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 MODULATORS CROSS-REFERENCE

[0001] This application claims the benefit of US Provisional Application No. 63 / 652,278 filed May28, 2024, which is incorporated by reference in its entirety herein. BACKGROUND

[0002] AKT is a protein kinase and mediates cell survival and proliferation by inhibiting pathwayswhich 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 saidinhibitory 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 apharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein, R is optionally substituted aryl, or optionally substituted heteroaryl; w, x, y, and z are each independently N or C-R1; each R1is independently H, D, halogen, -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 to form a carbocycle or heterocycle;R5and R6are each independently selected from the group consisting of H, D, -OR17, - SR17, -NH2, -CN, halogen, -CO2R17, CON(R17)2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R5and R6together form an oxo or thio; or R5and R6join to form an optionally substituted carbocycle or optionally substituted heterocycle; Z1is N or C-R7; Z2is N or C-R8; X1, X2, and X3are independently selected from O, S, N(R18), or C(R19)(R20), with the provision that X2and X3are not both O or S; R7, R8, R18, R19and R20are each independently selected from the group consisting of H, D, -OR17, -SR17, -NH2, -CN, halogen, -CO2R17, CON(R17)2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each R17is independently selected from H, optionally substituted C1-C6 alkyl; n is 0 or 1; m is 0, 1, 2, or 3; 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; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 0, 1, or 2; 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; and R9ais 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;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 #O$ &7hA '

[0005] One embodiment provides a compound having the structure of Formula (II), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein, R is optionally substituted aryl, or optionally substituted heteroaryl; w, x, y, and z are each independently N or C-R1; each R1is independently H, D, halogen, -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 to form a carbocycle or heterocycle; Z3is N or C-R22; X4is O or S; R21and R22are each independently selected from the group consisting of H, D, -OR17, -SR17, -NH2, -CN, halogen, -CO2R17, CON(R17)2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R17is selected from H, optionally substituted C1-C6 alkyl; n is 0 or 1; 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; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 0, 1, or 2; LCG is a group selected from the group consisting of: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; and R9ais 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;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 #O$ &7hA '

[0006] One embodiment provides a compound having the structure of Formula (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein, R is optionally substituted aryl, or optionally substituted heteroaryl; w, x, y, and z are each independently N or C-R1; each R1is independently H, D, halogen, -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 to form a carbocycle or heterocycle; Z4is N or C-R24; X5is O or S; R23and R24are each independently selected from the group consisting of H, D, -OR17, -SR17, -NH2, -CN, halogen, -CO2R17, CON(R17)2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R17is selected from H, optionally substituted C1-C6 alkyl;n is 0 or 1; 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; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 0, 1, or 2; LCG is a group selected from the group consisting of: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; and R9ais 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;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

[0007] One embodiment provides a pharmaceutical composition comprising a compound of Formula(I)-(III), or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and at least one pharmaceutically acceptable excipient.

[0008] One embodiment provides a method of treating a disease or disorder in a patient in needthereof comprising administering to the patient a compound of Formula (I)-(III), or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof. Another embodiment provides the method wherein the disease or disorder is cancer. INCORPORATION BY REFERENCE

[0009] All publications, patents, and patent applications mentioned in this specification are hereinincorporated by reference for the specific purposes identified herein. DETAILED DESCRIPTION OF THE INVENTION

[0010] As used herein and in the appended claims, the singular forms "a," "and," and "the" includeplural 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 anycomposition of matter, composition, method, or process, or the like, described herein, "consist of" or "consist essentially of" the described features. Definitions

[0011] As used in the specification and appended claims, unless specified to the contrary, thefollowing terms have the meaning indicated below.

[0012] "Amino" refers to the –NH2 radical.

[0013] "Cyano" refers to the -CN radical.

[0014] "Nitro" refers to the -NO2 radical.

[0015] "Oxa" refers to the -O- radical.

[0016] "Oxo" refers to the =O radical.

[0017] "Thioxo" refers to the =S radical.

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

[0019] "Oximo" refers to the =N-OH radical.

[0020] "Hydrazino" refers to the =N-NH2 radical.

[0021] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbonand hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C1-C8alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3alkyl). 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., C1alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1- methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso- 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, -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). 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.

[0022] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula –O-alkyl, wherealkyl is an alkyl chain as defined above.

[0023] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely ofcarbon 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 (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -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).

[0024] "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).

[0025] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chainlinking 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, n-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., C1-C8alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3alkylene).In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C1alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C5-C8 alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -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] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbonchain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkenylene comprises two to eight carbon atoms (e.g., C2-C8alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (e.g., C2-C5alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (e.g., C2-C4alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (e.g., C2-C3alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (e.g., C2alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., C5-C8alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C3-C5alkenylene). Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted by one or more 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).

[0027] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbonchain 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-C5alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (e.g., C2-C4alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C2-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., C5-C8 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, -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 (optionallysubstituted 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).

[0028] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbonring 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) p–electron system in accordance with the Hückel 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.

[0029] "Aralkyl" refers to a radical of the formula -Rc-aryl where Rc is an alkylene chain as definedabove, 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.

[0030] "Aralkenyl" refers to a radical of the formula –Rd-aryl where Rd is an alkenylene chain asdefined 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.

[0031] "Aralkynyl" refers to a radical of the formula -Re-aryl, where Re is an alkynylene chain asdefined 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.

[0032] "Aralkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc-arylwhere 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.

[0033] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radicalconsisting 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 (i.e., containing single C-C bonds only) or unsaturated (i.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 (i.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 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.

[0034] "Carbocyclylalkyl" refers to a radical of the formula –Rc-carbocyclyl where Rc is an alkylenechain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0035] "Carbocyclylalkynyl" refers to a radical of the formula –Rc-carbocyclyl where Rc is analkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0036] "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.

[0037] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.

[0038] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or morefluoro 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.

[0039] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical that comprisestwo 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 orbridged 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[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl,isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb- C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb- N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0040] "N-heterocyclyl" or “N-attached heterocyclyl” refers to a heterocyclyl radical as definedabove 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 N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals.Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1- piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, and imidazolidinyl.

[0041] "C-heterocyclyl" or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined abovecontaining 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.

[0042] "Heterocyclylalkyl" refers to a radical of the formula –Rc-heterocyclyl where Rc is an alkylenechain 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.

[0043] "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.

[0044] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical thatcomprises 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, i.e., it contains a cyclic, delocalized (4n+2) p–electron system in accordance with the Hückel 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[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]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.

[0045] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogenand 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 N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0046] "C-heteroaryl" refers to a heteroaryl radical as defined above and where the point ofattachment 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.

[0047] "Heteroarylalkyl" refers to a radical of the formula –Rc-heteroaryl, where Rc is an alkylenechain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0048] "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.

[0049] The compounds disclosed herein, in some embodiments, contain one or more asymmetriccenters and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)-. 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 andoptically 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 doublebond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0050] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule toanother 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:

[0051] The compounds disclosed herein, in some embodiments, are used in different enrichedisotopic forms, e.g., enriched in the content of2H,3H,11C,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.

[0052] Unless otherwise stated, structures depicted herein are intended to include compounds whichdiffer 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.

[0053] The compounds of the present disclosure optionally contain unnatural proportions of atomicisotopes at one or more atoms that constitute such compounds. For example, the compoundsmay be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,11C,13C,14C,15C,12N,13N,15N,16N, 16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35Cl,37Cl,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.

[0054] In certain embodiments, the compounds disclosed herein have some or all of the 1H atomsreplaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0055] Deuterium substituted compounds are synthesized using various methods such as describedin: 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.

[0056] Deuterated starting materials are readily available and are subjected to the synthetic methodsdescribed 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.

[0057] Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, such asiodomethane-d3 (CD3I), are readily available and may be employed to transfer a deuterium- substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD3I is illustrated, by way of example only, in the reaction schemes below.

[0058] Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAlD4), are employed totransfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD4 is illustrated, by way of example only, in the reaction schemes below.

[0059] Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbonlinkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.

[0060] In one embodiment, the compounds disclosed herein contain one deuterium atom. In anotherembodiment, 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-exchangeable1H 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.

[0061] "Pharmaceutically acceptable salt" includes both acid and base addition salts. Apharmaceutically acceptable salt of any one of the AKT1 inhibitory compounds describedherein 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.

[0062] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain thebiological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid,phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0063] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biologicaleffectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0064] "Pharmaceutically acceptable solvate" refers to a composition of matter that is the solventaddition 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.

[0065] The term “subject” or “patient” encompasses mammals. Examples of mammals include, butare 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.

[0066] As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are usedinterchangeably. 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

[0067] AKT, also known as protein kinase B (PKB), is a serine / threonine protein kinase with threeisoforms, 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).

[0068] 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-apoptoticproteins, and mediate cellular growth factors, promoting cell survival. AKT is a major NX`W\][OKV OPPOM]X[ XP W^MUOK[ PKM]X[&TKYYK6 #APk6$% `RSMR VKb USWT 5>F \SQWKUSWQ ]X ]ROnucleus of a cell.

[0069] AKT1 is ubiquitously expressed, whereas AKT2 is primarily expressed in insulin-responsivetissues, 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.

[0070] AKT is a key downstream mediator of the phosphoinositide-3-kinase (PI3K) signalingYK]R`Kb' C=,>\ K[O KM]S_K]ON Lb NSPPO[OW] MXVYX^WN\' :X[ OaKVYUO% C=,>f% C=,>i% KWNC=,>g% K[O KM]S_K]ON Lb Oa][KMOUU^UK[ USQKWN\ LSWNSWQ ]X K ][KW\VOVL[KWO QUbMXY[X]OSW `S]ROWcbVK]SM KM]S_S]b% [OMOY]X[ ]b[X\SWO TSWK\O\ #DF>\$' =W MXW][K\]% C=,>j S\ KM]S_K]ON Lb ;&protein-compound receptors (GPCRs) and by RAS family of GTPases.

[0071] 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

[0072] AKT is activated by a second phosphorylation at the regulatory serine residue, Ser473. Knownphosphorylating 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).

[0073] mTOR is a key component in the AKT signaling pathway, which is a downstream member ofAKT 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 (mTORC2), 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.

[0074] AKT is known as a survival kinase and mediates cell survival and proliferation by inhibitingpathways 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.

[0075] Additionally, AKT1 has been found to be involved in invasion and migration of cancerouscells (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.

[0076] Furthermore, overexpression of AKT has been correlated to resistance to chemotherapeuticagents such as cisplatin, methotrexate, and paclitaxel. Thus, there remains a need to find AKT inhibitors given its role in cell survival and cancer proliferation.

[0077] 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.

[0078] The E17K mutation enhances migration of breast cancer cells, and also enhances resistance tochemotherapeutic 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.

[0079] A major pathway that activates PI3K-AKT signaling pathway is somatic cell mutations, withthe 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.

[0080] AKT1(E17K) mutations mediate the PI3K-AKT signaling cascade by expanding PIP lipidspecificity, which causes conformational changes. This also enhances subcellular localization to accelerate localization of the PH structural domain to the plasma membrane. The E17Kmutation increases PIP3 binding specificity by 7-fold and phosphatidylinositol-(4,5)- bisphosphate (PIP2) by 100-fold.

[0081] The AKT1(E17K) mutation also causes rapid conformational changes in the AKT1 PHstructural 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.

[0082] Given the conformational and signaling effects of the AKT1(E17K) mutation, this target maybe useful for targeted treatment of cancers. Prior Art AKT1 Inhibitors

[0083] Most AKT inhibitors targeting the ATP binding site are non-selective against the threeisoforms, 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.

[0084] There are also ATP non-competitive AKT inhibitors which are allosteric modulators whichhave 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

[0085] In one aspect, provided herein is an AKT1 inhibitory compound.

[0086] One embodiment provides a compound having the structure of Formula (I), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein, R is optionally substituted aryl, or optionally substituted heteroaryl; w, x, y, and z are each independently N or C-R1;each R1is independently H, D, halogen, -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 to form a carbocycle or heterocycle; R5and R6are each independently selected from the group consisting of H, D, -OR17, - SR17, -NH2, -CN, halogen, -CO2R17, CON(R17)2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R5and R6together form an oxo or thio; or R5and R6join to form an optionally substituted carbocycle or optionally substituted heterocycle; Z1is N or C-R7; Z2is N or C-R8; X1, X2, and X3are independently selected from O, S, N(R18), or C(R19)(R20), with the provision that X2and X3are not both O or S; R7, R8, R18, R19and R20are each independently selected from the group consisting of H, D, -OR17, -SR17, -NH2, -CN, halogen, -CO2R17, CON(R17)2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each R17is independently selected from H, optionally substituted C1-C6 alkyl; n is 0 or 1; m is 0, 1, 2, or 3; 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; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0;h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 0, 1, or 2; LCG is a group selected from the group consisting of: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; and R9ais 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;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 #O$ &7hA '

[0087] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein Z1is N. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Z1is C-R7.

[0088] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein Z2is N. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Z2is C-R8.

[0089] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein X1is O. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X1is N(R18). Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X1is C(R19)(R20).

[0090] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein X2is O. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is N(R18). Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is C(R19)(R20).

[0091] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein X3is C(R19)(R20).

[0092] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein R7is H.

[0093] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein R8is H.

[0094] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein R18is H. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R18is an optionally substituted C1-C6 alkyl. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R18is an optionally substituted C1-C2 alkyl. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R18is -CH3. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R18is - CH2CH3. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R18is -CD3.

[0095] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein R19is H.

[0096] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein R20is H.

[0097] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein m is 0. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein m is 1. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein m is 2. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein m is 3.

[0098] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein R5and R6are each independently selected from the group consisting of H, D, -OR17, -SR17, -NH2, -CN, halogen, -CO2R17, CON(R17)2, optionally substituted C1-C6 alkyl, or optionally substituted C3-C7 carbocyclyl. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R5is H. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R6is H. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R5and R6are each independently selected from the group consisting of optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R5and R6together form an oxo.

[0099] One embodiment provides a compound having the structure of Formula (II), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein, R is optionally substituted aryl, or optionally substituted heteroaryl; w, x, y, and z are each independently N or C-R1; each R1is independently H, D, halogen, -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 to form a carbocycle or heterocycle; Z3is N or C-R22; X4is O or S; R21and R22are each independently selected from the group consisting of H, D, -OR17, -SR17, -NH2, -CN, halogen, -CO2R17, CON(R17)2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R17is selected from H, optionally substituted C1-C6 alkyl; n is 0 or 1; 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; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 0, 1, or 2; LCG is a group selected from the group consisting of: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; and R9ais 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;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 #O$ &7hA '

[0100] Another embodiment provides the compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or deuteroisotope thereof, wherein Z3is N. Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Z3is C-R22.

[0101] Another embodiment provides the compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or deuteroisotope thereof, wherein X4is O.

[0102] Another embodiment provides the compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or deuteroisotope thereof, wherein R17is H. Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R17is optionally substituted C1-C6 alkyl.

[0103] Another embodiment provides the compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or deuteroisotope thereof, wherein R21is selected from the group consisting of H, D, -OR17, -SR17, -NH2, -CN, halogen, -CO2R17, CON(R17)2, optionally substituted C1-C6 alkyl, and optionally substituted C3-C7 carbocyclyl. Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R21is selected from the group consisting of optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0104] Another embodiment provides the compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or deuteroisotope thereof, wherein R22is selected from the group consisting of H, D, -OR17, -SR17, -NH2, -CN, halogen, -CO2R17, CON(R17)2, optionally substituted C1-C6 alkyl, and optionally substituted C3-C7 carbocyclyl. Another embodimentprovides the compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R22is selected from the group consisting of optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0105] One embodiment provides a compound having the structure of Formula (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein, R is optionally substituted aryl, or optionally substituted heteroaryl; w, x, y, and z are each independently N or C-R1; each R1is independently H, D, halogen, -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 to form a carbocycle or heterocycle; Z4is N or C-R24; X5is O or S; R23and R24are each independently selected from the group consisting of H, D, -OR17, -SR17, -NH2, -CN, halogen, -CO2R17, CON(R17)2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R17is selected from H, optionally substituted C1-C6 alkyl; n is 0 or 1; 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; a1 is 0, 1, 2, 3, or 4;b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 0, 1, or 2; LCG is a group selected from the group consisting of: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; and R9ais 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;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

[0106] Another embodiment provides the compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or deuteroisotope thereof, wherein Z4is N. Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Z4is C-R24.

