)piperidin-4- yl)carbamateTo a solution of Intermediate 5 (300 mg, 809 pmol) in DMF (3 mL) were added tert-butyl piperidin-4-ylcarbamate (178 mg, 890 pmol), K2CO3 (559 mg, 4.04 mmol), Nal (24.3 mg, 162 pmol). The mixture was stirred at 25 °C for 2 hr under N2. The mixture was diluted with water (10 mL) and extracted with EtOAc (8 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous ,N fial2teSreO4d and concentrated. After purification by silica gel flash chromatography (Eluent of 0 ~ 10% MeOH in CH2CI2), the title compound (335 mg, yield: 77%) was obtained as a light yellow solid. MS: m / z = 535.2 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d2) 6 12.92 (s, 1H), 8.67 (s, 1H), 8.39 (d, J= 3.2 Hz, 1H), 8.21 (d, J= 5.2 Hz, 1H), 7.53 - 7.43 (m, 4H), 7.39 - 7.33 (m, 3H), 7.31 - 7.28 (m, 2H), 6.86 - 6.71 (m, 1H),3.61 - 3.34 (m, 3H), 3.30 - 3.15 (m, 2H), 2.87 - 2.68 (m, 2H), 1.97 - 1.80 (m, 2H), 1.74 - 1.61 (m, 2H), 1.37 (s, 9H).Step 2: l -(4-(6-Phenyl- IT / -imidazo[4,5-g]quinoxalin-7-yl)benzyl)piperidin-4-amineTo a solution of tert-butyl (l-(4-(6-phenyl-U7-imidazo[4,5-g]quinoxalin-7-yl)benzyl)piperidin- 4-yl)carbamate (335 mg, 627 pmol) in 1,4-dioxane (2 mL) was added HCl / dioxane (2 M, 2 mL). The mixture was stirred at 25 °C for 2 hr. The pH of the mixture was adjusted to about 8 with sat. aq. NaHCCh. The mixture was extracted with EtOAc (8 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The title compound (Intermediate 22, 253 mg, yield: 93%) was obtained as a light yellow solid, which was used in the next step without further purification. MS: m / z = 435.1 [M + H]+.

[0262] Intermediate 23 & 24: 2-(4-(Chloromethyl)phenyl)-3-phenylpyrido[2,3-Z>]pyrazine & 3- (4-(chloromethyl)phenyl)-2-phenylpyrido[2,3-Z>]pyrazineStep 1 : Methyl 4-(3-phenylpyrido[2,3-Z>]pyrazin-2-yl)benzoate & methyl 4-(2-phenylpyrido[2,3- Z>]pyrazin-3 -yl)benzoateTo a solution of methyl 4-(2-oxo-2-phenylacetyl)benzoate (2 g, 7.46 mmol, refer to Intermediate 5 for detail procedures) in z-PrOH (100 mL) were added K2CO3 (5.15 g, 37.3 mmol) and pyridine-2, 3 -diamine (895 mg, 8.20 mmol). The mixture was stirred at 80 °C for 16 hr. The reaction mixture was poured into H2O (50 mL) and extracted with CH2Q2 (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 24% EtOAc in petroleum ether), a mixture of the title compounds (526 mg, yield: 21%) was obtained as a yellow solid. MS: m / z =342.2[M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) 89.31 - 9.13 (m, 4.0 Hz, 1H), 8.75 - 8.56 (m, 1H), 8.01 - 7.87 (m, 3H), 7.66 (t, J= 8.4 Hz, 2H), 7.57 - 7.48 (m, 2H), 7.46 - 7.36 (m, 3H), 3.87 (s, 3H).Step 2: (4-(3-Phenylpyrido[2,3-Z>]pyrazin-2-yl)phenyl)methanol & (4-(2-phenylpyrido[2,3-Z>]pyrazin-3 -yl)phenyl)m ethanolTo a solution of methyl 4-(3-phenylpyrido[2,3-Z>]pyrazin-2-yl)benzoate and methyl 4-(2- phenylpyrido[2,3-b]pyrazin-3-yl)benzoate) (a mixture, 506 mg, 1.48 mmol) in THF (10 mL) was degassed and purged with N2 three times. LiAlHj (2.5 M, 711 pL) was added at 0°C under N2. The reaction mixture was quenched with Na2SO4 IOH2O (1 g) at 0 °C, filtered and concentrated under reduced pressure. After purification by prep-HPLC (column : column: CD06-Waters Xbidge C18 150 x 40 x 10 pm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 20% - 50% B over 10 min), a mixture of the title compounds (365 mg, yield: 79%) was obtained as a yellow solid. MS: m / z =314.0 [M + H]+Step 3: 2-(4-(Chloromethyl)phenyl)-3-phenylpyrido[2,3-Z>]pyrazine & 3-(4- (chloromethyl)phenyl)-2-phenylpyrido[2,3-Z>]pyrazineTo a solution of (4-(3-phenylpyrido[2,3-Z>]pyrazin-2-yl)phenyl)methanol and (4-(2- phenylpyrido[2,3-Z>]pyrazin-3-yl)phenyl)methanol) (a mixture, 264 mg, 843 pmol) in CH2CI2 (4 mL) was added SOCI2 (2 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated to give a mixture of the title compounds (Intermediate 23 and 24, HC1 salt, 310 mg) as a yellow solid. MS: m / z = 332.1, 334.1 [M + H]+.

[0263] Intermediate 25: 4-(2,6-diazaspiro[3.3]heptan-2-yl)pyrimidine-2-carbonitrileStep 1 : tert-Butyl 6-(2-cyanopyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylateTo a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (180 mg, 908 pmol) and 4- chloropyrimidine-2-carbonitrile (127 mg, 908 pmol) in ACN (10 mL) were added Nal (27.2mg, 182 pmol) and K2CO3 (376 mg, 2.76 mmol). The mixture was stirred at 80 °C for 2 hr. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over , filteredN anad2SO4 concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0 ~ 48% EtOAc in petroleum ether), the title compound (216 mg, yield: 78%) was obtained as an off white solid. MS: m / z = 301.9 [M + H]+.1H NMR(400 MHz, Dimethylsulfoxide-d6) 8 8.22 (d, J= 6.0 Hz, 1H), 6.63 (d, J= 6.0 Hz, 1H), 4.23 (s, 3H), 4.03 (s, 3H), 3.31 (s, 2H), 1.37 (s, 9H).Step 2: 4-(2,6-Diazaspiro[3.3]heptan-2-yl)pyrimidine-2-carbonitrileTo a solution of tert-butyl 6-(2-cyanopyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (180 mg, 597 pmol) in CH2CI2 (5 mL) was added TFA (13.5 mmol, 1 mL). The mixture wasstirred at 25 °C for 1 hr. The mixture was concentrated under reduced pressure to give the title compound (Intermediate 25, 201 mg, TFA salt, crude) as a light yellow oil.

[0264] Intermediate 26: 4-(2,7-Diazaspiro[3.5]nonan-7-yl)pyrimidine-2-carbonitrileStep 1 : tert-Butyl 7-(2-cyanopyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylateTo a solution of tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (500 mg, 2.21 mmol) and 4- chloropyrimidine-2-carbonitrile (308 mg, 2.21 mmol) in ACN (10 mL) were added Nal (33 mg, 221 pmol) and K2CO3 (916 mg, 6.63 mmol). The mixture was stirred at 80 °C for 16 hr. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over , filteredN anad2SO4 concentrated under reduced pressure. The title compound (720 mg, yield: 97%) was obtained as a light yellow solid. MS: m / z = 330.2 [M + H]+.JH NMR(400MHz, Dimethylsulfoxide-d6) 5 .22 (d, .7= 6.0 Hz, 1H), 7.13 (d, J= 6.8 Hz, 1H), 3.65 - 3.53 (m, 8H), 1.74 - 1.69 (m, 4H), 1.38 (s, 9H).Step 2: 4-(2,7-Diazaspiro[3.5]nonan-7-yl)pyrimidine-2-carbonitrileTo a solution of tert-butyl 7-(2-cyanopyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (110 mg, 334 pmol) in CH2CI2 (5 mL) was added TFA (13.5 mmol, 1 mL). The mixture was stirred at 25 °C for 1 hr. The mixture was concentrated under reduced pressure to give the title compound (Intermediate 26, 110 mg, TFA salt, crude) as a yellow oil. MS: m / z = 230.0 [M + H]+.

[0265] Intermediate 27: 2-(4-(Chloromethyl)phenyl)-3-phenyl-l,5-naphthyridineStep 1 : 2-(4-(((tert-Butyldimethylsilyl)oxy)methyl)phenyl)-3-phenyl-l,5-naphthyridineTo a solution of l-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-2-phenylethan-l-one (2 g, 5.87 mmol) in DMF (20 mL) were added K2CO3 (812 mg, 5.87 mmol) and tert-butyl (2-formylpyri din-3 -yl)carbamate (1.31 g, 5.87 mmol). The mixture was stirred at 80 °C for 16 hr. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 10% EtOAc in petroleum ether), the title compound (450 mg, yield: 9.5%) was obtained as a yellow solid. MS: m / z = 427.4 [M + H]+.Step 2: (4-(3-Phenyl-l,5-naphthyridin-2-yl)phenyl)methanolTo a solution of 2-(4-(((terLbutyldimethylsilyl)oxy)methyl)phenyl)-3-phenyl-l,5-naphthyridine (450 mg, 1.05 mmol) in THF (5 mL) was added TBAF (3.16 mL, 1 M in THF). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL x 5), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, the title compound (300 mg) was obtained as a yellow solid. MS: m / z = 313.1 [M + H]+.Step 3: 2-(4-(Chloromethyl)phenyl)-3-phenyl-l,5-naphthyridineTo a solution of (4-(3-phenyl-l,5-naphthyridin-2-yl)phenyl)methanol (300 mg, 960 pmol) in CH2Q2 (10 mL) was added SOCI2 (1 mL). The mixture was stirred at 40 °C for 0.5 hr. The reaction was concentrated under reduced pressure, the title compound (Intermediate 27, 317 mg) was obtained as a brown solid. MS: m / z = 331.0, 333.0 [M + H]+.

[0266] Intermediate 28: 2-(4-(Chloromethyl)phenyl)-3-phenylimidazo[l,2-rz]pyrimidine-7- carb oxami deStep 1 : 2-(4-(((tert-butyl dimethylsilyl)oxy)methyl)phenyl)-7-chl oro-3 -phenylimidazof 1,2- a]pyrimidineTo a solution of 2-bromo-l-(4-(((terLbutyldimethylsilyl)oxy)methyl)phenyl)-2-phenylethan-l- one (2.0 g, 4.77 mmol, refer to Intermediate 7 for detail procedures) in z-PrOH (20 mL) were added 4-chloropyrimidin-2-amine (515 mg, 3.97 mmol) and NaHCCh (401 mg, 4.77 mmol). The mixture was stirred at 80 °C for 48 hr. The reaction mixture was quenched with H2O (50 mL) and then extracted with EtOAc (50 mL x 2). The combined organic layers were washedwith brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 10% EtOAc in petroleum ether), the title compound (160 mg, yield: 8.8%) was obtained as a light yellow solid. MS: m / z =450.2, 452.2 [M + H]+. 'H NMR (400 MHz, Chloroformd6) 58.12 (d, J= 7.2 Hz, 1H), 7.73 - 7.65 (m, 2H), 7.61 - 7.50 (m, 3H), 7.46 - 7.41 (m, 2H), 7.26 - 7.22 (m, 2H), 6.81 (d, J= 7.2 Hz, 1H), 4.72 (s, 2H), 0.93 (s, 9H), 0.09 (s, 6H).Step 2: Ethyl 2-(4-((( / er / -Butyldimethylsilyl)oxy)methyl)phenyl)-3-phenylimidazo[l,2- a]pyrimidine-7-carboxylateTo a solution of 2-(4-(((tertb- utyldimethylsilyl)oxy)methyl)phenyl)-7-chloro-3- phenylimidazo[l,2-a]pyrimidine (160 mg, 356 pmol) in EtOH (5 mL) were added TEA (108 mg, 1.07 mmol) and Pd(dppf)C12 (52 mg, 71.1 pmol) under Ar. The suspension was degassed and purged with CO three times. The mixture was stirred under CO (50 psi) at 80 °C for 44 hr. The reaction was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 25% EtOAc in petroleum ether), the title compound (77 mg, yield: 44%) was obtained as a yellow solid. MS: m / z = 488.3 [M + H]+.1H NMR (400 MHz, DimethylsulfoxidesL) 8 8.63 (d, J= 7.2 Hz, 1H), 7.65 - 7.58 (m, 5H), 7.58 - 7.53 (m, 3H), 7.29 (d, J= 8.0 Hz, 2H), 4.71 (s, 2H), 4.48 - 4.37 (m, 2H), 1.43 - 1.33 (m, 3H), 0.90 (s, 9H), 0.08 (s, 6H).Step 3 : 2-(4-((( / er / -Butyldimethylsilyl)oxy)methyl)phenyl)-3-phenylimidazo[l,2-a]pyrimidine- 7-carboxamideA solution of ethyl 2-(4-((( / er / -butyldimethylsilyl)oxy)methyl)phenyl)-3-phenylimidazo[l,2- a]pyrimidine-7-carboxylate (77 mg, 158 pmol) in 7 MNHs in MeOH (5 mL) was stirred at 55 °C for 16 hr. The reaction was concentrated under reduced pressure to give the title compound (72.4 mg) as a yellow solid. MS: m / z = 459.3 [M + H]+. 'H NMR (400 MHz, DimethylsulfoxidesL) 6 8.60 (d, J= 7.2 Hz, 1H), 8.39 (br s, 1H), 7.82 (br s, 1H), 7.63 - 7.54 (m, 8H), 7.27 (d, J= 8.0 Hz, 2H), 4.70 (s, 2H), 0.90 (s, 9H), 0.08 (s, 6H).Step 4: 2-(4-(Hydroxymethyl)phenyl)-3-phenylimidazo[l,2-a]pyrimidine-7-carboxamide To a solution of 2-(4-(((terLbutyldimethylsilyl)oxy)methyl)phenyl)-3-phenylimidazo[l,2- a]pyrimidine-7-carboxamide (72 mg, 157 pmol) in THF (3 mL) was added TBAF (1 M in THF, 314 pL). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was quenched with H2O (20 mL) and extracted with EtOAc (25 mL x 2). The combined organic layers were washed with brine (50 mL x 5), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The title compound (54 mg) was obtained as a yellow solid. MS: m / z = 345.2 [M + H]+.Step 5: 2-(4-(Chloromethyl)phenyl)-3-phenylimidazo[l,2-a]pyrimidine-7-carboxamideTo a solution of 2-(4-(hydroxymethyl)phenyl)-3-phenylimidazo[l,2-a]pyrimidine-7- carboxamide (54 mg, 157 pmol) in CH2Q2 (3 mL) was added SOCI2 (0.3 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction was concentrated under reduced pressure to give the title compound (Intermediate 28, 56.8 mg) as a yellow solid. MS: m / z = 363.1, 364.9 [M + H]+.

[0267] Intermediate 29: 6-Bromo-l-methyl-7-phenyl-3,4-dihydro-l,5-naphthyridin-2(U7)-oneStep 1 : l-Methyl-7-phenyl-3,4-dihydro-l,5-naphthyridin-2(U7)-oneA solution of 7-phenyl-3,4-dihydro-l,5-naphthyridin-2(U7)-one (300 mg, 1.34 mmol, refer to Intermediate 11 for detail procedures) in THF (10 mL) was cooled to 0 °C. NaH (64.2 mg, 1.61 mmol, 60% purity) was added, and the mixture was stirred for 15 mins. Mel (380 mg, 167 pL) was added. The reaction mixture was stirred at 0 °C for 2 hr under N2. The reaction mixture was diluted with water (10 mL) slowly under N2. The aqueous phase was extracted with EtOAc (10 mL x 2). The combined organic layers was washed with brine (10 mL), dried over anhydrous Na2S,O fi4ltered and concentrated. The title compound (319 mg) was obtained as a green solid, which was used in the next step directly. MS: m / z = 239 [M + H]+.JH NMR (400 MHz, Dimethylsulfoxide-d2) 8 8.44 (d, J= 1.6 Hz, 1H), 7.81 - 7.73 (m, 2H), 7.65 (d, J= 1.6 Hz, 1H), 7.54 - 7.48 (m, 2H), 7.46 - 7.40 (m, 1H), 3.33 - 3.32 (m, 3H), 3.09 - 3.03 (m, 2H), 2.74 - 2.68 (m, 2H).Step 2: 6-Bromo-l -methyl -7-phenyl-3,4-dihydro-l,5-naphthyridin-2(U7)-oneTo a solution of l-methyl-7-phenyl-3,4-dihydro-l,5-naphthyridin-2(U7)-one (260 mg, 1.09 mmol) in DMF (5 mL) was added NBS (233 mg, 1.31 mmol). The reaction mixture was stirred at 100 °C for 12 hr. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated. After purification by silica gel flash chromatography (Elutent of 45 - 80% EtOAc in petroleum ether), the title compound (Intermediate 29, 80 mg, yield: 23% for 2 steps) was obtained as a white solid. MS: m / z = 317, 319 [M + H]+.

[0268] Intermediate 30: 2-(4-(Chloromethyl)phenyl)-3-(4-fluorophenyl)- l ,6-naphthyri dinercarb ox am ideStep 1 : 3-Bromo-7-chloro-l,6-naphthyridin-2(U7)-oneA solution of 7-chloro-l,6-naphthyridin-2(U7)-one (1 g, 5.54 mmol) in AcOH (12 mL) and TFA(8 mL) was stirred at 20 °C for 20 mins. NBS (1.08 g, 6.09 mmol) was added. The resulting mixture was stirred at 70 °C for 12 hr. The pH of the mixture was adjusted to 7 - 8 with sat. NaHCCh (100 mL). The mixture was extracted with CH2Q2 (100 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. After purification by silica gel flash chromatography (Eluent of 0% ~ 4% Methanol in CH2Q2), the title compound (470 mg, yield: 33%) was obtained as a yellow solid. MS: m / z = 259.0, 260.9 [M + H]+. 'HNMR (400 MHz, Dimethylsulfoxide-t / 6) 8 12.64 (s, 1H), 8.70 (s, 1H), 8.61 (s, 1H), 7.23 (s, 1H).Step 2: 7-Chloro-3-(4-fluorophenyl)-l,6-naphthyridin-2(177)-oneTo a mixture of 3-bromo-7-chloro-l,6-naphthyridin-2(U7)-one (470 mg, 1.81 mmol) and (4- fluorophenyl)boronic acid (253 mg, 1.81 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) were added Pd(dppf)C12 (133 mg, 181 pmol) and K2CO3 (751 mg, 5.43 mmol). The reaction mixture was purged with N2 three times and stirred at 80 °C for 1 hr under N2. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. After purification by silica gel flash chromatography (Eluent of 0% ~ 5% Methanol in CH2Q2), the title compound (450 mg, yield: 91%) was obtained as a yellow solid. MS: m / z = 274.9 [M + H]+. 'HNMR (400 MHz, Dimethylsulfoxide-t / 6) 6 12.37 (s, 1H), 8.75 (s, 1H), 8.22 (s, 1H), 7.83 - 7.75 (m, 2H), 7.32 - 7.26 (m, 2H), 7.24 (s, 1H).Step 3: Methyl 3-(4-fluorophenyl)-2-oxo-l,2-dihydro-l,6-naphthyridine-7-carboxylate To a solution of 7-chloro-3-(4-fluorophenyl)-l,6-naphthyridin-2(U7)-one (450 mg, 1.64 mmol) in MeOH (10 mL) were added TEA (684 pL, 4.91 mmol) and Pd(dppf)C12 (360 mg, 492 pmol).The reaction mixture was purged with CO three times and stirred at 80 °C for 12 hr under CO (50 Psi). The mixture was concentrated. After purification by silica gel flash chromatography (Eluent of 0% ~ 5% Methanol in CH2Q2), the title compound (450 mg, yield: 92%) was obtained as a brown solid. MS: m / z = 299.1 [M + H]+.JH NMR (400 MHz, Dimethylsulfoxide- e) 5 12.49 (s, 1H), 8.99 (s, 1H), 8.31 (s, 1H), 7.94 (s, 1H), 7.87 - 7.80 (m, 2H), 7.35 - 7.27 (m, 2H), 3.91 (s, 3H).Step 4: Methyl 2-chloro-3-(4-fluorophenyl)-l,6-naphthyridine-7-carboxylateA solution of methyl 3-(4-fluorophenyl)-2-oxo-l,2-dihydro-l,6-naphthyridine-7-carboxylate (380 mg, 1.27 mmol) in POCI3 (3 mL) was stirred at 100 °C for 2 hr. The mixture was cooled to 20 °C. The mixture was poured into H2O (5 mL). The pH of the mixture was adjusted to 7 - 8 with sat. NaHCCh (10 mL). The aqueous layer was extracted with CH2Q2 (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous , Na2SO4 filtered, and concentrated. The title compound (404 mg) was obtained as a brown solid, which was used in the next step without purification. MS: m / z = 317.0 [M + H]+.Step 5: Methyl 3-(4-fluorophenyl)-2-(4-(hydroxymethyl)phenyl)-l,6-naphthyridine-7- carb oxy lateTo a mixture of methyl 2-chloro-3-(4-fluorophenyl)-l,6-naphthyridine-7-carboxylate (404 mg, 1.27 mmol) and (4-(hydroxymethyl)phenyl)boronic acid (213 mg, 1.40 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) were added Pd(dppf)C12 (93.2 mg, 127 pmol) and CS2CO3 (1.25 g, 3.82 mmol). The reaction mixture was purged with N2 three times and stirred at 100 °C for 1 hr under N2. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous , Na2SO4 filtered, and concentrated. After purification by silica gel flash chromatography (Eluent of 0% ~ 10% Methanol in CH2Q2), the title compound (140 mg, yield: 28% for two steps) was obtained as a yellow solid. MS: m / z = 389.1 [M + H]+. 'HNMR (400 MHz, Dimethylsulfoxide- e) 5 9.55 (s, 1H), 8.72 (s, 1H), 8.58 (s, 1H), 7.41 - 7.35 (m, 4H), 7.32 - 7.27 (m, 2H), 7.26 - 7.19 (m, 2H), 5.26 (t, J= 6.0 Hz, 1H), 4.52 (d, J= 6.0 Hz, 2H), 3.97 (s, 3H).Step 6: 3-(4-Fluorophenyl)-2-(4-(hydroxymethyl)phenyl)-l,6-naphthyridine-7-carboxamide To a 30 mL autoclave were charged with methyl 3-(4-fluorophenyl)-2-(4- (hydroxymethyl)phenyl)-l,6-naphthyridine-7-carboxylate (140 mg, 361 pmol) and NHLMeOH (7M, 4 mL). The mixture was stirred under 15 psi at 55 °C for 12 hr. The mixture was concentrated. The title compound (135 mg) was obtained as a yellow solid, which was used in the next step without purification. MS: m / z = 374.1 [M + H]+.1H NMR (400 MHz,Dimethylsulfoxide-d2) 6 9.50 (s, 1H), 8.71 (s, 1H), 8.52 (s, 1H), 7.42 - 7.35 (m, 5H), 7.30 - 7.20 (m, 5H), 5.26 (t, J= 6.4 Hz, 1H), 4.51 (d, J= 6.4 Hz, 2H).Step 7: 2-(4-(Chloromethyl)phenyl)-3-(4-fluorophenyl)-l,6-naphthyridine-7-carboxamideTo a solution of 3-(4-fluorophenyl)-2-(4-(hydroxymethyl)phenyl)-l,6-naphthyridine-7- carboxamide (135 mg, 361 pmol) in CH2CI2 (2 mL) was added SOCI2 (78.5 pL, 1.08 mmol). The mixture was stirred at 20 °C for 0.5 hr. The mixture was concentrated. The title compound (Intermediate 30, 141 mg) was obtained as a yellow solid, which was used in the next step without purification. MS: m / z = 392.1 [M + H]+.

