AKT1 modulators

Abstract

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

Description

AKT1 MODULATORSCROSS REFERENCE

[0001] This application claims the benefit of US Provisional Application No. 63 / 562,149, filed March 6, 2024, US Provisional Application No. 63 / 570,085, filed March 26, 2024, and US Provisional Application No. 63 / 644,336, filed May 8, 2024, all of which are incorporated by reference in their entirety herein.BACKGROUND

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

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

[0004] The present disclosure provides compounds having the structure of Formula (I), and pharmaceutically acceptable salts or solvates thereofwherein:A is C-H and B is C-H; or A is C-H, and B is N; or A is N, and B is C-H; or A is N, and B is N;Z1is N, C-H, or C-R3;Z2is N, C-H, or C-R4;Z3is N, C-OH, or C-R9;R1is selected from optionally substituted aryl, or optionally substituted heteroaryl;R2is selected from hydrogen, halogen, -OH, -CN, -N(R9)2, -OR9, -SR9, -SO2R9, - CO2R9, -CON(R9)2, -SR9, -S(O)R9, - S(O)2R9, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 4-membered to 6- membered heterocyclyl, optionally substituted aryl, aryl substituted with an optionally substituted 4-membered to 6-membered heterocyclyl, optionally substituted heteroaryl or heteroaryl substituted with an optionally substituted 3-membered to 6-membered carbocyclyl;R3is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl;R4is selected from halogen, -CN, optionally substituted C1-C6 alkyl, or optionally substituted aryl;R5and R6are each independently hydrogen, deuterium, halogen, -OH, or optionally substituted C1-C6 alkyl; or R5and R6together form an oxo; or R5and R6join together to form a carbocycle or heterocycle;LCG is a group selected from the group consisting of:Q2is O or S;Q3is a bond, O, S, or N-R22;R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; andR22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle;(b)T1is N or C-R23;T2is N or C-R23;T3is N or C-R23;T4is N or C-R23;T5is O, S, or N-R24; each R23is 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 R24is hydrogen, or optionally substituted C1-C6 alkyl;T6is N or C-R25;T7is N or C-R25;T8is N or C-R25; each R25is 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 R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and(e) -ON ;L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the -(CO)q-Ar group;R8is optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, or optionally substituted heterocyclyl; each R9is hydrogen, or optionally substituted C1-C6 alkyl; m is 0, 1, or 2; n is 1, 2, or 3; and q is 0 or 1.

[0005] The present disclosure further provides compounds having the structure of Formula (la), and pharmaceutically acceptable salts or solvates thereof:X1is N or C-R7;X2is N or C-R7;X3is N or C-R7;X4is N or C-R7;Y is O, S, or N-R9;R1is selected from optionally substituted aryl, or optionally substituted heteroaryl;R2is selected from hydrogen, halogen, -OH, -CN, -N(R9)2, -OR9, -SR9, -SO2R9, - CO2R9, -CON(R9)2, -SR9, -S(O)R9, - S(O)2R9, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 4-membered to 6- membered heterocyclyl, optionally substituted aryl, aryl substituted with an optionally substituted 4-membered to 6-membered heterocyclyl, optionally substituted heteroaryl or heteroaryl substituted with an optionally substituted 3-membered to 6-membered carbocyclyl;R3is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl;R4is selected from halogen, -CN, optionally substituted C1-C6 alkyl, or optionally substituted aryl;R5and R6are each independently hydrogen, deuterium, halogen, -OH, or optionally substituted C1-C6 alkyl; or R5and R6together form an oxo; or R5and R6join together to form a carbocycle or heterocycle; each R7is 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;L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the -(CO)q-Ar group;R8is optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, or optionally substituted heterocyclyl; each R9is hydrogen, or optionally substituted C1-C6 alkyl; m is 0, 1, or 2; n is 1, 2, or 3; andq is 0 or 1.

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

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

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

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

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

[0011] " Amino" refers to the -NH2 radical.

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

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

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

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

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

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

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

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

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

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

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

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

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

[0025] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkenylene comprises two to eight carbon atoms (e.g., C2-C8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (e.g., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., Cs-Cs alkenylene). In other embodiments, an alkenylene comprises three to fivecarbon atoms (e.g., C3-C5 alkenylene). Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SIU, - OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, - N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0026] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C2-Cs alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C2-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C2alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., Cs-Cs alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C3-C5 alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -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(0)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] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, z.e., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Hiickel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, cyano, nitro, -Rb-ORa, -Rb-OC(O)- Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb- C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb- S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

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

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

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

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

[0032] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (z.e., containing single C-C bonds only) or unsaturated (z.e., containing one or more double bonds or triple bonds). A fully saturated carbocyclyl radical is also referred to as "cycloalkyl." Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (z.e., bicyclo[2.2.1]heptanyl), norbomenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, oxo, thioxo, cyano, nitro, -Rb-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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0050] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,nC,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in 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.

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

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

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

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

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

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

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

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

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

[0060] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the AKT1 inhibitory compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

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

[0062] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, A,7V-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, A-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

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

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

[0065] As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and / or a prophylactic benefit. By “therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.AKT1 Protein and Function

[0066] AKT, also known as protein kinase B (PKB), is a serine / threonine protein kinase with three isoforms, AKT1, AKT2, and AKT3. While the isoforms are encoded by different genes, they are highly homologous at the protein level and share a conserved domain structure comprising an N-terminal pleckstrin homology (PH) domain, a kinase domain, and a C- terminal regulatory domain comprising a hydrophobic moiety, which includes the regulatory serine residue (Nitulescu, G. M. et al., Int J Oncol., 2018; 53(6): 2319-2331).

[0067] AKT proteins play a crucial role in major cellular functions including cell cycle progression, cell size, regulation of glucose metabolism, transcription, protein synthesis, genome stability, and neovascularization. AKT proteins can block apoptosis by inactivation of pro-apoptotic proteins, and mediate cellular growth factors, promoting cell survival. AKT is a major downstream effector of nuclear factor-kappaB (NtkB), which may link AKT signaling to the nucleus of a cell.

[0068] AKT1 is ubiquitously expressed, whereas AKT2 is primarily expressed in insulin- responsive tissues, and AKT3 is primarily expressed in brain and testes. A shared phosphorylation site of AKT in the catalytic domain corresponds to a threonine residue; specifically, Thr308 in AKT1, Thr309 in AKT2, and Thr305 in AKT3. A shared phosphorylation site in the C-terminus of the protein cis a serine residue; specifically, Ser473 in AKT1, Ser474 in AKT2, and Ser472 in AKT3.