[0107] Another embodiment provides the compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or deuteroisotope thereof, wherein X4is O.

[0108] Another embodiment provides the compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or deuteroisotope thereof, wherein R17is H. Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R17is optionally substituted C1-C6 alkyl.

[0109] Another embodiment provides the compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or deuteroisotope thereof, wherein R23is selected from the group consisting of H, D, -OR17, -SR17, -NH2, -CN, halogen, -CO2R17, CON(R17)2, optionally substituted C1-C6 alkyl, and optionally substituted C3-C7 carbocyclyl. Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R23is selected from the group consisting of optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0110] Another embodiment provides the compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or deuteroisotope thereof, wherein R24is selected from the group consisting of H, D, -OR17, -SR17, -NH2, -CN, halogen, -CO2R17, CON(R17)2, optionally substituted C1-C6 alkyl, and optionally substituted C3-C7 carbocyclyl. Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R24is selected from the group consisting of optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0111] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R is optionally substituted aryl. Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R is optionally substituted phenyl. Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R is optionally substituted heteroaryl. Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R is optionally substituted pyridine.

[0112] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein w is C-R1.

[0113] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein x is C-R1.

[0114] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein y is C-R1.

[0115] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein z is C-R1.

[0116] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein w, x, y, and z are C-R1.

[0117] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is H.

[0118] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R2and R3are H.

[0119] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein n is 0.

[0120] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein n is 1.

[0121] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is selected from:

[0122] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is:.

[0123] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R4is H.

[0124] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is selected from:.

[0125] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is:.

[0126] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is -N(R4)-.

[0127] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is selected from:.

[0128] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is:.

[0129] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically 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; and R9ais 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.

[0130] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically 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.

[0131] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is:.

[0132] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is:

[0133] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is:.

[0134] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is: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.

[0135] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically 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.

[0136] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is:.

[0137] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R13is H.

[0138] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R14is H.

[0139] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R15is H.

[0140] Another embodiment provides the compound of Formula (I), (II), or (III), or aYRK[VKMO^]SMKUUb KMMOY]KLUO \KU]% \XU_K]O% X[ NO^]O[XS\X]XYO ]RO[OXP% `RO[OSW ?7; S\ &7hA'

[0141] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is:.

[0142] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R4is H.

[0143] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is:.

[0144] Another embodiment provides the compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is:.

[0145] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein Z1is N. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Z1is C-R7.

[0146] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein R7is H.

[0147] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein Z2is N. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Z2is C-R8.

[0148] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein R8is H.

[0149] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein X1is N(R18).

[0150] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein R18is an optionally substituted C1-C6 alkyl. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R18is an optionally substituted C1-C2 alkyl. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R18is -CH3. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R18is -CH2CH3. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R18is - CD3. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R18is H.

[0151] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein X2is O.

[0152] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein X3is C(R19)(R20).

[0153] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein R19is H.

[0154] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein R20is H.

[0155] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein m is 1.

[0156] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein R5and R6together form an oxo.

[0157] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein R is optionally substituted aryl. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R is optionally substituted phenyl.

[0158] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein w, x, y, and z are C-R1.

[0159] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein R1is H.

[0160] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein R2and R3are H.

[0161] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein n is 0.

[0162] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein L is:.

[0163] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein R4is H.

[0164] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein L is:.

[0165] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein L is: .

[0166] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein LCG is:.

[0167] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein LCG is:.

[0168] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein R13is H.

[0169] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein R14is H.

[0170] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein R15is H.

[0171] One embodiment provides an AKT1 inhibitory compound, or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, having a structure presented in Table 1. Table 1

[0172] Another embodiment provides an AKT1 inhibitory compound, or a pharmaceuticallyacceptable salt, solvate, or deuteroisotope thereof, having a structure presented in Table 2. Table 2Preparation of Compounds

[0173] The compounds used in the synthetic chemistry reactions described herein are made accordingto 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).

[0174] Suitable reference books and treatise that detail the synthesis of reactants useful in thepreparation 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) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[0175] Specific and analogous reactants are optionally identified through the indices of knownchemicals 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

[0176] In certain embodiments, the AKT1 inhibitory compound described herein is administered as apure chemical. In other embodiments, the AKT1 inhibitory compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0177] Provided herein is a pharmaceutical composition comprising at least one AKT1 inhibitorycompound 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.

[0178] One embodiment provides a pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and a compound of Formula (I)-(III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof.

[0179] One embodiment provides a method of preparing a pharmaceutical composition comprisingmixing a compound of Formula (I)-(III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable carrier.

[0180] In certain embodiments, the AKT1 inhibitory compound as described by Formula (I)-(III), ora 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.

[0181] One embodiment provides a pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and a compound of Table 1 or 2, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof.

[0182] One embodiment provides a method of preparing a pharmaceutical composition comprisingmixing a compound of Table 1 or 2, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable carrier.

[0183] In certain embodiments, the AKT1 inhibitory compound as described by Table 1 or 2, or apharmaceutically 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.

[0184] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard orsoft 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)).

[0185] In some embodiments, the AKT1 inhibitory compound as described by Formula (I)-(III), orTable 1 or 2, 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.

[0186] The dose of the composition comprising at least one AKT1 inhibitory compound as describedherein 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.

[0187] Pharmaceutical compositions are administered in a manner appropriate to the disease to betreated (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 aregenerally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0188] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more,per day. Methods of Treatment

[0189] One embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, for use in a method of treatment of the human or animal body.

[0190] One embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, for use in a method of treatment of cancer or neoplastic disease.

[0191] One embodiment provides a pharmaceutical composition comprising a compound of Formula(I)-(III), 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.

[0192] One embodiment provides a use of a compound of Formula (I)-(III), or a pharmaceuticallyacceptable salt, solvate, or deuteroisotope thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

[0193] 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)-(III), 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)-(III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient.

[0194] One embodiment provides a compound of Table 1 or 2, or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, for use in a method of treatment of the human or animal body.

[0195] One embodiment provides a compound of Table 1 or 2, or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, for use in a method of treatment of cancer or neoplastic disease.

[0196] One embodiment provides a pharmaceutical composition comprising a compound of Table 1or 2, 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.

[0197] One embodiment provides a use of a compound of Table 1 or 2, or a pharmaceuticallyacceptable salt, solvate, or deuteroisotope thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

[0198] 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 2, 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 2, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient.

[0199] Provided herein is the method wherein the pharmaceutical composition is administered orally.Provided herein is the method wherein the pharmaceutical composition is administered by injection.