[0269] Intermediate 31 : 6-(4-(Chloromethyl)phenyl)-7-phenyl-l,5-naphthyridine-3- carb oxami deStep 1 : 7-Bromo-2-(4-((( / c / 7-butyldimethylsilyl)oxy)methyl)phenyl)-3-phenyl- l ,5-naphthyridine To a solution of l-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-2-phenylethan-l-one (1.3 g, 3.82 mmol, refer to Intermediate 1 for detail procedures) in z-PrOH (15 mL) were added 3- amino-5-bromopicolinaldehyde (921 mg, 4.58 mmol) and K2CO3 (2.64 g, 19.1 mmol). The mixture was stirred at 80 °C for 36 hr. The mixture was diluted with H2O (30 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (30mL), dried over anhydrous Na2SO4, filtered, and concentrated. After purification by silica gel flash chromatography (Eluent of 0% - 8% EtOAc in hexane), the title compound (830 mg, yield: 43%) was obtained as yellow oil.1H NMR (400 MHz, Dimethylsulfoxide- e) 8 9.11 (d, J= 2.0 Hz, 1H), 8.80 (s, 1H), 8.40 (s, 1H), 7.39 - 7.29 (m, 7H), 7.24 (d, J= 8.0 Hz, 2H), 4.71 (s, 2H), 0.89 (s, 9H), 0.06 (s, 6H).Step 2: Methyl 6-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-7-phenyl-l,5-naphthyridine- 3 -carboxylateTo a solution of 7-bromo-2-(4-(((terLbutyldimethylsilyl)oxy)methyl)phenyl)-3-phenyl-l,5- naphthyridine (730 mg, 1.44 mmol) in MeOH (10 mL) were added TEA (438 mg, 4.33 mmol, 603 pL) and Pd(dppf)C12 (211 mg, 289 pmol). The reaction mixture was degassed and purged with CO three times. The mixture was heated to 80 °C under CO (50 Psi) for 12 hr. The mixture was cooled, filtered, and the filter cake was washed with MeOH (30 mL x 3). The filtrate was concentrated. After purification by silica gel flash chromatography (Eluent of 0% ~ 8% EtOAc in hexane), the title compound (550 mg, yield 79%) was obtained as yellow oil. MS: m / z = 485.2 [M + H]+.1H NMR (400 MHz, Dimethyl sulfoxi de-tZ6) 5 9.43 (d, J= 2.0 Hz, 1H), 8.89 (s, 1H), 8.46 (s, 1H), 7.40 - 7.31 (m, 7H), 7.25 (d, J= 8.0 Hz, 2H), 4.72 (s, 2H), 3.99 (s, 3H), 0.89 (s, 9H), 0.06 (s, 6H).Step 3 : 6-(4-(((tert-butyl dimethylsilyl)oxy)methyl)phenyl)-7-phenyl- l ,5-naphthyridine-3- carboxamideA mixture of methyl 6-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-7-phenyl-l,5- naphthyridine-3-carboxylate (450 mg, 929 pmol) in NHLMeOH (7 M, 30 mL) was stirred at 55 °C for 28 hr. The mixture was concentrated to give the title compound (436 mg) as a white solid, which was used in the next step directly. MS: m / z = 470.2 [M + H]+.Step 4: 6-(4-(Hydroxymethyl)phenyl)-7-phenyl-l,5-naphthyridine-3-carboxamideTo a solution of 6-(4-(((terLbutyldimethylsilyl)oxy)methyl)phenyl)-7-phenyl-l,5-naphthyridine- 3-carboxamide (150 mg, 319 pmol) in THF (1.5 mL) was added TBAF (1 M in THF, 639 pL). The mixture was stirred at 25 °C for 1 hr. The mixture was poured to H2O (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The title compound (114 mg,) was obtained as a yellow solid, which was used in the next step directly. MS: m / z = 356.0 [M + H]+.Step 5: 6-(4-(Chloromethyl)phenyl)-7-phenyl-l,5-naphthyridine-3-carboxamideA mixture of 6-(4-(hydroxymethyl)phenyl)-7-phenyl-l,5-naphthyridine-3-carboxamide (114 mg, 319 pmol) in CH2Q2 (2 mL) was added SOCI2 (152 mg, 92.8 pL), the mixture was stirred at 25 °C for 2 hr. The mixture was concentrated to give the title compound (Intermediate 31, 119 mg) as a yellow solid, which was used in the next step directly. MS: m / z = 374.0 [M + H]+.

[0270] Intermediate 32: 2-(4-(Chloromethyl)phenyl)-3-phenyl-5J / -pyrano[4,3-Z>]pyridin-5-oneStep 1 : Methyl 2-amino-6-(4-(hydroxymethyl)phenyl)nicotinateA mixture of methyl 2-amino-6-chloronicotinate (3 g, 16.1 mmol), (4-(hydroxymethyl)phenyl)boronic acid (2.69 g, 17.7 mmol), Pd(dppf)C12 (1.18 g, 1.61 mmol), andCS2CO3 (15.72g, 48.2 mmol) in 1,4-dioxane (30 mL) and H2O (5 mL) was degassed, purged with N2 three times, and stirred at 90 °C for 4 hr under N2 atmosphere. The reaction mixture was quenched with EtOAc (100 mL), filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 3% MeOH in CH2Q2), the title compound (4.1 g, yield: 91%) was obtained as a yellow solid. MS: m / z = 259.0 [M + H]+.JH NMR (400 MHz, Dimethylsulfoxide-d2) 8 8.12 (d, J= 8.0 Hz, 1H), 8.04 (d, J= 8.4 Hz, 2H), 7.42 (d, J= 8.0 Hz, 2H), 7.30 - 7.17 (m, 3H), 5.28 (t, J= 5.2 Hz, 1H), 4.56 (d, J= 4.4 Hz, 2H), 3.83 (s, 3H).Step 2: Methyl 2-amino-6-(4-(((terLbutyldimethylsilyl)oxy)methyl)phenyl)nicotinateTo a solution of methyl 2-amino-6-(4-(hydroxymethyl)phenyl)nicotinate (4 g, 15.5 mmol) in CH2CI2 (40 mL) were added TEA (3.13 g, 31.0 mmol), DMAP (189 mg, 1.55 mmol) and TBSC1 (3.50 g, 23.2 mmol). The mixture was degassed, purged with N2 three times, and stirred at 25 °C for 1 hr under N2 atmosphere. The reaction mixture was diluted with CH2Q2 (200 mL), washed with brine (200 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. After trituration with petroleum ether at 25 °C for 20 mins, the title compound(4.15 g, yield: 68%) was obtained as a gray solid. MS: m / z = 373.2 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 6 8.12 (d, J= 8.0 Hz, 1H), 8.05 (d, J= 8.4 Hz, 2H), 7.41 (d, J= 8.0 Hz, 2H), 7.28 - 7.17 (m, 3H), 4.77 (s, 2H), 3.83 (s, 3H), 0.91 (s, 9H), 0.09 (s, 6H).Step 3: Methyl 2-amino-5-bromo-6-(4-((( / c / 7-butyldimethylsilyl)oxy)methyl)phenyl)nicotinateTo a solution of methyl 2-amino-6-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)nicotinate (4 g, 10.7 mmol) in CH2CI2 (40 mL) was added NBS (3.82 g, 21.5 mmol). The mixture was degassed, purged with N2 three times, and stirred at 0 °C for 1 hr under N2 atmosphere. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over , filtered aNnda2SO4 concentrated under reduced pressure. The title compound (4.85 g) was obtained as an orange oil which was used into the next step directly. MS: m / z = 451.0, 452.8 [M + H]+.Step 4: Methyl 2-amino-6-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-5-phenylnicotinate To a solution of methyl 2-amino-5-bromo-6-(4-((( / c / 7- butyldimethylsilyl)oxy)methyl)phenyl)nicotinate (4.85 g, 10.7 mmol), phenylboronic acid (1.57 g, 12.9 mmol) in 1,4-dioxane (50 mL) and H2O (10 mL) were added Pd(dppf)C12 (786 mg, 1.07 mmol) and CS2CO3 (10.5 g, 32.2 mmol). The mixture was degassed, purged with N2 three times, and stirred at 90 °C for 2 hr under N2 atmosphere. The reaction mixture was diluted with EtOAc (100 mL) and then filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 20% EtOAc in petroleum ether), the title compound (1.24 g, yield: 24% for two steps) was obtained as a yellow solid. MS: m / z = 449.6 [M + H]+.JH NMR (400 MHz, Dimethylsulfoxide-tfc) 8 8.02 (s, 1H), 7.30 - 7.21 (m, 7H), 7.19 - 7.14 (m, 2H), 7.12 - 7.07 (m, 2H), 4.67 (s, 2H), 3.84 (s, 3H), 0.87 (s, 9H), 0.04 (s, 6H).Step 5: Methyl 2-bromo-6-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-5-phenylnicotinate To a solution of methyl 2-amino-6-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-5- phenylnicotinate (1 g, 2.23 mmol) in CH2Br2 (10 mL) were added slowly tert-butyl nitrite (460 mg, 4.46 mmol) and A-benzyl-A,A-diethylethanaminium bromide (910 mg, 3.34 mmol) in an ice bath. The mixture was degassed, purged with N2 three times, and stirred at 25 °C for 16 hr under N2. The reaction mixture was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 4% EtOAc in petroleum ether), the title compound (330 mg, yield: 28%) was obtained as a colorless oil. MS: m / z = 512.3, 514.2 [M + H]+. ' H NMR (400 MHz, Chloroformd6) 5 8.22 - 8.09 (m, 1H), 7.37 (d, J= 8.0 Hz, 2H), 7.32 - 7.29 (m, 3H), 7.21 - 7.16 (m, 4H), 4.71 (s, 2H), 3.97 (s, 3H), 0.92 (s, 9H), 0.07 (s, 6H).Step 6: Methyl (£)-6-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-2-(2-ethoxyvinyl)-5- phenylnicotinateTo a solution of methyl 2-bromo-6-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-5- phenylnicotinate (300 mg, 585 pmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (174 mg, 878 pmol) in 1,4-dioxane (5 mL) and H2O (1 mL) were added Pd(dppf)C12 (42.8 mg, 58.5 pmol) and CS2CO3 (572 mg, 1.76 mmol). The mixture wasdegassed, purged with N2 three times, and stirred at 90 °C for 2 hr under N2 atmosphere. The reaction mixture was quenched with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 12% EtOAc in petroleum ether), the title compound (120 mg, yield: 39%) was obtained as a yellow oil. MS: m / z = 504.2 [M + H]+. 'H NMR (400 MHz, Chloroform-t / ) 5 8.18 (s, 1H), 8.05 (d, J= 12.4 Hz, 1H), 7.38 (d, J= 8.0 Hz, 2H), 7.32 - 7.28 (m, 1H), 7.23 - 7.14 (m, 5H), 7.08 - 6.96 (m, 2H), 4.72 (s, 2H), 4.05 (q, J= 7.2 Hz, 2H), 3.92 (s, 3H), 1.40 - 1.37 (m, 3H), 0.93 (s, 9H), 0.08 (s, 6H).Step 7 : 2-(4-(Hydroxymethyl)phenyl)-3-phenyl-5J7-pyrano[4,3-Z>]pyridin-5-oneA solution of methyl (E)-6-(4-(((te / 7-butyldimethylsilyl)oxy)methyl)phenyl)-2-(2-ethoxyvinyl)- 5 -phenylnicotinate (100 mg, 199 pmol) in H2SO4 (2 mL, purity: 98%) was degassed, purged with N2 three times, and stirred at 0 °C for 2 hr under N2. The reaction mixture was poured into H2O (30 mL) at 0 °C and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with sat. NaHCCh (50 mL x 3), brine (50 mL x 3) , dried over Na2SO4, filtered and concentrated under reduced pressure. The title compound (38 mg) was obtained as an orange solid which was used into the next step directly. MS: m / z = 330.0 [M + H]+.Step 8: 2-(4-(Chloromethyl)phenyl)-3-phenyl-5J / -pyrano[4,3-Z>]pyridin-5-oneTo a solution of 2-(4-(hydroxymethyl)phenyl)-3-phenyl-5J7-pyrano[4,3-Z>]pyridin-5-one (33 mg, 100 pmol) in CH2Q2 (2 mL) was added SOCI2 (0.4 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (Intermediate 32, 38.5 mg, HC1 salt) as a yellow solid, which was used in the next step directly. MS: m / z = 348.0, 349.9 [M + H]+.

[0271] Intermediate 33 : 3-(4-(Chloromethyl)phenyl)-2-phenylpyrido[2,3-Z>]pyrazine-6- carb oxami deStep 1 : 6-Bromo-2-phenylpyrido[2,3-Z>]pyrazin-3-olTo a solution of ethyl 2-oxo-2-phenylacetate (5.69 g, 31.9 mmol) in DMF (30 mL) were added DIEA (5.50 g, 42.6 mmol) and 6-bromopyridine-2,3-diamine (4 g, 21.3 mmol). The mixture was stirred at 80 °C for 60 hr. The mixture was diluted with H2O (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 20% EtOAc in Petroleum ether), the title compound (600 mg, yield: 9%) was obtained. MS: m / z = 302.0, 304.0 [M + H]+. 'H NMR (400 MHz, Dimethysulfoxide-d6) 8 13.20 (br s, 1H), 8.27 - 8.26 (m, 1H), 8.25 - 8.24 (m, 1H), 8.16 (d, J= 8.0 Hz, 1H), 7.58 - 7.56 (m, 1H), 7.55 - 7.52 (m, 2H), 7.51 - 7.49 (m, 1H).Step 2: Methyl 3-hydroxy-2-phenylpyrido[2,3-Z>]pyrazine-6-carboxylateTo a solution of 6-bromo-2-phenylpyrido[2,3-Z>]pyrazin-3-ol (600 mg, 1.99 mmol) in MeOH (5 mL) and EtOAc (2 mL) were added Pd(dppf)C12 (289 mg, 395 pmol) and TEA (824 pL, 5.97 mmol) under N2. The suspension was degassed and purged with CO three times. The mixture was stirred under CO (50 psi) at 80 °C for 16 hr. The reaction mixture was quenched with H2O (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0 ~ 40% EtOAc in Petroleum ether), the title compound (110 mg, yield: 20%) was obtained. MS: m / z = 282.1 [M + H]+. 'H NMR (400 MHz, Dimethysulfoxide-d2) 6 13.25 (br s, 1H), 8.40 (d, J= 8.0 Hz, 1H), 8.31 - 8.26 (m, 2H), 8.00 (d, J= 8.0 Hz, 1H), 7.58 - 7.50 (m, 3H), 3.93 (s, 3H).Step 3: Methyl 3-chloro-2-phenylpyrido[2,3-Z>]pyrazine-6-carboxylateTo a solution of methyl 3-hydroxy-2-phenylpyrido[2,3-Z>]pyrazine-6-carboxylate (110 mg, 391 pmol) in POCI3 (3 mL). The mixture was stirred at 100 °C for 16 hr. The reaction mixture waspoured into H2O (20 mL) at 30°C. The pH of the reaction was adjusted to about 7 with sat.NaHCCh (30 mL). The reaction mixture was extracted with CH2Q2 (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous , filtered,N aan2dSO4 concentrated under reduce pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 25% EtOAc in hexanes), the title compound (110 mg, yield: 94%) was obtained. MS: m / z = 299.9, 302.0 [M + H]+. 'HNMR (400 MHz, Dimethysulfoxide-d2) 8 8.81 (d, J= 8.4 Hz, 1H), 8.47 (d, J= 8.4 Hz, 1H), 7.95 - 7.83 (m, 2H), 7.65 - 7.56 (m, 3H), 4.01 (s, 3H). Step 4: Methyl 3-(4-(hydroxymethyl)phenyl)-2-phenylpyrido[2,3-Z>]pyrazine-6-carboxylate A mixture of methyl 3-chloro-2-phenylpyrido[2,3-Z>]pyrazine-6-carboxylate (105 mg, 350 pmol) and (4-(hydroxymethyl)phenyl) boronic acid (63.9 mg, 420 pmol), CS2CO3 (228 mg, 701 pmol), and Pd(dppf)C12 (25.6 mg, 35.0 pmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was degassed and purged with N2 three times, and stirred under N2 at 90 °C for 2 hr. The reaction mixture was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 50% EtOAc in hexanes), the title compound (60 mg, yield: 46%) was obtained. MS: m / z = 372.0 [M + H]+. 'HNMR (400 MHz, Dimethysulfoxide-d2) 6 8.76 (d, J= 8.8 Hz, 1H), 8.43 (d, J= 8.8 Hz, 1H), 7.56 - 7.51 (m, 4H), 7.47 - 7.39 (m, 3H), 7.33 (d, J= 8.0 Hz, 2H), 5.29 (t, J= 6.0 Hz, 1H), 4.54 (d, J= 6.0 Hz, 2H), 4.01 (s, 3H).Step 5 : 3-(4-(Hydroxymethyl)phenyl)-2-phenylpyrido[2,3-Z>]pyrazine-6-carboxamideTo a solution of 3-(4-(hydroxymethyl)phenyl)-2-phenylpyrido[2,3-Z>]pyrazine-6-carboxylate (60.0 mg, 162 pmol) in NH3 (7 M in MeOH, 5 mL). The mixture was stirred at 50 °C for 16 hr. The reaction mixture was concentrated under reduced pressure. The title compound (57 mg) was obtained. MS: m / z = 357.1 [M + H]+.Step 6: 3-(4-(Chloromethyl)phenyl)-2-phenylpyrido[2,3-Z>]pyrazine-6-carboxamideTo a solution of 3-(4-(hydroxymethyl)phenyl)-2-phenylpyrido[2,3-Z>]pyrazine-6-carboxamide (50.0 mg, 140 pmol) in CH2CI2 (2 mL) was added SOCI2 (0.5 mL). The mixture was stirred at 40 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (Intermediate 33, 52 mg). MS: m / z = 375.0, 377.0 [M + H]+.