[0069] AKT is a key downstream mediator of the phosphoinositide-3 -kinase (PI3K) signaling pathway. PI3Ks are activated by different compounds. For example, PI3Ka, PI3KP, and PI3K5, are activated by extracellular ligands binding to a transmembrane glycoprotein with enzymatic activity, receptor tyrosine kinases (RTKs). In contrast, PI3Ky is activated by G- protein-compound receptors (GPCRs) and by RAS family of GTPases.

[0070] 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

[0071] AKT is activated by a second phosphorylation at the regulatory serine residue, Ser473. Known phosphorylating agents of AKT at Ser473 include, but are not limited to PDK-1, integrin-linked kinase (ILK), members of the PI3K-related kinase (PIKK) family, and mammalian target of rapamycin (mTOR) (Nitulescu, G. M. et al., Int J Oncol., 2018; 53(6): 2319-2331).

[0072] mTOR is a key component in the AKT signaling pathway, which is a downstream member of AKT and important regulator for cell metabolism and growth. mTOR is also an activator which can directly phosphorylate AKT’s regulatory serine residue, Ser473. mTOR forms a complex with rapamycin-insensitive companion of mTOR (RICTOR) (and other proteins) to form mTOR complex 2 (mT0RC2), which can directly phosphorylate AKT Ser473. AKT can affect cell survival and growth because it can influence the tuberous sclerosis complex (TSC) 1 / 2 along the mTORC signaling pathway and inhibit pro-apoptotic proteins or signals.

[0073] AKT is known as a survival kinase and mediates cell survival and proliferation by inhibiting pathways including, but not limited to Bcl2 and MDM2, which promotes apoptosis. Studies have shown that the AKT signaling cascade have 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 enhancedproliferation, 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.

[0074] Additionally, AKT1 has been found to be involved in invasion and migration of cancerous cells (Alwhaibi, A. et al., Pharmacol Res., 2019, 145: 104270). Researchers found that silencing the AKT1 isoform can abrogate specific types of cancer cell migration. However, there have been other studies which have demonstrated that activated AKT1 resulted in less metastatic propensity for lung metastatic lesion cells and breast cancer cells. AKT1 has also been identified as a key protein involved in angiogenesis, lung cancer, and tumorigenesis.

[0075] Furthermore, overexpression of AKT has been correlated to resistance to chemotherapeutic agents such as cisplatin, methotrexate, and paclitaxel. Thus, there remains a need to find AKT inhibitors given its role in cell survival and cancer proliferation.

[0076] 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.

[0077] The E17K mutation enhances migration of breast cancer cells, and also enhances resistance to chemotherapeutic drugs. However, the E17K mutation can also selectively destroy chemo-resistant tumor-promoting AKT1 quiescent cancer cells, suggesting that the AKT1(E17K) mutation is crucial in the oncogenic / anti-tumor mechanism.

[0078] A major pathway that activates PI3K-AKT signaling pathway is somatic cell mutations, with the E17K mutation being the highest frequency of AKT1 mutations. It is nearly exclusively present in AKT1. The AKT1(E17K) is a recurrent somatic cell mutation predominantly in breast cancer, ovarian cancer, meningioma, and Proteus syndrome.

[0079] AKT1(E17K) mutations mediate the PI3K-AKT signaling cascade by expanding PIP lipid specificity, which causes conformational changes. This also enhances subcellularlocalization to accelerate localization of the PH structural domain to the plasma membrane. The E17K mutation increases PIP3 binding specificity by 7-fold and phosphatidylinositol - (4,5)-bisphosphate (PIP2) by 100-fold.

[0080] The AKT1(E17K) mutation also causes rapid conformational changes in the AKT1 PH structural domain. The conformational changes to this domain result in a 4.5-fold increase in its membrane localization, which can result in excessive phosphorylation. The AKT1(E17K) mutation can also result in enhanced subcellular localization by increasing the transient expression.

[0081] Given the conformational and signaling effects of the AKT1(E17K) mutation, this target may be useful for targeted treatment of cancers.Prior Art AKT1 Inhibitors

[0082] Most AKT inhibitors targeting the ATP binding site are non-selective against the three isoforms, as well as having poor to no selectivity against other structurally similar kinases. Thus, there remains a need to develop new and novel AKT inhibitors. These ATP targeting inhibitors are classified as aminofurazans, azepane derivatives, isoquinoline-5- sulfonamides, phenylpyrazole derivatives, thiophene carboxamide derivatives, and thiazole carboxamide derivatives.

[0083] There are also ATP non-competitive AKT inhibitors which are allosteric modulators which has 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

[0084] In one aspect, provided herein is an AKT1 inhibitory compound as described in the listing of embodiments provided below.

[0085] Embodiment 1 : A compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:wherein:A is C-H and B is C-H; or A is C-H, and B is N; or A is N, and B is C-H; or A is N, and B is N;Z1is N, C-H, or C-R3;Z2is N, C-H, or C-R4;Z3is N, C-OH, or C-R9;R1is selected from optionally substituted aryl, or optionally substituted heteroaryl;R2is selected from hydrogen, halogen, -OH, -CN, -N(R9)2, -OR9, -SR9, -SO2R9, - CO2R9, -CON(R9)2, -SR9, -S(O)R9, - S(O)2R9, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 4-membered to 6- membered heterocyclyl, optionally substituted aryl, aryl substituted with an optionally substituted 4-membered to 6-membered heterocyclyl, optionally substituted heteroaryl or heteroaryl substituted with an optionally substituted 3-membered to 6-membered carbocyclyl;R3is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl;R4is selected from halogen, -CN, optionally substituted C1-C6 alkyl, or optionally substituted aryl;R5and R6are each independently hydrogen, deuterium, halogen, -OH, or optionally substituted C1-C6 alkyl; or R5and R6together form an oxo; or R5and R6join together to form a carbocycle or heterocycle;LCG is a group selected from the group consisting of:Q2is O or S;Q3is a bond, O, S, or N-R22;R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; andR22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle;(b)T1is N or C-R23;T2is N or C-R23;T3is N or C-R23;T4is N or C-R23;T5is O, S, or N-R24; each R23is 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 R24is hydrogen, or optionally substituted C1-C6 alkyl;T6is N or C-R25;T7is N or C-R25;T8is N or C-R25; each R25is 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 R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and(e) -ON ;L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the -(CO)q-Ar group;R8is optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, or optionally substituted heterocyclyl; each R9is hydrogen, or optionally substituted C1-C6 alkyl; m is 0, 1, or 2; n is 1, 2, or 3; and q is 0 or 1.