[0200] One embodiment provides a method of inhibiting an AKT1 enzyme comprising contacting theAKT1 enzyme with a compound of Formula (I)-(III), or Table 1 or 2. 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. Methods of Treatment: Numbered Embodiments [Embodiment 1] A method of treating a cancer in a patient in need thereof, comprisingadministering to the patient a compound of Formula (I), (II), (III), or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof. [Embodiment 2] A method of treating a cancer in a patient in need thereof, comprisingadministering to the patient a compound of Table 1, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof. [Embodiment 3] A method of treating a cancer in a patient in need thereof, comprisingadministering to the patient a compound, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, selected from the group consisting of: 4-((1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(1-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-(4-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperazin-1-yl)pyrimidine-2-carbonitrile; 4-((1-(4-(1-ethyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 6-(4-((7-acryloyl-2,7-diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-7-phenyl-1H- pyrido[2,3-b][1,4]oxazin-2(3H)-one; 4-(4-(4-(1-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperazin-1-yl)pyrimidine-2-carbonitrile; 4-((1-(4-(3-oxo-6-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)benzyl)piperidin- 4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(4-ethyl-3-oxo-6-phenyl-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazin-7- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(4-(methyl-d3)-3-oxo-6-phenyl-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazin-7- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; and 4-((1-(4-(3-oxo-6-phenyl-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazin-7- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile.[Embodiment 4] A method of treating a cancer in a patient in need thereof, comprisingadministering to the patient: (a) a compound of Formula (I), (II), (III), or 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.[Embodiment 5] A method of treating a cancer in a patient in need thereof, comprisingadministering to the patient:(a) a compound of Table 1, or 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.[Embodiment 6] A method of treating a cancer in a patient in need thereof, comprisingadministering to the patient: (a) a compound, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, selected from the group consisting of: 4-((1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(1-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-(4-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperazin-1-yl)pyrimidine-2-carbonitrile; 4-((1-(4-(1-ethyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 6-(4-((7-acryloyl-2,7-diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-7-phenyl-1H- pyrido[2,3-b][1,4]oxazin-2(3H)-one; 4-(4-(4-(1-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperazin-1-yl)pyrimidine-2-carbonitrile; 4-((1-(4-(3-oxo-6-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)benzyl)piperidin- 4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(4-ethyl-3-oxo-6-phenyl-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazin-7- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-((1-(4-(4-(methyl-d3)-3-oxo-6-phenyl-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazin-7- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; and 4-((1-(4-(3-oxo-6-phenyl-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazin-7- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 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.[Embodiment 7] The method of any one of embodiments 7-9, wherein at least one oncologytherapeutic is selected from an endocrine therapy, a hormonal therapy, a SERM therapy, a SERD therapy, an aromatase inhibitor, or an androgen deprivation therapy.[Embodiment 8] The method of embodiment 10, wherein the endocrine therapy, a hormonaltherapy, 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,.[Embodiment 9] The method of any one of embodiments 7-9, wherein at least one oncologytherapeutic is a taxane.[Embodiment 10] The method of embodiment 12, wherein the taxane is selected from paclitaxel,docetaxel, cabazitaxel, or abraxane.[Embodiment 11] The method of any one of embodiments 7-9, wherein at least one oncologytherapeutic is a platinum agent.[Embodiment 12] The method of embodiment 14, wherein the platinum agent is selected fromcisplatin, carboplatin, or oxaliplatin.[Embodiment 13] The method of any one of embodiments 7-9, wherein at least one oncologytherapeutic is an anthracycline.[Embodiment 14] The method of embodiment 16, wherein the anthracycline is selected fromdoxorubicin or epirubicin.[Embodiment 15] The method of any one of embodiments 7-9, wherein at least one oncologytherapeutic is an anti-metabolite.[Embodiment 16] The method of embodiment 18, wherein the anti-metabolite is selected frommethotrexate, fluorouracil, pemetrexed, irinotecan, topotecan, capecitabine or gemcitabine.[Embodiment 17] The method of any one of embodiments 7-9, wherein at least one oncologytherapeutic is an alkylating agent.[Embodiment 18] The method of embodiment 20, wherein the alkylating agent is selected fromifosfamide, trabectedin, cyclophosphamide, melphalan, or dacarbazine.[Embodiment 19] The method of any one of embodiments 7-9, wherein at least one oncologytherapeutic is a microtubule affecting agent.[Embodiment 20] The method of embodiment 22, wherein the microtubule affecting agent isselected from ixabepilone, viborelbine, or eribulin.[Embodiment 21] The method of any one of embodiments 7-9, wherein at least one oncologytherapeutic is an immune checkpoint inhibitor.[Embodiment 22] The method of embodiment 24, wherein the immune checkpoint inhibitor isselected 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.[Embodiment 23] The method of embodiment 25, wherein the CTLA-4 inhibitor is selected fromipilimumab or tremelimumab.[Embodiment 24] The method of embodiment 25, wherein the PD-1 inhibitor is selected fromspartalizumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, durvalumab, dostarlimab, retifanlimab, or toripalimab.[Embodiment 25] The method of embodiment 25, wherein the bi-specific PD-1 / CTLA4 inhibitoris selected from AK104, MGD019, XmAb20717, or MEDI5752.[Embodiment 26] The method of any one of embodiments 7-9, wherein at least one oncologytherapeutic is a kinase inhibitor.[Embodiment 27] The method of embodiment 29, wherein the kinase inhibitor is selected fromlenvatinib, pazopanib, imatinib, sorafenib, or avutometinib.[Embodiment 28] The method of any one of embodiments 7-9, wherein at least one oncologytherapeutic is a PI3K inhibitor.[Embodiment 29] The method of embodiment 31, wherein the PI3K inhibitor is selected fromcopanlisib, alpelisib, idelalisib, duvelisib, or umbralisib.[Embodiment 30] The method of any one of embodiments 7-9, wherein at least one oncologytherapeutic is a HER2 inhibitor.[Embodiment 31] The method of embodiment 33, wherein the HER2 inhibitor is selected fromlapatinib, neratinib, tucatinib, pyrotinib, or afatinib.[Embodiment 32] The method of any one of embodiments 7-9, wherein at least one oncologytherapeutic is an antibody.[Embodiment 33] The method of embodiment 35, wherein the antibody is selected fromtrastuzumab, pertuzumab, margetuxumab, bevacizumab, or rituximab.[Embodiment 34] The method of any one of embodiments 7-9, wherein at least one oncologytherapeutic is a PARP inhibitor.[Embodiment 35] The method of embodiment 37, wherein the PARP inhibitor is selected fromolaparib, rucaparib, talazoparib, or niraparib.[Embodiment 36] The method of any one of embodiments 7-9, wherein at least one oncologytherapeutic is an antibody drug conjugate (ADC).[Embodiment 37] The method of embodiment 39, wherein the antibody drug conjugate isselected 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.[Embodiment 38] The method of any one of embodiments 7-9, wherein at least one oncologytherapeutic is a radiopharmaceutical.[Embodiment 39] The method of embodiment 41, wherein the radiopharmaceutical is[111In] / [89Zr]-trastuzumab.[Embodiment 40] The method of any one of embodiments 7-9, wherein at least one oncologytherapeutic is a NTRK inhibitor.[Embodiment 41] The method of embodiment 43, wherein the NTRK inhibitor is selected fromentrectinib or larotrectinib.[Embodiment 42] The method of any one of embodiments 7-9, wherein at least one oncologytherapeutic is a RET inhibitor.[Embodiment 43] The method of embodiment 45, wherein the RET inhibitor is selpercatinib orpralsetinib.[Embodiment 44] The method of any one of embodiments 7-9, wherein at least one oncologytherapeutic is an EGFR inhibitor.[Embodiment 45] The method of embodiment 47, wherein the EGFR inhibitor is erlotinib,osimertinib, neratinib, cetuximab, gefitinib, panitumumab, dacomitinib, afatinib, lapatinib, necitumumab, mobocertinib, or vandetanib.[Embodiment 46] The method of any one of embodiments 7-9, wherein at least one oncologytherapeutic is a mTOR inhibitor.[Embodiment 47] The method of embodiment 49, wherein the mTOR inhibitor is deforolimus,everolimus, sirolimus, or temsirolimus.[Embodiment 48] The method of any one of embodiments 7-9, wherein at least one oncologytherapeutic is a RAF inhibitor.[Embodiment 49] The method of embodiment 51, wherein the RAF inhibitor is vemurafenib,dabrafenib, encorafenib, tovorafenib, naporafenib, belvarafenib, or exarafenib.[Embodiment 50] The method of any one of embodiments 7-9, wherein at least one oncologytherapeutic is a MEK inhibitor.[Embodiment 51] The method of embodiment 53, wherein the MEK inhibitor is binimetinib,cobimetinib, trametinib, selumetinib, pimasertib, avutometinib, IMM-1-104, or NST-628.[Embodiment 52] The method of any one of embodiments 7-9, wherein at least one oncologytherapeutic is a CDK inhibitor.[Embodiment 53] The method of embodiment 55, wherein the CDK inhibitor is selected frompalbociclib, abemaciclib, ribociclib, tagtociclib, ebvaciclib, lerociclib, PF-07220060, BLU- 222, INX-315, or AVZO-021.[Embodiment 54] A method of treating a cancer in a patient in need thereof, comprisingadministering to the patient: (a) a compound of Formula (I), (II), (III), or 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.[Embodiment 55] A method of treating a cancer in a patient in need thereof, comprisingadministering to the patient: (a) a compound of Table 1, or 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.[Embodiment 56] A method of treating a cancer in a patient in need thereof, comprisingadministering to the patient: (a) a compound, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, selected from the group consisting of: 4-((1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(1-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-(4-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperazin-1-yl)pyrimidine-2-carbonitrile; 4-((1-(4-(1-ethyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 6-(4-((7-acryloyl-2,7-diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-7-phenyl-1H- pyrido[2,3-b][1,4]oxazin-2(3H)-one; 4-(4-(4-(1-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperazin-1-yl)pyrimidine-2-carbonitrile; 4-((1-(4-(3-oxo-6-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)benzyl)piperidin- 4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(4-ethyl-3-oxo-6-phenyl-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazin-7- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(4-(methyl-d3)-3-oxo-6-phenyl-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazin-7- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; and 4-((1-(4-(3-oxo-6-phenyl-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazin-7- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; and (b) at least one oncology therapeutic selected from CAR-T therapy, tumor-infiltrating lymphocytes (TIL) or a neoantigen vaccine.[Embodiment 57] The method of any one of embodiments 1-59, wherein the cancer is breastcancer.[Embodiment 58] The method of embodiment 60, wherein the cancer is a hormone receptorpositive (HR+) breast cancer.[Embodiment 59] The method of embodiment 60, wherein the cancer is a human epidermalgrowth factor receptor 2 negative (HER2-) breast cancer.[Embodiment 60] The method of embodiment 60, wherein the cancer is a HR+ / HER2- breastcancer.[Embodiment 61] The method of embodiment 60, wherein the cancer is a HR+ / HER2-low breastcancer.[Embodiment 62] The method of embodiment 60, wherein the cancer is a HR+ / HER2+ breastcancer.[Embodiment 63] The method of embodiment 60, wherein the cancer is a triple negative breastcancer (TNBC).[Embodiment 64] The method of embodiment 60, wherein the cancer is an invasive breast cancer.[Embodiment 65] The method of any one of embodiments 1-59, wherein the cancer is uterinecancer.[Embodiment 66] The method of embodiment 68, wherein the cancer is uterine sarcoma.[Embodiment 67] The method of embodiment 68, wherein the cancer is endometrial cancer.[Embodiment 68] The method of embodiment 68, wherein the cancer is Type I endometrialcancer.[Embodiment 69] The method of embodiment 68, wherein the cancer is Type II endometrialcancer.[Embodiment 70] The method of embodiment 72, wherein the cancer is Type II endometrialpapillary serous carcinoma.[Embodiment 71] The method of embodiment 72, wherein the cancer is Type II endometrial clearcell carcinoma.[Embodiment 72] The method of embodiment 72, wherein the cancer is Type II endometrialundifferentiated carcinoma.[Embodiment 73] The method of embodiment 72, wherein the cancer is Type II endometrioidcarcinoma.[Embodiment 74] The method of embodiment 68, wherein the cancer is microsatellite instability(MSI) high and / or DNA mismatch repair (MMR) deficient.[Embodiment 75] The method of embodiment 68, wherein the cancer is tumor mutational burden(TMB) high.[Embodiment 76] The method of embodiment 68, wherein the cancer is HER2-.[Embodiment 77] The method of any one of embodiments 1-59, wherein the cancer is cervicalcancer.[Embodiment 78] The method of embodiment 80, wherein the cancer is a cervical squamous cellcarcinoma.[Embodiment 79] The method of embodiment 80, wherein the cancer is a cervicaladenocarcinoma.[Embodiment 80] The method of any one of embodiments 1-59, wherein the cancer is prostatecancer.[Embodiment 81] The method of embodiment 83, wherein the cancer is prostate adenocarcinoma.[Embodiment 82] The method of embodiment 83, wherein the cancer is prostate neuroendocrinecancer.[Embodiment 83] The method of embodiment 83, wherein the cancer is prostate small cellneuroendocrine cancer.[Embodiment 84] The method of embodiment 83, wherein the cancer is prostate large cellcarcinoma.[Embodiment 85] The method of embodiment 83, wherein the cancer is prostate transitional cellcarcinoma.[Embodiment 86] The method of embodiment 83, wherein the cancer is prostate sarcoma.[Embodiment 87] The method of any one of embodiments 1-59, wherein the cancer is bladdercancer.[Embodiment 88] The method of embodiment 90, wherein the cancer is urothelial cancer.[Embodiment 89] The method of embodiment 90, wherein the cancer is squamous cell cancer ofthe bladder.[Embodiment 90] The method of embodiment 90, wherein the cancer is small cell cancer of thebladder.[Embodiment 91] The method of embodiment 90, wherein the cancer is adenocarcinoma of thebladder.[Embodiment 92] The method of any one of embodiments 1-59, wherein the cancer is lungcancer.[Embodiment 93] The method of any one of embodiments 1-59, wherein the cancer is non-smallcell lung cancer.[Embodiment 94] The method of any one of embodiments 1-59, wherein the cancer is non-squamous non-small cell lung cancer.[Embodiment 95] The method of any one of embodiments 1-59, wherein the cancer is squamousnon-small cell lung cancer.[Embodiment 96] The method of any one of embodiments 1-59, wherein the cancer is coloncancer.[Embodiment 97] The method of any one of embodiments 1-59, wherein the cancer is analcancer.[Embodiment 98] The method of any one of embodiments 1-59, wherein the cancer is ameningioma.[Embodiment 99] The method of any one of embodiments 1-59, wherein the cancer is a glioma.[Embodiment 100] The method of any one of embodiments 1-59, wherein the cancer is pancreaticcancer.[Embodiment 101] The method of embodiment 103, wherein the cancer is exocrine pancreaticcancer.[Embodiment 102] The method of embodiment 103, wherein the cancer is neuroendocrinepancreatic cancer.[Embodiment 103] The method of any one of embodiments 1-59, wherein the cancer is thyroidcancer.[Embodiment 104] The method of any one of embodiments 1-59, wherein the cancer ismyxofibrosarcoma.[Embodiment 105] The method of any one of embodiments 1-59, wherein the cancer is parotidgland cancer.[Embodiment 106] The method of any one of embodiments 1-59, wherein the cancer is esophagealcancer.[Embodiment 107] The method of any one of embodiments 1-59, wherein the cancer is stomachcancer.[Embodiment 108] The method of any one of embodiments 1-59, wherein the cancer is skincancer.[Embodiment 109] The method of embodiment 111, wherein the cancer is nonmelanoma skincancer.[Embodiment 110] The method of embodiment 112, wherein the cancer is squamousnonmelanoma skin cancer.[Embodiment 111] The method of embodiment 112, wherein the cancer is non-squamousnonmelanoma skin cancer.[Embodiment 112] The method of any one of embodiments 1-59, wherein the cancer is ovariancancer.[Embodiment 113] The method of embodiment 115, wherein the cancer is epithelial ovariancancer.[Embodiment 114] The method of embodiment 115, wherein the cancer is serous epithelial ovariancancer.[Embodiment 115] The method of embodiment 115, wherein the cancer is endometrioid ovariancancer.[Embodiment 116] The method of embodiment 115, wherein the cancer is clear cell ovariancancer.[Embodiment 117] The method of embodiment 115, wherein the cancer is mucinous ovariancancer.[Embodiment 118] The method of any one of embodiments 1-59, wherein the cancer is adenoidcystic carcinoma.[Embodiment 119] The method of any one of embodiments 1-59, wherein the cancer is renal cellcancer.[Embodiment 120] The method of any one of embodiments 1-59, wherein the cancer is appendixcancer.[Embodiment 121] The method of any one of embodiments 1-59, wherein the cancer is multiplemyeloma.[Embodiment 122] The method of any one of embodiments 1-59, wherein the cancer is acutemyeloid leukemia.[Embodiment 123] The method of any one of embodiments 1-59, wherein the cancer is cancer ofunknown primary.[Embodiment 124] The method of any one of embodiments 1-59, wherein the cancer is locallyadvanced.[Embodiment 125] The method of any one of the preceding embodiments, wherein the cancer ismetastatic.[Embodiment 126] The method of any one of the preceding embodiments, wherein the method isadjuvant therapy following surgical resection.[Embodiment 127] The method of any one of the preceding embodiments, wherein the method isneo-adjuvant therapy.[Embodiment 128] The method of any one of the preceding embodiments, wherein the method isfirst-line systemic therapy for locally advanced or metastatic disease.[Embodiment 129] The method of any one of the preceding embodiments, wherein the patient hasrelapsed after prior therapy.[Embodiment 130] The method of any one of the preceding embodiments, wherein the patient hasacquired resistance to prior therapy.[Embodiment 131] The method of any one of the preceding embodiments, wherein the patient isrefractory to therapy.[Embodiment 132] The method of any one of embodiments 60-67, wherein the patient has shownprogression on at least one CDK4 / 6 inhibitor.[Embodiment 133] The method of any one of embodiments 60-67, wherein the patient has shownprogression on at least one endocrine-based regimen.[Embodiment 134] The method of any one of the preceding embodiments, wherein the patient hasshown progression on cytotoxic chemotherapy.[Embodiment 135] The method of any one of the preceding embodiments, wherein the cancer ischaracterized by existence of AKT1-E17K mutation.[Embodiment 136] The method of any one of the preceding embodiments, wherein the cancerexhibits one or more co-occurring alterations selected from a PIK3CA alteration, a PIK3R1 alteration, an AKT1 alteration, and PTEN alteration.[Embodiment 137] The method of any one of the preceding embodiments, wherein the patientexhibits risk factors for hyperglycemia.[Embodiment 138] The method of any one of the preceding embodiments, wherein the patientexhibits risk factors selected from obesity, body mass index greater than or equal to 30, fasting blood glucose over 160 mg / dL, HbA1c greater than 6.0.[Embodiment 139] The method of any one of the preceding embodiments, wherein the patientexhibits 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.[Embodiment 140] The method of any one of the preceding embodiments, wherein the compoundof Formula (I), (II), (III), or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, is administered orally.[Embodiment 141] The method of any one of the preceding embodiments, wherein the compoundof Table 1, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, is administered orally.[Embodiment 142] The method of any one of the preceding embodiments, wherein the compound,or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, selected from the group consisting of: 4-((1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(1-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-(4-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperazin-1-yl)pyrimidine-2-carbonitrile; 4-((1-(4-(1-ethyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 6-(4-((7-acryloyl-2,7-diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-7-phenyl-1H- pyrido[2,3-b][1,4]oxazin-2(3H)-one; 4-(4-(4-(1-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperazin-1-yl)pyrimidine-2-carbonitrile; 4-((1-(4-(3-oxo-6-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)benzyl)piperidin- 4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(4-ethyl-3-oxo-6-phenyl-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazin-7- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(4-(methyl-d3)-3-oxo-6-phenyl-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazin-7- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; and 4-((1-(4-(3-oxo-6-phenyl-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazin-7- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; is administered orally. [Embodiment 143] The method of any one of the preceding embodiments, wherein the oraladministration occurs once per day, twice per day, three times per day, every other day, or one to six days per week.

[0201] Other embodiments and uses will be apparent to one skilled in the art in light of the presentdisclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way. EXAMPLES I. Chemical Synthesis

[0202] In some embodiments, the AKT1 inhibitory compounds disclosed herein are synthesizedaccording 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 oC degrees Celsius gH chemical shift in parts per million downfield from tetramethylsilane DCM dichloromethane (CH2Cl2)DIAD diisopropyl azodicarboxylate DIEA diisopropylethylamine DMF dimethylformamide DMSO dimethylsulfoxide EA ethyl acetate EtOAc ethyl acetate ESI electrospray ionization Et ethyl g gram(s) h hour(s) HPLC high performance liquid chromatography Hz hertzJ coupling constant (in NMR spectrometry)LCMS liquid chromatography mass spectrometry" microm multiplet (spectral); meter(s); milli M molar M+parent molecular ion Me methyl MsCl methanesulfonyl chloride MHz megahertz min minute(s) mol mole(s); molecular (as in mol wt) mL milliliter MS 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 ether RT room temperature s singlet (spectral) t triplet (spectral)SFC Supercritical fluid chromatography T temperature TFA trifluoroacetic acid THF tetrahydrofuran TPP triphenylphosphineExperimental Procedures

[0203] Intermediate 1: Methyl 4-(2-oxo-2-phenylacetyl)benzoateStep 1: Methyl 4-(phenylethynyl)benzoate A 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)2Cl2 (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 the mixture was stirred at 35 °C for 16 hr under N2atmosphere. 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]+.1H NMR (400 MHz, Dimethysulfoxide-d6$ g 1')- & 0'2. #V% +<$% 0'0- & 0' / 0 #V% +<$% 0' / . & 0'.. #V% +<$%7.51 - 7.42 (m, 3H), 3.87 (s, 3H). Step 2: Methyl 4-(2-oxo-2-phenylacetyl)benzoate FX K \XU^]SXW XP VO]RbU -&#YROWbUO]RbWbU$LOWcXK]O #.) VQ% +*+ lVXU$ SW 8@EB #+ V?$ `O[Oadded Pd(OAc)2 #*, VQ% .0'2 lVXU$ KWN 7^6[ #*,') VQ% 2)' / lVXU$' FRO VSa]^[O `K\ \]S[[ONat 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 (Intermediate 1, 78 mg, yield: 68%) was obtained as a yellow solid. MS: m / z = 269.0 [M + H]+. 1H NMR (400 MHz, Dimethysulfoxide-d6$ g 1'++ & 1'*, #V% +<$% 1'** & 1'). #V% +<$%8.00 - 7.92 (m, 2H), 7.86 - 7.77 (m, 1H), 7.68 - 7.61 (m, 2H), 3.91 (s, 3H).

[0204] Intermediate 2 & 3: 5-(4-(Hydroxymethyl)phenyl)-3-methyl-6-phenylpyrazin-2(1H)-one & 6-(4-(Hydroxymethyl)phenyl)-3-methyl-5-phenylpyrazin-2(1H)-oneStep 1: Methyl 4-(6-methyl-5-oxo-3-phenyl-4,5-dihydropyrazin-2-yl)benzoate & methyl 4-(5- methyl-6-oxo-3-phenyl-1,6-dihydropyrazin-2-yl)benzoate To a solution of Intermediate 1 (1.58 g, 5.89 mmol) in EtOH (30 mL) were added 2- aminopropanamide (1.56 g, 17.7 mmol) and HOAc (3.77 mL, 69.0 mmol). The mixture was stirred at 90 °C at 16 hr. The pH of the resulting reaction mixture was adjusted to 8 with aq.5 M NaOH. The mixture was extracted with CH2Cl2 (100 mL x 4). 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 mixture of the title compounds (400 mg, yield: 21%) was obtained as a yellow solid. MS: m / z = 321.0 [M + H]+.1H NMR (400 MHz,Dimethylsulfoxide-d6$ g 12.74 - 12.02 (m, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.4 Hz,1H), 7.44 (d, J = 8.4 Hz, 1H), 7.42 - 7.32 (m, 2H), 7.32 - 7.24 (m, 2H), 7.24 - 7.16 (m, 2H), 3.83 (d, J = 13.6 Hz, 3H), 2.40 ( d, J = 5.2 Hz, 3H) Step 2: 5-(4-(Hydroxymethyl)phenyl)-3-methyl-6-phenylpyrazin-2(1H)-one & 6-(4- (Hydroxymethyl)phenyl)-3-methyl-5-phenylpyrazin-2(1H)-one To a solution of a mixture of methyl 4-(6-methyl-5-oxo-3-phenyl-4,5-dihydropyrazin-2- yl)benzoate and methyl 4-(5-methyl-6-oxo-3-phenyl-1,6-dihydropyrazin-2-yl)benzoate (400 mg, 1.26 mmol) in THF (10 mL) was degassed and purged with N2three times. To the mixture was added LiAlH4 (2.5 M, 0.9 mL) at 0 °C under N2 atmosphere. The mixture was stirred at 25 °C for 1 hr under N2 atmosphere. The reaction mixture was quenched with Na2SO4·10H2O (1 g) at 0 °C, filtered, and concentrated under reduced pressure. Afterpurification by prep&<C?7#MXU^VW 378) / & GK]O[\ HLSNQO 7*1 *.) a -) a *) lV4 VXLSUOphase: [water (NH4HCO3) - ACN]; gradient:15% - 45% B over 10 min), the title compound (Intermeidate 2, 146 mg, yield: 40%) was obtained as an off white solid, and the title compound (Intermediate 3, 105 mg, yield: 28%) was obtained as an off white solid. Spectrafor Intermediate 2: MS: m / z = 293.1 [M + H]+. 1H NMR (400 MHz, Dimethysulfoxide-d6$ g12.54 - 12.14 (m, 1H), 7.40 - 7.24 (m, 5H), 7.23 - 7.06 (m, 4H), 5.31 - 4.97 (m, 1H), 4.43 (d, J = 5.6 Hz, 2H), 2.38 (s, 3H). Spectra for Intermediate 3: MS: m / z = 293.1 [M + H]+.1H NMR(400 MHz, Dimethysulfoxide-d6$ g *+' / 2 & **'2) #V% *<$% 0',0 & 0')0 #V% 2<$% .',) & .'*2 #V%1H), 4.49 (d, J = 6.0 Hz, 2H), 2.38 (s, 3H).