[0272] Intermediate 34: 2-(4-(Chloromethyl)phenyl)-A-methoxy-3-phenyl-l,6-naphthyridine-7- carb oxami deStep 1 : 2-(4-(Hydroxymethyl)phenyl)-3-phenyl-l,6-naphthyridine-7-carboxylic acidTo a solution of ethyl 2-(4-(((terLbutyldimethylsilyl)oxy)methyl)phenyl)-3-phenyl-l,6- naphthyridine-7-carboxylate (440 mg, 882 pmol, refer to Intermediate 16 for detail procedures) in MeOH (10 mL) was added LiOH H2O (111 mg, 2.65 mmol). The mixture was stirred at 60 °C for 2 hr. The reaction was concentrated under reduced pressure to give the title compound (314 mg). MS: m / z = 357.0 [M + H]+.Step 2: 2-(4-(Hydroxymethyl)phenyl)-7V-methoxy-3-phenyl-l,6-naphthyridine-7-carboxamide To a solution of 2-(4-(hydroxymethyl)phenyl)-3-phenyl-l,6-naphthyridine-7-carboxylic acid (100 mg, 281 pmol) and O-methylhydroxylamine (46.9 mg, 561 pmol, HC1 salt) in EtOAc (5 mL) were added T4P (404 mg, 561 pmol, 50% purity in EtOAc) and DIEA (109 mg, 842 pmol). The mixture was stirred at 25 °C for 16 hr. The reaction was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 63% EtOAc in petroleum ether), the title compound (100 mg, yield: 46% for two steps) was obtained. MS: m / z = 386.1 [M + H]+. ‘H NMR (400 MHz, Dimethylsulfoxide-d2) 5 11.06 - 10.81 (m, 1H), 9.52 - 9.45 (m, 1H), 8.73 - 8.65 (m, 1H), 8.51 - 8.41 (m, 1H), 7.44 - 7.35 (m, 5H), 7.34 - 7.30 (m, 2H), 7.28 - 7.24 (m, 2H), 5.38 - 5.10 (m, 1H), 4.51 (s, 2H), 3.77 (s, 3H).Step 3 : 2-(4-(Chloromethyl)phenyl)-A-methoxy-3-phenyl-l,6-naphthyridine-7-carboxamide To a solution of 2-(4-(hydroxymethyl)phenyl)-A-methoxy-3-phenyl-l,6-naphthyridine-7- carboxamide (90 mg, 234 pmol) in CH2C12(3 mL) was added SOCI2 (0.5 mL). The mixture was stirred at 25 °C for 0.5 hr. The pH of the reaction mixture was adjusted to about 7~8 at 0 °C with solid K2CO3. The reaction was concentrated under reduced pressure to give the title compound (Intermediate 34, 94 mg). MS: m / z = 404.0, 405.9 [M + H]+.

[0273] Intermediate 35: 2-(4-(Chloromethyl-t / 2)phenyl)-3-phenyl-l,6-naphthyridine-7- carb oxami deStep 1 : 4-(Hydroxymethyl-d2 (benzonitrileTo a solution of methyl 4-cyanobenzoate (1 g, 6.21 mmol) in THF (15 mL) was added LiAlD4 (236 mg, 6.21 mmol) at -78°C under N2. The resulting mixture was stirred at -78 °C for 2 hr under N2. The reaction mixture was quenched with Na2SO4 10 H2O (500 mg) at 0 °C, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 30% EtOAc in Petroleum ether), the title compound (690 mg, yield: 82%) was obtained. 'HNMR (400 MHz, Dimethysulfoxide-d6) 8 7.80 - 7.79 (m, 1H), 7.78 - 7.77 (m, 1H), 7.53 - 7.51 (m, 1H), 7.51 - 7.49 (m, 1H), 5.41 (s, 1H).Step 2: 4-((tert-Butyldimethylsilyl(oxy(methydl-2 (benzonitrileTo a solution of 4-(hydroxymethyl-d2)benzonitrile (690 mg, 5.11 mmol) in CH2Q2 (10 mL) were added imidazole (695 mg, 10.2 mmol) and TBSC1 (1.15 g, 7.66 mmol). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was quenched with H2O (30mL) and extracted with CH2Q2 (30 mL x2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% EtOAc in petroleum ether), the title compound (1.1 g, yield: 86%) was obtained. 'HNMR (400 MHz, Dimethysulfoxide-d6) 6 7.83 - 7.81 (m, 1H), 7.81 - 7.79 (m, 1H), 7.52 - 7.50 (m, 1H), 7.50 - 7.48 (m, 1H), 0.90 (s, 9H), 0.08 (s, 6H).Step 3 : I -(4-(((tert-Butyldimethylsilyl)oxy)methyl-d2)phenyl)-2-phenylethan- l -oneTo a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl-t / 2)benzonitrile (1.1 g, 4.41 mmol) in THF (10 mL) was added benzyl magnesium Chloride (8.82 mL, 1 M in THF) at 0 °C under N2. The mixture was stirred under N2 at 25 °C for 1 hr. The reaction mixture was quenched with sat. NH4CI (20 mL) at 0 °C and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50mL), dried over anhydrous , filteNread2,S anOd4 concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 1% EtOAc in Petroleum ether), the title compound (1.5 g, yield: 99%) was obtained. MS: m / z =343.2 [M + H]+. D%: 2D% = 98.06%. 'H NMR (400 MHz, Dimethysulfoxide-d2) 8 8.03 (d, J= 8.4 Hz, 2H), 7.45 (d, J= 8.0 Hz, 2H), 7.31 - 7.22 (m, 5H), 4.36 (s, 2H), 0.91 (s, 9H), 0.08 (s, 6H).Step 4: 2-(4-(((tert-butyl dirnethylsilyl)oxy)rnethyl-d2)phenyl)-7-chloro-3-phenyl- l ,6- naphthyridineTo a solution of l -(4-(((tert-butyldimethylsilyl)oxy)methyl-d2)phenyl)-2-phenylethan- l -one (1.5 g, 4.38 mmol) in z-PrOH (20 mL) were added K2CO3 (3.03 g, 21.9 mmol) and 4-amino-6- chloronicotinaldehyde (686 mg, 4.38 mmol). The mixture was stirred at 80 °C for 40 hr. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 5% EtOAc in Petroleum ether), the title compound (670 mg, yield: 33%) was obtained. MS: m / z = 463.2, 465.2 [M + H]+. D%: 2D% = 98.0%. 'HNMR (400 MHz, Dimethysulfoxide-d6) 6 9.35 (s, 1H), 8.64 (s, 1H), 8.09 (s, 1H), 7.39 - 7.37 (m, 1H), 7.37 - 7.33 (m, 4H), 7.29 - 7.26 (m, 2H), 7.24 (d, J= 8.0 Hz, 2H), 0.88 (s, 9H), 0.05 (s, 6H).Step 5: Ethyl 2-(4-(((tert-butyl dimethylsilyl)oxy)rnethyl-t / 2)phenyl)-3-phenyl-l,6-naphthyridine- 7-carboxylateTo a solution of 2-(4-(((tert-butyldimethylsilyl)oxy)methyl-t / 2)phenyl)-7-chloro-3-phenyl-l,6- naphthyridine (670 mg, 1.45 mmol) in EtOH (10 mL) were added Pd(dppf)C12 (212 mg, 289 pmol) and TEA (439 mg, 4.34 mmol) under N2. The suspension was degassed, purged with CO three times, and stirred under CO (50 psi) at 80 °C for 48 hr. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 20% EtOAc in Petroleum ether), the title compound (600 mg, yield: 83%) was obtained. MS: m / z =501.2 [M + H]+. D%: 2D% = 97.87%. 'H NMR (400 MHz, Dimethysulfoxide-d2) 6 9.55 (s, 1H), 8.71 (s, 1H), 8.58 (s, 1H), 7.41 (d, J= 8.0 Hz, 2H), 7.37 - 7.30 (m, 5H), 7.26 (d, J= 8.4 Hz, 2H),4.43 (q, J= 7.2 Hz, 2H), 1.40 (t, J= 7.2 Hz, 3H), 0.89 (s, 9H), 0.06 (s, 6H).Step 6: 2-(4-(((tert-Butyldimethylsilyl)oxy)methyl-t / 2)phenyl)-3-phenyl-l,6-naphthyridine-7- carb oxami deA solution of ethyl 2-(4-((( / cv / -butyl di methyl silyl )oxy)methyl-t / 2)phenyl)-3 -phenyl - 1 ,6- naphthyridine-7-carboxylate (600 mg, 1.20 mmol) in NH3 (10 mL, 7 M in MeOH) was stirred at 50 °C for 16 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (565 mg). MS: m / z = 472.3 [M + H]+. D%: 2D% = 97.93%. 'H NMR (400 MHz, Dimethysulfoxide-d6) 8 9.51 (s, 1H), 8.71 (s, 1H), 8.52 (s, 1H), 8.35 (br s, 1H), 7.86 (br s, 1H), 7.41 (d, J= 8.0 Hz, 2H), 7.37 - 7.33 (m, 3H), 7.33 - 7.29 (m, 2H), 7.26 (d, J= 8.0 Hz, 2H), 0.89 (s, 9H), 0.06 (s, 6H).Step 7: 2-(4-(Hydroxymethyl-d2)phenyl)-3-phenyl-l,6-naphthyridine-7-carboxamide To a solution of 2-(4-(((terLbutyldimethylsilyl)oxy)methyl-t / 2)phenyl)-3-phenyl-l,6- naphthyridine-7-carboxamide (565 mg, 1.20 mmol) in THF (10 mL) was added TBAF (3 mL, 1 M in THF). The mixture was stirred at 25 °C for 1 hr. The mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL x 5), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (426 mg). MS: m / z = 358.0 [M + H]+.Step 8: 2-(4-(Chloromethyl-t / 2)phenyl)-3-phenyl-l,6-naphthyridine-7-carboxamideTo a solution of 2-(4-(Hydroxymethyl-t / 2)phenyl)-3-phenyl-l,6-naphthyridine-7-carboxamide (426 mg, 1.19 mmol) in CH2Q2 (10 mL) was added SOCI2 (2 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (Intermediate 35, 448 mg). MS: m / z = 376.2, 378.2 [M + H]+.

[0274] Intermediate 36: 2-(4-(Hydroxymethyl)phenyl)-5-methyl-3-phenyl-l,6-naphthyridine-7- carb oxami deStep 1 : 6-Chloro-3-iodo-2-methylpyridin-4-amineTo a solution of 2-chloro-6-methylpyridin-4-amine (5 g, 35.1 mmol) in EtOH (150 mL) were added Ag2SO4 (10.9 g, 35.1 mmol) and I2 (8.90 g, 35.1 mmol). The mixture was stirred at 25 °C for 16 hr. The mixture was diluted with EtOAc (100 mL) and TEA (5 mL). The resulting mixture was stirred at 25 °C for 10 min. The resulting mixture was filtered. The filter cake was washed with EtOAc (100 mL x 3). The filtrate was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 10% EtOAc in Petroleum ether), the title compound (2.5 g, yield: 27%) was obtained. MS: m / z = 268.8, 270.8 [M + H]+.JH NMR (400 MHz, Chloroformd6) 5 6.44 (s, 1H), 4.79 (br s, 2H), 2.65 (s, 3H).Step 2: Ethyl (E)-3-(4-amino-6-chloro-2-methylpyri din-3 -yl)acrylateA mixture of 6-chloro-3-iodo-2-methylpyridin-4-amine (2 g, 7.45 mmol), ethyl (E)-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)acrylate (1.68 g, 7.45 mmol), CS2CO3 (4.85 g, 14.9 mmol), and Pd(dppf)C12 (545 mg, 745 pmol) in 1,4-di oxane (20 mL) and H2O (4 mL) was degassed, purged with N2 three times, and stirred at 90 °C for 16 hr under N2. The reaction mixture was quenched with H2O (50mL) and extracted with EtOAc (50 mL x2). The combined organic layers were washed with brine (50mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 20% EtOAc in Petroleum ether), the title compound (1.6 g, yield: 89%) was obtained. MS: m / z = 241.0, 242.9 [M + H]+. 'HNMR (400 MHz, DimethysulfoxidesL) 8 7.57 - 7.51 (m, 1H), 6.53 (s, 1H), 6.45 (br s, 2H), 6.28 - 6.21 (m, 1H), 4.19 (q, J = 7.2 Hz, 2H), 2.32 (s, 3H), 1.26 (t, J=7.2 Hz, 3H).Step 3: 7-Chloro-5-methyl-l,6-naphthyridin-2-olTo a solution of ethyl (E)-3-(4-amino-6-chloro-2-methylpyridin-3-yl)acrylate (1.58 g, 6.56 mmol) in EtOH (20 mL) was added NaSMe (1.18 g, 16.8 mmol). The mixture was stirred at 25 °C for 2 hr. The reaction was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 6% MeOH in CH2Q2), the title compound (940 mg, yield: 74%) was obtained. MS: m / z = 195.1, 197.0 [M + H]+. 'HNMR (400 MHz, Dimethysulfoxide-d6) 8 12.07 (br s, 1H), 8.12 - 8.07 (m, 1H), 7.09 (s, 1H), 6.57 (d, J= 9.6 Hz, 1H), 2.65 (s, 3H).Step 4: 3-Bromo-7-chloro-5-methyl-l,6-naphthyridin-2-olTo a solution of 7-chloro-5-methyl-l,6-naphthyridin-2-ol (840 mg, 4.32 mmol) in DMF (10 mL) was added NBS (2.30 g, 13.0 mmol). The mixture was stirred at 80 °C for 16 hr. The reaction mixture was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 6% MeOH in CH2Q2), the title compound (1 g, yield: 85%) was obtained. MS: m / z = 275.0, 277.0 [M + H]+. ' H NMR (400 MHz, Dimethysulfoxide-d6) 6 12.58 (br s, 1H), 8.61 (s, 1H), 7.13 (s, 1H), 2.66 (s, 3H).Step 5: 7-Chloro-5-methyl-3-phenyl-l,6-naphthyridin-2-olA mixture of 3-bromo-7-chloro-5-methyl-l,6-naphthyridin-2-ol (1 g, 3.66 mmol), phenylboronic acid (446 mg, 3.66 mmol), Pd(dppf)C12 (268 mg, 365 pmol) and K3PO4 (1.55 g, 7.31 mmol) in 1,4-di oxane (10 mL) and H2O (2 mL) was degassed, purged with N2 three times, and stirred at 90 °C for 16 hr under N2. The reaction mixture was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 15% EtOAc in Petroleum ether), the title compound (650 mg, yield: 66%) was obtained. MS: m / z = 271.1, 273.0 [M + H]+. ' H NMR (400 MHz, Dimethysulfoxide-d2) 6 12.28 (br s, 1H), 8.14 (s, 1H), 7.79 - 7.35 (m, 2H), 7.48 - 7.38 (m, 3H), 7.12 (s, 1H), 2.73 (s, 3H).Step 6: Ethyl 2-hydroxy-5-methyl-3-phenyl-l,6-naphthyridine-7-carboxylateTo a solution of 7-chloro-5-methyl-3-phenyl-l,6-naphthyridin-2-ol (200 mg, 739 pmol) in EtOH (5 mL) were added Pd(dppf)C12 (108 mg, 148 pmol) and TEA (224 mg, 2.22 mmol) under N2. The suspension was degassed, purged with CO three times, and stirred under CO (50 psi) at 80 °C for 40 hr. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 10% EtOAc in Petroleum ether), the title compound (220 mg, yield: 97%) was obtained. MS: m / z = 309.1 [M + H]+. 'H NMR (400 MHz,Dimethysulfoxide-d6) 6 12.40 (s, 1H), 8.22 (s, 1H), 7.83 (s, 1H), 7.82 - 7.78 (m, 2H), 7.48 - 7.40 (m, 3H), 4.36 (q, J= 7.2 Hz, 2H), 2.80 (s, 3H), 1.34 (t, J= 7.2 Hz, 3H).Step 7: Ethyl 2-chloro-5-methyl-3-phenyl-l,6-naphthyridine-7-carboxylateA solution of ethyl 2-hydroxy-5-methyl-3-phenyl-l,6-naphthyridine-7-carboxylate (220 mg, 714 pmol) in POCI3 (5 mL) was stirred at 100 °C for 16 hr. The reaction mixture was poured into H2O (20 mL) at 25 °C. The pH of the reaction mixture was adjusted to about 7 with sat. NaHCCL (30 mL). The mixture was extracted with CH2Q2 (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduce pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 15% EtOAc in Petroleum ether), the title compound (120 mg, yield: 51%) was obtained. MS: m / z = 1 , 329.0 [M + H]+. 'H NMR (400 MHz, Dimethysulfoxide-d2) 8 8.74 (s, 1H), 8.35 (s, 1H), 7.67 - 7.63 (m, 2H), 7.59 - 7.53 (m, 3H), 4.42 (q, J= 7.2 Hz, 2H), 2.99 (s, 3H), 1.39 (t, J= 7.2 Hz, 3H).Step 8: Ethyl 2-(4-(hydroxymethyl)phenyl)-5-methyl-3-phenyl-l,6-naphthyridine-7-carboxylate A mixture of ethyl 2-chloro-5-methyl-3-phenyl-l,6-naphthyridine-7-carboxylate (100 mg, 306 pmol), (4-(hydroxymethyl)phenyl)boronic acid (46.5 mg, 306 pmol), CS2CO3 (199 mg, 612 pmol), and Pd(dppf)C12 (22.4 mg, 30.6 pmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was degassed, purged with N2 three times, and stirred at 90 °C for 2 hr under N2. The mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 35% EtOAc in Petroleum ether), the title compound (97 mg, yield: 80%) was obtained. MS: m / z = 399.2 [M + H]+.XH NMR (400 MHz, Dimethysulfoxide-d2) 6 8.65 (s, 1H), 8.43 (s, 1H), 7.40 - 7.36 (m, 7H), 7.26 (d, J= 8.0 Hz, 2H), 5.25 (t, J= 6.0 Hz, 1H), 4.52 - 4.49 (m, 2H), 4.40 - 4.39 (m, 2H), 3.01 (s, 3H), 1.39 (t, J= 7.2 Hz, 3H).Step 9: 2-(4-(Hydroxymethyl)phenyl)-5-methyl-3-phenyl-l,6-naphthyridine-7-carboxamide A solution of ethyl 2-(4-(hydroxymethyl)phenyl)-5-methyl-3-phenyl-l,6-naphthyridine-7- carboxylate (97 mg, 243 pmol) in NH3 (10 mL, 7 M in MeOH) was stirred at 50 °C for 16 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (Intermediate 36, 89 mg). MS: m / z = 370.3 [M + H]+. 'HNMR (400 MHz, Dimethysulfoxide- d6) 5 8.63 (s, 1H), 8.35 (s, 1H), 8.27 - 8.23 (m, 1H), 7.85 - 7.79 (m, 1H), 7.41 - 7.35 (m, 7H), 7.26 (d, J= 8.0 Hz, 2H), 5.24 (t, J= 6.0 Hz, 1H), 4.52 - 4.49 (m, 2H), 3.03 (s, 3H).