[0086] Embodiment 2: A compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:wherein:A is C-H and B is C-H; or A is C-H, and B is N; or A is N, and B is C-H; or A is N, and B is N;Z1is N, C-H, or C-R3;Z2is N, C-H, or C-R4;Z3is N, C-OH, or C-R9;R1is selected from optionally substituted aryl, or optionally substituted heteroaryl;R2is selected from hydrogen, halogen, -OH, -CN, -N(R9)2, -OR9, -SR9, -SO2R9, - CO2R9, -CON(R9)2, -SR9, -S(O)R9, - S(O)2R9, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 4-membered to 6- membered heterocyclyl, optionally substituted aryl, aryl substituted with an optionally substituted 4-membered to 6-membered heterocyclyl, optionally substituted heteroaryl or heteroaryl substituted with an optionally substituted 3-membered to 6-membered carbocyclyl;R3is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl;R4is selected from halogen, -CN, optionally substituted C1-C6 alkyl, or optionally substituted aryl;R5and R6are each independently hydrogen, deuterium, halogen, -OH, or optionally substituted C1-C6 alkyl; or R5and R6together form an oxo; or R5and R6join together to form a carbocycle or heterocycle;LCG is a group selected from the group consisting of:Q1is O or S;Q2is O or S;Q3is a bond, O, S, or N-R22;R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; andR22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle;(b)T1is N or C-R23;T2is N or C-R23;T3is N or C-R23;T4is N or C-R23;T5is O, S, orN-R24; each R23is 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 R24is hydrogen, or optionally substituted C1-C6 alkyl;T6is N or C-R25;T7is N or C-R25;T8is N or C-R25; each R25is 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 R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and(e) -C=N ;L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the -(CO)q-Ar group;R8is optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, or optionally substituted heterocyclyl; each R9is hydrogen, or optionally substituted C1-C6 alkyl; m is 0, 1, or 2; n is 1, 2, or 3; and q is 0 or 1.

[0087] Embodiment 3: A compound having the structure of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:wherein:A is C-H and B is C-H; or A is C-H, and B is N; or A is N, and B is C-H; or A is N, and B is N;Z1is N, C-H, or C-R3;Z2is N, C-H, or C-R4;Z3is N, C-OH, or C-R9;R1is selected from optionally substituted aryl, or optionally substituted heteroaryl; R2is selected from hydrogen, halogen, -OH, -CN, -N(R9)2, -OR9, -SR9, -SO2R9, - CO2R9, -CON(R9)2, -SR9, -S(O)R9, - S(O)2R9, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 4-membered to 6-membered heterocyclyl, optionally substituted aryl, aryl substituted with an optionally substituted 4-membered to 6- membered heterocyclyl, optionally substituted heteroaryl or heteroaryl substituted with an optionally substituted 3-membered to 6-membered carbocyclyl;R3is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl;R4is selected from halogen, -CN, optionally substituted C1-C6 alkyl, or optionally substituted aryl;R5and R6are each independently hydrogen, deuterium, halogen, -OH, or optionally substituted C1-C6 alkyl; or R5and R6together form an oxo; or R5and R6join together to form a carbocycle or heterocycle;LCG is a group selected from the group consisting of:Q2is O or S;Q3is a bond, O, S, or N-R22;R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; andR22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle;(b)T1is N or C-R23;T2is N or C-R23;T3is N or C-R23;T4is N or C-R23;T5is O, S, or N-R24; each R23is 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 R24is hydrogen, or optionally substituted C1-C6 alkyl;T6is N or C-R25;T7is N or C-R25;T8is N or C-R25; each R25is 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 R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and(e) -C=N ;L is a divalent radical selected from:asterisk (*) indicates the bond to the -(CO)q-Ar group;R8is optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, or optionally substituted heterocyclyl; each R9is hydrogen, or optionally substituted C1-C6 alkyl; m is 0, 1, or 2; n is 1, 2, or 3; and q is 0 or 1.

[0088] Embodiment 4: The compound of any one of Embodiments 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein LCG is:, whereinQ1is O or S;Q2is O or S;Q3is a bond, O, S, or N-R22;R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; andR22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21 and R22 join together to form a heterocycle.

[0089] Embodiment 5: The compound of any one of Embodiments 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein LCG is:; whereinT6is N or C-R25;T7is N or C-R25;T8is N or C-R25; each R25is 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.

[0090] Embodiment 6: The compound of any one of Embodiments 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein LCG is :wherein, each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy.

[0091] Embodiment 7: The compound of any one of Embodiments 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein LCG is -C=N.

[0092] Embodiment 8: The compound of any one of Embodiments 1-7, or a pharmaceutically acceptable salt or solvate thereof, wherein A is C-H, and B is N.

[0093] Embodiment 9: The compound of any one of Embodiments 1-7, or a pharmaceutically acceptable salt or solvate thereof, wherein A is N, and B is C-H.

[0094] Embodiment 10: The compound of any one of Embodiments 1-7, or a pharmaceutically acceptable salt or solvate thereof, wherein A is N, and B is N.

[0095] Embodiment 11 : The compound of any one of Embodiments 1-7, or a pharmaceutically acceptable salt or solvate thereof, wherein A is C-H and B is C-H.

[0096] Embodiment 12: A compound having the structure of Formula (la), or a pharmaceutically acceptable salt or solvate thereof:X1is N or C-R7;X2is N or C-R7;X3is N or C-R7;X4is N or C-R7;Y is O, S, or N-R9;R1is selected from optionally substituted aryl, or optionally substituted heteroaryl;R2is selected from hydrogen, halogen, -OH, -CN, -N(R9)2, -OR9, -SR9, -SO2R9, - CO2R9, -CON(R9)2, -SR9, -S(O)R9, - S(O)2R9, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 4-membered to 6- membered heterocyclyl, optionally substituted aryl, aryl substituted with an optionallysubstituted 4-membered to 6-membered heterocyclyl, optionally substituted heteroaryl or heteroaryl substituted with an optionally substituted 3-membered to 6-membered carbocyclyl;R3is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl;R4is selected from halogen, -CN, optionally substituted C1-C6 alkyl, or optionally substituted aryl;R5and R6are each independently hydrogen, deuterium, halogen, -OH, or optionally substituted C1-C6 alkyl; or R5and R6together form an oxo; or R5and R6join together to form a carbocycle or heterocycle; each R7is 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;L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the -(CO)q-Ar group;R8is optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, or optionally substituted heterocyclyl; each R9is hydrogen, or optionally substituted C1-C6 alkyl;m is 0, 1, or 2; n is 1, 2, or 3; and q is 0 or 1.