[0205] Intermediate 4: 5-(4-(Chloromethyl)phenyl)-3-methyl-6-phenylpyrazin-2(1H)-oneTo a solution of 5-(4-(hydroxymethyl)phenyl)-3-methyl-6-phenylpyrazin-2(1H)-one (146 mg, -22 lVXU$ SW 7<2Cl2 (5 mL) was added SOCl2 (1 mL). The mixture was stirred at 25 °C for1hr. The reaction mixture was concentrated. The title compound (Intermediate 4, HCl salt, 174 mg) was obtained as a yellow solid. MS: m / z = 311.1, 313.0 [M + H]+.

[0206] Intermediate 5: 4-(Piperidin-4-ylamino)pyrimidine-2-carbonitrileStep 1: tert-Butyl 4-((2-cyanopyrimidin-4-yl)amino)piperidine-1-carboxylate To a solution of tert-butyl 4-aminopiperidine-1-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 Q% 1'22 VVXU$ KWN AK= #12'1 VQ% .22 lVXU$' FRO VSa]^[O `K\ \]S[[ON K] 1) d7 PX[ *R[' FROreaction 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 ~ 50% EtOAc in petroleum ether) to give the title compound (860 mg, yield: 92%) as a white solid. 1H NMR (400 MHz, Dimethylsulfoxide-d6$ g 1'*, &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-carbonitrile To a solution of tert-Butyl 4-((2-cyanopyrimidin-4-yl)amino)piperidine-1-carboxylate (110 VQ% , / + lVXU$ SW 87@ #, V?$ `K\ KNNON F:5 #0 / 0 VQ% / '0, VVXU$' FRO VSa]^[O `K\stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure. The title compound (Intermediate 5, 120 mg, yield: 100%, TFA salt) was used in the next step without further purification. MS: m / z = 204.0 [M + H]+.

[0207] Intermediate 6 & 7: 6-(4-(Hydroxymethyl)phenyl)-3-isobutyl-5-phenylpyrazin-2(1H)-one &5-(4-(hydroxymethyl)phenyl)-3-isobutyl-6-phenylpyrazin-2(1H)-oneIntermediate 6 & 7 were prepared in a manner similar to Intermediate 2 & 3. Spectra for Intermediate 6: MS: m / z = 335.1 [M + H]+. 1H NMR (400 MHz, Dimethysulfoxide-d6$ g *+' / 0- 12.14 (m, 1H), 7.38 - 7.26 (m, 5H), 7.20 - 7.05 (m, 4H), 5.22 - 5.01 (m, 1H), 4.54 - 4.32 (m, 2H), 2.64 - 2.62 (m, 2H), 2.26 - 2.14 (m, 1H), 0.96 (d, J = 6.8 Hz, 6H). Spectra for Intermediate 7: MS: m / z = 335.2 [M + H]+. 1H NMR (400 MHz, Dimethysulfoxide-d6$ g *+'.1- 11.92 (m, 1H), 7.51 - 6.96 (m, 9H), 5.48 - 5.08 (m, 1H), 4.50 (d, J = 5.6 Hz, 2H), 2.64 (d, J = 7.2 Hz, 2H), 2.21 (m,1H), 0.97 (d, J = 6.8 Hz, 6H).

[0208] Intermediate 8: 6-(4-(Chloromethyl)phenyl)-3-isobutyl-5-phenylpyrazin-2(1H)-oneIntermediate 8 was prepared in a manner similar to Intermediate 4. MS: m / z = 353.2, 355.2 [M + H]+.

[0209] Intermediate 9: 6-Bromo-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-oneStep 1: Ethyl 2-((5-bromo-3-nitropyridin-2-yl)oxy)acetate To a solution of 5-bromo-2-chloro-3-nitropyridine (1 g, 4.21 mmol) and ethyl 2- hydroxyacetate (482 mg, 4.63 mmol) in THF (50 mL) was added NaH (185 mg, 4.63 mmol, 60% purity) in an ice bath. The mixture was degassed, purged with N2three times, and stirred at 0 °C for 16 hr under N2. The reaction mixture was quenched with H2O (50 mL) at 0 °C and extracted with EtOAc (50 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% ~ 5% EtOAc in petroleum ether), the title compound (954 mg, yield: 74%) was obtained as a yellow oil.1H NMR (400MHz, Chloroform-d$ g 1'-. #N% J = 2.4 Hz, 1H), 8.39 (d, J = 2.4 Hz, 1H), 5.04 (s, 2H), 4.23 (q,J = 7.2 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H). Step 2: Ethyl 2-((3-nitro-5-phenylpyridin-2-yl)oxy)acetate A mixture of ethyl 2-((5-bromo-3-nitropyridin-2-yl)oxy)acetate (850 mg, 2.79 mmol),phenylboronic acid (408 mg, 3.34 mmol), Pd(dppf)Cl2 #+)- VQ% +02 lVXU$% KWN 7\2CO3 (2.72g, 8.36 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) was degassed and purged with N2 three times, and the mixture was stirred at 90 °C for 2 hr under N2atmosphere. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 5% EtOAc in petroleum ether), the title compound (504 mg yield: 59%) was obtained as an off white solid. MS: m / z = 303.1 [M+H]+.1H NMR (400MHz, Chloroform-d$ g 1'.1 & 1'.) #V% +<$% 0'.2 & 0',2 #V% .<$% .'*) #\% +<$% -'+ / #Z% J = 7.2Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H). Step 3: 7-Phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one To a solution of ethyl 2-((3-nitro-5-phenylpyridin-2-yl)oxy)acetate (450 mg, 1.49 mmol) in AcOH (5 mL) was added Fe (416 mg, 7.44 mmol) slowly. The mixture was degassed, purged with N2three times, and stirred at 70 °C for 3 hr under N2. The reaction mixture was concentrated under reduced pressure. After trituration with 1 N HCl (20 mL) at 25 °C for 30 mins, the title compound (284 mg, yield: 84%) was obtained as a gray solid. MS: m / z = 226.9[M+H]+. 1H NMR (400 MHz, Dimethylsulfoxide-d6$ g *)'2+ #L[ \% *<$% 1')2 #\% *<$% 0' / - &7.55 (m, 2H), 7.52 - 7.34 (m, 4H), 4.82 (s, 2H). Step 4: 6-Bromo-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-oneTo a solution of 7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H$&XWO #.) VQ% ++* lVXU$ SW 8@:#* V?$ `K\ KNNON A6E #01'0 VQ% --+ lVXU$ \UX`Ub' FRO VSa]^[O `K\ NOQK\\ON% Y^[QON `S]RN2 three times, and stirred at 80 °C for 1 hr under N2. The reaction mixture was quenched with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with 4% LiCl(aq) (50 mL x 2), brine (50 mL ), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (Intermediate 9, 67.4 mg) as an off white solid, which was used directly in the next step. MS: m / z = 305.0, 306.8 [M+H]+.1H NMR (400 MHz, Methanol-d4$ g 0'-. & 0',1 #V% .<$% 0'+) #\% *<$% -'11 #\% +<$'

[0210] Intermediate 10: 4-((1-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileStep 1: 1-Bromo-4-(chloromethyl)benzene To a solution of (4-bromophenyl)methanol (5 g, 26.7 mmol) in CH2Cl2(50 mL) was added SOCl2(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, HCl salt) as a light- yellow oil. 1H NMR (400 MHz, Dimethylsulfoxide-d6$ g 0'.1 #N% J = 8.0 Hz, 2H), 7.40 (d, J =8.4 Hz, 2H), 4.74 (s, 2H). Step 2: 4-((1-(4-Bromobenzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile To a solution of 1-bromo-4-(chloromethyl)benzene (6.47 g, 26.7 mmol, HCl 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 NaI (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 CH2Cl2), 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]+.1H NMR (400 MHz, Dimethylsulfoxide-d6$ g 1')0 #N% J = 6.0 Hz, 1H), 8.01 (d, J = 7.2Hz, 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-((1-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile A mixture of 4-((1-(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(1,3,2-dioxaborolane) (9.14 g, 36.0 mmol), KOAc (5.30 g, 54.0 mmol) and Pd(dppf)Cl2 (1.32 g, 1.80 mmol) in 1,4-dioxane (70 mL) was degassed, purged with N2three times, and stirred at 90 °C for 2 hr under N2atmosphere. The reaction mixture was quenched with H2O (100 mL) at 25 °C and extracted with CH2Cl2(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 CH2Cl2), the title compound(Intermediate 10, 7.55 g, yield: 90%) was obtained as a black solid. MS: m / z = 420.2 [M + H]+. 1H NMR (400 MHz, Dimethylsulfoxide-d6$ g 8.08 (d, J = 6.0 Hz, 2H), 7.65 (d, J = 7.2Hz, 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).

[0211] Intermediate 11: 4-(Piperazin-1-yl)pyrimidine-2-carbonitrileStep 1: tert-Butyl 4-(2-cyanopyrimidin-4-yl)piperazine-1-carboxylate To 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#*'++ Q% 1'1 / VVXU$ KWN AK= #11'. VQ% .2) lVXU$' FRO VSa]^[O `K\ \]S[[ON K] 1) d7 PX[ * R['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$ g 1'+2 #N% 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-1-yl)pyrimidine-2-carbonitrile To a solution of tert-butyl 4-(2-cyanopyrimidin-4-yl)piperazine-1-carboxylate (140 mg, 483 lVXU$ SW 7<2Cl2 (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 11, 146 mg TFA salt, yield: 100%) was used in the next step without further purification. MS: m / z = 190.0 [M + H]+.

[0212] Intermediate 12: 6-(4-(Chloromethyl)phenyl)-3-methyl-5-phenylpyrazin-2(1H)-oneIntermediate 12 was prepared in a manner similar to Intermediate 4. MS: m / z = 311.1, 313.1 [M + H]+.

[0213] Intermediate 13: 5-(4-(Chloromethyl)phenyl)-3-isobutyl-6-phenylpyrazin-2(1H)-oneIntermediate 13 was prepared in a manner similar to Intermediate 4. MS: m / z = 353.2, 355.1 [M + H]+.

[0214] Intermediate 14: 6-(4-(Chloromethyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-oneStep 1: 6-(4-(Hydroxymethyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one A mixture of Intermediate 9 (540 mg, 1.77 mmol), (4-(hydroxymethyl)phenyl)boronic acid (322 mg, 2.12 mmol), Pd(dppf)Cl2 #*+2 VQ% *00 lVXU$% 7\2CO3 (1.73 g, 5.30 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) was degassed, purged with N2three times, and the mixture was stirred at 80 °C for 16 hr under N2atmosphere. The reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 50% EtOAc in petroleumether), the title compound (196 mg, yield: 33%) was obtained as a light yellow solid. MS: m / z =333.1 [M + H]+. 1H NMR (400 MHz, Dimethylsulfoxide-d6$ g 10.95 (s, 1H), 7.41 - 7.25 (m,3H), 7.22 - 7.08 (m, 7H), 5.15 (t, J = 5.6 Hz, 1H), 4.86 (s, 2H), 4.44 (d, J = 5.6 Hz, 2H). Step 2: 6-(4-(Chloromethyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one To a solution of 6-(4-(hydroxymethyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)- XWO #*2 / VQ% .2) lVXU$ SW 7<2Cl2 (10 mL) was added SOCl2 (3 mL). The mixture wasstirred at 40 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (Intermediate 14, 207 mg, HCl salt) as a yellow solid. MS: m / z = 351.0, 353.0 [M + H]+

[0215] Intermediate 15: 6-Bromo-1-methyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-oneStep 1: 1-Methyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one To a solution of 7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (refer to Intermediate 9 for NO]KSU Y[XMON^[O\% *,) VQ% .0. lVXU$ KWN >2CO3 (238 mg, 1.72 mmol) in MeCN (2 mL) wasadded MeI (163 mg, 1.15 mmol) slowly. The mixture was degassed, purged with N2three times, and stirred at 60 °C for 2 hr under N2. 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 (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 25% EtOAc in petroleum ether), the title compound (53 mg, yield: 38%) was obtained as an off white solid.MS: m / z = 241.0 [M+H]+. 1H NMR (400 MHz, Dimethylsulfoxide-d6$ g 1'* / #N% J = 2.4 Hz,1H), 7.78 - 7.72 (m, 3H), 7.52 - 7.47 (m, 2H), 7.43 - 7.38 (m, 1H), 4.89 (s, 2H), 3.36 (s, 3H). Step 2: 6-Bromo-1-methyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one To a solution of 1-methyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (51 mg, 212 lVXU$ SW 8@: #+ V?$ `K\ KNNON A6E #0.' / VQ% -+. lVXU$' FRO VSa]^[O `K\ NOQK\\ON%purged with N2 three times, and stirred at 80 °C for 4 hr under N2. 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 (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (Intermediate 15, 67.8 mg) as an off white solid, which was used in the next step directly. MS: m / z = 319.0, 321.0 [M+H]+.

[0216] Intermediate 16: 6-(4-(Chloromethyl)phenyl)-1-ethyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

[0217] Step 1: 1-Ethyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

[0218] To a solution of Intermediate 9 (600 mg, 2.65 mmol) and K2CO3 (1.10 g, 7.96 mmol) inMeCN (10 mL) was added iodoethane (827 mg, 5.30 mmol) slowly. The mixture was degassed, purged with N2three times, and stirred under N2at 60 °C for 2 hr. The reaction mixture was quenched with H2O (30 mL) at 25 °C and extracted with CH2Cl2 (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% ~ 25% EtOAc in petroleum ether), the title compound (265 mg, yield: 39%) was obtained. MS: m / z = 255.2 [M + H]+.1H NMR (400 MHz, Chloroform- d$ g 1'*1 & 1'). #V% *<$% 0'.. & 0'- / #V% -<$% 0'-- & 0'-) #V% +<$% -'1 / #\% +<$% -')- #Z% J =7.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H).

[0219] Step 2: 6-Bromo-1-ethyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

[0220] To a solution of 1-ethyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (265 mg, 1.04mmol) in DMF (5 mL) was added NBS (371 mg, 2.08 mmol). The mixture was stirred at 80 °C for 2 hr. The reaction mixture was quenched with H2O (30 mL) at 25 °C 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 to give the title compound (340 mg). MS: m / z = 332.9, 334.9 [M + H]+.1H NMR (400 MHz, Chloroform-d$ g 7.50 - 7.40 (m, 5H), 7.19 (s, 1H), 4.86 (s, 2H), 4.01 - 3.89 (m, 2H), 1.29 -1.22 (m, 3H).