[0275] Intermediate 37: 2-(4-Formylphenyl)-A-methoxy-5-methyl-3-phenyl-l,6-naphthyridine- 7-carboxamideStep 1 : 2-(4-(((tert-butyl dimethylsilyl)oxy)methyl)phenyl)-7-chloro-5-methyl-3-phenyl- l ,6- naphthyridineTo a mixture of l-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-2-phenylethan-l-one (1.86 g, 5.45 mmol, refer to Intermediate 1 for detail procedures) and 4-amino-6-chloro-2- methylnicotinaldehyde (620 mg, 3.63 mmol) in z-PrOH (10 mL) was added K2CO3 (2.51 g, 18.2 mmol). The mixture was stirred at 80 °C for 48 hr. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. After purification by silica gel flash chromatography (Eluent of 0% ~ 10% EtOAc in hexanes), the title compound (470 mg, yield: 27%) was obtained. MS: m / z =[M + H]+.JH NMR (400 MHz, Dimethylsulfoxide- tZ6) 5 8.61 (s, 1H), 7.92 (s, 1H), 7.40 - 7.30 (m, 7H), 7.25 (d, J= 8.0 Hz, 2H), 4.71 (s, 2H), 2.96 (s, 3H), 0.89 (s, 9H), 0.06 (s, 6H).Step 2: Ethyl 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-5-methyl-3-phenyl-l,6- naphthyridine-7-carboxylateTo a solution of 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-7-chloro-5-methyl-3-phenyl- 1,6-naphthyridine (470 mg, 989 pmol) in EtOH (10 mL) were added TEA (300 mg, 2.97 mmol) and Pd(dppf)C12 (217 mg, 297 pmol). The reaction mixture was degassed, purged with CO three times, and stirred under CO (50 Psi) at 80 °C for 48 hr. The mixture was concentrated. After purification by silica gel flash chromatography (Eluent of 0% ~ 13% EtOAc in petroleum ether), the title compound (507 mg, yield: 69%) was obtained. MS: m / z = 513.9 [M + H]+. 'HNMR (400 MHz, Dimethylsulfoxide-d6) 8 8.66 (s, 1H), 8.43 (s, 1H), 7.40 (d, J= 8.0 Hz, 2H), 7.38 - 7.33 (m, 5H), 7.26 (d, J= 8.0 Hz, 2H), 4.72 (s, 2H), 4.42 (q, J= 6.8 Hz, 2H), 3.02 (s, 3H), 1.39 (t, J= 6.8 Hz, 3H), 0.89 (s, 9H), 0.07 (s, 6H).Step 3: 2-(4-(Hydroxymethyl)phenyl)-5-methyl-3-phenyl-l,6-naphthyridine-7-carboxylic acidTo a solution of ethyl 2-(4-((( / c / 7-butyldimethylsilyl)oxy)methyl)phenyl)-5-methyl-3-phenyl- l,6-naphthyridine-7-carboxylate (314 mg, 612 pmol) in MeOH (5 mL) was added LiOH.J O (89.9 mg, 2.14 mmol). The reaction mixture was stirred at 60 °C for 8 hrs. The residue was concentrated to give the title compound (227 mg), which was used in the next step without further purification. MS: m / z = 371.0 [M+H]+.Step 4: 2-(4-(Hydroxymethyl)phenyl)-A-methoxy-5-methyl-3-phenyl-l,6-naphthyridine-7- carb oxami deTo a solution of 2-(4-(hydroxymethyl)phenyl)-5-methyl-3-phenyl-l,6-naphthyridine-7- carboxylic acid (190 mg, 513 pmol) and O-methylhydroxylamine (85.9 mg, 1.03 mmol, HC1) in EtOAc (4 mL) were added DIEA (199 mg, 1.54 mmol) and T4P (739 mg, 1.03 mmol, 50% purity). The mixture was stirred at 12 °C for 12 hr. The reaction mixture was concentrated.After purification by silica gel flash chromatography (Eluent of 0% ~3 % MeOH in CH2Q2), the title compound (190 mg, yield: 93% for two steps) was obtained. MS: m / z = 400.3 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-t / 6) 8 12.05 (s, 1H), 8.63 (s, 1H), 8.30 (s, 1H), 7.42 - 7.33 (m, 7H), 7.26 (d, J= 8.0 Hz, 2H), 5.24 (t, J= 5.6 Hz, 1H), 4.50 (d, J= 5.6 Hz, 2H), 3.77 (s, 3H), 3.03 (s, 3H).Step 5: 2-(4-Formylphenyl)-A-methoxy-5-methyl-3-phenyl-l,6-naphthyridine-7-carboxamideTo a solution of 2-(4-(hydroxymethyl)phenyl)-A-methoxy-5-methyl-3-phenyl-l,6-naphthyridine- 7-carboxamide (190 mg, 476 pmol) in CH2CI2 (2 mL) was added Mn02 (827 mg, 9.51 mmol). The mixture was stirred at 38 °C for 3 hr. The reaction mixture was filtered and concentrated to give the title compound (Intermediate 37, 172 mg), which was used in the next step without further purification. MS: m / z = 398.1 [M + H]+.

[0276] Intermediate 38: 2-(4-(Chloromethyl)phenyl)-3-phenylquinoline-6-carboxamideStep 1 : (4-(6-Bromo-3-phenylquinolin-2-yl)phenyl)methanolTo a solution of l -(4-((( / c / 7-butyldimethylsilyl)oxy)methyl)phenyl)-2-phenylethan- l -one (500 mg, 1.47 mmol, refer to Intermediate 1 for detail procedures) in EtOH (10 mL) were added 2- amino-5-bromobenzaldehyde (294 mg, 1.47 mmol) and KOH (98.9 mg, 1.76 mmol). The reaction mixture was stirred at 100 °C for 3 hr under N2. The reaction mixture was concentrated. After purification by silica gel flash chromatography (Eluent of 10% ~ 80% EtOAc in hexane), the title compound (240 mg, yield: 42%) was obtained. MS: m / z = 389.9, 391.9 [M + H]+. ' H NMR (400 MHz, Dimethylsulfoxide-t / 6) 8 8.40 (s, 1H), 8.35 (d, J= 2.0 Hz, 1H), 8.05 - 7.99 (m, 1H), 7.91 (dd, J= 9.2, 2.4 Hz, 1H), 7.37 - 7.31 (m, 5H), 7.29 - 7.25 (m, 2H), 7.23 (d, J= 8.4 Hz, 2H), 5.24 (t, J= 6.0 Hz, 1H), 4.49 (d, J= 6.0 Hz, 2H).Step 2: Methyl 2-(4-(hydroxymethyl)phenyl)-3-phenylquinoline-6-carboxylateTo a mixture of (4-(6-bromo-3-phenylquinolin-2-yl)phenyl)methanol (297 mg, 762 pmol) in MeOH (10 mL) were added TEA (2.29 mmol, 318 pL) and Pd(dppf)C12 (167 mg, 229 pmol). The reaction mixture was degassed, purged with CO three times, and stirred under CO (50 Psi) at 80 °C for 12 hr. The mixture was concentrated. After purification by silica gel flash chromatography (Eluent of 40% ~ 70% EtOAc in hexane), the title compound (220 mg, yield: 78%) was obtained. MS: m / z = 370.0 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide- e) 6 8.77 (s, 1H), 8.61 (s, 1H), 8.27 - 8.22 (m, 1H), 8.19 - 8.13 (m, 1H), 7.39 - 7.33 (m, 5H), 7.31 - 7.27 (m, 2H), 7.24 (d, J= 8.0 Hz, 2H), 5.23 (t, J= 6.0 Hz, 1H), 4.50 (d, J= 6.0 Hz, 2H), 3.95 (s, 3H).Step 3 : 2-(4-(Hydroxymethyl)phenyl)-3-phenylquinoline-6-carboxamideA mixture of methyl 2-(4-(hydroxymethyl)phenyl)-3-phenylquinoline-6-carboxylate (220 mg, 596 pmol) in NHLMeOH (7 M, 12 mL) in a 100 mL autoclave was stirred at 55 °C for 36 hr under 15 psi. The reaction mixture was concentrated. After purification by silica gel flash chromatography (Eluent of 2% ~ 10% MeOH in CH2CI2), the title compound (140 mg, yield: 66%) was obtained. MS: m / z = 355.0 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide- e) 6 8.60 (s, 1H), 8.41 (s, 1H), 8.26 - 8.18 (m, 2H), 8.11 (d, J= 8.8 Hz, 1H), 7.62 - 7.55 (m, 1H), 7.38 - 7.33 (m, 5H), 7.31 - 7.28 (m, 2H), 7.24 (d, J= 8.4 Hz, 2H), 5.22 (t, J= 6.0 Hz, 1H), 4.50 (d, J = 6.0 Hz, 2H).Step 4: 2-(4-(Chloromethyl)phenyl)-3-phenylquinoline-6-carboxamideTo a solution of 2-(4-(hydroxymethyl)phenyl)-3-phenylquinoline-6-carboxamide (140 mg, 395 pmol) in CH2CI2 (5 mL) was added SOCI2 (1.19 mmol, 86.1 pL). The reaction mixture was stirred at 20 °C for 1 hr. The reaction mixture was concentrated to give the title compound (Intermediate 38, 147 mg), which was used in the next step directly. MS: m / z = 373.0 [M + H]+.

[0277] Intermediate 39: Ethyl 2-chloro-8-fluoro-3-phenyl-l,6-naphthyridine-7-carboxylateStep 1 : Ethyl (£)-3-(4-amino-6-chloro-5-fluoropyridin-3-yl)acrylateTo a solution of 2-chl oro-3 -fluoro-5-iodopyridin-4-amine (3 g, 11.01 mmol) and ethyl (E)-3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)acrylate (3.24 g, 14.31 mmol) in DME (45 mL) and H2O (15 mL) were added Pd(PPhs)4 (1.27 g, 1.10 mmol) and Na2COs (2.33 g, 22.02 mmol) under N2. The suspension was degassed, purged with N2 three times, and stirred under N2 at 100 °C for 3 hr. The reaction was filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 15% EtOAc in petroleum ether), the title compound (2.45 g, yield: 68%) was obtained. MS: m / z = 244.9, 247.0 [M + H]+.Step 2: 7-Chloro-8-fluoro-l,6-naphthyridin-2-olTo a solution of ethyl (E)-3-(4-amino-6-chloro-5-fluoro-2-methylpyridin-3-yl)acrylate (2.45 g, 10.01 mmol) in EtOH (25 mL) was added EtONa (1.02 g, 15.02 mmol). The mixture was stirred at 80 °C for 2 hr. The reaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with EtOAc (25 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (1.15 g, yield: 58%). MS: m z = 198.9, 200.9 [M + H]+.XH NMR (400 MHz, Dimethylsulfoxide-d6) 8 12.47 (br s, 1H), 8.55 (s, 1H), 8.05 (dd, J= 1.6, 9.6 Hz, 1H), 6.66 (d, J = 10.0 Hz, 1H).19F NMR (400 MHz, Dimethylsulfoxide-d2) 6 -138.260.Step 3: 3-Bromo-7-chloro-8-fluoro-l,6-naphthyridin-2-olTo a solution of 7-chloro-8-fluoro-l,6-naphthyridin-2-ol (1.15 g, 5.79 mmol) in DMF (15 mL) was added NBS (6.18 g, 34.75 mmol). The mixture was stirred at 80 °C for 24 hr. The reaction mixture was quenched with H2O (200 mL) at 25 °C and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 17% EtOAc in petroleum ether), the title compound (1.75 g, yield: 55%) was obtained. MS: m / z = 276.8, 278.8 [M + H]+.XH NMR (400 MHz,Dimethylsulfoxide-d6) 6 13.14 - 12.84 (m, 1H), 8.69 - 8.62 (m, 1H), 8.56 - 8.52 (m, 1H).19F NMR (400 MHz, Dimethylsulfoxide-^) 5 -130.464, -131.290, -137.421, -138.262.Step 4: 7-Chloro-8-fluoro-3-phenyl-l,6-naphthyridin-2-olTo a solution of 3-bromo-7-chloro-8-fluoro-l,6-naphthyridin-2-ol (620 mg, 2.23 mmol) and phenylboronic acid (299.7 mg, 2.46 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) were added K3PO4 (1.42 g, 6.70 mmol) and Pd(dppf)C12 (164 mg, 223 pmol) under N2. The suspension was degassed and purged with N2 three times. The mixture was stirred at 80 °C for 3 hr under N2. The reaction mixture was quenched with H2O (100 mL) at 25 °C and extracted with EtOAc (50mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 18% EtOAc in petroleum ether), the title compound (238 mg, yield: 34%) was obtained.276.9 [M + H]+. 'HNMR (400MHz, Dimethylsulfoxide-d6) 5 12.68 (br s, 1H), 8.61 (s, 1H), 8.25 (br s, 1H), 7.73 (br d, J= 6.8 Hz, 2H), 7.49 - 7.42 (m, 3H).19F NMR (400 MHz, Dimethylsulfoxide-d2) 8 -138.327, -144.653. Step 5: Ethyl 8-fluoro-2-hydroxy-3-phenyl-l,6-naphthyridine-7-carboxylateTo a solution of 7-chloro-8-fluoro-3-phenyl-l,6-naphthyridin-2-ol (238 mg, 887 pmol) in EtOH (3 mL) were added Pd(dppf)C12 (127 mg, 173 pmol) and TEA (263 mg, 2.60 mmol) under N2. The suspension was degassed, purged with CO three times, and stirred under CO (50 psi) at 80 °C for 48 hr. The reaction was filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 38% EtOAc in petroleum ether), the title compound (260 mg, yield: 73%) was obtained. MS: m / z = 313.0 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) 6 912.72 (br s, 1H), 8.81 (s, 1H), 8.34 - 8.28 (m, 1H), 7.81 - 7.72 (m, 2H), 7.50 - 7.43 (m, 3H), 4.39 (q, J= 7.2 Hz, 2H), 1.34 (t, J= 7.2 Hz, 3H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 6 -137.884.Step 6: Ethyl 2-chloro-8-fluoro-3-phenyl-l,6-naphthyridine-7-carboxylateTo a solution of ethyl 8-fluoro-2-hydroxy-3-phenyl-l,6-naphthyridine-7-carboxylate (200 mg, 640 pmol) in POCI3 (3 mL) was stirred at 100 °C for 3 hr. The reaction mixture was poured into H2O (40 mL) at 25 °C. The pH of the mixture was adjusted to about 7 with aq. NaHCCL. The mixture was extracted with CH2Q2 (50 mL x 2). The organic phase were dried over anhydrous Na2SO4, filtered, and concentrated under reduce pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 30% EtOAc in petroleum ether), the title compound (Intermediate 39, 120 mg, yield: 53%) was obtained. MS: m / z = 331.0, 333.0 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d2) 6 9.36 (s, 1H), 8.84 (d, J= 1.6 Hz, 1H), 7.66 - 7.61 (m,2H), 7.61 - 7.52 (m, 3H), 4.45 (q, J= 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H).19F NMR (400 MHz, DimethylsulfoxidesL) 6 -133.759.

[0278] Intermediate 40: 4-Amino-6-chloro-5-fluoronicotinaldehydeStep 1 : (4-Amino-6-chloro-5-fluoropyridin-3-yl)methanolA solution of ethyl 4-amino-6-chloro-5-fluoronicotinate (5 g, 22.87 mmol) in THF (50 mL) was degassed and purged with N2 three times. To the mixture was added LAH in THF (2.5 M, 10.98 mL) at 0 °C under N2. The mixture was stirred at 25 °C for 1 hr under N2. The reaction mixture was quenched with Na2SO4' l OH2O (10 g) at 0 °C, filtered, and concentrated under reduced pressure to give the title compound (4 g, yield: 98%). MS: m / z = 177.1, 179.1 [M + H]+. 'H NMR (400 MHz, Chloroformd6) 5 7.73 (s, 1H), 6.33 (br s, 2H), 5.21 (t, J= 5.6 Hz, 1H), 4.42 (d, J= 5.6 Hz, 2H).19F NMR (400 MHz, Chloroformd6) 5 -145.966.Step 2: 4-Amino-6-chloro-5-fluoronicotinaldehydeA solution of (4-amino-6-chloro-5-fluoropyridin-3-yl)methanol (4 g, 22.65 mmol) in THF (15 mL) and CH2CI2 (30 mL) was degassed and purged with N2 three times. To the mixture was added PCC (12.21 g, 56.63 mmol) at 0 °C under N2. The resulting mixture was stirred at 25 °C for 3 hr. The reaction mixture was filtered and washed with CH2Q2 (300 mL x 2). The filtrate was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0%~27% EtOAc in hexanes), the title compound (Intermediate 40, 3.12 g, yield: 76%) was obtained. MS: m / z = 175.0, 176.9 [M + H]+. ' H NMR (400 MHz, DimethylsulfoxidesL) 5 9.95 (d, J= 2.0 Hz, 1H), 8.36 (s, 1H), 7.96 (br s, 2H).19F NMR (400 MHz, Dimethylsulfoxide- d / ) 8 -144.015.

[0279] Intermediate 41 : 2-(4-(Chloromethyl)phenyl)-8-methoxy-3-phenyl-l,6-naphthyridine-7- carb oxami deStep 1 : 2-(4-(((tert-butyl dimethylsilyl)oxy)methyl)phenyl)-7-chloro-8-fluoro-3-phenyl- l ,6- naphthyridineTo a solution of l -(4-((( / c / 7-butyldimethylsilyl)oxy)methyl)phenyl)-2-phenylethan- l -one (5.5 g, 16.15 mmol, refer to Intermediate 1 for detail procedures) and Intermediate 40 (3.10 g, 17.77 mmol) in z-PrOH (100 mL) was added K2CO3 (11.16 g, 80.76 mmol). The mixture was stirred at 80 °C for 16 hr. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (200mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0%~8% EtOAc in hexanes), the title compound (3.66 g, yield: 40%) was obtained. MS: m / z = 979.2, 982.6 [2M + Na]+.1H NMR (400 MHz, Chloroform^ / ) 5 8.94 (s, 1H), 8.28 (d, J= 1.6 Hz, 1H), 7.46 (d, J= 8.0 Hz, 2H), 7.37 - 7.30 (m, 3H), 7.26 - 7.21 (m, 4H), 4.74 (s, 2H), 0.96 - 0.90 (m, 9H), 0.15 - 0.03 (m, 6H).19F NMR (400 MHz, Chloroformd6) 5 -133.267.Step 2: Methyl 2-(4-((( / ez7-butyldimethylsilyl)oxy)methyl)phenyl)-8-fluoro-3-phenyl-l,6- naphthyridine-7-carboxylateTo a solution of 2-(4-((( / er / -butyldimethylsilyl)oxy)methyl)phenyl)-7-chloro-8-fluoro-3-phenyl- 1,6-naphthyridine (3.66 g, 7.64 mmol) in EtOH (40 mL) were added Pd(dppf)C12 (1.12 g, 1.53 mmol) and TEA (2.32 g, 22.92 mmol) under N2. The suspension was degassed, purged with CO three times, and stirred under CO (50 psi) at 80 °C for 48 hr. The reaction was filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 25% EtOAc in hexanes), the title compound (2.79 g, yield: 65%) was obtained. MS: m / z =517.1 [M + H]+. 'HNMR (400 MHz, Chloroform^ / ) 5 9.18 (s, 1H), 8.33 (s, 1H), 7.48 (d, J= 8.0 Hz, 2H), 7.40 - 7.30 (m, 3H), 7.29 - 7.24 (m, 4H), 4.74 (s, 2H), 4.57 (q, J= 7.2 Hz, 2H), 1.49 (t, J= 7.2 Hz, 3H), 0.93 (s, 9H), 0.08 (s, 6H).19F NMR (400 MHz, Chloroform^ / ) 5 - 130.295.Step 3: 2-(4-(Hydroxymethyl)phenyl)-8-methoxy-3-phenyl-l,6-naphthyridine-7-carboxylic acid To a solution of ethyl 2-(4-(((terLbutyldimethylsilyl)oxy)methyl)phenyl)-8-fluoro-3-phenyl-l,6- naphthyridine-7-carboxylate (100 mg, 194 pmol) in MeOH (3 mL) was added NaOMe (16 mg, 290 pmol). The mixture was stirred at 60 °C for 16 hr. The pH of the reaction mixture was adjusted to about 4 with aq. HC1 (1 N). The mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with aq. NaCl (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (70 mg, yield: 68%). MS: m / z = 387.0 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d2) 8 13.63 - 12.58 (m, 1H), 9.19 (s, 1H), 8.67 (s, 1H), 7.43 - 7.27 (m, 9H), 5.24 (br t, J= 5.2 Hz, 1H), 4.51 (br d, J= 4.8 Hz, 2H), 4.26 (s, 3H).Step 4: 2-(4-(Hydroxymethyl)phenyl)-8-methoxy-3-phenyl-l,6-naphthyridine-7-carboxamide To a solution of 2-(4-(hydroxymethyl)phenyl)-8-methoxy-3-phenyl-l,6-naphthyridine-7- carboxylic acid (70 mg, 181 pmol) in DMF (2 mL) were added NH4CI (29 mg, 543 pmol), DIEA (70 mg, 543 pmol), and HATU (103 mg, 272 pmol). The mixture was stirred at 25 °C for 3 hr. The reaction was filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 8% MeOH in CH2Q2), the title compound (70 mg, yield: 91%) was obtained. MS: m / z = 386.1 [M + H]+.Step 5: 2-(4-(Chloromethyl)phenyl)-8-methoxy-3-phenyl-l,6-naphthyridine-7-carboxamide To a solution of 2-(4-(hydroxymethyl)phenyl)-8-methoxy-3-phenyl-l,6-naphthyridine-7- carboxamide (70 mg, 182 pmol) in DCM (1 mL) was added SOCI2 (0.2 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (Intermediate 41, 73 mg), which was used in the next step directly. MS: m / z = 404.1, 406.1 [M + H]+.