[0097] Embodiment 13: A compound having the structure of Formula (la), or a pharmaceutically acceptable salt or solvate thereof:X1is N or C-R7;X2is N or C-R7;X3is N or C-R7;X4is N or C-R7;Y is O, S, or N-R9;R1is selected from optionally substituted aryl, or optionally substituted heteroaryl;R2is selected from hydrogen, halogen, -OH, -CN, -N(R9)2, -OR9, -SR9, -SO2R9, - CO2R9, -CON(R9)2, -SR9, -S(O)R9, - S(O)2R9, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 4-membered to 6-membered heterocyclyl, optionally substituted aryl, aryl substituted with an optionally substituted 4-membered to 6-membered heterocyclyl, optionally substituted heteroaryl or heteroaryl substituted with an optionally substituted 3-membered to 6-membered carbocyclyl;R3is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl;R4is selected from halogen, -CN, optionally substituted C1-C6 alkyl, or optionally substituted aryl;R5and R6are each independently hydrogen, deuterium, halogen, -OH, or optionally substituted C1-C6 alkyl; or R5and R6together form an oxo; or R5and R6join together to form a carbocycle or heterocycle; each R7is 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;L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the -(CO)q-Ar group;R8is optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, or optionally substituted heterocyclyl; each R9is hydrogen, or optionally substituted C1-C6 alkyl; m is 0, 1, or 2; n is 1, 2, or 3; and q is 0 or 1.

[0098] Embodiment 14: A compound having the structure of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof:X1is N or C-R7;X2is N or C-R7;X3is N or C-R7;X4is N or C-R7;Y is O, S, or N-R9;R1is selected from optionally substituted aryl, or optionally substituted heteroaryl; R2is selected from hydrogen, halogen, -OH, -CN, -N(R9)2, -OR9, -SR9, -SO2R9, - CO2R9, -CON(R9)2, -SR9, -S(O)R9, - S(O)2R9, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 4-membered to 6-membered heterocyclyl, optionally substituted aryl, aryl substituted with an optionally substituted 4-membered to 6-membered heterocyclyl, optionally substituted heteroaryl or heteroaryl substituted with an optionally substituted 3-membered to 6-membered carbocyclyl;R3is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl;R4is selected from halogen, -CN, optionally substituted C1-C6 alkyl, or optionally substituted aryl;R5and R6are each independently hydrogen, deuterium, halogen, -OH, or optionally substituted C1-C6 alkyl; or R5and R6together form an oxo; or R5and R6join together to form a carbocycle or heterocycle; each R7is 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;L is a divalent radical selected from:asterisk (*) indicates the bond to the -(CO)q-Ar group;R8is optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, or optionally substituted heterocyclyl; each R9is hydrogen, or optionally substituted C1-C6 alkyl; m is 0, 1, or 2; n is 1, 2, or 3; and q is 0 or 1.

[0099] Embodiment 15: The compound of any one of Embodiments 1-14, or pharmaceutically acceptable salt or solvate thereof, wherein Z1is N.

[0100] Embodiment 16: The compound of any one of Embodiments 1-15, or pharmaceutically acceptable salt or solvate thereof, wherein Z2is C-H.

[0101] Embodiment 17: The compound of any one of Embodiments 1-15, or pharmaceutically acceptable salt or solvate thereof, wherein Z2is C-R4.

[0102] Embodiment 18: The compound of any one of Embodiments 1-17, or pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted heteroaryl.

[0103] Embodiment 19: The compound of Embodiment 18, or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heteroaryl is an optionally substituted pyridinyl or optionally substituted pyridinyl N-oxide.

[0104] Embodiment 20: The compound of any one of Embodiments 1-19, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted aryl.

[0105] Embodiment 21 : The compound of Embodiment 20, or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted aryl is an optionally substituted phenyl.

[0106] Embodiment 22: The compound of any one of Embodiments 1-19, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted heteroaryl.

[0107] Embodiment 23: The compound of Embodiment 22, or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heteroaryl is an optionally substituted pyridinyl.

[0108] Embodiment 24: The compound of any one of Embodiments 1-23, or pharmaceutically acceptable salt or solvate thereof, wherein R5is hydrogen.

[0109] Embodiment 25: The compound of any one of Embodiments 1-24, or pharmaceutically acceptable salt or solvate thereof, wherein R6is hydrogen.

[0110] Embodiment 26: The compound of any one of Embodiments 1-23, or pharmaceutically acceptable salt or solvate thereof, wherein R5and R6together form an oxo. [OHl] Embodiment 27: The compound of any one of Embodiments 1-24, or pharmaceutically acceptable salt or solvate thereof, wherein R6is optionally substituted Cl- C6 alkyl.

[0112] Embodiment 28: The compound of any one of Embodiments 1-23, or pharmaceutically acceptable salt or solvate thereof, wherein R5and R6join together to form a carbocycle or heterocycle.

[0113] Embodiment 29: The compound of any one of Embodiments 1-28, or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:wherein the asterisk (*) indicates the bond to the -(CO)q-Ar group.

[0114] Embodiment 30: The compound of any one Embodiments 1-28, or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:wherein the asterisk (*) indicates the bond to the -(CO)q-Ar group.

[0115] Embodiment 31 : The compound of any one of Embodiments 1-28, or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:wherein the asterisk (*) indicates the bond to the -(CO)q-Ar group.

[0116] Embodiment 32: The compound of any one of Embodiments 1-28, or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:Ar group.

[0117] Embodiment 33: The compound of any one of Embodiments 1-28, or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:wherein the asterisk (*) indicates the bond to the -(CO)q-Ar group.

[0118] Embodiment 34: The compound of any one of Embodiments 1-33, or pharmaceutically acceptable salt or solvate thereof, wherein R8is optionally substituted Cl- C6 alkyl.

[0119] Embodiment 35: The compound of any one of Embodiments 1-34, or pharmaceutically acceptable salt or solvate thereof, wherein q is 0.

[0120] Embodiment 36: The compound of any one of Embodiments 1-34, or pharmaceutically acceptable salt or solvate thereof, wherein q is 1.

[0121] Embodiment 37: The compound of any one of Embodiments 1-3, or 12-14, or pharmaceutically acceptable salt or solvate thereof, wherein Ar is

[0122] Embodiment 38: The compound of any one of Embodiments 1-3, or 12-14, or pharmaceutically acceptable salt or solvate thereof, wherein Ar is

[0123] Embodiment 39: The compound of any one of Embodiments 1-3, or 12-14, or pharmaceutically acceptable salt or solvate thereof, wherein Ar is

[0124] Embodiment 40: The compound of any one of Embodiments 37-39, or pharmaceutically acceptable salt or solvate thereof, wherein X1, X2, and X3are C-H.

[0125] Embodiment 41 : The compound of any one of Embodiments 37-39, or pharmaceutically acceptable salt or solvate thereof, wherein X1is N; and X2, and X3are C-H.

[0126] Embodiment 42: The compound of any one of Embodiments 37-39, or pharmaceutically acceptable salt or solvate thereof, wherein X2is N; and X1, and X3are C-H.