[0221] Step 3: 1-Ethyl-6-(4-(hydroxymethyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

[0222] A mixture of 6-bromo-1-ethyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (340 mg,1.02 mmol), (4-(hydroxymethyl)phenyl)boronic acid (233 mg, 1.53 mmol), Cs2CO3(997 mg, 3.06 mmol), and Pd(dppf)Cl2 #0-'0 VQ% *)+ lVXU$ SW *%-&NSXaKWO #*) V?$ KWN <2O (2 mL)was degassed, purged with N2 three times, and stirred under N2 at 90 °C for 16 hr. The reaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with CH2Cl2(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 5% ~ 40% EtOAc in petroleum ether), the title compound (260 mg, yield: 67% for two steps) was obtained. MS: m / z = 361.2 [M + H]+.1H NMR (400 MHz, Chloroform-d$ g 0',- & 0'+2 #V% .<$% 0'+1 & 0'+0 #V% *<$% 0'++ & 0'* / #V% -<$% -'11 #\%2H), 4.65 (s, 2H), 4.05 - 3.98 (m, 2H), 1.31 (t, J = 7.2 Hz, 3H).

[0223] Step 4: 6-(4-(Chloromethyl)phenyl)-1-ethyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

[0224] To a solution of 1-ethyl-6-(4-(hydroxymethyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H$&XWO #+ / ) VQ% 0+* lVXU$ SW 7<2Cl2 (4 mL) was added SOCl2 (0.5 mL). The mixturewas stirred under N2 at 25 °C for 0.5 hr. The reaction was concentrated under reduced pressure to give the title compound (Intermediate 16, 273 mg). MS: m / z = 379.1, 381.0 [M + H]+.

[0225] Intermediate 17: 7-Bromo-4-ethyl-6-phenyl-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one

[0226] Step 1: 6-Bromo-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one

[0227] To a solution of 3,6-dibromopyrazin-2-amine (2 g, 7.91 mmol) in methyl 2-hydroxyacetate(7.12 g, 79.1 mmol) was added t-BuOK (2.66 g, 23.7 mmol). The mixture was stirred at 60 °C for 16 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 3), 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 (1.6 g, yield: 83%) was obtained. MS: m / z = 229.8, 231.8 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6$ g **'1. #L[ \% *<$% 0'2+ #\% *<$% -'12 #\% +<$'

[0228] Step 2: 6-Phenyl-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one

[0229] A mixture of 6-bromo-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one (500 mg, 2.17 mmol),phenylboronic acid (265 mg, 2.17 mmol), Cs2CO3 (2.12 g, 6.52 mmol) and Pd(dppf)Cl2 (159 VQ% +*0 lVXU$ SW *%-&NSXaKWO #*) V?$ `K\ NOQK\\ON% Y^[QON `S]R A2 three times, and stirredunder N2at 80 °C for 16 hr. The reaction mixture was quenched with H2O (50 mL) and extracted with CH2Cl2(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% ~ 40% EtOAc in petroleum ether), the title compound (220 mg, yield: 35%) was obtained. MS: m / z = 227.9 [M + H]+.1HNMR (400 MHz, Dimethylsulfoxide-d6$ g **'0) #L[ \% *<$% 1',1 #\% *<$% 0'21 #N% J = 7.2 Hz,2H), 7.52 - 7.47 (m, 2H), 7.45 - 7.40 (m, 1H), 4.92 (s, 2H).

[0230] Step 3: 4-Ethyl-6-phenyl-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one

[0231] To a solution of 6-phenyl-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one (220 mg, 968 mmol) inMeCN (5 mL) were added EtI (302 mg, 1.94 mmol) and K2CO3(401 mg, 2.90 mmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was quenched with H2O (50 mL) and extracted with CH2Cl2 (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), 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 (90 mg, yield: 36%) was obtained. MS: m / z = 256.1 [M +H]+. 1H NMR (400 MHz, Dimethylsulfoxide-d6$ g 1'-- #\% *<$% 1')1 & 1')) #V% +<$% 0'. / &7.41 (m, 3H), 5.02 (s, 2H), 4.16 - 4.07 (m, 2H), 1.29 - 1.23 (m, 3H).

[0232] Step 4: 7-Bromo-4-ethyl-6-phenyl-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one

[0233] To a solution of 4-ethyl-6-phenyl-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one (90 mg, 353mmol) in DMF (2 mL) was added NBS (126 mg, 705 mmol). The mixture was stirred at 80 °C for 4 hr. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (Intermediate 17, 105 mg) was obtained as a yellow solid. MS: m / z = 333.8, 335.7, [M + H]+.

[0234] Example 1: 4-((1-(4-(2-Oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileFX K \XU^]SXW XP =W]O[VONSK]O 2 # / 0'- VQ% ++* lVXU$% =W]O[VONSK]O *) #2+'0 VQ% ++* lVXU$ SW1,4-dioxane (1.5 mL) and H2O (0.3 mL) were added Pd(dppf)Cl2 #* / '+ VQ% ++'* lVXU$ KWNCs2CO3 #+* / VQ% / / , lVXU$' FRO VSa]^[O `K\ NOQK\\ON% Y^[QON `S]R A2 three times, andstirred at 90 °C for 2 hr under N2. The reaction mixture was diluted with EtOAc (30 mL ) and washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by prep-HPLC (column: CD02-Waters Xbidge BEH C18150 x 25 x 10 µm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 24% - 54% B over 10 min), the title compound (Example 1, 24.3 mg, yield: 21% for two steps) was obtained. MS: m / z =518.2 [M+H]+. 1H NMR (400 MHz, Dimethylsulfoxide-d6$ g *)'2- #L[ \% *<$% 1'*+ & 0'2- #V%2H), 7.33 - 7.25 (m, 3H), 7.21 - 7.09 (m, 7H), 6.65 (d, J = 6.0 Hz, 1H), 4.86 (s, 2H), 3.84 - 3.69 (m, 1H), 3.42 (s, 2H), 2.77 - 2.68 (m, 2H), 2.07 - 1.99 (m, 2H), 1.89 - 1.76 (m, 2H), 1.52 - 1.37 (m, 2H).

[0235] Example 2: 4-((1-(4-(6-Methyl-5-oxo-3-phenyl-4,5-dihydropyrazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileFX K \XU^]SXW XP =W]O[VONSK]O - #10 VQ% +.* lVXU% <7U \KU]$% =W]O[VONSK]O . #*)) VQ% ,*.lVXU% F:5 \KU]$ SW 8@: #- V?$ `O[O KNNON >2CO3 (173 mg, 1.25 mmol) and NaI (3.76 mg,+.'* lVXU$' FRO VSa]^[O `K\ \]S[[ON K] +. d7 PX[ * / R[' FRO [OKM]SXW VSa]^[O `K\ YX^[ON SW]XH2O (50 mL) and extracted with EtOAc (50 mL x 3). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by prep&<C?7 #MXU^VW378)0 & 8KS\XQOU EC&*))&1&B8E&C> *.) a +. a *) lV4 VXLSUO YRK\O3[water (NH4HCO3) - ACN]; gradient: 22% - 52% B over 10 min), the title compound (Example 2, 30.9 mg, yield: 13% for two steps) was obtained. MS: m / z = 478.2 [M + H]+.1H NMR (400 MHz, Dimethysulfoxide-d6$ g *+',. & *+')- #V% *<$% 1'** & 0'20 #V% +<$% 0',0 &7.27 (m, 5H), 7.15 - 7.10 (m, 4H), 6.71 - 6.59 (m, 1H), 3.85 - 3.69 (m, 1H), 3.41 (br s, 2H), 2.78 - 2.69 (m, 2H), 2.38 (s, 3H), 2.09 - 2.00 (m, 2H), 1.88 - 1.80 (m, 2H), 1.48 - 1.39 (m, 2H).

[0236] Example 3: 4-((1-(4-(5-Isobutyl-6-oxo-3-phenyl-1,6-dihydropyrazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 3 was prepared in a manner similar to Example 2. MS: m / z = 520.3 [M + H]+.1H NMR (400 MHz, Dimethysulfoxide-d6$ g *+'-* & **'2- #V% *<$% 1'*0 & 0'2* #V% +<$% 0',2 &7.25 (m, 5H), 7.19 - 7.06 (m, 4H), 6.71 - 6.60 (m, 1H), 3.86 - 3.67 (m, 1H), 3.41 (s, 2H), 2.78 - 2.69 (m, 2H), 2.64 (d, J = 6.8 Hz, 2H), 2.29 - 2.16 (m, 1H), 2.09 - 1.99 (m, 2H), 1.90 - 1.77 (m, 2H), 1.52 - 1.37 (m, 2H), 0.96 (d, J = 6.8 Hz, 6H).

[0237] Example 4: 4-(4-(4-(5-Isobutyl-6-oxo-3-phenyl-1,6-dihydropyrazin-2-yl)benzyl)piperazin-1-yl)pyrimidine-2-carbonitrileExample 4 was prepared in a manner similar to Example 2. MS: m / z = 506.3 [M + H]+.1H NMR (400 MHz, Dimethysulfoxide-d6$ g *+'-2 & **'1. #V% *<$% 1'+. #N% J = 6.4 Hz,1H), 7.38- 7.27 (m, 5H), 7.18 - 7.12 (m, 4H), 7.08 (d, J = 6.8 Hz, 1H), 3.72 - 3.54 (m, 4H), 3.47 (s, 2H), 2.64 (d, J = 7.2 Hz, 2H), 2.43 - 2.38 (m, 4H), 2.26 - 2.16 (m, 1H), 0.96 (d, J = 6.4 Hz, 6H).

[0238] Example 5: 4-((1-(4-(1-Methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 5 was prepared in a manner similar to Example 1. MS: m / z = 532.2 [M+H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) 8.13 - 7.96 (m, 2H), 7.52 (s, 1H), 7.33 - 7.28 (m, 3H), 7.24 - 7.13 (m, 6H), 6.66 (d, J = 6.0 Hz, 1H), 4.93 (s, 2H), 3.82 - 3.71 (m, 1H), 3.43 (s, 2H), 3.34 (s, 3H), 2.77 - 2.70 (m, 2H), 2.10 - 2.02 (m, 2H), 1.88 - 1.80 (m, 2H), 1.49 - 1.39 (m, 2H).

[0239] Example 6: 4-(4-(4-(6-Methyl-5-oxo-3-phenyl-4,5-dihydropyrazin-2-yl)benzyl)piperazin-1-yl)pyrimidine-2-carbonitrileExample 6 was prepared in a manner similar to Example 2. MS: m / z = 464.0 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6$ g 12.62 - 11.89 (m, 1H), 8.25 (d, J = 6.4 Hz,1H), 7.36- 7.24 (m, 5H), 7.18 - 7.11 (s, 4H), 7.08 (d, J = 6.8 Hz, 1H), 3.70 - 3.57 (m, 4H), 3.46 (br s, 2H), 2.43 - 2.38 (m, 4H), 2.38 - 2.34 (m, 3H).

[0240] Example 7: 4-(4-(4-(5-Methyl-6-oxo-3-phenyl-1,6-dihydropyrazin-2-yl)benzyl)piperazin-1-yl)pyrimidine-2-carbonitrileExample 7 was prepared in a manner similar to Example 2. MS: m / z = 464.1 [M + H]+.1H NMR (400 MHz, Chloroform-d$ g 1'*2 #N% J = 6.4 Hz, 1H), 7.36 - 7.27 (m, 5H), 7.24 - 7.22(m, 2H), 6.65 - 6.52 (d, J = 6.4 Hz, 1H), 5.46 - 5.29 (m, 2H), 3.78 - 3.61 (m, 4H), 3.59 - 3.51 (m, 2H), 2.55 (s, 3H), 2.53 - 2.46 (m, 4H).

[0241] Example 8: 4-((1-(4-(5-Methyl-6-oxo-3-phenyl-1,6-dihydropyrazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 8 was prepared in a manner similar to Example 2. MS: m / z = 478.2 [M + H]+.1H NMR (400 MHz, Dimethysulfoxide-d6$ g *+'.2 & **' / - #V% *<$% 1'* / & 0'2, #V% +<$% 0',) &7.13 (m, 9H), 6.74 - 6.60 (m, 1H), 3.85 - 3.70 (m, 1H), 3.48 (s, 2H), 2.79 - 2.70 (m, 2H), 2.38 (s, 3H), 2.12 - 2.04 (m, 2H), 1.89 - 1.80 (m, 2H), 1.50 - 1.39 (m, 2H).

[0242] Example 9: 4-(4-(4-(6-Isobutyl-5-oxo-3-phenyl-4,5-dihydropyrazin-2-yl)benzyl)piperazin-1-yl)pyrimidine-2-carbonitrileExample 9 was prepared in a manner similar to Example 2. MS: m / z = 506.3 [M + H]+.1H NMR (400 MHz, Chloroform-d$ g 1'*2 #N% J = 6.4 Hz, 1H), 7.37 - 7.27 (m, 6H), 7.25 - 7.20(m, 3H), 6.58 (J = 6.4 Hz, 1H), 3.82 - 3.61 (m, 4H), 3.57 (s, 2H), 2.82 - 2.73 (m, 2H), 2.56 - 2.48 (m, 4H), 2.41 - 2.26 (m, 1H), 1.03 (d, J = 6.4 Hz, 6H).

[0243] Example 10: 4-((1-(4-(6-Isobutyl-5-oxo-3-phenyl-4,5-dihydropyrazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 10 was prepared in a manner similar to Example 2. MS: m / z = 520.2 [M + H]+.1H NMR (400 MHz, Chloroform-d$ g 1'+- & 1'). #V% *<$% 0',. & 0'+0 #V% .<$% 0'+- & 0'+) #V%3H), 6.42 (d, J = 6.4 Hz 1H), 5.43 - 4.83 (m, 1H), 4.32 - 3.73 (m, 1H), 3.59 (s, 2H), 2.99 - 2.81 (m, 2H), 2.80 - 2.75 (m, 2H), 2.39 - 2.30 (m, 1H), 2.30 - 2.19 (m, 2H), 2.08 - 1.98 (m, 2H), 1.60 - 1.55 (m, 2H), 1.03 (d, J = 6.8 Hz, 6H).

[0244] Example 11: 4-(4-(4-(2-Oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)benzyl)piperazin-1-yl)pyrimidine-2-carbonitrileExample 11 was prepared in a manner similar to Example 2. MS: m / z = 504.2 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6$ g *)'20 #L[ \% *<$% 1'+. #N% J = 6.4 Hz, 1H), 7.31 -7.27 (m, 3H), 7.20 - 7.18 (m, 1H), 7.16 (s, 4H), 7.14 - 7.11 (m, 2H), 7.10 - 7.07 (m, 1H), 4.86 (s, 2H), 3.70 - 3.56 (m, 4H), 3.48 (s, 2H), 2.43 - 2.37 (m, 4H).

[0245] Example 12: 4-((1-(4-(1-Ethyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileFX K \XU^]SXW XP =W]O[VONSK]O * / # / ) VQ% *.1 lVXU$ KWN =W]O[VONSK]O . #.)', VQ% *.1 lVXU%TFA salt) in DMF (3 mL) were added K2CO3 #*)2 VQ% 02+ lVXU$ KWN AK= #+',0 VQ% *.'1lVXU$' FRO VSa]^[O `K\ \]S[[ON K] +. d7 PX[ * / R[' FRO [OKM]SXW VSa]^[O `K\ Z^OWMRON `S]RH2O (20 mL) at 25 °C and extracted with CH2Cl2 (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- C> *.) a +. a *) lV4 VXLSUO YRK\O3 I`K]O[ #A<4HCO3) - ACN]; gradient: 38% - 68% B over10 min), the title compound (Example 12, 49.7 mg, yield: 58% for two steps) was obtained. MS: m / z = 546.2 [M + H]+. 1H NMR (400 MHz, Dimethylsulfoxide-d6$ g 1'+. & 0'2, #V% +<$%7.54 (s, 1H), 7.34 - 7.27 (m, 3H), 7.24 - 7.19 (m, 2H), 7.19 - 7.12 (m, 4H), 6.66 (d, J = 5.6 Hz, 1H), 4.92 (s, 2H), 4.01 (q, J = 6.8 Hz, 2H), 3.85 - 3.65 (m, 1H), 3.43 (s, 2H), 2.78 - 2.68 (m, 2H), 2.11 - 1.99 (m, 2H), 1.89 - 1.72 (m, 2H), 1.55 - 1.37 (m, 2H), 1.17 (t, J = 7.2 Hz, 3H).