[0280] Intermediate 42: 2-(4-(Chloromethyl)phenyl)-8-fluoro-5-methyl-3-phenyl-l,6- naphthyridine-7-carboxamideIntermediate 42Step 1 : 2-Chloro-3-fluoro-5-iodo-6-methylpyridin-4-amineA solution of 2-chl oro-3 -fluoro-6-methylpyridin-4-amine (920 mg, 5.73 mmol) and 4- methylbenzenesulfonic acid (49.3 mg, 286 pmol) in MeCN (20 mL) was degassed and purged with N2 three times. To the mixture was added NIS (1.55 g, 6.88 mmol). The mixture was stirred under N2 at 70 °C for 3 hr. The reaction mixture was quenched with H2O (50 mL) at 25 °C and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure.After purification by silica gel flash chromatography (Eluent of 0% ~ 10% EtOAc in petroleum ether), the title compound (1.45 g, yield: 87%) was obtained. MS: m / z =286.8, 288.9 [M + H]+.1H NMR (400 MHz, Chloroformd6) 5 4.87 (br s, 2H), 2.64 (s, 3H).19F NMR (400 MHz, Chloroform-t / ) 5 -142.318.Step 2: Ethyl (£)-3-(4-amino-6-chloro-5-fluoro-2-methylpyridin-3-yl)acrylateTo a solution of 2-chl oro-3 -fluoro-5-iodo-6-methylpyridin-4-amine (1.45 g, 5.06 mmol) and ethyl (£)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)acrylate (1.49 g, 6.58 mmol) in DME (30 mL) and H2O (10 mL) were added Pd(PPhs)4 (585 mg, 506 pmol) and ISfeCOs (1.07 g, 10.1 mmol). The mixture was degassed, purged with N2 three times, and stirred at 95 °C for 6 hr under N2. The reaction was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 8% EtOAc in petroleum ether), the title compound (655 mg, yield: 50%) was obtained. MS: m / z = 259.2, 261.2 [M + H]+. 'H NMR (400 MHz,Chloroform-t / ) 5 7.61 (d, J= 16.4 Hz, 1H), 6.31 (d, J= 16.4 Hz, 1H), 4.63 (br s, 2H), 4.33 - 4.25 (m, 2H), 2.43 (s, 3H), 1.38 - 1.32 (m, 3H).19F NMR (400 MHz, Chloroform^ / ) 5 -146.686.Step 3: 7-Chloro-8-fluoro-5-methyl-l,6-naphthyridin-2-olTo a solution of ethyl (E)-3-(4-amino-6-chloro-5-fluoro-2-methylpyridin-3-yl)acrylate (800 mg, 3.09 mmol) in EtOH (10 mL) was added sodium methanethiolate (130 mg, 1.85 mmol). The mixture was degassed, purged with N2 three times, and stirred at 25 °C for 2 hr under N2. The reaction was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 87% EtOAc in petroleum ether and 0% ~ 10% MeOH in CH2CI2), the title compound (600 mg, yield: 91%) was obtained. MS: m / z = 213.0, 215.0 [M + H]+.XH NMR (400 MHz, Dimethylsulfoxide-d2) 8 12.36 (br s, 1H), 8.13 - 8.01 (m, 1H), 6.62 (d, J= 10.0 Hz, 1H), 2.61 (s, 3H).19F NMR (400 MHz, Dimethylsulfoxide-d2) 6 -141.656.Step 4: 3-Bromo-7-chloro-8-fluoro-5-methyl-l,6-naphthyridin-2-olTo a solution of 7-chloro-8-fluoro-5-methyl-l,6-naphthyridin-2-ol (175 mg, 815 pmol) in DMF (4 mL) was added NBS (435 mg, 2.44 mmol). The mixture was degassed, purged with N2 three times, and stirred at 80 °C for 48 hr under N2. The reaction was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 20% EtOAc in petroleum ether), the title compound (83 mg, yield: 32%) was obtained. MS: m / z = 291.0, 293.0 [M + H]+.XH NMR (400 MHz, Dimethylsulfoxide-d2) 6 13.08 - 12.69 (m, 1H), 8.71 - 8.55 (m, 1H), 2.64 (s, 3H).Step 5: 7-Chloro-8-fluoro-5-methyl-3-phenyl-l,6-naphthyridin-2-olTo a solution of 3-bromo-7-chloro-8-fluoro-5-methyl-l,6-naphthyridin-2-ol (185 mg, 635 pmol) and phenylboronic acid (69.6 mg, 571 pmol) in 1,4-dioxane (5 mL) and H2O (1 mL) were added K3PO4 (404 mg, 1.90 mmol) and Pd(dppf)C12 (46.4 mg, 63.5 pmol). The mixture was degassed, purged with N2 three times, and stirred at 80 °C for 3 hr under N2. The reaction was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 16% EtOAc in petroleum ether), the title compound (100 mg, yield: 39%) was obtained. MS: m / z = 288.9, 290.9 [M + H]+. 'HNMR (400 MHz, Dimethylsulfoxide-d2) 6 12.58 (br s, 1H), 8.16 - 8.10 (m, 1H), 7.79 - 7.73 (m, 2H), 7.48 - 7.41 (m, 3H), 2.71 (s, 3H).Step 6: Ethyl 8-fluoro-2-hydroxy-5-methyl-3-phenyl-l,6-naphthyridine-7-carboxylateTo a solution of 7-chloro-8-fluoro-5-methyl-3-phenyl-l,6-naphthyridin-2-ol (100 mg, 346 pmol) in EtOH (5 mL) were added Pd(dppf)C12 (50.7 mg, 69.3 pmol) and TEA (105 mg, 1.04 mmol) under Ar. The suspension was degassed, purged with CO three times, and stirred under CO (50 psi) at 80 °C for 48 hr. The reaction was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 30% EtOAc in petroleum ether),the title compound (80 mg, yield: 54%) was obtained. MS: m / z = 327.0 [M + H]+.1H NMR (400 MHz, Chloroformd6) 5 9.41 - 9.21 (m, 1H), 7.99 (s, 1H), 7.76 - 7.71 (m, 2H), 7.52 - 7.47 (m, 3H), 4.58 - 4.48 (m, 2H), 2.84 (s, 3H), 1.49 - 1.44 (m, 3H).19F NMR (400 MHz, Chloroform-d) 5 -144.900.Step 7: Ethyl 2-chloro-8-fluoro-5-methyl-3-phenyl-l,6-naphthyridine-7-carboxylateA solution of ethyl 8-fluoro-2-hydroxy-5-methyl-3 -phenyl- l,6-naphthyridine-7-carboxylate (120 mg, 368 pmol) in POCI3 (1 mL) was stirred at 100 °C for 16 hr. The reaction mixture was poured into H2O (40 mL) at 30 °C. The pH of the mixture was adjusted to about 7 with aq. NaHCCL. The mixure was extracted with CH2Q2 (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduce pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 50% EtOAc in petroleum ether), the title compound (100 mg, yield: 69%) was obtained. MS: m / z = 345.0, 346.9 [M + H]+. ' H NMR (400 MHz, DimethylsulfoxidesL) 5 8.76 - 8.72 (m, 1H), 7.67 - 7.65 (m, 1H), 7.59 - 7.53 (m, 4H), 4.48 - 4.39 (m, 2H), 2.92 (s, 3H), 1.40 - 1.35 (m, 3H).19F NMR (400 MHz, DimethylsulfoxidesL) 5 -137.053.Step 8: Ethyl 8-fluoro-2-(4-(hydroxymethyl)phenyl)-5-methyl-3-phenyl-l,6-naphthyridine-7- carboxylateTo a solution of ethyl 2-chloro-8-fluoro-5-methyl-3-phenyl-l,6-naphthyridine-7-carboxylate (85 mg, 247 pmol) and (4-(hydroxymethyl)phenyl)boronic acid (37.5 mg, 247 pmol) in 1,4-dioxane (5 mL) and H2O (1 mL) were added CS2CO3 (241 mg, 740 pmol) and Pd(dppf)C12 (36.1 mg, 49.3 pmol). The mixture was degassed, purged with N2 three times, and stirred at 90 °C for 2 hr under N2. The reaction was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 30% EtOAc in petroleum ether), the title compound (55 mg, yield: 49%) was obtained. MS: m / z = 417.2 [M + H]+. 'H NMR (400 MHz, DimethylsulfoxidesL) 58.72 - 8.62 (m, 1H), 7.42 - 7.36 (m, 7H), 7.31 - 7.25 (m, 2H), 5.30 - 5.20 (m, 1H), 4.52 - 4.49 (m, 2H), 4.47 - 4.40 (m, 2H), 2.95 (s, 3H), 1.38 (t, J= 7.2 Hz, 3H).19F NMR (400 MHz, DimethylsulfoxidesL) 5 -136.941.Step 9: 8-Fluoro-2-(4-(hydroxymethyl)phenyl)-5-methyl-3-phenyl-l,6-naphthyridine-7- carb oxami deA solution of ethyl 8-fluoro-2-(4-(hydroxymethyl)phenyl)-5-methyl-3-phenyl-l,6-naphthyridine- 7-carboxylate (55 mg, 132 pmol) in NH3 (7 M in MeOH, 5 mL) was stirred at 50 °C for 16 hr. The reaction was concentrated under reduced pressure to give the title compound (51 mg). MS: m / z = 388.1 [M + H]+.Step 10: 2-(4-(Chloromethyl)phenyl)-8-fluoro-5-methyl-3-phenyl-l,6-naphthyridine-7-carboxamideTo a solution of 8-fluoro-2-(4-(hydroxymethyl)phenyl)-5-methyl-3-phenyl-l,6-naphthyridine-7- carboxamide (50 mg, 129 pmol) in CH2Q2 (2 mL) was added SOCI2 (0.1 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction was concentrated under reduced pressure to give the title compound (Intermediate 42, 52.4 mg). MS: m / z = 406.1, 408.0 [M + H]+.

[0281] Intermediate 43: 2-Amino-4-bromo-5-fluorobenzaldehydeTo a solution of (2-amino-4-bromo-5-fluorophenyl)methanol (2 g, 8.06 mmol) in EtOH (30 mL) H2O (5 mL) and AcOH (10 mL) was added Fe (2.25 g, 40.32 mmol). The resulting mixture was stirred at 80 °C for 1 hr. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0%~7% EtOAc in petroleum ether), the title compound (Intermediate 43, 250 mg, yield: 12%) was obtained. MS: m / z = 217.9, 219.9 [M + H]+. 'HNMR (400 MHz, Chloroform- d) 5 9.77 (s, 1H), 7.22 (dd, J= 8.0, 0.8 Hz, 1H), 6.89 (d, J= 5.2 Hz, 1H), 6.34 - 5.65 (m, 2H).19F NMR (400 MHz, Chloroformd6) 5 -123.848.

[0282] Intermediate 44: 2-(4-(Chloromethyl)phenyl)-6-fluoro-3-phenylquinoline-7- carb oxami deStep 1 : (4-(7-Bromo-6-fluoro-3-phenylquinolin-2-yl)phenyl)methanolTo a solution of l-(4-((( / er / -butyldimethylsilyl)oxy)methyl)phenyl)-2-phenylethan-l-one (330 mg, 969 pmol, refer to Intermediate 1 for detail procedures) and Intermediate 43 (232 mg, 1.07 mmol) in DMF (5 mL) was added K2CO3 (670 mg, 4.85 mmol). The mixture was stirred at 120 °C for 16 hr. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (25mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4,filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0%~17% EtOAc in petroleum ether), the title compound (85 mg, yield: 16%) was obtained. MS: m / z = 407.9, 409.9 [M + H]+. ' H NMR (400 MHz, Chloroform- d) 5 8.47 (d, J= 6.8 Hz, 1H), 8.09 (s, 1H), 7.54 (d, J= 8.4 Hz, 1H), 7.45 - 7.39 (m, 3H), 7.33 - 7.28 (m, 4H), 7.25 - 7.21 (m, 2H), 4.69 (s, 2H), 3.13 - 2.97 (m, 1H).19F NMR (400 MHz, Chloroform-t / ) 5 -108.319.Step 2: Methyl 6-fluoro-2-(4-(hydroxymethyl)phenyl)-3-phenylquinoline-7-carboxylate To a solution of (4-(7-bromo-8-fluoro-3-phenylquinolin-2-yl)phenyl)methanol (85 mg, 208 pmol) in MeOH (3 mL) was added Pd(dppf)C12 (30 mg, 42 pmol) and TEA (63 mg, 625 pmol) under N2. The suspension was degassed, purged with CO three times, and stirred under CO (50 psi) at 50 °C for 16 hr. The reaction was filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 27% EtOAc in petroleum ether), the title compound (48 mg, yield: 55%) was obtained. MS: m / z =388.1 [M + H]+. *HNMR (400 MHz, Chloroform-t / ) 5 8.88 (br d, J= 6.8 Hz, 1H), 8.13 (s, 1H), 7.56 (d, J= 10.8 Hz, 1H), 7.45 (d, J= 8.4 Hz, 2H), 7.36 - 7.31 (m, 3H), 7.31 - 7.28 (m, 2H), 7.26 - 7.22 (m, 2H), 4.70 - 4.69 (m, 2H), 4.02 (s, 3H).19F NMR (400 MHz, Chloroformd6) 5 -113.835.Step 3 : 6-Fluoro-2-(4-(hydroxymethyl)phenyl)-3-phenylquinoline-7-carboxamideA solution of methyl 6-fluoro-2-(4-(hydroxymethyl)phenyl)-3-phenylquinoline-7-carboxylate (48 mg, 124 pmol) in NH3 in MeOH (7 M, 3 mL) was stirred at 55 °C for 16 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (37 mg, yield: 67%), which was used in the next step directly. MS: m / z = 373.1 [M + H]+.Step 4: 2-(4-(Chloromethyl)phenyl)-6-fluoro-3-phenylquinoline-7-carboxamideTo a solution of 6-fluoro-2-(4-(hydroxymethyl)phenyl)-3-phenylquinoline-7-carboxamide (37 mg, 99 pmol) in DCM (1 mL) was added SOCI2 (0.1 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (Intermediate 44, 38 mg), which was used in the next step directly. MS: m / z = 391.2, 393.1 [M + H]+.

[0283] Intermediate 45: 4-(2,7-Diazaspiro[3.5]nonan-2-yl)pyrimidine-2-carbonitrileIntermediate 45 was prepared in a manner similar to Intermediate 2. MS: m / z = 230.0 [M + H]+.

[0284] Intermediate 46: 7-(4-((( / e / 7-Butyldimethylsilyl)oxy)methyl)phenyl)-6-phenyl-l,8- naphthyridine-2-carboxamideStep 1 : 7-Bromo-2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-3-phenyl-l ,8-naphthyridine To a mixture of l -(4-(((tertb- utyldimethylsilyl)oxy)methyl)phenyl)-2-phenylethan- l -one (1.55 g, 4.55 mmol, refer to Intermediate 1 for detail procedures) and 2-amino-6-bromonicotinaldehyde (1.01 g, 5.01 mmol) in z-PrOH (30 mL) was added K2CO3 (3.15 g, 22.8 mmol) at 25 °C. The reaction mixture was stirred at 80 °C for 24 hr under N2. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. After purification by silica gel flash chromatography (Eluent of 7 - 10% EtOAc in hexane), the title compound (1.05 g, yield: 46%) was obtained. MS: m / z = 504.9, 506.9 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d2) 8 9.84 (s, 1H), 8.57 (s, 1H), 8.48 (d, J= 8.4 Hz, 1H), 7.93 - 7.89 (m, 2H), 7.87 (d, J= 8.4 Hz, 1H), 7.39 (d, J= 8.0 Hz, 2H), 7.36 - 7.34 (m, 1H), 7.30- 7.28 (m, 1H), 7.25 (d, J= 8.0 Hz, 1H), 6.92 (d, J= 7.6 Hz, 1H), 4.72 (s, 2H), 0.89 (s, 9H), 0.06 (s, 6H). Step 2: Methyl 7-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-6-phenyl-l,8-naphthyridine- 2-carboxylateTo a mixture of 7-bromo-2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-3-phenyl-l,8- naphthyridine (1.05 g, 2.07 mmol) in MeOH (20 mL) were added Pd(dppf)C12 (454 mg, 620 pmol) and TEA (6.20 mmol, 863 pL). The reaction mixture was purged with CO three times and stirred under CO (50 Psi) at 80 °C for 12 hr. The reaction mixture was concentrated. After purification by silica gel flash chromatography (Eluent of 0 - 13% EtOAc in hexane), the title compound (170 mg, yield: 17%) was obtained. MS: m / z = 485.1 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d2) 6 8.72 (d, J= 8.4 Hz, 1H), 8.60 (s, 1H), 8.24 (d, J= 8.0 Hz, 1H), 7.42 (d, J= 8.0 Hz, 2H), 7.38 - 7.29 (m, 5H), 7.26 (d, J= 8.0 Hz, 2H), 4.73 (s, 2H), 3.99 (s, 3H), 0.89 (s, 9H), 0.06 (s, 6H).Step 3 : 7-(4-(((tert-butyl dimethylsilyl)oxy)methyl)phenyl)-6-phenyl- l ,8-naphthyridine-2- carboxamideA mixture of methyl 7-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-6-phenyl-l,8- naphthyridine-2-carboxylate (120 mg, 248 pmol) in NH3 (7M in MeOH, 3 mL) was stirred at 55 °C for 12 hr. The reaction mixture was concentrated to give the title compound (Intermediate 46, 100 mg, yield: 86%), which was used in the next step directly. MS: m / z = 470.1 [M + H]+.

[0285] Example 1 : 4-((l-(4-(3-Oxo-9-phenyl-2,3-dihydro-[l,2,4]triazolo[3,4- f] [ 1 ,6]naphthyridin-8-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileTo a solution of Intermediate 1 (34.5 mg, 81.4 pmol, HC1 salt) and Intermediate 2 (25.8 mg, 81.4 pmol, TFA salt) in DMF (3 mL) were added K2CO3 (56.3 mg, 407 pmol) and Nal (2.44 mg, 16.3 pmol). The mixture was stirred at 40 °C for 2 hr. The reaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with CH2Q2 (25 mL x 2). The combined organic layers were washed with brine (50 mL x 5), dried over , fNilate2rSedO4 and concentrated under reduced pressure. After purification by / i / c -HPLC (column: CD07-Daisogel SP-100-8-ODS-PK 150 x 25 x 10 pm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 35% - 55% B over 10 min), the title compound (16.7 mg, yield: 36% for three steps) was obtained as a yellow lyophilized powder. MS: m / z = 554.2 [M + H]+. 'HNMR (400 MHz, Dimethylsulfoxide-d2) 8 10.80 - 9.82 (m, 1H), 8.38 (s, 1H), 8.17 - 7.99 (m, 2H), 7.90 (d, J= 7.6 Hz, 1H), 7.36 - 7.27 (m, 7H), 7.24 - 7.19 (m, 2H), 6.96 (d, J= 7.6 Hz, 1H), 6.66 (d, J= 6.4 Hz, 1H), 3.85 - 3.67 (m, 1H), 3.47 (s, 2H), 2.81 - 2.70 (m, 2H), 2.13 - 2.01 (m, 2H), 1.89 - 1.77 (m, 2H), 1.51 - 1.38 (m, 2H).

[0286] Example 2: 4-(4-(4-(3-Oxo-9-phenyl-2,3-dihydro-[l,2,4]triazolo[3,4- f] [ 1 ,6]naphthyridin-8-yl)benzyl)piperazin- 1 -yl)pyrimidine-2-carbonitrileTo a solution of Intermediate 1 (114 mg, 269 pmol, HC1 salt) and Intermediate 3 (81. 7 mg, 269 pmol, TFA salt) in DMF (5 mL) were added K2CO3 (186 mg, 1.35 mmol) and Nal (8.07 mg, 53.9 pmol). The mixture was stirred at 40 °C for 2 hr. The reaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with CH2Q2 (25 mL x 2). The combined organic layers were washed with brine (50 mL x 5), dried over Na2SO4, filtered and concentrated under reducedpressure. After purification by prep-HPLC (column: CD02-Waters Xbidge BEH C18 150 x 25 x 10 pm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 24% - 54% B over 10 min), the title compound (Example 2, 7.8 mg, yield: 5.3%) was obtained as an off-white lyophilized powder. MS: m / z = 540.2[M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d2) 8 12.65 (br s, 1H), 8.38 (s, 1H), 8.25 (d, J= 6.4 Hz, 1H), 7.90 (d, J= 7.6 Hz, 1H), 7.36 - 7.31 (m, 5H), 7.30 - 7.23 (m, 4H), 7.10 (d, J= 6.4 Hz, 1H), 6.96 (d, J= 7.6 Hz, 1H), 3.75 - 3.59 (m, 4H), 3.52 (s, 2H), 2.45 - 2.39 (m, 4H).

[0287] Example 3: 4-((l-(4-(5-Oxo-3-phenyl-5,6-dihydro-l,6-naphthyridin-2- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 3 was prepared in a manner similar to Example 1. MS: m / z = 514.1 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d2) 6 11.77 - 11.34 (m, 1H), 8.38 (s, 1H), 8.13 - 7.98 (m, 2H), 7.49 (d, J= 7.2 Hz, 1H), 7.35 - 7.28 (m, 5H), 7.25 - 7.19 (m, 4H), 6.76 - 6.61 (m, 2H), 4.01 - 3.66 (m, 1H), 3.47 (s, 2H), 2.78 - 2.69 (m, 2H), 2.14 - 2.01 (m, 2H), 1.88 - 1.75 (m, 2H), 1.51 - 1.38 (m, 2H).

[0288] Example 4: 4-(4-(4-(5-Oxo-3-phenyl-5,6-dihydro-l,6-naphthyridin-2- yl)benzyl)piperazin-l-yl)pyrimidine-2-carbonitrileExample 4 was prepared in a manner similar to Example 2. MS: m / z = 500.2 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d2) 6 11.71 - 11.47 (m, 1H), 8.45 - 8.31 (m, 1H), 8.25 (d, J= 6.4 Hz, 1H), 7.52 - 7.46 (m, 1H), 7.35 - 7.29 (m, 5H), 7.28 - 7.22 (m, 4H), 7.10 (d, J= 6.4 Hz, 1H), 6.69 (d, J= 7.2 Hz, 1H), 3.77 - 3.57 (m, 4H), 3.52 (s, 2H), 2.45 - 2.37 (m, 4H).