[0127] Embodiment 43: The compound of any one of Embodiments 37-39, or pharmaceutically acceptable salt or solvate thereof, wherein X3is N; and X1, and X2are C-H.

[0128] Embodiment 44: The compound of any one of Embodiments 37-39, or pharmaceutically acceptable salt or solvate thereof, wherein X1is N; and X2, and X3are C-H.

[0129] Embodiment 45: The compound of any one of Embodiments 37-39, or pharmaceutically acceptable salt or solvate thereof, wherein Y is O.

[0130] Embodiment 46: The compound of any one of Embodiments 37-39, or pharmaceutically acceptable salt or solvate thereof, wherein Y is S.

[0131] Embodiment 47: The compound of any one of Embodiments 37-39, or pharmaceutically acceptable salt or solvate thereof, wherein Y is N-H.

[0132] Embodiment 48: The compound of any one of Embodiments 37-39, or pharmaceutically acceptable salt or solvate thereof, wherein Y is N-R9, wherein R9is optionally substituted C1-C6 alkyl.

[0133] Embodiment 49: The compound of any one of Embodiments 1-3, or 12-14, or pharmaceutically acceptable salt or solvate thereof, wherein Ar is

[0134] Embodiment 50: The compound of Embodiment 49, or pharmaceutically acceptable salt or solvate thereof, wherein X1is N.

[0135] Embodiment 51 : The compound of Embodiment 49, or pharmaceutically acceptable salt or solvate thereof, wherein X2is N.

[0136] Embodiment 52: The compound of Embodiment 49, or pharmaceutically acceptable salt or solvate thereof, wherein X3is N.

[0137] Embodiment 53: The compound of Embodiment 49, or pharmaceutically acceptable salt or solvate thereof, wherein X4is N.

[0138] Embodiment 54: The compound of Embodiment 49, or pharmaceutically acceptable salt or solvate thereof, wherein X1is C-H.

[0139] Embodiment 55: The compound of Embodiment 49, or pharmaceutically acceptable salt or solvate thereof, wherein X2is C-H.

[0140] Embodiment 56: The compound of Embodiment 49, or pharmaceutically acceptable salt or solvate thereof, wherein X3is C-H.

[0141] Embodiment 57: The compound of Embodiment 49, or pharmaceutically acceptable salt or solvate thereof, wherein X4is C-H.

[0142] Embodiment 58: The compound of any one of Embodiments 1-57, or pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted Cl- C6 alkyl.

[0143] Embodiment 59: The compound of any one of Embodiments 1-57, or pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted aryl.

[0144] Embodiment 60: The compound of any one of Embodiments 1-59, or pharmaceutically acceptable salt or solvate thereof, wherein R4is optionally substituted Cl- C6 alkyl.

[0145] Embodiment 61 : The compound of any one of Embodiments 1-59, or pharmaceutically acceptable salt or solvate thereof, wherein R4is optionally substituted aryl.

[0146] One embodiment provides a compound having the structure of Formula (X), or a pharmaceutically acceptable salt or solvate thereof:wherein:A is C-H and B is C-H; or A is C-H, and B is N; or A is N, and B is C-H; or A is N, and B is N;Z1is N, C-H, or C-R3;Z2is N, C-H, or C-R4;Z3is N, C-OH, or C-R9;R1is selected from optionally substituted aryl, or optionally substituted heteroaryl;R2is selected from hydrogen, halogen, -OH, -CN, -N(R9)2, -OR9, -SR9, -SO2R9, - CO2R9, -CON(R9)2, -SR9, -S(O)R9, - S(O)2R9, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 4-membered to 6- membered heterocyclyl, optionally substituted aryl, aryl substituted with an optionally substituted 4-membered to 6-membered heterocyclyl, optionally substituted heteroaryl or heteroaryl substituted with an optionally substituted 3-membered to 6-membered carbocyclyl;R3is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl;R4is selected from halogen, -CN, optionally substituted C1-C6 alkyl, or optionally substituted aryl;R5and R6are each independently hydrogen, deuterium, halogen, -OH, or optionally substituted C1-C6 alkyl; or R5and R6together form an oxo; or R5and R6join together to form a carbocycle or heterocycle;LCG is a group selected from the group consisting of:Q2is O or S;Q3is a bond, O, S, or N-R22;R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; andR22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle;(b)X1is N or C-R7;X2is N or C-R7;X3is N or C-R7;X4is N or C-R7;Y is O, S, or N-R9; each R7is 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; andT6is N or C-R25;T7is N or C-R25;T8is N or C-R25; each R25is 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 R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and(e) -ON ;L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the -(CO)q-Ar group;R8is optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, or optionally substituted heterocyclyl; each R9is hydrogen, or optionally substituted C1-C6 alkyl; m is 0, 1, or 2; n is 1, 2, or 3; and q is 0 or 1.

[0147] In some embodiments, L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the -(CO)q-Ar group.

[0148] In some embodiments, LCG is:, whereinQ1is O or S;Q2is O or S;Q3is a bond, O, S, or N-R22;R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; andR22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle.

[0149] In some embodiments, LCG is:; whereinT6is N or C-R25;T7is N or C-R25;T8is N or C-R25; each R25is 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.

[0150] In some embodiments, LCG is :wherein, each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy.

[0151] In some embodiments, LCG is -C=N.

[0152] In some embodiments, A is C-H, and B is N.

[0153] In some embodiments, A is N, and B is C-H.

[0154] In some embodiments, A is N, and B is N.

[0155] In some embodiments, A is C-H and B is C-H.

[0156] One embodiment provides an AKT1 inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 1.Table 1

[0157] Another embodiment provides an AKT1 inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 2.Table 2

[0158] One embodiment provides an AKT1 inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 3.Table 3

[0159] One embodiment provides an AKT1 inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 4.Table 4

[0160] One embodiment provides an AKT1 inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 5.Table 5-Z<3--frOl--CO I--801--on--Ill--m--Ell-Preparation of Compounds

[0161] The compounds used in the synthetic chemistry reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and / or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0162] Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additionalsuitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[0163] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (contact the American Chemical Society, Washington, D.C. for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference useful for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.Pharmaceutical Compositions

[0164] In certain embodiments, the AKT1 inhibitory compound described herein is administered as a pure chemical. In other embodiments, the AKT1 inhibitory compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologicallysuitable (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)).

[0165] Provided herein is a pharmaceutical composition comprising at least one AKT1 inhibitory compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or the patient) of the composition.

[0166] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof.

[0167] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0168] In certain embodiments, the AKT1 inhibitory compound as described by Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0169] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt or solvate thereof.