[0246] Example 14: 6-(4-((7-Acryloyl-2,7-diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-1-ethyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-oneStep 1: tert-Butyl 2-(4-(1-ethyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate FX K \XU^]SXW XP =W]O[VONSK]O * / #*.) VQ% ,2 / lVXU$ KWN tert-butyl 2,7-diazaspiro[3.5]nonane-0&MK[LXabUK]O #*+. VQ% -0. lVXU% <7U \KU]$ SW 8@: #, V?$ `O[O KNNON >2CO3 (274 mg, 1.98VVXU$ KWN AK= #**'2 VQ% 02'+ lVXU$' FRO VSa]^[O `K\ \]S[[ON K] +. d7 PX[ * / R[' FRO [OKM]SXWmixture was quenched with H2O (20 mL) at 25 °C and extracted with CH2Cl2(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% ~ 3% MeOH in CH2Cl2), the title compound (100 mg, yield: 43%) was obtained. MS: m / z = 569.3 [M + H]+. 1H NMR (400 MHz, Chloroform-d$ g 0',+ &7.26 (m, 5H), 7.26 - 7.25 (m, 1H), 7.21 - 7.15 (m, 2H), 7.12 - 7.07 (m, 2H), 4.87 (s, 2H), 4.01 (q, J = 7.2 Hz, 2H), 3.59 (s, 2H), 3.33 - 3.26 (m, 4H), 3.07 - 2.93 (m, 4H), 1.70 - 1.65 (m, 4H), 1.44 (s, 9H), 1.31 (t, J = 7.2 Hz, 3H). Step 2: 6-(4-((2,7-Diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-1-ethyl-7-phenyl-1H-pyrido[2,3- b][1,4]oxazin-2(3H)-one To a solution of tert-butyl 2-(4-(1-ethyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3- LJI*%-JXaKcSW& / &bU$LOWcbU$&+%0&NSKcK\YS[XI,'.JWXWKWO&0&MK[LXabUK]O #*)) VQ% *0 / lVXU$ SW1,4-dioxane (1 mL) was added 2 M HCl in 1,4-dioxane (2 M, 2 mL). The mixture was stirredat 25 °C for 0.5 hr. The reaction mixture was quenched with Na2CO3aq. (15 mL, pH adjusted to~ 7) at 25 °C and extracted with CH2Cl2 (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 (82 mg). MS: m / z = 469.2 [M + H]+. Step 3: 6-(4-((7-Acryloyl-2,7-diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-1-ethyl-7-phenyl-1H- pyrido[2,3-b][1,4]oxazin-2(3H)-one To a solution of 6-(4-((2,7-diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-1-ethyl-7-phenyl-1H- pyrido[2,3-b][1,4]oxazin-2(3H$&XWO #1+ VQ% *0. lVXU$ SW 7<2Cl2 (5 mL) were added TEA#11'. VQ% 10. lVXU$ KWN KM[bUXbU MRUX[SNO #*.'1 VQ% *0. lVXU$' FRO VSa]^[O `K\ \]S[[ON K] )°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 prep-TLC (SiO2, MeOH : CH2Cl2= 1"10), the title compound (Example 14, 50.4 mg, yield: 55% for two steps) was obtained.MS: m / z = 523.1 [M + H]+. 1H NMR (400 MHz, Dimethylsulfoxide-d6$ g 0'., #\% *<$% 0',. &7.27 (m, 3H), 7.24 - 7.18 (m, 2H), 7.17 - 7.13 (m, 2H), 7.12 - 7.08 (m, 2H), 6.78 (dd, J = 16.8, 10.4 Hz, 1H), 6.05 (dd, J = 16.8, 2.4 Hz, 1H), 5.69 - 5.58 (m, 1H), 4.91 (s, 2H), 4.00 (q, J = 6.8 Hz, 2H), 3.53 (s, 2H), 3.47 - 3.40 (m, 4H), 2.99 - 2.88 (m, 4H), 1.68 - 1.56 (m, 4H), 1.17 (t, J = 6.8 Hz, 3H).

[0247] Example 15: 6-(4-((7-Acryloyl-2,7-diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-oneExample 15 was prepared in a matter similar to Example 14. MS: m / z = 495.2 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6$ g *)'2+ #L[ \% *<$% 0',. & 0'+. #V% ,<$% 0'+* & 0'*1(m, 1H), 7.17 - 7.04 (m, 6H), 6.85 - 6.70 (m, 1H), 6.11 - 5.98 (m, 1H), 5.69 - 5.57 (m, 1H), 4.85 (s, 2H), 3.52 (s, 2H), 3.48 - 3.39 (m, 4H), 3.01 - 2.87 (m, 4H), 1.74 - 1.51 (m, 4H).

[0248] Example 16: 4-(4-(4-(1-Methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)benzyl)piperazin-1-yl)pyrimidine-2-carbonitrileStep 1: 6-(4-(Hydroxymethyl)phenyl)-1-methyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)- one To a solution of Intermediate 15 (250 mg, 783 mmol) and (4-(hydroxymethyl)phenyl)boronic acid (131 mg, 862 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) were added Pd(dppf)Cl2 (57.3 mg, 78.3 mmol) and Cs2CO3 (766 mg, 2.35 mmol). The mixture was degassed, purged with N2 three times, and stirred under N2 at 80 °C for 16 hr. The reaction mixture was quenched with H2O (20 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. After purification by silica gel flash chromatography (Eluent of 0% ~ 45% EtOAc in petroleum ether), the title compound (150 mg, yield: 52%) was obtained. MS: m / z =347.1 [M + H]+. 1H NMR (400 MHz, Chloroform-d$ g 0',0 & 0'+1 #V% .<$% 0'+0 & 0'+. #V% +<$%7.22 - 7.19 (m, 3H), 4.91 (s, 2H), 4.65 (d, J = 5.6 Hz, 2H), 3.40 (s, 3H). Step 2: 6-(4-(Chloromethyl)phenyl)-1-methyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)- one To a solution of 6-(4-(hydroxymethyl)phenyl)-1-methyl-7-phenyl-1H-pyrido[2,3- b][1,4]oxazin-2(3H)-one (50 mg, 144 mmol) in CH2Cl2 (3 mL) was added SOCl2 (489 mg, 432 mmol). The mixture was stirred at 40 °C for 0.5 hr. The reaction was concentrated under reduced pressure to give the title compound (52 mg). MS: m / z = 365.1, 367.1 [M + H]+. Step 3: 4-(4-(4-(1-Methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperazin-1-yl)pyrimidine-2-carbonitrile To a solution of 6-(4-(chloromethyl)phenyl)-1-methyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin- 2(3H)-one (52 mg, 143 mmol) and Intermediate 11 (43.2 mg, 143 mmol, TFA salt) in DMF (1mL) were added K2CO3 (98.5 mg, 713 mVXU$ KWN AK= #+'*- VQ% *-', lVXU$' FRO VSa]^[O `K\stirred at 30 °C for 16 hr. The reaction mixture was quenched with H2O (10 mL) at 25 °C and extracted with CH2Cl2 (10 mL x 2). The combined organic layers were washed with brine (10mL x3), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by prep-HPLC (column: CD02-Waters Xbidge BEH C18150 x 25 x 10 mm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 35% - 65% B over 14 min), the title compound (Example 16, 24.1 mg, yield: 33% for two steps) was obtained. MS: m / z = 518.1 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6$ g 1'+. #N% J = 6.4 Hz, 1H), 7.52 (s, 1H), 7.33 - 7.27 (m, 3H), 7.23- 7.16 (m, 6H), 7.08 (d, J = 6.4 Hz, 1H), 4.93 (s, 2H), 3.74 - 3.55 (m, 4H), 3.48 (s, 2H), 3.34 (s, 3H), 2.43 - 2.37 (m, 4H).

[0249] Example 18: 4-((1-(4-(3-Oxo-6-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileStep 1: 6-Phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one A mixture of 6-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (3 g, 13.2 mmol), phenylboronic acid (1.76 g, 14.5 mmol), Cs2CO3 (12.9 g, 39.5 mmol), and Pd(dppf)Cl2 (963 mg, 1.32 mmol) in 1,4-dioxane (30 mL) and H2O (6 mL) was degassed, purged with N2three times, and stirred under N2at 90 °C for 4 hr. The reaction mixture was quenched with H2O (50 mL) at 25 °C and extracted with CH2Cl2 (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% ~ 30% EtOAc in petroleum ether), the title compound (2.5 g, yield: 84%) was obtained. MS: m / z = 226.1 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6$ g *)'01 #\% *<$% 0'.0 & 0'.+ #V% +<$% 0'-1 & 0'-* #V% +<$% 0', / &7.31 (m, 1H), 7.23 - 7.18 (m, 1H), 7.16 - 7.13 (m, 1H), 7.06 - 7.00 (m, 1H), 4.61 (s, 2H). Step 2: 7-Bromo-6-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one To a solution of 6-phenyl-2H-benzo[b][1,4]oxazin-3(4H$&XWO #*)) VQ% --- lVXU$ SW 8@: #*V?$ `K\ KNNON A6E #*.1 VQ% 111 lVXU$' FRO VSa]^[O `K\ \]S[[ON K] +. d7 PX[ + R[' FROreaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with CH2Cl2(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 to give the title compound (130 mg). MS: m / z = 304.0, 306.0 [M + H]+. 1H NMR (400 MHz, Dimethylsulfoxide-d6$ g *)'10 #\% *<$%7.47 - 7.37 (m, 3H), 7.35 - 7.30 (m, 3H), 6.87 - 6.84 (m, 1H), 4.65 (s, 2H). Step 3: 4-((1-(4-(3-Oxo-6-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)benzyl)piperidin- 4-yl)amino)pyrimidine-2-carbonitrileA mixture of 7-bromo-6-phenyl-2H-benzo[b][1,4]oxazin-3(4H$&XWO #*+) VQ% ,2. lVXU$%=W]O[VONSK]O *) #* / . VQ% ,2. lVXU$% 7\2CO3 (386 mg, 1.18 mmol), and Pd(dppf)Cl2 (57.7 mg,01'2 lVXU$ SW *%-&NSXaKWO #. V?$ KWN <2O (1 mL) was degassed, purged with N2 three times,and stirred under N2at 90 °C for 2 hr. The reaction mixture was quenched with H2O (10 mL) at 25 °C and extracted with CH2Cl2 (15 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 20% ~ 82% EtOAc in petroleum ether), the title compound (Example 18, 79.2 mg, yield: 38% for two steps) was obtained. MS: m / z = 517.3 [M + H]+. 1H NMR (400 MHz, Methanol-d4$ g 1') / & 0'2. #V% *<$%7.21 - 7.14 (m, 5H), 7.09 - 7.03 (m, 4H), 7.00 (s, 1H), 6.94 (s, 1H), 6.64 - 6.55 (m, 1H), 4.65 (s, 2H), 4.00 - 3.82 (m, 1H), 3.52 (s, 2H), 2.92 - 2.84 (m, 2H), 2.24 - 2.13 (m, 2H), 2.01 - 1.93 (m, 2H), 1.62 - 1.51 (m, 2H).

[0250] Example 19: 4-((1-(4-(4-Ethyl-3-oxo-6-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileStep 1: 4-Ethyl-6-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one To a solution of 6-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one (300 mg, 1.33 mmol. Refer to Example 18 for detail procedures) in MeCN (5 mL) were added K2CO3(552 mg, 4.00 mmol) and iodoethane (415 mg, 2.66 mmol). The mixture was stirred at 60 °C for 16 hr. The reaction mixture was quenched with H2O (30 mL) at 25 °C and extracted with EtOAc (25 mL x 2). The combined organic layers were washed with brine (30 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 (270 mg, yield: 79%) was obtained. MS: m / z = 254.0 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide- d6$ g 0'0, & 0' / , #V% +<$% 0'-2 & 0'-+ #V% +<$% 0'-) & 0',, #V% +<$% 0',* & 0'+0 #V% *<$% 0')2 #N%J = 8.4 Hz, 1H), 4.66 (s, 2H), 4.10 - 4.01 (m, 2H), 1.24 - 1.13 (m, 3H). Step 2: 7-Bromo-4-ethyl-6-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one To a solution of 4-ethyl-6-phenyl-2H-benzo[b][1,4]oxazin-3(4H$&XWO #0) VQ% +0 / lVXU$ SW8@: #* V?$ `K\ KNNON A6E #21'- VQ% .., lVXU$' FRO VSa]^[O `K\ \]S[[ON K] +. d7 PX[ * R['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 overanhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (91.8 mg). MS: m / z = 332.0, 334.0 [M + H]+. 1H NMR (400 MHz, Dimethylsulfoxide-d6$ g7.49 - 7.44 (m, 2H), 7.43 - 7.39 (m, 3H), 7.38 (s, 1H), 7.15 (s, 1H), 4.71 (s, 2H), 3.99 - 3.92 (m, 2H), 1.14 - 1.10 (m, 3H). Step 3: 4-((1-(4-(4-Ethyl-3-oxo-6-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile A mixture of 7-bromo-4-ethyl-6-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one (90 mg, 271 lVXU$% #**- VQ% +0- lVXU$% 7\2CO3 #+ / . VQ% 1*, lVXU$% CN#NYYP$7U2 #,2'0 VQ% .-'+ lVXU$ SW1,4-dioxane (5 mL) and H2O (1 mL) was degassed, purged with N2 three times, and stirred under N2at 90 °C for 2 hr. The reaction mixture was quenched with H2O (10 mL) at 25 °C and extracted with CH2Cl2(15 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 20% ~ 78% EtOAc in petroleum ether), the title compound (Example 19, 66.2 mg, yield: 41% for two steps) was obtained. MS: m / z = 545.0 [M + H]+. 1H NMR (400 MHz, Dimethylsulfoxide-d6$ g 1'+0 & 0'2, #V% +<$% 0'+1- 7.19 (m, 3H), 7.17 - 7.08 (m, 5H), 7.07 - 6.99 (m, 3H), 6.73 - 6.59 (m, 1H), 4.72 (s, 2H), 4.10 - 3.95 (m, 2H), 3.86 - 3.68 (m, 1H), 3.43 (s, 2H), 2.79 - 2.69 (m, 2H), 2.12 - 1.99 (m, 2H), 1.88 - 1.75 (m, 2H), 1.51 - 1.35 (m, 2H), 1.19 (t, J = 6.8 Hz, 3H).