[0289] Example 5: 4-(4-(4-(6-Phenyl-lJH-imidazo[4,5-g]quinoxalin-7-yl)benzyl)piperazin-l- yl)pyrimidine-2-carbonitrileExample 5 was prepared in a manner similar to Example 2. MS: m / z =524.2 [M + H]+.1H NMR (400 MHz, Dimethysulfoxide-d2) 8 13.07 - 12.62 (m, 1H), 8.67 (s, 1H), 8.38 - 8.17 (m, 3H), 7.52 - 7.44 (m, 4H), 7.40 - 7.29 (m, 5H), 7.10 (d, J = 6.4, 1H), 3.74 - 3.61 (m, 4H), 3.56 (s, 2H), 2.47 - 2.42 (m, 4H).

[0290] Example 6: 4-((l-(4-(6-Phenyl-1H-imidazo[4,5-g]quinoxalin-7-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrileExample 6 was prepared in a manner similar to Example 1. MS: m / z = 538.3 [M + H]+.1H NMR (400 MHz, Dimethysulfoxide-d2) 6 13.17 - 12.58 (m, 1H), 8.67 (s, 1H), 8.40 - 8.22 (m, 2H), 8.18 - 7.97 (m, 2H), 7.52 - 7.47 (m, 2H), 7.47 - 7.42 (m, 2H), 7.40 - 7.33 (m, 3H), 7.31 - 7.23 (m, 2H), 6.66 (d, J= 6.0 Hz, 1H), 3.87 - 3.72 (m, 1H), 3.51 (s, 2H), 2.88 - 2.72 (m, 2H), 2.18 - 2.02 (m, 2H), 1.94 - 1.79 (m, 2H), 1.55 - 1.39 (m, 2H).

[0291] Example 7: 2-(4-((4-((2-Cyanopyrimidin-4-yl)amino)piperidin-l-yl)methyl)phenyl)-3- phenylimidazo[l,2-b]pyridazine-6-carboxamideExample 7 was prepared in a manner similar to Example 1. MS: m / z = 530.2 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d2) 6 8.31 (d, J= 9.6 Hz, 1H), 8.13 - 8.00 (m, 2H), 7.94 - 7.87 (m, 1H), 7.73 (d, J= 9.6 Hz, 1H), 7.67 - 7.64 (m, 2H), 7.63 - 7.58 (m, 3H), 7.55 - 7.49 (m, 3H), 7.29 (d, J= 7.2 Hz, 2H), 6.66 (d, J= 6.4 Hz, 1H), 3.90 - 3.68 (m, 1H), 3.48 (s, 2H), 2.82 - 2.76 (m, 2H), 2.14 - 2.05 (m, 2H), 1.89 - 1.80 (m, 2H), 1.50 - 1.39 (m, 2H).

[0292] Example 8: 2-(4-((4-(2-Cyanopyrimidin-4-yl)piperazin-l-yl)methyl)phenyl)-3- phenylimidazo[l,2-b]pyridazine-6-carboxamideExample 8 was prepared in a manner similar to Example 2. MS: m / z = 516.2 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d2) 6 8.33 - 8.28 (m, 1H), 8.28 - 8.23 (m, 1H), 7.94 - 7.88 (m,1H), 7.73 (d, J= 9.2 Hz, 1H), 7.68 - 7.59 (m, 5H), 7.56 - 7.48 (m, 3H), 7.35 - 7.29 (m, 2H), 7.09 (d, J= 6.4 Hz, 1H), 3.76 - 3.59 (m, 4H), 3.53 (s, 2H), 2.47 - 2.40 (m, 4H).

[0293] Example 9: 4-((l-(4-(3-Phenylimidazo[l,2-b]pyridazin-2-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrileExample 9 was prepared in a manner similar to Example 1. MS: m / z = 487.1 [M + H]+.1H NMR (400 MHz, Dimethyl sulfoxide^) 8 8.48 (dd, J= 4.0, 1.6 Hz, 1H), 8.20 (dd, J= 9.2, 1.6 Hz, 1H), 8.12 - 7.98 (m, 2H), 7.64 - 7.57 (m, 2H), 7.55 - 7.48 (m, 5H), 7.31 - 7.25 (m, 3H), 6.71 - 6.63 (m, 1H), 3.86 - 3.71 (m, 1H), 3.46 (s, 2H), 2.82 - 2.75 (m, 2H), 2.14 - 2.04 (m, 2H), 1.91 - 1.80 (m, 2H), 1.49 - 1.39 (m, 2H).

[0294] Example 10: 4-(4-(4-(3-Phenylimidazo[l,2-b]pyridazin-2-yl)benzyl)piperazin-l- yl)pyrimidine-2-carbonitrileExample 10 was prepared in a manner similar to Example 1. MS: m / z =473.2 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d2) 6 8.48 (d, J= 4.0 Hz, 1H), 8.25 (d, J= 6.4 Hz, 1H), 8.20 (d, J= 9.6 Hz, 1H), 7.61 (d, J= 8.0 Hz, 2H), 7.57 - 7.49 (m, 5H), 7.32 - 7.26 (m, 3H), 7.09 (d, J= 6.4 Hz, 1H), 3.77 - 3.57 (m, 4H), 3.52 (s, 2H), 2.46 - 2.42 (m, 4H).

[0295] Example 11 : 3-Methoxy-4-((l-(4-(5-oxo-3-phenyl-5,6-dihydro-l,6-naphthyridin-2- yl)benzyl)piperidin-4-yl)amino)cy cl obut-3-ene- 1,2-dioneStep 1 : tert-Butyl (l-(4-(5-oxo-3-phenyl-5,6-dihydro-l,6-naphthyridin-2-yl)benzyl)piperidin-4- yl)carbamateTo a solution of Intermediate 6 (116 mg, 334 pmol) and tert-butyl piperidin-4-ylcarbamate (80.4 mg, 401 pmol) in DMF (3 mL) were added Nal (10.0 mg, 66.9 pmol) and K2CO3 (231 mg, 1.67 mmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with CH2Q2 (25 mL x 2). The combined organic layers were washed with brine (50 mL x 5), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 5% MeOH in CH2Q2), the title compound (120 mg, yield: 70%) was obtained as a yellow solid. MS: m / z = 511.1 [M + H]+. 'HNMR (400 MHz, Chloroformd6) 5 10.56 (br s, 1H), 8.68 (s, 1H), 7.43 - 7.32 (m, 3H), 7.30 - 7.26 (m, 3H), 7.25 - 7.20 (m, 4H), 6.91 (d, J= 7.6 Hz, 1H), 4.51 - 4.35 (m, 1H), 3.56 - 3.32 (m, 3H), 2.88 - 2.67 (m, 2H), 2.13 - 2.03 (m, 2H), 1.94 - 1.86 (m, 2H), 1.50 - 1.38 (m, 11H).Step 2: 2-(4-((4-Aminopiperidin-l-yl)methyl)phenyl)-3-phenyl-l,6-naphthyridin-5(6rt)-one To a solution of tert-butyl (l-(4-(5-oxo-3-phenyl-5,6-dihydro-l,6-naphthyridin-2- yl)benzyl)piperidin-4-yl)carbamate (120 mg, 235 pmol) in 1,4-dioxane (1 mL) was added HC1 in 1,4-dioxane (2 M,5 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was quenched with aqueous Na2COs (20 mL, adjusted to pH ~ 7) at 25 °C, and extracted with CH2Q2 (25 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The title compound (96 mg) was obtained as a yellow solid. MS: m / z = 411.0 [M + H]+.Step 3 : 3-Methoxy-4-((l-(4-(5-oxo-3-phenyl-5,6-dihydro-l,6-naphthyridin-2- yl)benzyl)piperidin-4-yl)amino)cy cl obut-3-ene- 1,2-dioneTo a solution of 2-(4-((4-aminopiperidin-l-yl)methyl)phenyl)-3-phenyl-l,6-naphthyridin-5(6rt)- one (50 mg, 122 pmol) in MeOH (1 mL) was added TEA (61.6 mg, 609 pmol) and 3,4- dimethoxycy cl obut-3-ene- 1,2-dione (20.8 mg, 146 pmol) at 0 °C. The mixture was stirred at 25 °C for 14 hr. The solid was collected by filtration, washed with MeOH (10 mL x 2) and ACN (10 mL), and concentrated under reduced pressure to give the title compound (Example 11, 41.3 mg, yield: 61% for two steps) as a light-yellow solid. MS: m / z = 521.2 [M + H]+.1H NMR (400 MHz, DimethylsulfoxidesL) 5 11.90 - 11.13 (m, 1H), 9.00 - 8.54 (m, 1H), 8.38 (s, 1H), 7.49 (d, J= 7.2 Hz, 1H), 7.33 - 7.29 (m, 5H), 7.25 - 7.18 (m, 4H), 6.68 (d, J= 7.2 Hz, 1H), 4.33 - 4.23 (m, 3H), 3.93 - 3.72 (m, 0.5H), 3.45 (s, 2H), 3.38 - 3.34 (m, 0.5H), 2.80 - 2.71 (m, 2H), 2.01 - 1.90 (m, 2H), 1.83 - 1.74 (m, 2H), 1.59 - 1.47 (m, 2H).

[0296] Example 17: A-(l-(4-(5-Oxo-3-phenyl-5,6-dihydro-l,6-naphthyridin-2- yl)benzyl)piperidin-4-yl)acrylamideTo a solution of 2-(4-((4-aminopiperidin-l-yl)methyl)phenyl)-3-phenyl-l,6-naphthyridin-5(6rt)- one (46 mg, 112 pmol, refer to Example 11 for detail procedures) in CH2Q2 (5 mL) were added TEA (56.7 mg, 560 pmol) and acryloyl chloride (10.1 mg, 112 pmol). The mixture was stirred at 0 °C for 0.5 hr. The reaction mixture was quenched with MeOH (0.2 mL) at 0 °C, dried over anhydrous Na2S,O fi4ltered and concentrated under reduced pressure. After purification by prep- TLC (SiO2, MeOH : CH2Q2 = 1 : 10), the title compound (Example 17, 24.2 mg, yield: 46%) was obtained as an off-white solid. MS: m / z = 465.2 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) 8 11.66 - 11.47 (m, 1H), 8.38 (s, 1H), 7.98 (d, J= 7.6 Hz, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.34 - 7.27 (m, 5H), 7.25 - 7.19 (m, 4H), 6.68 (d, J= 7.2 Hz, 1H), 6.26 - 6.15 (m, 1H), 6.10 - 6.01 (m, 1H), 5.59 - 5.51 (m, 1H), 3.66 - 3.55 (m, 1H), 3.44 (s, 2H), 2.78 - 2.69 (m, 2H), 2.04 - 1.96 (m, 2H), 1.77 - 1.67 (m, 2H), 1.45 - 1.34 (m, 2H).

[0297] Example 18: 2-(4-((7-Acryloyl-2,7-diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-3- phenylimidazo[l,2-Z>]pyridazine-6-carboxamideStep 1 : tert-Butyl 2-(4-(6-carbamoyl-3-phenylimidazo[l,2-Z>]pyridazin-2-yl)benzyl)-2,7- diazaspiro[3.5]nonane-7-carboxylateTo a solution of Intermediate 7 (169 mg, 422 pmol), tert-butyl 2,7-diazaspiro[3.5]nonane-7- carboxylate (122 mg, 464 pmol, HC1 salt) in DMF (3 mL) were added K2CO3 (292 mg, 2.11 mmol) and Nal (12.7 mg, 84.4 pmol). The mixture was degassed, purged with N2 three times, and stirred at 25 °C for 16 hr under N2. The reaction mixture was quenched with H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 8% MeOH in CH2Q2), the title compound (95 mg, yield: 41%) was obtained as a yellow solid. MS: m / z = 553.4 [M+H]+.Step 2: 2-(4-((2,7-Diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-3-phenylimidazo[l,2-Z>]pyridazine- 6-carboxamideTo a solution of tert-butyl 2-(4-(6-carbamoyl-3-phenylimidazo[l,2-Z>]pyridazin-2-yl)benzyl)-2,7- diazaspiro[3.5]nonane-7-carboxylate (89 mg, 161 pmol) in 1,4-di oxane (0.1 mL) was added HC1 in 1,4-di oxane (2 M, 2 mL). The mixture was degassed, purged with N2 three times, and stirred at 25 °C for 1 hr under N2. The reaction mixture was quenched with H2O (10 mL). The pH of the mixture was adjusted to 8 with sat. NaHCCL. The result mixture was extracted with CH2C12 / MeOH=10 / l (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (Example 18, 72.9 mg) as a yellow solid, which was used directly in the next step. MS: m / z = 453.1 [M+H]+. Step 3: 2-(4-((7-Acryloyl-2,7-diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-3-phenylimidazo[l,2- Z>]pyridazine-6-carboxamideTo a solution of 2-(4-((2,7-diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-3-phenylimidazo[l,2- Z>]pyridazine-6-carboxamide (78 mg, 172 pmol) and TEA (34.9 mg, 345 pmol) in CH2Q2 (5 mL) was added acryloyl chloride (17.2 mg, 190 pmol) in CH2CI2 (1 mL) dropwise in an ice bath. The mixture was degassed, purged with N2 three times, and stirred at 0 °C for 1 hr under N2. The reaction mixture was quenched with H2O (0.5 mL) at 0 °C, dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by / v -TLC (SiCL, CH2Q2: MeOH = 10: 1), the title compoud (Example 18, 27.6 mg, yield: 31% for two steps) was obtained as a yellow powder. MS: m / z = 507.3 [M+H]+. ' H NMR (400 MHz, Dimethylsulfoxide-d6) 5 8.30 (d, J= 9.6 Hz, 1H), 7.95 - 7.84 (m, 1H), 7.73 (d, J= 9.2 Hz, 1H), 7.66 - 7.63 (m, 2H), 7.59 - 7.49 (m, 6H), 7.28 - 7.23 (m, 2H), 6.78 (dd, J= 16.8, 10.4 Hz, 1H), 6.09 - 6.02 (m, 1H), 5.66 - 5.60 (m, 1H), 3.59 (s, 2H), 3.47 - 3.41 (m, 4H), 2.98 (s, 4H), 1.68 - 1.60 (m, 4H).

[0298] Example 19: 4-((l-(4-(3-Phenylquinoxalin-2-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrileTo a solution of Intermediate 2 (131 mg, 646 pmol) in DMF (3 mL) were added K2CO3 (325 mg, 2.35 mmol) and Nal (26.4 mg, 176 pmol). The mixture was stirred at 20 °C for 0.5 hr. Then Intermediate 9 (194 mg, 588 pmol) was added. The mixture was stirred at 20 °C for 12 hr. H2O (40 mL) was added. The aqueous layer was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous , filteredN anad2SO4concentrated. After purification by / i / c / i-HPLC (column: Welch Xtimate C18 150 x 30 mm x 5 pm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 62% - 92% B over 7 min), the title compound (Example 19, 146 mg, yield: 50%) was obtained as a white powder. MS: m / z = 498.2 [M + H]+.XH NMR (400 MHz, Dimethylsulfoxide-t / 6) 8 8.25 - 8.12 (m, 2H), 8.10 - 7.95 (m, 2H), 7.92 - 7.85 (m, 2H), 7.55 - 7.20 (m, 9H), 6.66 (d, J= 6.0 Hz, 1H), 3.90 - 3.70 (m, 1H), 3.50 (s, 2H), 2.85 - 2.70 (m, 2H), 2.18 - 2.00 (m, 2H), 1.91 - 1.72 (m, 2H), 1.55 - 1.40 (m, 2H).

[0299] Example 20: 2-(4-((7-Acryloyl-2,7-diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-3-phenyl- l,6-naphthyridin-5(6J7)-oneStep 1 : tert-Butyl 2-(4-(5-oxo-3-phenyl-5,6-dihydro-l,6-naphthyridin-2-yl)benzyl)-2,7- diazaspiro[3.5]nonane-7-carboxylateTo a solution of Intermediate 6 (233 mg, 608 pmol, HC1 salt) and tert-butyl 2,7- diazaspiro[3.5]nonane-7-carboxylate (208 mg, 790 pmol, HC1 salt) in DMF (4 mL) were added K2CO3 (420 mg, 3.04 mmol) and Nal (18.2 mg, 122 pmol). The mixture was stirred at 30 °C for 16 hr. The reaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with CH2Q2 (25 mL x 2). The combined organic layers were washed with brine (50 mL x 5), dried over anhydrous Na2,S fOilt4ered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 3% MeOH in CH2Q2), the title compound (180 mg, yield: 51%) was obtained as a yellow solid. MS: m / z = 537.2 [M + H]+.JH NMR (400 MHz, Chloroform-t / ) 59.47 - 9.25 (m, 1H), 8.69 (s, 1H), 7.44 - 7.38 (m, 2H), 7.36 - 7.32 (m, 1H), 7.32 - 7.29 (m, 3H), 7.26 - 7.19 (m, 4H), 6.90 (d, J= 7.6 Hz, 1H), 3.75 - 3.59 (m, 2H), 3.38 - 3.29 (m, 4H), 3.22 - 2.83 (m, 4H), 1.75 - 1.67 (m, 4H), 1.47 (s, 9H).Step 2: 2-(4-((2,7-Diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-3-phenyl-l,6-naphthyridin-5(6J7)- oneTo a solution of tert-butyl 2-(4-(5-oxo-3-phenyl-5,6-dihydro-l,6-naphthyridin-2-yl)benzyl)-2,7- diazaspiro[3.5]nonane-7-carboxylate (180 mg, 335 pmol) in 1,4-dioxane (1 mL) was added HC1 in 1,4-dioxane (2 M, 6 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixturewas quenched with Na2COs aqueous (20 mL, adjusted to pH ~ 7) at 25 °C, and extracted with CH2Q2 (25 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, 2-(4-((2,7- diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-3-phenyl-l,6-naphthyridin-5(6J7)-one (146 mg) was obtained as a yellow solid. MS: m / z = 437.2 [M + H]+.Step 3: 2-(4-((7-Acryloyl-2,7-diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-3-phenyl-l,6- naphthyridin-5(6J7)-oneTo a solution of 2-(4-((2,7-diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-3-phenyl-l,6- naphthyridin-5(6J7)-one (146 mg, 334 pmol) in CH2Q2 (10 mL) were added TEA (169 mg, 1.67 mmol) and acryloyl chloride (30.3 mg, 334 pmol). The mixture was stirred at 0 °C for 0.5 hr. The reaction mixture was quenched with MeOH (0.5 mL) at 0 °C, and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by / vc -TLC (SiO2, MeOH : CH2Q2 = 1 : 10), the title compound (Example 20, 85.3 mg, yield: 50% for two steps) was obtained as an off-white solid. MS: m / z = 491.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 8 11.70 - 11.31 (m, 1H), 8.37 (s, 1H), 7.49 (d, J= 7.6 Hz, 1H), 7.35 - 7.28 (m, 5H), 7.26 - 7.22 (m, 2H), 7.19 - 7.15 (m, 2H), 6.78 (dd, J= 16.4, 10.4 Hz, 1H), 6.68 (d, J= 7.6 Hz, 1H), 6.05 (dd, J= 16.4, 2.4 Hz, 1H), 5.65 - 5.60 (m, 1H), 3.56 (s, 2H), 3.45 - 3.40 (m, 4H), 2.97 - 2.91 (m, 4H), 1.68 - 1.58 (m, 4H).