[0170] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0171] In certain embodiments, the AKT1 inhibitory compound as described by Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other organic small molecules,such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0172] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0173] In some embodiments, the AKT1 inhibitory compound as described by Formula (I) or (II) or Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt or solvate 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 nonaqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like.

[0174] The dose of the composition comprising at least one AKT1 inhibitory compound as described herein differs depending upon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors.

[0175] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0176] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.Methods of Treatment

[0177] One embodiment provides a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0178] One embodiment provides a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.

[0179] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or neoplastic disease.

[0180] One embodiment provides a use of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

[0181] 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) or (II), or a pharmaceutically acceptable salt or solvate 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) or (II), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0182] One embodiment provides a compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0183] One embodiment provides a compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.

[0184] One embodiment provides a pharmaceutical composition comprising a compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or neoplastic disease.

[0185] One embodiment provides a use of a compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

[0186] 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, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt or solvate 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, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0187] 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.

[0188] One embodiment provides a method of inhibiting a AKT1 enzyme comprising contacting the AKT1 enzyme with a compound of Formula (I) or (II), or Table 1, Table 2, Table 3, Table 4, or Table 5. Another embodiment provides the method of inhibiting a AKT1 enzyme, wherein the AKT1 enzyme is contacted in an in vivo setting. Another embodiment provides the method of inhibiting a 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, comprising administering to the patient a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof.[Embodiment 2] A method of treating a cancer in a patient in need thereof, comprising administering to the patient a compound of Tables 1-4, or a pharmaceutically acceptable salt or solvate thereof.[Embodiment 3] A method of treating a cancer in a patient in need thereof, comprising administering to the patient a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:4-((l-((4-(2-(2-aminopyri din-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3- yl)phenyl)methyl-d2)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-((l-(4-(2-(2-aminopyridin-3-yl)-5-(6-ethylpyridin-3-yl)-3H-imidazo[4,5-b]pyri din-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-(4-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3- yl)benzyl)piperazin-l-yl)pyrimidine-2-carbonitrile;4-((l-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)-lH-imidazo[4,5-c]pyridin-l- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-((l-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)-lH-imidazo[4,5-b]pyridin-l- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-(( 1 -(4-(2-(2-aminopyri din-3 -yl)-6-(5 -fluoropyri din-2 -yl)- 1 H-imidazo [4, 5 -c]pyridin- 1 - yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-(( 1 -(4-(2-(2-aminopyri din-3 -yl)-6-(5 -fluoropyri din-2 -yl)- 1 H-imidazo [4, 5 -b]pyridin- 1 - yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-(4-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3- yl)benzyl)-4,7-diazaspiro[2.5]octan-7-yl)pyrimidine-2-carbonitrile;3-((l-(4-(2-(2-aminopyri din-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3- yl)benzyl)piperidin-4-yl)amino)-4-m ethoxy cy cl obut-3-ene- 1,2-dione;N-(l -(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3- yl)benzyl)piperidin-4-yl)ethenesulfonamide;4-((l-((5-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyridin-3- yl)pyri din-2 -yl)methyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-((l-(4-(8-(2-aminopyridin-3-yl)-2-(4-fluorophenyl)-9H-purin-9-yl)benzyl)piperi din-4- yl)amino)pyrimidine-2-carbonitrile;4-((l-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)-lH-imidazo[4,5-b]pyrazin-l- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-(( 1 -(4-(2-(2-aminopyri din-3 -yl)-6-(5 -fluoropyri din-2 -yl)- 1 H-imidazo [4, 5 -b]pyrazin- 1 - yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; and4-((l-(4-(8-(2-aminopyri din-3 -yl)-2-(5 -fluoropyri din-2 -yl)-9H-purin-9-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile.[Embodiment 4] A method of treating a cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof.[Embodiment 5] A method of treating a cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a compound of Tables 1-4, or a pharmaceutically acceptable salt or solvate thereof.[Embodiment 6] A method of treating a cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a compound, or pharmaceutically acceptable salt or solvate thereof, selected from:4-((l-((4-(2-(2-aminopyri din-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3- yl)phenyl)methyl-d2)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-((l-(4-(2-(2-aminopyridin-3-yl)-5-(6-ethylpyridin-3-yl)-3H-imidazo[4,5-b]pyri din-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-(4-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3- yl)benzyl)piperazin-l-yl)pyrimidine-2-carbonitrile;4-((l-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)-lH-imidazo[4,5-c]pyridin-l- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-((l-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)-lH-imidazo[4,5-b]pyridin-l- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-(( 1 -(4-(2-(2-aminopyri din-3 -yl)-6-(5 -fluoropyri din-2 -yl)- 1 H-imidazo [4, 5 -c]pyridin- 1 - yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-(( 1 -(4-(2-(2-aminopyri din-3 -yl)-6-(5 -fluoropyri din-2 -yl)- 1 H-imidazo [4, 5 -b]pyridin- 1 - yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-(4-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3- yl)benzyl)-4,7-diazaspiro[2.5]octan-7-yl)pyrimidine-2-carbonitrile;3-((l-(4-(2-(2-aminopyri din-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3- yl)benzyl)piperidin-4-yl)amino)-4-m ethoxy cy cl obut-3-ene- 1,2-dione;N-(l -(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3- yl)benzyl)piperidin-4-yl)ethenesulfonamide;4-((l-((5-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyridin-3- yl)pyri din-2 -yl)methyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-((l-(4-(8-(2-aminopyridin-3-yl)-2-(4-fluorophenyl)-9H-purin-9-yl)benzyl)piperi din-4- yl)amino)pyrimidine-2-carbonitrile;4-((l-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)-lH-imidazo[4,5-b]pyrazin-l- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-(( 1 -(4-(2-(2-aminopyri din-3 -yl)-6-(5 -fluoropyri din-2 -yl)- 1 H-imidazo [4, 5 -b]pyrazin- 1 - yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; and4-((l-(4-(8-(2-aminopyri din-3 -yl)-2-(5-fluoropyri din-2 -yl)-9H-purin-9-yl)benzyl)piperi din-4- yl)amino)pyrimidine-2-carbonitrile.