[0251] Example 20: 4-((1-(4-(4-Ethyl-3-oxo-6-phenyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileStep 1: 6-Phenyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one A mixture of 6-bromo-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (1.0 g, 4.37 mmol), phenylboronic acid (532 mg, 4.37 mmol), Cs2CO3(4.27 g, 13.1 mmol), and Pd(dppf)Cl2(319 VQ% -,0 lVXU$ SW *%-&NSXaKWO #*) V?$ KWN <2O (2 mL) was degassed, purged with N2 threetimes, and stirred under N2 at 90 °C for 2 hr. The reaction mixture was quenched with H2O (20mL) 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. After purification by silica gel flash chromatography (Eluent of 5% ~ 35% EtOAc in petroleum ether), the title compound (950 mg, yield: 94%) was obtained. MS: m / z = 227.0 [M+ H]+. 1H NMR (400 MHz, Dimethylsulfoxide-d6$ g **',+ #\% *<$% 1'). & 0'2) #V% +<$% 0'.0 &7.35 (m, 5H), 4.68 (s, 2H). Step 2: 4-Ethyl-6-phenyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one To a solution of 6-phenyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (350 mg, 1.55 mmol) in MeCN (5 mL) were added K2CO3 (641 mg, 4.64 mmol) and iodoethane (483 mg, 3.09 mmol). The mixture was stirred at 65 °C for 16 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. After purification by silica gel flash chromatography (Eluent of 0% ~ 10% EtOAc in petroleum ether), the title compound (350 mg, yield: 86%) was obtained. MS: m / z = 255.1 [M+ H]+. 1H NMR (400 MHz, Dimethylsulfoxide-d6$ g 1') / & 1')) #V% +<$% 0' / . & 0'.2 #V% *<$%7.51 - 7.44 (m, 3H), 7.42 - 7.37 (m, 1H), 4.79 (s, 2H), 4.16 (q, J = 6.8 Hz, 2H), 1.28 - 1.24 (m, 3H). Step 3: 7-Bromo-4-ethyl-6-phenyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-oneTo a solution of 4-ethyl-6-phenyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H$&XWO #*)) VQ% ,2, lVXU$SW 8@: #* V?$ `K\ KNNON A6E #*). VQ% .2) lVXU$' FRO VSa]^[O `K\ \]S[[ON K] ,. d7 PX[ +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 x 5), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound(130 mg). MS: m / z = 333.0, 334.9 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6$ g 0'1*(s, 1H), 7.68 - 7.59 (m, 2H), 7.51 - 7.40 (m, 3H), 4.83 (s, 2H), 4.06 - 3.98 (m, 2H), 1.21 - 1.13 (m, 3H). Step 4: 4-((1-(4-(4-Ethyl-3-oxo-6-phenyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile A mixture of 7-bromo-4-ethyl-6-phenyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (130 mg, 390lVXU$% =W]O[VONSK]O *) #* / - VQ% ,2) lVXU$% 7\2CO3 (381 mg, 1.17 mmol), and Pd(dppf)Cl2#+1' / VQ% ,2') lVXU$ SW *%-&NSXaKWO #. V?$ KWN <2O (1 mL) was degassed, purged with N2three times, and stirred under N2 at 90 °C for 2 hr. The reaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with CH2Cl2 (25 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated underreduced pressure. After purification by silica gel flash chromatography (Eluent of 10% ~ 72% EtOAc in petroleum ether), the title compound (Example 20, 138 mg, yield: 62% for two steps) was obtained. MS: m / z = 546.3 [M + H]+. 1H NMR (400 MHz, Dimethylsulfoxide-d6$ g 8.23 -7.97 (m, 2H), 7.43 (s, 1H), 7.27 - 7.18 (m, 7H), 7.14 - 7.08 (m, 2H), 6.83 - 6.58 (m, 1H), 4.83 (s, 2H), 4.15 - 4.06 (m, 2H), 3.90 - 3.69 (m, 1H), 3.46 (s, 2H), 2.82 - 2.69 (m, 2H), 2.13 - 2.00 (m, 2H), 1.90 - 1.77 (m, 2H), 1.51 - 1.38 (m, 2H), 1.27 - 1.19 (m, 3H).

[0252] Example 23: 4-((1-(4-(4-Ethyl-3-oxo-6-phenyl-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazin-7-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileA mixture of Intermediate 17, Intermediate 10 (132 mg, 314 mmol), Cs2CO3(307 mg, 943 mmol) and Pd(dppf)Cl2 #+,') VQ% ,*'- lVXU$ SW *%-&NSXaKWO #. V?$ KWN <2O (1 mL) was degassedand purged with N2 three times. The mixture was stirred under N2 at 80 °C for 2 hr. The reaction mixture was quenched with H2O (20 mL) and extracted with CH2Cl2 (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% ~ 3% MeOH in CH2Cl2), the title compound (Example 23, 83.3 mg, yield: 45% for two steps) was obtained. MS: m / z = 547.2 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6$ g 1'* / & 0'22 #V% +<$% 0', / & 0',) #V% .<$% 0'+0 & 0'+* #V% -<$% / ' / / #N%J = 5.6 Hz, 1H), 5.06 (s, 2H), 4.11 - 4.03 (m, 2H), 3.86 - 3.68 (m, 1H), 3.47 (s, 2H), 2.80 - 2.71 (m, 2H), 2.10 - 2.03 (m, 2H), 1.89 - 1.81 (m, 2H), 1.50 - 1.41 (m, 2H), 1.27 - 1.21 (m, 3H).

[0253] Example 30: 4-((1-(4-(7-Phenyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyrazin-6-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileStep 1: 2-((6-Amino-3-bromopyrazin-2-yl)oxy)ethan-1-ol To a solution of ethane-1,2-diol (40 mL) in THF (40 mL) was added NaH (3.07 g, 76.8 mmol, 60% in oil) slowly in an ice bath. The mixture was stirred at 0 °C for 0.5 hr before 5-bromo-6- chloropyrazin-2-amine (8 g, 38.4 mmol) was added. The resulting mixture was degassed, purged with N2 three times, and stirred under N2 at 70 °C for 16 hr. The reaction mixture was quenched with H2O (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (500 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (8.98 g). MS: m / z = 234.0, 236.0 [M + H]+.1HNMR (400 MHz, Dimethylsulfoxide-d6$ g 0'+, #\% *<$% / '.- #L[ \% +<$% -'1+ #]% J = 5.2 Hz, 1H),4.25 (t, J = 5.2 Hz, 2H), 3.75 - 3.63 (m, 2H). Step 2: (E)-N'-(5-Bromo-6-(2-hydroxyethoxy)pyrazin-2-yl)-N,N-dimethylformimidamide A solution of 2-((6-amino-3-bromopyrazin-2-yl)oxy)ethan-1-ol (8.98 g, 38.4 mmol) in DMF- DMA (45 mL) was degassed, purged with N2three times, and stirred under N2at 50 °C for 1 hr. The reaction mixture was quenched with H2O (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (500 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (11.1 g). MS: m / z= 288.9, 290.9 [M + H]+. 1H NMR (400 MHz, Dimethylsulfoxide-d6$ g 1'-1 #\% *<$% 0'.* #\%1H), 4.86 (t, J = 5.2 Hz, 1H), 4.40 - 4.35 (m, 2H), 3.77 - 3.70 (m, 2H), 3.13 (s, 3H), 3.01 (s, 3H). Step 3: (E)-N'-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyrazin-6-yl)-N,N-dimethylformimidamide A mixture of (E)-N'-(5-bromo-6-(2-hydroxyethoxy)pyrazin-2-yl)-N,N-dimethylformimidamide (11.1 g, 38.4 mmol), Pd(OAc)2(862 mg, 3.84 mmol), BINAP (4.78 g, 7.68 mmol) and Cs2CO3(37.5 g, 115 mmol) in toluene (200 mL) was degassed, purged with N2three times, and stirred under N2 at 90 °C for 16 hr. The reaction mixture was quenched with H2O (500 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (500mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 100% EtOAc in petroleumO]RO[$ KWN ][S]^[K]SXW `S]R 9]B5M K] +. m PX[ *. VSW% ]RO ]S]UO MXVYX^WN #+',. Q% bSOUN3 +2"for three steps) was obtained. MS: m / z = 209.0 [M + H]+.1H NMR (400 MHz,Dimethylsulfoxide-d6$ g 1'+. #\% *<$% 0',- #\% *<$% -'-) & -',+ #V% -<$% ,') / #\% ,<$% +'2. #\%3H). Step 4: 2,3-Dihydro-[1,4]dioxino[2,3-b]pyrazin-6-amine To a solution of (E)-N'-(2,3-dihydro-[1,4]dioxino[2,3-b]pyrazin-6-yl)-N,N- dimethylformimidamide (2.35 g, 11.3 mmol) in EtOH (30 mL) was added ethane-1,2-diamine (3.87 g, 64.4 mmol). The mixture was degassed, purged with N2three times, and stirred under N2at 80 °C for 16 hr. The reaction mixture was quenched with H2O (100 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (150 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound(1.35 g). MS: m / z = 154.0 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6$ g 0')- #\% *<$%5.79 (br s, 2H), 4.33 - 4.29 (m, 2H), 4.27 - 4.22 (m, 2H). Step 5: 6-Bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyrazineTo a solution of 2,3-dihydro-[1,4]dioxino[2,3-bJYb[KcSW& / &KVSWO #*)) VQ% / ., lVXU$ SW <2O#* V?$ KWN <6[ #110 l?% / '., VVXU% -)" `(` SW `K]O[$ `K\ KNNON AKAB2 (67.6 mg, 980lVXU$ \UX`Ub SW KW SMO LK]R' FRO VSa]^[O `K\ \]S[[ON K] ) d7 PX[ . VSW LOPX[O 7^6[ #*10 VQ%1.31 mmol) was added. The mixture was degassed, purged with N2three times, and stirred under N2at 0 °C for 1 hr. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (80 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound(142 mg). 1H NMR (400 MHz, Dimethylsulfoxide-d6$ g 0'20 #\% *<$% -'.* & -'-0 #V% -<$'Step 6: 6-Phenyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyrazine To a solution of 6-bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyrazine (1.56 g, 7.19 mmol) phenylboronic acid (964 mg, 7.91 mmol,) in H2O (3 mL) and 1,4-dioxane (15 mL) were addedPd(dppf)Cl2 #.+ / VQ% 0*2 lVXU$ KWN 7\2CO3 (7.03 g, 21.6 mmol). The mixture was degassed,purged with N2 three times, and stirred under N2 at 90 °C for 2 hr. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (80 mL x 2), 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 (400 mg, yield: 26% for three steps) wasobtained. MS: m / z = 215.1 [M + H]+. 1H NMR (400 MHz, Dimethylsulfoxide-d6$ g 1'-* #\%1H), 7.99 - 7.93 (m, 2H), 7.50 - 7.39 (m, 3H), 4.51(s, 4H). Step 7: 6-Bromo-7-phenyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyrazine To a solution of 6-phenyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyrazine (390 mg, 1.82 mmol) in DMF (5 mL) was added NBS (1.30 g, 7.28 mmol). The mixture was degassed, purged with N2 three times, and stirred under N2 at 80 °C for 72 hr. The reaction mixture was quenched with H2O (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL x 3), 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 (171 mg, yield: 31%) was obtained. MS: m / z = 293.0, 294.9 [M + H]+. 1H NMR (400 MHz, Chloroform-d$ g 0'0, & 0' / 1 #V% +<$% 0'-0 & 0',2 #V% ,<$% -'.+ #\%4H). Step 8: 4-((1-(4-(7-Phenyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyrazin-6-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile To a solution of 6-bromo-7-phenyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyrazine (80 mg, 273 lVXU$% =W]O[VONSK]O *) #*+) VQ% +10 lVXU$ SW *%-&NSXaKWO #+ V?$ KWN <2O (0.4 mL) wereadded Pd(dppf)Cl2 #+)') VQ% +0', lVXU$ KWN 7\2CO3 #+ / 0 VQ% 1*2 lVXU$' FRO VSa]^[O `K\degassed, purged with N2 three times, and stirred under N2 at 90 °C for 2 hr. The reaction mixture was quenched with EtOAc (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by prep&<C?7 #MXU^VW378+-&HCF 7*1 *.) a +. a 0 lV4mobile phase: [water (NH4HCO3) - ACN]; gradient: 35% - 65% B over 10 min), the title compound (Example 30, 48.0 mg, yield: 35%) was obtained. MS: m / z = 506.2 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6$ g 1'** & 0'21 #V% +<$% 0'+2 & 0'+ / #V% .<$% 0'+- & 0'*2(m, 4H), 6.66 (d, J = 6.0 Hz, 1H), 4.55 (s, 4H), 3.83 - 3.71 (m, 1H), 3.46 (s, 2H), 2.78 - 2.71 (m, 2H), 2.12 - 2.03 (m, 2H), 1.89 - 1.80 (m, 2H), 1.50 - 1.38 (m, 2H).

[0254] Example 31: 4-((1-(4-(4-(Methyl-d3)-3-oxo-6-phenyl-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazin-7-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileStep 1: 4-(Methyl-d3)-6-phenyl-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one To a solution of 6-phenyl-2H-pyrazino[2,3-b][1,4]oxazin-3(4H$&XWO #*-) VQ% / * / lVXU% [OPO[to Intermediate 17 for detail procedures) in MeCN (6 mL) were added Cs2CO3 (602 mg, 1.85mmol) and iodomethane-d3 #*,- VQ% 2+- lVXU$' FRO VSa]^[O `K\ \]S[[ON K] 1) d7 PX[ )'. R['The reaction mixture was quenched with H2O (30 mL) at 25 °C and extracted with CH2Cl2 (25 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (150 mg). MS: m / z = 245.2 [M + H]+. D%: 3D% = 99.41%. Step 2: 7-Bromo-4-(methyl-d3)-6-phenyl-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one To a solution of 4-(methyl-d3)-6-phenyl-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one (150 mg, / *- lVXU$ SW 8@: #+ V?$ `K\ KNNON A6E #+*2 VQ% *'+, VVXU$' FRO VSa]^[O `K\ \]S[[ON K]80 °C for 2 hr. The reaction mixture was quenched with H2O (10 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 (198 mg). MS: m / z = 323.1, 325.1 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 0'0. & 0' / - #V% +<$% 0'. / & 0'-+ #V% ,<$% .') / #\% +<$' Step 3: 4-((1-(4-(4-(Methyl-d3)-3-oxo-6-phenyl-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazin-7- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile A mixture of 7-bromo-4-(methyl-d3)-6-phenyl-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one (195 VQ% / ), lVXU$% =W]O[VONSK]O *) #+., VQ% / ), lVXU$% 7\2CO3 (590 mg, 1.81 mmol), and Pd(dppf)Cl2#--'+ VQ% / )', lVXU$ SW *%-&NSXaKWO #. V?$ KWN <2O (1 mL) was degassed, purged with N2three times, and stirred under N2 at 90 °C for 4 hr. The reaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with CH2Cl2(25 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 100% EtOAc in petroleum ether), the title compound (Example 31, 181 mg, yield: 53% for three steps) was obtained. MS: m / z = 536.4 [M + H]+. D%: 3D% = 99.52%.1H NMR (400 MHz, Dimethylsulfoxide-d6$ g 8.23 - 7.98 (m, 2H), 7.39 - 7.29 (m, 5H), 7.29 - 7.20 (m, 4H),6.66 (d, J = 6.0, 1H), 5.07 (s, 2H), 3.87 - 3.68 (m, 1H), 3.47 (s, 2H), 2.82 - 2.70 (m, 2H), 2.15 - 2.01 (m, 2H), 1.91 - 1.75 (m, 2H), 1.53 - 1.38 (m, 2H).

[0255] Example 32: 4-((1-(4-(3-Oxo-6-phenyl-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazin-7-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileStep 1: 7-Bromo-6-phenyl-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-oneTo a solution of 6-phenyl-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one (345 mg, 1.52 mmol, refer to Intermediate 17) in DMF (5 mL) was added NBS (405 mg, 2.28 mmol). The mixture was stirred at 80 °C for 0.7 hr. 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 (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (460 mg). MS: m / z = 306.0, 308.0 [M + H]+.1H NMR (400 MHz, Dimethysulfoxide-d6$ g **'1(br s, 1H), 7.73 - 7.21 (m, 5H), 4.95 (s, 2H). Step 2: 4-((1-(4-(3-Oxo-6-phenyl-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazin-7- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile A mixture of 7-bromo-6-phenyl-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one (230 mg, 751 lVXU$% =W]O[VONSK]O *) #,*. VQ% 0.* lVXU$% 7\2CO3 (734 mg, 2.25 mmol), and Pd(dppf)Cl2#..') VQ% 0.'* lVXU$ SW *%-&NSXaKWO #*) V?$ KWN <2O (2 mL) was degassed, purged with N2three times, and stirred under N2 at 80 °C for 16 hr. The reaction mixture was quenched with H2O (30 mL) at 25 °C and extracted with CH2Cl2(30 mL x 2). The combined organic layers were washed with brine (25 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by prep-HPLC (column: CD20 - Waters Xbidge 69< 7*1 +.) a +. a *) lV4 VXLSUO YRK\O3 I`K]O[ #A<4HCO3) - ACN]; gradient: 28% - 58%B over 15 min), the title compound (Example 32, 51.6 mg, yield: 14% for two steps) wasobtained. MS: m / z = 519.4 [M + H]+. 1H NMR (400 MHz, Dimethylsulfoxide-d6$ g 11.75 (s,1H), 8.24 - 7.93 (m, 2H), 7.33 - 7.27 (m, 5H), 7.26 - 7.17 (m, 4H), 6.66 (d, J = 5.6 Hz, 1H), 4.96 (s, 2H), 3.85 - 3.70 (m, 1H), 3.46 (s, 2H), 2.82 - 2.70 (m, 2H), 2.14 - 2.01 (m, 2H), 1.90 - 1.79 (m, 2H), 1.50 - 1.38 (m, 2H).