[0300] Example 23: 2-(4-((4-((2-Cyanopyrimidin-4-yl)amino)piperidin-l-yl)methyl)phenyl)-A- methyl-3-phenylimidazo[l,2-Z>]pyridazine-6-carboxamideStep 1 : 2-(4-(((tert-Butyldimethylsilyl)oxy)methyl)phenyl)-A-methyl-3-phenylimidazo[l,2- Z>]pyridazine-6-carboxamideTo a solution of methyl 2-(4-(((terLbutyldimethylsilyl)oxy)methyl)phenyl)-3- phenylimidazo[l,2-Z>]pyridazine-6-carboxylate (500 mg, 1.06 mmol, refer to Intermediate 7 for detail procedures) in MeOH (5 mL) was added methanamine (1.09 g, 10.6 mmol, 30% purity in MeOH). The mixture was stirred at 50 °C for 6 hr. The reaction mixture was concentratedunder reduced pressure to give the title compound (499 mg) as a yellow solid, which was used directly in the next step. MS: m / z = 473.7 [M + H]+.Step 2: 2-(4-(Hydroxymethyl)phenyl)-7V-methyl-3-phenylimidazo[l,2-Z>]pyridazine-6- carboxamideTo a solution of 2-(4-(((terLbutyldimethylsilyl)oxy)methyl)phenyl)-A-methyl-3- phenylimidazo[l,2-Z>]pyridazine-6-carboxamide (499 mg, 1.06 mmol) in THF (5 mL) was added TBAF (1.58 mL, 1 M in THF). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with EtOAc (15 mL x 2). The combined organic layers were washed with brine (30 mL x 5), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (378 mg) as a yellow solid, which was used directly in the next step. MS: m / z = 359.1 [M + H]+.Step 3 : 2-(4-(Chloromethyl)phenyl)-7V-methyl-3-phenylimidazo[l,2-Z>]pyridazine-6-carboxamide To a solution of 2-(4-(hydroxymethyl)phenyl)-7V-methyl-3-phenylimidazo[l,2-Z>]pyridazine-6- carboxamide (378 mg, 1.06 mmol) in CH2Q2 (4 mL) was added SOCI2 (1 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (210 mg, yield: 53% for three steps) as a yellow solid, which was used directly in the next step. MS: m / z = 377.0, 378.9 [M + H]+.Step 4: 2-(4-((4-((2-Cyanopyrimidin-4-yl)amino)piperidin-l-yl)methyl)phenyl)-A-methyl-3- phenylimidazo[l,2-Z>]pyridazine-6-carboxamideTo a solution of 2-(4-(chloromethyl)phenyl)-7V-methyl-3-phenylimidazo[l,2-Z>]pyridazine-6- carboxamide (239 mg, 635 pmol) and Intermediate 2 (201 mg, 635 pmol, TFA salt) in DMF (3 mL) were added K2CO3 (439 mg, 3.17 mmol) and Nal (19.0 mg, 127 pmol). The mixture was degassed, purged with N2 three times, and stirred at 35 °C for 16 hr under N2. The reaction mixture was concentrated under reduced pressure. After purification by prep-HPLC (column: CD02-Waters Xbidge BEH C18 150 x 25 x 10 pm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 27% - 57% B over 10 min), the title compound (Example 23, 46.6 mg, yield: 13%) was obtained as a yellow lyophilized powder. MS: m / z = 544.2 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) 8 8.30 (d, J= 9.2 Hz, 1H), 8.23 (d, J= 4.4 Hz, 1H), 8.12 - 7.98 (m, 2H), 7.71 (d, J= 9.2 Hz, 1H), 7.66 - 7.62 (m, 2H), 7.61 - 7.49 (m, 5H), 7.33 - 7.24 (m, 2H), 6.66 (d, J = 6.0 Hz, 1H), 3.84 - 3.73 (m, 1H), 3.48 (s, 2H), 2.84 - 2.74 (m, 5H), 2.16 - 2.04 (m, 2H), 1.91 - 1.77 (m, 2H), 1.51 - 1.40 (m, 2H).

[0301] Example 27: 2-Hydroxy-4-(4-(4-(5-oxo-3-phenyl-5,6-dihydro-l,6-naphthyridin-2- yl)benzyl)piperazin-l-yl)benzaldehydeTo a solution of Intermediate 6 (116 mg, 303 pmol, HC1 salt) and Intermediate 10 (96.9 mg, 303 pmol, TFA salt) in DMF (5 mL) were added K2CO3 (209 mg, 1.51 mmol) and Nal (4.54 mg, 30.3 pmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with CH2CI2 (25 mL x 2). The combined organic layers were washed with brine (50 mL x 5), dried over anhydrous , filteredN aan2dSO4 concentrated under reduced pressure. After purification by prep-HPLC (column: CD02-Waters Xbidge BEH C18 150 x 25 x 10 pm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 33% - 63% B over 10 min), the title compound (Example 27, 75.6 mg, yield: 48%) was obtained as an off-white powder. MS: m / z = 517.2 [M + H]+.JH NMR (400 MHz, Dimethylsulfoxide-d6) 5 11.65 - 11.47 (m, 1H), 11.23 - 10.95 (m, 1H), 9.72 (s, 1H), 8.40 - 8.37 (m, 1H), 7.53 - 7.45 (m, 2H), 7.35 - 7.29 (m, 5H), 7.27 - 7.22 (m, 4H), 6.69 (d, J= 7.6 Hz, 1H), 6.58 (dd, J= 9.2, 2.0 Hz, 1H), 6.30 (d, J= 2.0 Hz, 1H), 3.51 (s, 2H), 3.41 - 3.35 (m, 4H), 2.47 - 2.41 (m, 4H).

[0302] Example 36: 2-(4-((3-Formyl-4-hydroxybenzamido)methyl)phenyl)-3- phenylimidazo[l,2-Z>]pyridazine-6-carboxamideStep 1 : 2-(4-(Aminomethyl)phenyl)-3-phenylimidazo[l,2-Z>]pyridazine-6-carboxamideTo a solution of Intermediate 7 (237 mg, 654 pmol) in THF (5 mL) were added NH3 H2O (1.64 g, 13.1 mmol, 28% purity), K2CO3 (271 mg, 1.96 mmol) and Nal (19.6 mg, 130 pmol). The mixture was degassed and purged with N2 three times and stirred at 25 °C for 16 hr under N2. The reaction mixture was quenched with H2O (20 mL) and extracted with C^CL / MeOH = 10 / 1 (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 9% MeOH in CH2Q2), the title compound (73 mg, yield: 32%) was obtained as a yellow solid. MS: m / z = 344.0 [M + H]+.XH NMR (400 MHz, Dimethylsulfoxide-d2) 8 8.30 (d, J= 9.2 Hz, 1H), 7.89 (br s, 1H), 7.73 (d, J= 9.2 Hz, 1H), 7.67 - 7.63 (m, 2H), 7.61 - 7.47 (m, 6H), 7.35 - 7.29 (m, 2H), 3.74 (s, 2H)Step 2: 2-(4-((3-Formyl-4-hydroxybenzamido)methyl)phenyl)-3-phenylimidazo[l,2-Z>]pyridazine-6-carboxamideA mixture of 3-formyl-4-hydroxybenzoic acid (34.6 mg, 208 pmol), EDCI (54.4 mg, 284 pmol), HOBt (38.4 mg, 284 pmol) and DIEA (97.9 mg, 757 pmol) in DMF (3 mL) was degassed, purged with N2 three times, and stirred at 25 °C for 30 min. Then 2-(4-(aminomethyl)phenyl)-3- phenylimidazo[l,2-Z>]pyridazine-6-carboxamide (65 mg, 189 pmol) was added. The result mixture was stirred at 25 °C for 2 hr under N2. The reaction mixture was filtered and concentrated under reduced pressure. After purification by prep-HPLC (column: CD07- Daisogel SP-100-8-ODS-PK 150 x 25 x 10 pm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 14% - 44% B over 10 min) and then purified by / ?re / ?-TLC(EtOAc / petroleum ether = 1 / 0), the title compound (Example 36, 2.6 mg, yield: 2.7%) was obtained as a yellow solid. MS: m / z = 492.1 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d2) 5 11.68 - 10.78 (m, 1H), 10.30 (s, 1H), 9.07 - 8.97 (m, 1H), 8.31 (d, J= 9.6 Hz, 1H), 8.26 - 8.22 (m, 1H), 8.05 - 7.99 (m, 1H), 7.90 (br s, 1H), 7.73 (d, J= 9.2 Hz, 1H), 7.67 - 7.63 (m, 2H), 7.62 - 7.58 (m, 3H), 7.56 - 7.48 (m, 3H), 7.31 - 7.28 (m, 2H), 7.00 (d, J= 8.8 Hz, 1H), 4.47 (d, J= 5.6 Hz, 2H).

[0303] Example 41 : 4-((l-(4-(5-Oxo-3-phenyl-5,6,7,8-tetrahydro-l,6-naphthyridin-2- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileTo a solution of Intermediate 13 (37 mg, 106 pmol) and Intermediate 2 (33.7 mg, 106 pmol, TFA salt) in DMF (1 mL) were added K2CO3 (73.3 mg, 530 pmol) and Nal (3.18 mg, 21.2 pmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with CH2Q2 (25 mL x 2). The combined organic layers were washed with brine (50 mL x 5), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by prep-HPLC (column: CD07-Daisogel SP-100-8-ODS-PK 150 x 25 x 10 pm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 26% - 56% B over 10 min), the title compound (Example 41, 34.1 mg, yield: 61% for two steps) was obtained as an off-white lyophilized powder. MS: m / z = 516.2 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 5 8.18 (s, 1H), 8.10 - 8.05 (m, 2H), 8.02 (d, J= 7.2 Hz, 1H), 7.32 - 7.25 (m, 5H), 7.21 - 7.17 (m, 4H), 6.66 (d, .7= 6.4 Hz, 1H), 3.83 - 3.70 (m, 1H), 3.57 - 3.51 (m, 2H), 3.45 (s, 2H), 3.16 - 3.10 (m, 2H), 2.78 - 2.70 (m, 2H), 2.11 - 2.02 (m, 2H), 1.91 - 1.78 (m, 2H), 1.53 - 1.38 (m, 2H).

[0304] Example 42: 2-(4-((4-(2-Cyanopyrimidin-4-yl)piperazin-l-yl)methyl)phenyl)-A-methyl- 3-phenylimidazo[l,2-Z>]pyridazine-6-carboxamideTo a solution of 2-(4-(chloromethyl)phenyl)-7V-methyl-3-phenylimidazo[l,2-Z>]pyridazine-6- carboxamide (50 mg, 133 pmol, refer to Example 23 for detail procedures), Intermediate 3 (44.3 mg, 146 pmol, TFA salt) in DMF (2 mL) were added K2CO3 (91.7 mg, 663 pmol) and Nal (4.0 mg, 26.5 pmol). The mixture was stirred at 35 °C for 16 hr. The reaction mixture was concentrated under reduced pressure. After purification by prep-HPLC (column: CD07- Daisogel SP-100-8-ODS-PK 150 x 25 x 10 pm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 32% - 62% B over 10 min), the title compound (Example 42, 16.2 mg, yield: 23%) was obtained as a yellow lyophilized powder. MS: m / z = 530.2 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) 8 8.31 (d, J= 9.6 Hz, 1H), 8.27 - 8.21 (m, 2H), 7.72 (d, J= 9.6 Hz, 1H), 7.66 - 7.62 (m, 2H), 7.61 - 7.58 (m, 2H), 7.57 - 7.50 (m, 3H), 7.35 - 7.28 (m, 2H), 7.09 (d, J= 6.8 Hz, 1H), 3.74 - 3.57 (m, 4H), 3.53 (s, 2H), 2.82 (d, J= 4.8 Hz, 3H), 2.47 - 2.42 (m, 4H).

[0305] Example 47 & 48: 4-((l-(4-(3-Phenylpyrido[3,4-Z>]pyrazin-2-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile & 4-((l-(4-(2-Phenylpyrido[3,4-Z>]pyrazin-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileStep 1 : Methyl 4-(3-phenylpyrido[3,4-Z>]pyrazin-2-yl)benzoate & methyl 4-(2-phenylpyrido[3,4- Z>]pyrazin-3 -yl)benzoateTo a mixture of pyridine-3,4-diamine (550 mg, 5.04 mmol) in EtOH (2 mL) was added methyl 4- (2-oxo-2-phenylacetyl)benzoate (1.49 g, 5.54 mmol, refer to Intermediate 5 for detail procedures). The mixture was stirred at 80 °C for 2 hr. The mixture was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 30% EtOAc in petroleum ether), the mixture of the title compounds (1.58 g, yield 92%) was obtained as a yellow solid. MS: m / z = 342.0 [M + H]+. H NMR (400 MHz, Dimethylsulfoxide- e) 5 9.59(s, 1H), 8.92 - 8.83 (m, 1H), 8.15 - 8.08 (m, 1H), 7.99 - 7.90 (m, 2H), 7.69 - 7.62 (m, 2H), 7.55 - 7.48 (m, 2H), 7.46 - 7.36 (m, 3H), 3.87 (s, 3H).Step 2: (4-(3-Phenylpyrido[3,4-Z>]pyrazin-2-yl)phenyl)methanol & (4-(2-phenylpyrido[3,4- Z>]pyrazin-3 -yl)phenyl)m ethanolTo a mixture of methyl 4-(3-phenylpyrido[3,4-Z>]pyrazin-2-yl)benzoate and methyl 4-(2- phenylpyrido[3,4-Z>]pyrazin-3-yl)benzoate (1.58 g, 4.63 mmol) in THF (15 mL) was slowly added LiAIT (2.5 M in THF, 3.70 mL) at 0 °C under N2. The mixture was stirred at 20 °C for 2 hr. The residue was quenched with Na2SO4 IOH2O in portions till no bubbles were formed. The result mixture was stirred at 20 °C for 20 min and filtered. The filter cake was washed with THF (30 mL x 2), and the combined filtrate was concentrated. After purification by silica gel flash chromatography (Eluent of 0% ~ 10% Methanol in CH2Q2), the title compounds (130 mg, yield: 9.0%) were obtained as a yellow solid. MS: m / z = 314.0 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d2) 8 9.57 - 9.51 (m, 1H), 8.91 - 8.81 (m, 1H), 8.11 - 8.03 (m, 1H), 7.54 - 7.51 (m, 2H), 7.50 - 7.46 (m, 2H), 7.43 - 7.37 (m, 3H), 7.33 - 7.29 (m, 2H), 5.33 - 5.24 (m, 1H), 4.55 - 4.51 (m, 2H).Step 3: 2-(4-(Chloromethyl)phenyl)-3-phenylpyrido[3,4-Z>]pyrazine & 3-(4- (chloromethyl)phenyl)-2-phenylpyrido[3,4-Z>]pyrazineTo a mixture of (4-(3-phenylpyrido[3,4-Z>]pyrazin-2-yl)phenyl)methanol and (4-(2- phenylpyrido[3,4-Z>]pyrazin-3-yl)phenyl)methanol (130 mg, 415 pmol) in CH2CI2 (2 mL) was added SOCI2 (90.4 pL, 1.24 mmol). The mixture was stirred at 20 °C for 0.5 hr and concentrated under reduced pressure to give the title compounds (137.65 mg) as a yellow solid and used for the next step directly. MS: m / z = 331.9, 333.9 [M + H]+.Step 4: 4-((l-(4-(3-Phenylpyrido[3,4-Z>]pyrazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2- carbonitrile & 4-((l-(4-(2-phenylpyrido[3,4-Z>]pyrazin-3-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrileTo a mixture of 2-(4-(chloromethyl)phenyl)-3-phenylpyrido[3,4-Z>]pyrazine and 3-(4- (chloromethyl)phenyl)-2-phenylpyrido[3,4-Z>]pyrazine (138 mg, 415 pmol) and Intermediate 2 (92.8 mg, 456 pmol) in DMF (4 mL) were added K2CO3 (344 mg, 2.49 mmol) and Nal (12.4 mg, 83.0 pmol). The mixture was stirred at 20 °C for 12 hr. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by / / ty -HPLC (column: Welch Xtimate C18 150 x 25mm x 5pm; mobile phase: [water (NH3H2O + NH4HCO3) - ACN]; gradient :47% - 77% B over 11 min) and SFC (column: ChiralPak IH, 250 x 50 mm, 10 pm; mobile phase: [CO2-EtOH(0.1%NH3H2O)]; B%:55%, isocratic elution mode), the title compound (Example 47, 31.3 mg, yield: 15 % for two steps) was obtained as a white solid and the other title compound (Example 48, 26.6 mg, yield: 13 % for two steps) was obtained as a white solid. Spectra for Example 47: MS: m / z = 499.2 [M + H]+. 'H NMR (400 MHz, Dimethyl sulfoxide-t / 6) 8 9.55 (s, 1H), 8.87 (d, J= 6.0 Hz, 1H), 8.14 - 7.96 (m, 3H), 7.52 - 7.49 (m, 2H), 7.49 - 7.45 (m, 2H), 7.43 - 7.36 (m, 3H), 7.33 - 7.26 (m, 2H), 6.66 (d, .7= 5.6 Hz, 1H), 3.91 - 3.66 (m, 1H), 3.51 (s, 2H), 2.82 - 2.72 (m, 2H), 2.15 - 2.04 (m, 2H), 1.92 - 1.78 (m, 2H), 1.52 - 1.39 (m, 2H). Spectra for Example 48: MS: m / z = 499.2 [M + H]+. 'HNMR (400 MHz, Dimethylsulfoxide-t / 6) 6 9.55 (s, 1H), 8.87 (d, J= 5.6 Hz, 1H), 8.14 - 7.96 (m, 3H), 7.52 - 7.49 (m, 2H), 7.49 - 7.43 (m, 3H), 7.41 - 7.36 (m, 2H), 7.33 - 7.28 (m, 2H), 6.66 (d, J= 6.8 Hz, 1H), 3.87 - 3.71 (m, 1H), 3.51 (s, 2H), 2.82 - 2.72 (m, 2H), 2.15 - 2.00 (m, 2H), 1.89 - 1.78 (m, 2H), 1.52 - 1.41 (m, 2H).

[0306] Example 53: l-(2-(4-(3-Phenylquinoxalin-2-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7- yl)prop-2-en- 1 -oneStep 1 : tert-Butyl 2-(4-(3-phenylquinoxalin-2-yl)benzyl)-2,7-diazaspiro[3.5]nonane-7- carb oxy lateTo a solution of Intermediate 9 (165 mg, 499 pmol) in DMF (2 mL) were added tert-butyl 2,7- diazaspiro[3.5]nonane-7-carboxylate (124 mg, 549 pmol), K2CO3 (276 mg, 2.00 mmol) and Nal (22.5 mg, 150 pmol). The mixture was stirred at 30 °C for 12 hr. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with H2O (30 mL x 4) and brine (30mL), dried over anhydrous , filterNeda2 anSdO4 concentrated. After purification by silica gel flash chromatography (Eluent of 0% ~ 5% MeOH in CH2Q2), the title compound (150 mg, 288 pmol, yield: 58%) was obtained as a yellow solid. MS: m / z = 521.5 [M + H]+. 'HNMR (400 MHz, Dimethylsulfoxide-t / 6) 6 8.20 - 8.10 (m, 2H), 7.91 - 7.85 (m, 2H), 7.50 - 7.31 (m, 7H), 7.24 (d, J= 7.6 Hz, 2H), 3.80 - 3.78 (m, 1H), 3.65 - 3.55 (m, 3H), 3.28 - 3.18 (m, 6H), 2.94 (s, 4H), 1.38 (s, 9H).Step 2: 2-(4-((2,7-Diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-3-phenylquinoxalineA mixture of tert-butyl 2-(4-(3-phenylquinoxalin-2-yl)benzyl)-2,7-diazaspiro[3.5]nonane-7- carboxylate (150 mg, 288 pmol) in 1,4-dioxane (2 mL) was added HCl / dioxane (2 M, 3 mL). The mixture was stirred at 20 °C for 12 hr and diluted with sat. NaHCCL (20 mL). The mixture was extracted with CH2CI2 (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. The title compound (121 mg, 288 pmol) was obtained as a yellow solid, which was used directly in the next step. MS: m / z = 421.1 [M + H]+.Step 3: l-(2-(4-(3-Phenylquinoxalin-2-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)prop-2-en-l-one To a solution of 2-(4-((2,7-diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-3-phenylquinoxaline (121 mg, 288 pmol) in CH2CI2 (15 mL) was added TEA (146 mg, 1.44 mmol) at 0°C. The mixture was degassed and purged with N2 three times. Acryloyl chloride (26.1 mg, 288 pmol) was added at 0°C. The mixture was stirred at 0 °C for 2 hr. The mixture was quenched with MeOH (0.5 mL) and stirred at 20 °C for 15 mins. The mixture was diluted with H2O (20 mL) and extracted with CH2Q2 (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. After purification by silica gel flash chromatography (Eluent of 0% ~ 8% MeOH in CH2Q2) and prep-TLC (C^CL / MeOH = 10 / 1), the title compound (Example 53, 37.5 mg, yield: 27% for two steps) was obtained as a white powder. MS: m / z = 475.1 [M + H]+. 'HNMR (400 MHz, Dimethyl sulfoxi de-t / r,) 5 8.18 - 8.12 (m, 2H), 7.91 - 7.85 (m, 2H), 7.52 - 7.35 (m, 7H), 7.25 (d, J= 7.6 Hz, 2H), 6.83 - 6.73 (m, 1H), 6.06 (dd, J= 16.4, 2.0 Hz, 1H), 5.67 - 5.57 (m, 1H), 3.61 (s, 2H), 3.44 (br s, 4H), 2.98 (s, 4H), 1.68 - 1.60 (m, 4H).

[0307] Example 54: 4-((l-(4-(l-Methyl-6-phenyl-1H-imidazo[4,5-g]quinoxalin-7- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileStep 1 : 7-(4-(Chloromethyl)phenyl)-l -methyl-6-phenyl-l -imidazo[4,5-g]quinoxalineTo a solution of Intermediate 14 (80 mg, 218 pmol) in DCM (0.8 mL) was added SOCh (77.9 mg, 655 pmol). The mixture was stirred at 25 °C for 0.5 hr under N2. The residue was concentrated to give the title compound (84 mg) as a yellow solid, which was used in the next step without further purification. MS: m / z = 385.0 , 387.0[M + H]+.Step 2: 4-((l-(4-(l-Methyl-6-phenyl-1H-imidazo[4,5-g]quinoxalin-7-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrileTo a solution of 7-(4-(chloromethyl)phenyl)-l-methyl-6-phenyl-1H-imidazo[4,5-g]quinoxaline (74 mg, 192 pmol) in DMF (1 mL) were added Intermediate 2 (43 mg, 212 pmol), Nal (5.77 mg, 38.5 pmol), and K2CO3 (160 mg, 1.15 mmol). The mixture was stirred at 30 °C for 4 hr under N2. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous , filtered Na2SO4 and concentrated. After purification by prep-HPLC (column: Welch Xtimate Cl 8 150 x 25mm x 5 pm; mobile phase: [water (NH3H2O + NH4HCO3) - ACN]; gradient: 29% - 59% B over 9 min), the title compound (Example 54, 63.5 mg, yield: 56% for two steps) was obtained as a light yellow solid. MS: m / z = 552.4 [M + H]+.JH NMR (400 MHz, Dimethylsulfoxide-de) 5 8.63 (s, 1H), 8.38 (s, 1H), 8.34 (s, 1H), 8.08 (d, J= 6.00 Hz, 1H), 8.04 (d, J= 7.6 Hz, 1H), 7. 53 - 7. 49 (m, 2H), 7.45 (d, J= 8.00 Hz, 2H), 7. 41 - 7. 35 (m, 3H), 7.29 (d, J= 8.00 Hz, 2H), 6.67 (d, J= 6.00 Hz, 1H), 4.01 (s, 3H), 3.79 (br s, 1H), 3.51 (s, 2H), 2. 82 - 2. 74 (m, 2H), 2. 14 - 2. 07 (m, 2H), 1. 90 - 1. 81 (m, 2H), 1. 51 - 1. 42 (m, 2H).