[Embodiment 7] A method of treating a cancer in a patient in need thereof, comprising administering to the patient:(a) a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate 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 8] A method of treating a cancer in a patient in need thereof, comprising administering to the patient:(a) a compound of Tables 1-4, or a pharmaceutically acceptable salt or solvate 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 9] A method of treating a cancer in a patient in need thereof, comprising administering to the patient:(a) a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from: 4-((l-((4-(2-(2-aminopyri din-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3- yl)phenyl)methyl-d2)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-((l-(4-(2-(2-aminopyridin-3-yl)-5-(6-ethylpyridin-3-yl)-3H-imidazo[4,5-b]pyri din-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-(4-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3- yl)benzyl)piperazin-l-yl)pyrimidine-2-carbonitrile;4-((l-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)-lH-imidazo[4,5-c]pyridin-l- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-((l-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)-lH-imidazo[4,5-b]pyridin-l- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-(( 1 -(4-(2-(2-aminopyri din-3 -yl)-6-(5 -fluoropyri din-2 -yl)- 1 H-imidazo [4, 5 -c]pyridin- 1 - yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-(( 1 -(4-(2-(2-aminopyri din-3 -yl)-6-(5 -fluoropyri din-2 -yl)- 1 H-imidazo [4, 5 -b]pyridin- 1 - yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-(4-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3- yl)benzyl)-4,7-diazaspiro[2.5]octan-7-yl)pyrimidine-2-carbonitrile;3-((l-(4-(2-(2-aminopyri din-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3- yl)benzyl)piperidin-4-yl)amino)-4-m ethoxy cy cl obut-3-ene- 1,2-dione;N-(l -(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3- yl)benzyl)piperidin-4-yl)ethenesulfonamide;4-((l-((5-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyridin-3- yl)pyri din-2 -yl)methyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-((l-(4-(8-(2-aminopyridin-3-yl)-2-(4-fluorophenyl)-9H-purin-9-yl)benzyl)piperi din-4- yl)amino)pyrimidine-2-carbonitrile;4-((l-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)-lH-imidazo[4,5-b]pyrazin-l- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-(( 1 -(4-(2-(2-aminopyri din-3 -yl)-6-(5 -fluoropyri din-2 -yl)- 1 H-imidazo [4, 5 -b]pyrazin- 1 - yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; and4-((l-(4-(8-(2-aminopyri din-3 -yl)-2-(5 -fluoropyri din-2 -yl)-9H-purin-9-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 10] The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is selected from an endocrine therapy, a hormonal therapy, a SERM therapy, a SERD therapy, an aromatase inhibitor, or an androgen deprivation therapy. [Embodiment 11] The method of embodiment 10, wherein the endocrine therapy, a hormonal therapy, a SERM therapy, a SERD therapy, an aromatase inhibitor, or an androgen deprivation therapy is selected from megestrol, exemestane, anastrozole, letrozole, tamoxifen, torimifene, raloxifene, fulvestrant, camizestrant, elacestrant, amcenestrant, giredestrant, imlunestrant, rintodestrant, SHR9549, ZN-c5, D0502, vepdegrestrant, palazestrant, AC682, DT2216, apalutamide, bicalutamide, darolutamide, enzalutamide, flutamide, nilutamide, abiraterone, buserelin, goserelin, leuprorelin, triptorelin, degarelix, or relugolix,.[Embodiment 12] The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a taxane.[Embodiment 13] The method of embodiment 12, wherein the taxane is selected from paclitaxel, docetaxel, cabazitaxel, or abraxane.[Embodiment 14] The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a platinum agent.[Embodiment 15] The method of embodiment 14, wherein the platinum agent is selected from cisplatin, carboplatin, or oxaliplatin.[Embodiment 16] The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is an anthracycline.[Embodiment 17] The method of embodiment 16, wherein the anthracy cline is selected from doxorubicin or epirubicin.[Embodiment 18] The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is an anti-metabolite.[Embodiment 19] The method of embodiment 18, wherein the anti-metabolite is selected from methotrexate, fluorouracil, pemetrexed, irinotecan, topotecan, capecitabine or gemcitabine.[Embodiment 20] The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is an alkylating agent.[Embodiment 21] The method of embodiment 20, wherein the alkylating agent is selected from ifosfamide, trabectedin, cyclophosphamide, melphalan, or dacarbazine. [Embodiment 22] The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a microtubule affecting agent.[Embodiment 23] The method of embodiment 22, wherein the microtubule affecting agent is selected from ixabepilone, viborelbine, or eribulin.[Embodiment 24] The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is an immune checkpoint inhibitor.[Embodiment 25] The method of embodiment 24, wherein the immune checkpoint inhibitor is selected from a CTLA-4 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a LAG-3 inhibitor, a TIGIT inhibitor, or a bi-specific PD-1 / CTLA4 inhibitor.[Embodiment 26] The method of embodiment 25, wherein the CTLA-4 inhibitor is selected from ipilimumab or tremelimumab.[Embodiment 27] The method of embodiment 25, wherein the PD-1 inhibitor is selected from spartalizumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, durvalumab, dostarlimab, retifanlimab, or toripalimab.[Embodiment 28] The method of embodiment 25, wherein the bi-specific PD-1 / CTLA4 inhibitor is selected from AK104, MGD019, XmAb20717, or MEDI5752.[Embodiment 29] The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a kinase inhibitor.[Embodiment 30] The method of embodiment 29, wherein the kinase inhibitor is selected from lenvatinib, pazopanib, imatinib, sorafenib, or avutometinib.[Embodiment 31] The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a PI3K inhibitor.[Embodiment 32] The method of embodiment 31, wherein the PI3K inhibitor is selected from copanlisib, alpelisib, idelalisib, duvelisib, or umbralisib.[Embodiment 33] The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a HER2 inhibitor.[Embodiment 34] The method of embodiment 33, wherein the HER2 inhibitor is selected from lapatinib, neratinib, tucatinib, pyrotinib, or afatinib.[Embodiment 35] The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is an antibody.[Embodiment 36] The method of embodiment 35, wherein the antibody is selected from trastuzumab, pertuzumab, margetuxumab, bevacizumab, or rituximab.[Embodiment 37] The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a PARP inhibitor.[Embodiment 38] The method of embodiment 37, wherein the PARP inhibitor is selected from olaparib, rucaparib, talazoparib, or niraparib.[Embodiment 39] The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is an antibody drug conjugate (ADC).