[0256] Each compound in Table 3 was prepared in a similar manner (using appropriately substitutedreagents) as described in the preceding examples. Table 3II. Biological Evaluation Example 1: NanoBRET Target Engagement (TE) Assay

[0257] NanoBRET is a highly specific and validated cell-based technique for assessing targetengagement (Vasta et al., 2018, Cell Chem Biol.25(2):206-214). The NanoBRET™ Target Engagement (TE) Intracellular Kinase Assays are based on the NanoBRET™ System (Promega Corporation), an energy transfer technique designed to measure molecular proximity in living cells. The NanoBRET™ TE Assays measure the apparent affinity of test compounds by competitive displacement of the NanoBRET™ tracer compound, which is a cell permeable molecule engineered to be reversibly bound to a NanoLuc® luciferase-kinase fusion expressed in cells. For compound screening, when a test compound binds to the selected kinase, the BRET signal is attenuated. For kinase inhibitors in particular,intracellular target selectivity is fundamental to pharmacological mechanism and allows the proteins of interest to be in the correct cellular confirmation. Although non-cell-based techniques have been developed to measure kinase binding or enzymatic inhibition with accuracy and precision, such approaches can fail to accurately predict engagement of the full- length target protein in the more complex and biologically relevant cellular context (Knight and Shokat, 2005, Chem. Biol.12, 621–637; Smyth and Collins, 2009, J. Chem. Biol.2, 131– 151). The NanoBRET assay procedure was used to interrogate the compounds against the full length AKT E17K per manufacturers suggestions. Briefly, HEK-293 cells (ATCC Cat # CRL-1573) were used for transfection purposes using FuGENE HD Transfection Reagent (Promega Cat # E2311). All cells were evaluated for viability prior to transfection and optimization of the transfection was done prior to experimentation. Greater than 95% viability was used for all experiments. Following transfection, cells were washed and resuspended in Opti-MEM. NanoBRET assays were performed in white, 384-well plates (Corning) at a density of 2x105cells / well. All example compounds were prepared as concentrated stock solutions in DMSO (Sigma-Aldrich). Compounds are dissolved in DMSO to make 10 mM stock solution. Example compounds were transferred as 40uL of 10 mM stock solution to a 384 pp-plate (LABCYTE, PP-0200) and diluted in 3-fold, 10-point dilution_SK ][KW\PO[[SWQ *+ l? MXVYX^WN SW]X +- l? 8@EB Lb 5Y[SMX] USZ^SN RKWNUO[' 5 ?KLMb]OECHO 550 compound dispenser was used to facilitate compound transfer directly to cells. Cells were equilibrated for 2 hr with energy transfer probes and example compound prior to BRET measurements. The AKTE17K (Promega Cat # NV2421) as well as specific probe (NanoBRET tracer, Promega Cat # N264B) was prepared at a concentration of 20X in tracer dilution buffer (12.5 mM HEPES, 31.25% PEG-400, pH 7.5). For target engagement analysis, the energy transfer probes were added to the cells at concentrations optimized for the target in question (AKT E17K). Following compound incubation, NanoBRET NanoGlo Substrate (Promega Cat # N157D) and Extracellular Nanoluc Inhibitor (Promega Cat # N235C) was added according to the manufacturer’s recommended protocol, and luminescence was measured on Envision Reader (Perkin Elmer) Multimode Luminometer equipped with 450nmBPfilter (donor)and 600nmLPfilter (acceptor), using 0.5 s integration time. Milli-BRET units (mBU) are calculated by multiplying the raw BRET values by 1000. Apparent tracer affinity values (EC50) were determined using the sigmoidal dose-response (variable slope). Competitive displacement data were then plotted and data were fit to determine the EC50 value for each example compound. Table 4 provides the assay results for select examples. Activityis defined as “+”, for EC50greater 600 nanomolar; “++” for EC50between 60-600 nanomolar; “+++” for EC50 between 15-60 nanomolar; and “++++”, for EC50 less than 15 nanomolar. Table 4III. Preparation of Pharmaceutical Dosage Forms

[0258] Example 1: Oral capsule

[0259] The active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt, solvate,or deuteroisotope thereof. A capsule for oral administration is prepared by mixing 1-1000 mg of active ingredient with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration.

[0260] Example 2: Solution for injection

[0261] The active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt, solvate,or deuteroisotope thereof, and is formulated as a solution in sesame oil at a concentration of 50 mg-eq / mL.

[0262] The examples and embodiments described herein are for illustrative purposes only and variousmodifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

CLAIMS We claim:

1. A compound having the structure of Formula (I), or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof:wherein, R is optionally substituted aryl, or optionally substituted heteroaryl; w, x, y, and z are each independently N or C-R1; each R1is independently H, D, halogen, -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 to form a carbocycle or heterocycle; R5and R6are each independently selected from the group consisting of H, D, -OR17, - SR17, -NH2, -CN, halogen, -CO2R17, CON(R17)2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R5and R6together form an oxo or thio; or R5and R6join to form an optionally substituted carbocycle or optionally substituted heterocycle; Z1is N or C-R7; Z2is N or C-R8; X1, X2, and X3are independently selected from O, S, N(R18), or C(R19)(R20), with the provision that X2and X3are not both O or S; R7, R8, R18, R19and R20are each independently selected from the group consisting of H, D, -OR17, -SR17, -NH2, -CN, halogen, -CO2R17, CON(R17)2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each R17is independently selected from H, optionally substituted C1-C6 alkyl; n is 0 or 1;m is 0, 1, 2, or 3; 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; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 0, 1, or 2; LCG is a group selected from the group consisting of: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; and R9ais 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;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 #O$ &7hA '2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein Z1is N.

3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein Z1is C-R7.

4. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, wherein Z2is N.

5. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein Z2is C-R8.

6. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, wherein X1is O.

7. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein X1is N(R18).

8. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein X1is C(R19)(R20).

9. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, wherein X2is O.

10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein X2is N(R18).

11. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein X2is C(R19)(R20).

12. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, wherein X3is C(R19)(R20).

13. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, wherein R7is H.

14. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, wherein R8is H.

15. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, wherein R18is H.

16. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R18is an optionally substituted C1-C6 alkyl.

17. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R18is an optionally substituted C1-C2 alkyl.

18. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R18is -CH3.

19. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R18is -CH2CH3.

20. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R18is -CD3.

21. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, wherein R19is H.

22. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, wherein R20is H.

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

24. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein m is 1.

25. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein m is 2.

26. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein m is 3.

27. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, wherein R5and R6are each independently selected from the group consisting of H, D, -OR17, -SR17, -NH2, -CN, halogen, -CO2R17, CON(R17)2, optionally substituted C1-C6 alkyl, or optionally substituted C3-C7 carbocyclyl.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R5is H.

29. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R6is H.

30. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R5and R6are each independently selected from the groupconsisting of optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

31. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R5and R6together form an oxo.

32. A compound having the structure of Formula (II), or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof:wherein, R is optionally substituted aryl, or optionally substituted heteroaryl; w, x, y, and z are each independently N or C-R1; each R1is independently H, D, halogen, -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 to form a carbocycle or heterocycle; Z3is N or C-R22; X4is O or S; R21and R22are each independently selected from the group consisting of H, D, -OR17, -SR17, -NH2, -CN, halogen, -CO2R17, CON(R17)2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R17is selected from H, optionally substituted C1-C6 alkyl; n is 0 or 1; 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; a1 is 0, 1, 2, 3, or 4;b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 0, 1, or 2; 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; and R9ais 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;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 KUTXab4 KWe#O$ &7hA '33. The compound of claim 32, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein Z3is N.

34. The compound of claim 32, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein Z3is C-R22.

35. The compound of any one of claims 32-34, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein X4is O.

36. The compound of any one of claims 32-35, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R17is H.

37. The compound of any one of claims 32-35, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R17is optionally substituted C1-C6 alkyl.

38. The compound of any one of claims 32-37, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R21is selected from the group consisting of H, D, -OR17, - SR17, -NH2, -CN, halogen, -CO2R17, CON(R17)2, optionally substituted C1-C6 alkyl, and optionally substituted C3-C7 carbocyclyl.

39. The compound of any one of claims 32-37, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R21is selected from the group consisting of optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

40. The compound of any one of claims 32-39, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R22is selected from the group consisting of H, D, -OR17, - SR17, -NH2, -CN, halogen, -CO2R17, CON(R17)2, optionally substituted C1-C6 alkyl, and optionally substituted C3-C7 carbocyclyl.

41. The compound of any one of claims 32-39, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R22is selected from the group consisting of optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

42. A compound having the structure of Formula (III), or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof:wherein, R is optionally substituted aryl, or optionally substituted heteroaryl; w, x, y, and z are each independently N or C-R1; each R1is independently H, D, halogen, -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 to form a carbocycle or heterocycle; Z4is N or C-R24; X5is O or S; R23and R24are each independently selected from the group consisting of H, D, -OR17, -SR17, -NH2, -CN, halogen, -CO2R17, CON(R17)2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R17is selected from H, optionally substituted C1-C6 alkyl; n is 0 or 1; 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; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 0, 1, or 2; LCG is a group selected from the group consisting of: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; and R9ais 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 al€;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 alko€ and43. The compound of claim 42, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein Z4is N.

44. The compound of claim 42, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein Z4is C-R24.

45. The compound of any one of claims 42-44, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein X4is O.

46. The compound of any one of claims 42-45, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R17is H.

47. The compound of any one of claims 42-45, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R17is optionally substituted C1-C6 alkyl.

48. The compound of any one of claims 42-47, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R23is selected from the group consisting of H, D, -OR17, - SR17, -NH2, -CN, halogen, -CO2R17, CON(R17)2, optionally substituted C1-C6 alkyl, and optionally substituted C3-C7 carbocyclyl.

49. The compound of any one of claims 42-47, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R23is selected from the group consisting of optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

50. The compound of any one of claims 42-49, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R24is selected from the group consisting of H, D, -OR17, - SR17, -NH2, -CN, halogen, -CO2R17, CON(R17)2, optionally substituted C1-C6 alkyl, and optionally substituted C3-C7 carbocyclyl.

51. The compound of any one of claims 42-49, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R24is selected from the group consisting of optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

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

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

54. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R is optionally substituted heteroaryl.

55. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R is optionally substituted pyridine.

56. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, wherein w is C-R1.

57. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, wherein x is C-R1.

58. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, wherein y is C-R1.

59. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, wherein z is C-R1.

60. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, wherein w, x, y, and z are C-R1.

61. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, wherein R1is H.

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

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

64. The compound of any one of claims 1-62, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein n is 1.

65. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, wherein L is selected from:

66. The compound of claim 65, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein L is:.

67. The compound of claim 66, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein R4is H.

68. The compound of any one of claims 1-64, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein L is selected from:.

69. The compound of claim 68, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein L is:.

70. The compound of any one of claims 1-64, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein L is -N(R4)-.

71. The compound of any one of claims 1-64, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein L is selected from:.

72. The compound of claim 71, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein L is: .

73. The compound of any one of the preceding claims, 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; and R9ais 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.

74. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope 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.

75. The compound of claim 74, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein LCG is:.

76. The compound of claim 75, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein LCG is:.

77. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein LCG is:.

78. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein LCG is: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.

79. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope 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.

80. The compound of claim 79, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein LCG is:.

81. The compound of claim 80, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein R13is H.

82. The compound of claim 80, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein R14is H.

83. The compound of claim 80, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein R15is H.

84. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, orNO^]O[XS\X]XYO ]RO[OXP% `RO[OSW ?7; S\ &7hA'85. The compound of any one of claims 1-64, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein L is:.

86. The compound of claim 85, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R4is H.

87. The compound of any one of claims 1-64, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein L is:.

88. The compound of any one of claims 1-64, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein L is:.

89. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein Z1is N.

90. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein Z1is C-R7.

91. The compound of claim 90, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein R7is H.

92. The compound of any one of claims 89-91, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein Z2is N.

93. The compound of any one of claims 89-91, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein Z2is C-R8.

94. The compound of claim 93, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein R8is H.

95. The compound of any one of claims 89-94, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein X1is N(R18).

96. The compound of claim 95, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein R18is an optionally substituted C1-C6 alkyl.

97. The compound of claim 95, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein R18is an optionally substituted C1-C2 alkyl.

98. The compound of claim 95, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein R18is -CH3.

99. The compound of claim 95, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein R18is -CH2CH3.

100. The compound of claim 95, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein R18is -CD3.

101. The compound of claim 95, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein R18is H.

102. The compound of any one of claims 89-101, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein X2is O.

103. The compound of any one of claims 89-102, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein X3is C(R19)(R20).

104. The compound of claim 103, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein R19is H.

105. The compound of claim 103, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein R20is H.

106. The compound of any one of claims 89-105, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein m is 1.

107. The compound of any one of claims 89-106, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R5and R6together form an oxo.

108. The compound of any one of claims 89-107, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R is optionally substituted aryl.

109. The compound of any one of claims 81-108, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R is optionally substituted phenyl.

110. The compound of any one of claims 81-109, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein w, x, y, and z are C-R1.

111. The compound of claim 110, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein R1is H.

112. The compound of any one of claims 89-111, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R2and R3are H.

113. The compound of any one of claims 89-112, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein n is 0.

114. The compound of any one of claims 89-113, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein L is:.

115. The compound of claim 114, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein R4is H.

116. The compound of any one of claims 89-113, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein L is:.

117. The compound of any one of claims 89-113, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein L is: .

118. The compound of any one of claims 89-117, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein LCG is:.

119. The compound of any one of claims 89-117, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein LCG is:.

120. The compound of claim 119, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein R13is H.

121. The compound of claim 119, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein R14is H.

122. The compound of claim 119, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein R15is H.

123. A compound, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, asdescribed in Table 1.

124. A compound, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, asdescribed in Table 2.

125. A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, as described in any one of the preceding claims and a pharmaceutically acceptable excipient.

126. A method of preparing a pharmaceutical composition comprising mixing a compound, orpharmaceutically acceptable salt, solvate, or deuteroisotope thereof, of any one of claims 1- 124, and a pharmaceutically acceptable carrier.

127. A compound of any one of claims 1-124, or pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, for use in a method of treatment of the human or animal body.

128. A compound of any one of claims 1-124, or pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, for use in a method of treatment of cancer or neoplastic disease.

129. Use of a compound of any one of claims 1-124, or pharmaceutically acceptable salt, solvate,or deuteroisotope thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

130. A method of treating cancer in a patient in need thereof, comprising administering to thepatient a compound as described in any one of claims 1-124, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof.

131. A method of treating cancer in a patient in need thereof, comprising administering to thepatient a pharmaceutical composition comprising a compound as described in any one of claims 1-124, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient.

132. A method of inhibiting an AKT1 enzyme comprising contacting the enzyme with a compoundof any one of claims 1-124, wherein the AKT1 enzyme is contacted in an in vitro setting.

133. A method of inhibiting an AKT1 enzyme comprising contacting the enzyme with a compoundof any one of claims 1-124, wherein the AKT1 enzyme is contacted in an in vivo setting.

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