[0308] Example 55: 4-((l-(4-(l-Methyl-7-phenyl-1H-imidazo[4,5-g]quinoxalin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 55 was prepared in a manner similar to Example 54. MS: m / z = 552.3 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-t / 6) 8 8.61 (s, 1H), 8.38 (s, 1H), 8.31 (s, 1H), 8.08 (d, J= 5.2 Hz, 1H), 8.00 (d, J= 6.00 Hz, 1H), 7.50 (d, J= 7.60 Hz, 2H), 7.46 (d, J= 7.60 Hz, 2H), 7. 40 - 7. 34 (m, 3H), 7.29 (d, J= 7.6 Hz, 2H), 6.67 (d, J= 5.60 Hz, 1H), 4.01 (s, 3H), 3. 86 - 3. 72 (m, 1H), 3.52 (s, 2H), 2.78 (d, J= 12.0 Hz, 2H), 2. 15 - 2. 06 (m, 2H), 1.91 - 1.87 (m, 2H), 1. 54 - 1. 41 (m, 2H).

[0309] Example 56: 2-(4-((4-Acrylamidopiperidin-l-yl)methyl)phenyl)-3-phenylimidazo[l,2- b]pyridazine-6-carboxamideStep 1 : tert-Butyl (l-(4-(6-carbamoyl-3-phenylimidazo[l,2-b]pyridazin-2-yl)benzyl)piperidin-4- yl)carbamateTo a solution of Intermediate 7 (185 mg, 510 pmol) and tert-butyl piperidin-4-ylcarbamate (123 mg, 612 pmol) in DMF (5 mL) were added Nal (15.3mg, 102 pmol) and K2CO3 (352 mg, 2.55 mmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with CH2Q2 (25 mL x 2). The combined organic layers were washed with brine (50 mL x 5), dried over anhydrous , filterNeda2 anSdO c4oncentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 4% MeOH in CH2Q2), the title compound (140 mg, yield: 52%) was obtained as a yellow solid. MS: m / z = 527.1 [M + H]+.1H NMR (400 MHz, Chloroformd6) 58.11 (d, J= 9.6 Hz, 1H), 7.92 (d, J= 9.2 Hz, 1H), 7.71 - 7.64 (m, 2H), 7.62 - 7.57 (m, 2H), 7.54 - 7.47 (m, 3H), 7.32 - 7.26 (m, 2H), 7.14 - 7.08 (m, 1H), 5.63 - 5.49 (m, 1H), 4.56 - 4.34 (m, 1H), 3.60 - 3.40 (m, 3H), 2.94 - 2.75 (m, 2H), 2.18 - 2.06 (m, 2H), 1.94 - 1.89 (m, 2H), 1.47 - 1.40 (m, 11H).Step 2: 2-(4-((4-Aminopiperidin-l-yl)methyl)phenyl)-3-phenylimidazo[l,2-b]pyridazine-6- carboxamideTo a solution of tert-butyl (l-(4-(6-carbamoyl-3-phenylimidazo[l,2-b]pyridazin-2- yl)benzyl)piperidin-4-yl)carbamate (140 mg, 266 pmol) in 1,4-dioxane (1 mL) was added HC1 in 1,4-di oxane (2 M, 5 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was quenched with aqueous ISfeCCL (20 mL, adjusted pH to ~ 7) at 25 °C, and extracted with CH2Q2 (25 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2S,O fi4ltered and concentrated under reduced pressure. The title compound (113.3 mg) was obtained as a yellow solid. MS: m / z = 427.0 [M + H]+.Step 3 : 2-(4-((4-Acrylamidopiperidin-l-yl)methyl)phenyl)-3-phenylimidazo[l,2-b]pyridazine-6- carboxamideTo a solution of 2-(4-((4-aminopiperidin-l-yl)methyl)phenyl)-3-phenylimidazo[l,2- b]pyridazine-6-carboxamide (100 mg, 234 pmol) in CH2Q2 (5 mL) were added TEA (119 mg, 1.17 mmol) and acryloyl chloride (21.2 mg, 234 pmol) at 0 °C. The mixture was stirred at 0 °Cfor 0.5 hr. The reaction mixture was quenched with MeOH (0.5 mL) at 0 °C, concentrated under reduced pressure. After purification by / 'c -TLC (SiO2, MeOH : CH2Q2 = 1 : 10), the title compound (Example 56, 41.1 mg, yield: 36%) was obtained as a yellow powder. MS: m / z = 481.0 [M + H]+. 'HNMR (400 MHz, Dimethylsulfoxide-d2) 88.30 (d, J= 9.2 Hz, 1H), 7.99 (br d, J= 6.8 Hz, 1H), 7.89 (br s, 1H), 7.73 (d, J= 9.6 Hz, 1H), 7.68 - 7.49 (m, 8H), 7.31 - 7.24 (m, 2H), 6.28 - 6.15 (m, 1H), 6.11 - 6.00 (m, 1H), 5.55 (dd, J= 10.0, 2.0 Hz, 1H), 3.66 - 3.55 (m, 1H), 3.46 (s, 2H), 2.86 - 2.68 (m, 2H), 2.10 - 1.92 (m, 2H), 1.79 - 1.68 (m, 2H), 1.48 - 1.35 (m, 2H).

[0310] Example 57: 3-Phenyl-2-(4-((4-(vinylsulfonamido)piperidin-l- yl)methyl)phenyl)imidazo[l,2-b]pyridazine-6-carboxamideTo a solution of 2-(4-((4-aminopiperidin-l-yl)methyl)phenyl)-3-phenylimidazo[l,2- b]pyridazine-6-carboxamide (100 mg, 234 pmol, refer to Example 56 for detail procedures) in CH2Q2 (5 mL) were added TEA (119 mg, 1.17 mmol) and 2-chloroethane-l -sulfonyl chloride (38.2 mg, 234 pmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. The reaction mixture was quenched with MeOH (0.5 mL) at 0 °C and concentrated under reduced pressure. After purification by / 'c -TLC (SiO2, MeOH : CH2Q2 = 1 : 10), the title compound (Example 57, 30.5 mg, yield: 23%) was obtained as a yellow solid. MS: m / z = 517.0 [M + H]+. 'HNMR (400 MHz, Dimethylsulfoxide-d6) 68.30 (d, J= 9.6 Hz, 1H), 7.89 (br s, 1H), 7.73 (d, J= 9.2 Hz, 1H), 7.67 - 7.63 (m, 2H), 7.61 - 7.49 (m, 6H), 7.36 - 7.30 (m, 1H), 7.26 (d, J= 8.0 Hz, 2H), 6.73 (dd, J= 16.4, 10.0 Hz, 1H), 6.01 (d, J= 16.4 Hz, 1H), 5.90 (d, J= 10.0 Hz, 1H), 3.43 (s, 2H), 3.01 - 2.91 (m, 1H), 2.76 - 2.70 (m, 2H), 2.00 - 1.93 (m, 2H), 1.80 - 1.71 (m, 2H), 1.49 - 1.41 (m, 2H).

[0311] Example 58: 2-(4-((4-(3-Formyl-4-hydroxybenzamido)piperidin-l-yl)methyl)phenyl)-3- phenylimidazo[l,2-b]pyridazine-6-carboxamideA mixture of 3-formyl-4-hydroxybenzoic acid (39.0 mg, 234 pmol), EDCI (67.4 mg, 352 pmol), HOBt (47.5 mg, 352 pmol) and DIEA (121 mg, 938 pmol) in DMF (3 mL) was degassed and purged with N2 three times. The mixture was stirred at 25 °C for 30 min. Then 2-(4-((4- aminopiperidin- 1 -yl)methyl)phenyl)-3 -phenylimidazo[ 1 ,2-b]pyridazine-6-carboxamide (100 mg,234 pmol, refer to Example 56 for detail procedures) was added. The result mixture was stirred at 25 °C for 16 hr under N2. The reaction mixture was filtered. After purification by / i / c -HPLC (column: 2_Phenomenex Gemini Cl 8 70 x 40 mm x 3 pm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 11% - 41% B over 9 min), the tit...

Claims

1. CLAIMSWe claim:

1. A compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein,Ring A is an optionally substituted monocyclic, bicyclic, or tricyclic heteroaryl; w, x, y, and z are each independently N or C-R1; each R1is independently selected from H, D, halogen, or -CN;R2and R3are each independently H, D, halogen, -OH, -CN, or optionally substituted Cl- C6 alkyl; or R2and R3together form an oxo; or R2and R3join together to form a carbocycle or heterocycle;L is selected from -N(R4)-, -O-, or a divalent radical selected from:wherein the asterisk (*) indicates the bond towards the LCG; each R4is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl; each R25are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R25together form an oxo; or two independently selected R25join together to form a carbocycle or heterocycle; al is 0, 1, 2, 3, or 4; bl is 0, 1, 2, 3, or 4; cl is 1, 2, 3, or 4; dl is 1, 2, 3, or 4; el is 0, 1, 2, 3, or 4; fl is 0, 1, 2, 3, or 4; provided that e and f are not both 0; gl is 0, 1, 2, 3, or 4; provided that e and g are not both 0; hl is 0, 1, 2, 3, or 4; provided that gl and hl are not both 0; and provided that fl and hl are not both 0; p is 1, 2, 3, or 4; q is 0, 1, or 2; n is 0 or 1;LCG is a group selected from the group consisting of:Q2is O or S;Q3is a bond, O, S, N-R9a;R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R9is absent and Q3and L join together to form a heterocycle; andR9ais selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R9and R9ajoin together to form a heterocycle;(b)T1is N or C-R10;T2is N or C-R10;T3is N or C-R10;T4is N or C-R10;T5is O, S, orN-R11; each R10is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R11is hydrogen, or optionally substituted C1-C6 alkyl;T6is N or C-R12;T7is N or C-R12;T8is N or C-R12; each R12is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl;wherein each R13, R14, R15, and R16is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and(e) -C=N .

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (II), wherein Ring A is:wherein,R5is optionally substituted aryl, or optionally substituted heteroaryl;A1is selected from N, C-H, or C-R23;A2is selected from N, C-H, or C-R24;R21, R22, R23, and R24are independently selected from H, D, halogen, -OR26, -SR26, - N(R26)2, -CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -CO2R26,-CON(R26)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each R26is independently H or optionally substituted C1-C6 alkyl.

3. The compound of claim 2, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (Ila),4. The compound of claim 3, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A1is N.

5. The compound of claim 3 or 4, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A2is C-H.

6. The compound of claim 3, 4, or 5, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R21and R22are H.

7. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (III), wherein Ring A is:wherein,R5IS optionally substituted aryl, or optionally substituted heteroaryl;A1is selected from N, C-H, or C-R23;A2is selected from N, C-H, or C-R24;R21, R22, R23, and R24are independently selected from H, D, halogen, -OR26, -SR26, - N(R26)2, -CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -CO2R26, -CON(R26)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; andeach R26is independently H or optionally substituted C1-C6 alkyl.

8. The compound of claim 7, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (Illa),(Illa).

9. The compound of claim 8, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A1is N.

10. The compound of claim 8 or 9, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A2is C-H.

11. The compound of claim 8, 9, or 10, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R21and R22are H.

12. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (IV-i), wherein Ring A is:wherein,R5is optionally substituted aryl, or optionally substituted heteroaryl;A5is selected from N, C-H, or C-R29;A6is selected from N, C-H, or C-R30; each R37is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclyl;R29and R30are independently selected from H, D, halogen, -OR26, -SR26, -N(R26)2, -CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -CO2R26, -CON(R26)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R30and R37join together to form a C1-C6 alkylene;each R26is independently H or optionally substituted C1-C6 alkyl.

13. The compound of claim 12, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (IVa-i), wherein Ring A is:wherein,R5is optionally substituted aryl, or optionally substituted heteroaryl;A5is selected from N, C-H, or C-R29;A6is selected from N, C-H, or C-R30;R37is H or optionally substituted C1-C6 alkyl;R29and R30are independently selected from H, D, halogen, -OR26, -SR26, -N(R26)2, -CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -CO2R26, -CON(R26)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R30and R37join together to form a C1-C6 alkylene; each R26is independently H or optionally substituted C1-C6 alkyl.

14. The compound of claim 13, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (IVb-i),15. The compound of claim 14, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A5is C-H.

16. The compound of claim 14 or 15, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A6is C-H.

17. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (V), wherein Ring A is:wherein,R5is optionally substituted aryl, or optionally substituted heteroaryl;A1is selected from N, C-H, or C-R23;A2is selected from N, C-H, or C-R24;A3is selected from N, C-H, or C-R27;A4is selected from N, C-H, or C-R28;J1-!2- J3is selected from: -N=CH-N(R26)-; -N(R26)-CH=N-; -N=CH-O-; or -O-CH=N-;R23, R24, R27, and R28are independently selected from H, D, halogen, -OR26, -SR26, - N(R26)2, -CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -CO2R26, -CON(R26)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each R26is independently H or optionally substituted C1-C6 alkyl.

18. The compound of claim 17, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (Va),19. The compound of claim 18, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A1is N.

20. The compound of claim 18 or 19, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A2is N.

21. The compound of claim 18, 19, or 20, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A3is C-H.

22. The compound of claim 18, 19, 20, or 21, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A4is C-H.

23. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (Vl-i), wherein Ring A is:wherein,R5is optionally substituted aryl, or optionally substituted heteroaryl;A1is selected from N, C-H, or C-R23;A2is selected from N, C-H, or C-R24;A3is selected from N, C-H, or C-R27;A4is selected from N, C-H, or C-R28;A7is selected from N, C-H, or C-R31;A8is selected from N, C-H, or C-R32;R23, R24, R27, R28, R31, and R32are independently selected from H, D, halogen, -OR26, - SR26, -N(R26)2, -CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, - CO2R26, -CON(R26)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each R26is independently H, -OH, -©(optionally substituted C1-C6 alkyl), or optionally substituted C1-C6 alkyl.

24. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (VII), wherein Ring A is:wherein,R5is optionally substituted aryl, or optionally substituted heteroaryl;A1is selected from N, C-H, or C-R23;A2is selected from N, C-H, or C-R24;A9is selected from N, C-H, or C-R33;A10is selected from N, C-H, or C-R34;R23R24, R33anj R34arejnciepenciently selected from H, D, halogen, -OR26, -SR26, - N(R26)2, -CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -COzR26, -CON(R26)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; orR33and R34together form -(C(R36)2)tl-NHCO-(C(R36)2)t2-; tl is 0, 1, or 2; t2 is 0, 1, or 2; provided that at least one of tl or t2 is not 0; each R26is independently H or optionally substituted C1-C6 alkyl; and each R36is independently H, halogen, or optionally substituted C1-C6 alkyl.

25. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (VIII), wherein Ring A is:wherein,R5is optionally substituted aryl, or optionally substituted heteroaryl;A5is selected from N, C-H, or C-R29;A6is selected from N, C-H, or C-R30;A11is selected from N, C-H, or C-R35;R29, R30and R35are independently selected from H, D, halogen, -OR26, -SR26, -N(R26)2, - CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -COzR26, - CON(R26)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each R26is independently H or optionally substituted C1-C6 alkyl.

26. The compound of claim 25, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (Villa),(Vllla).

27. The compound of claim 26, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A5is C-H.

28. The compound of claim 26 or 27, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A6is C-H.

29. The compound of claim 26, 27, or 28, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A11is C-H.

30. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (IX), wherein Ring A is:wherein,R5is optionally substituted aryl, or optionally substituted heteroaryl;A1is selected from N, C-H, or C-R23;A2is selected from N, C-H, or C-R24;A12is selected from N-H, or CR38R39;A13is selected from N-H, or CR40R41;A14is selected from N-H, or CR42R43;A15is selected from N-H, or CR44R45;R23, R24, R38, R39, R40, R41, R42, R43, R44, and R45are independently selected from H, D, halogen, -OR26, -SR26, -N(R26)2, -CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -CO2R26, -CON(R26)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;R38and R39join to form an oxo;R39and R40join to form a bond;R40and R41join to form an oxo;R41and R42join to form a bond;R42and R43join to form an oxo;R43and R44join to form a bond;R44and R45join to form an oxo; and each R26is independently H or optionally substituted C1-C6 alkyl.

31. The compound of claim 30, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A12is C-H2.

32. The compound of claim 30, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A13is C-H2.

33. The compound of claim 30, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A14is C-H2.

34. The compound of claim 30, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A15is C-H2.

35. The compound of claim 30, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A12is N-H.

36. The compound of claim 30, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A13is N-H.

37. The compound of claim 30, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A14is N-H.

38. The compound of claim 30, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A15is N-H.

39. The compound of claim 30, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R38and R39join to form an oxo.

40. The compound of claim 30, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R39and R40join to form a bond.

41. The compound of claim 30, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R40and R41join to form an oxo.

42. The compound of claim 30, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R41and R42join to form a bond.

43. The compound of claim 30, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R42and R43join to form an oxo.

44. The compound of claim 30, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R43and R44join to form a bond.

45. The compound of claim 30, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R44and R45join to form an oxo.

46. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (X), wherein Ring A is:wherein,R5is optionally substituted aryl, or optionally substituted heteroaryl;A1IS selected from N, C-H, or C-R23;A2is selected from N, C-H, or C-R24; andR21, R22, R23, and R24are independently selected from H, D, halogen, -OR26, -SR26, - N(R26)2, -CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -CO2R26, -CON(R26)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

47. The compound of claim 46, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (Xa),48. The compound of claim 47, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A1is N.

49. The compound of claim 47 or 48, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A2is C-H.

50. The compound of claim 46, 47, 48, or 49, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R21and R22are H.

51. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R5is optionally substituted aryl.

52. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R5is optionally substituted phenyl.

53. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R5is optionally substituted heteroaryl.

54. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R5is optionally substituted pyridine.

55. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R2and R3are H.

56. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein n is 0.

57. The compound of any one of claims 1-56, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein n is 1.

58. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is selected from:

59. The compound of claim 58, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is:

60. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is selected from:

61. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is:

62. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is -N(R4)-.

63. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is selected from:

64. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is:Q1is O or S;Q2is O or S;Q3is a bond, O, S, N-R9a;R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R9is absent and Q3and L join together to form a heterocycle; andR9ais selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R9and R9ajoin together to form a heterocycle.

65. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is:T1is N or C-R10;T2is N or C-R10;T3is N or C-R10;T4is N or C-R10;T5is O, S, or N-R11; each R10is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; and each R11is hydrogen, or optionally substituted C1-C6 alkyl.

66. The compound of claim 65, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is:

67. The compound of claim 66, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is:

68. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is:

69. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is:T8is N or C-R12; each R12is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl.

70. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is:wherein each R13, R14, R15, and R16is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy.

71. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is -C=N.

72. The compound of any one of claims 1-71, or a pharmaceutically acceptable salt, solvate,* or deuteroisotope thereof, wherein L is:.

73. The compound of any one of claims 1-71, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is:

74. A compound, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, as described in Table 1.

75. A compound, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, as described in Table 2.

76. A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, as described in any one of claims 1-75 and a pharmaceutically acceptable excipient.

77. A method of preparing a pharmaceutical composition comprising mixing a compound, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, of any one of claims 1-75, and a pharmaceutically acceptable carrier.

78. A compound of any one of claims 1-75, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treatment of the human or animal body.

79. A compound of any one of claims 1-75, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treatment of cancer or neoplastic disease.

80. Use of a compound of any one of claims 1-75, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

81. A method of treating cancer in a patient in need thereof, comprising administering to the patient a compound as described in any one of claims 1-75, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof.

82. A method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound as described in any one of claims 1-75, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient.

83. A method of inhibiting an AKT1 enzyme comprising contacting the enzyme with a compound of any one of claims 1-75, wherein the AKT1 enzyme is contacted in an in vitro setting.

84. A method of inhibiting an AKT1 enzyme comprising contacting the enzyme with a compound of any one of claims 1-75, wherein the AKT1 enzyme is contacted in an in vivo setting.

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