[Embodiment 40] The method of embodiment 39, wherein the antibody drug conjugate is selected from ado-trastuzumab emtansine, fam-trastuzumab deruxtecan-nxki, sacituzumab govitecan, disitamab vedotin, tisotumab vedotin, raludotatug deruxtecan, ARX-788, datopotamab deruxtecan, patritumab deruxtecan, ladiratuzumab vedotin, HS-20089, pertuzumab, or margetuximab.[Embodiment 41] The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a radiopharmaceutical.[Embodiment 42] The method of embodiment 41, wherein the radiopharmaceutical is [11 Hn] / [89Zr]-trastuzumab.[Embodiment 43] The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a NTRK inhibitor.[Embodiment 44] The method of embodiment 43, wherein the NTRK inhibitor is selected from entrectinib or larotrectinib.[Embodiment 45] The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a RET inhibitor.[Embodiment 46] The method of embodiment 45, wherein the RET inhibitor is selpercatinib or pralsetinib.[Embodiment 47] The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is an EGFR inhibitor.[Embodiment 48] The method of embodiment 47, wherein the EGFR inhibitor is erlotinib, osimertinib, neratinib, cetuximab, gefitinib, panitumumab, dacomitinib, afatinib, lapatinib, necitumumab, mobocertinib, or vandetanib.[Embodiment 49] The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a mTOR inhibitor.[Embodiment 50] The method of embodiment 49, wherein the mTOR inhibitor is deforolimus, everolimus, sirolimus, or temsirolimus.[Embodiment 51] The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a RAF inhibitor.[Embodiment 52] The method of embodiment 51, wherein the RAF inhibitor is vemurafenib, dabrafenib, encorafenib, tovorafenib, naporafenib, belvarafenib, or exarafenib. [Embodiment 53] The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a MEK inhibitor.[Embodiment 54] The method of embodiment 53, wherein the MEK inhibitor is binimetinib, cobimetinib, trametinib, selumetinib, pimasertib, avutometinib, IMM-1-104, or NST-628.[Embodiment 55] The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a CDK inhibitor.[Embodiment 56] The method of embodiment 55, wherein the CDK inhibitor is selected from palbociclib, abemaciclib, ribociclib, tagtociclib, ebvaciclib, lerociclib, PF-07220060, BLU-222, INX-315, or AVZO-021.[Embodiment 57] A method of treating a cancer in a patient in need thereof, comprising administering to the patient:(a) a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof; and(b) at least one oncology therapeutic selected from CAR-T therapy, tumor-infiltrating lymphocytes (TIL) or a neoantigen vaccine.[Embodiment 58] A method of treating a cancer in a patient in need thereof, comprising administering to the patient:(a) a compound of Tables 1-4, or a pharmaceutically acceptable salt or solvate thereof; and(b) at least one oncology therapeutic selected from CAR-T therapy, tumor-infiltrating lymphocytes (TIL) or a neoantigen vaccine.[Embodiment 59] A method of treating a cancer in a patient in need thereof, comprising administering to the patient:(a) a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from: 4-((l-((4-(2-(2-aminopyri din-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3- yl)phenyl)methyl-d2)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-((l-(4-(2-(2-aminopyridin-3-yl)-5-(6-ethylpyridin-3-yl)-3H-imidazo[4,5-b]pyri din-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-(4-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3- yl)benzyl)piperazin-l-yl)pyrimidine-2-carbonitrile;4-((l-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)-lH-imidazo[4,5-c]pyridin-l- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-((l-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)-lH-imidazo[4,5-b]pyridin-l- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-(( 1 -(4-(2-(2-aminopyri din-3 -yl)-6-(5 -fluoropyri din-2 -yl)- 1 H-imidazo [4, 5 -c]pyridin- 1 - yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-(( 1 -(4-(2-(2-aminopyri din-3 -yl)-6-(5 -fluoropyri din-2 -yl)- 1 H-imidazo [4, 5 -b]pyridin- 1 - yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-(4-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3- yl)benzyl)-4,7-diazaspiro[2.5]octan-7-yl)pyrimidine-2-carbonitrile;3-((l-(4-(2-(2-aminopyri din-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3- yl)benzyl)piperidin-4-yl)amino)-4-m ethoxy cy cl obut-3-ene- 1,2-dione;N-(l -(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3- yl)benzyl)piperidin-4-yl)ethenesulfonamide;4-((l-((5-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyridin-3- yl)pyri din-2 -yl)methyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-((l-(4-(8-(2-aminopyridin-3-yl)-2-(4-fluorophenyl)-9H-purin-9-yl)benzyl)piperi din-4- yl)amino)pyrimidine-2-carbonitrile;4-((l-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)-lH-imidazo[4,5-b]pyrazin-l- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-(( 1 -(4-(2-(2-aminopyri din-3 -yl)-6-(5 -fluoropyri din-2 -yl)- 1 H-imidazo [4, 5 -b]pyrazin- 1 - yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; and4-((l-(4-(8-(2-aminopyri din-3 -yl)-2-(5-fluoropyri din-2 -yl)-9H-purin-9-yl)benzyl)piperi din-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 60] The method of any one of embodiments 1-59, wherein the cancer is breast cancer.[Embodiment 61] The method of embodiment 60, wherein the cancer is a hormone receptor positive (HR+) breast cancer.[Embodiment 62] The method of embodiment 60, wherein the cancer is a human epidermal growth factor receptor 2 negative (HER2-) breast cancer.[Embodiment 63] The method of embodiment 60, wherein the cancer is a HR+ / HER2- breast cancer.[Embodiment 64] The method of embodiment 60, wherein the cancer is a HR+ / HER2- low breast cancer.[Embodiment 65] The method of embodiment 60, wherein the cancer is a HR+ / HER2+ breast cancer.[Embodiment 66] The method of embodiment 60, wherein the cancer is a triple negative breast cancer (TNBC).[Embodiment 67]method of embodiment 60, wherein the cancer is an invasive breast cancer.[Embodiment 68] The method of any one of embodiments 1-59, wherein the cancer is uterine cancer.[Embodiment 69] The method of embodiment 68, wherein the cancer is uterine sarcoma.[Embodiment 70] The method of embodiment 68, wherein the cancer is endometrial cancer.[Embodiment 71] The method of embodiment 68, wherein the cancer is Type I endometrial cancer.[Embodiment 72] The method of embodiment 68, wherein the cancer is Type II endometrial cancer.[Embodiment 73] The method of embodiment 72, wherein the cancer is Type II endometrial papillary serous carcinoma.[Embodiment 74] The method of embodiment 72, wherein the cancer is Type II endometrial clear cell carcinoma.[Embodiment 75] The method of embodiment 72, wherein the cancer is Type II endometrial undifferentiated carcinoma.[Embodiment 76] The method of embodiment 72, wherein the cancer is Type II endometrioid carcinoma.[Embodiment 77] The method of embodiment 68, wherein the cancer is microsatellite instability (MSI) high and / or DNA mismatch repair (MMR) deficient.[Embodiment 78] The method of embodiment 68, wherein the cancer is tumor mutational burden (TMB) high.[Embodiment 79] The method of embodiment 68, wherein the cancer is HER2-.[Embodiment 80] The method of any one of embodiments 1-59, wherein the cancer is cervical cancer.[Embodiment 81] The method of embodiment 80, wherein the cancer is a cervical squamous cell carcinoma.[Embodiment 82] The method of embodiment 80, wherein the cancer is a cervical adenocarcinoma.[Embodiment 83] The method of any one of embodiments 1-59, wherein the cancer is prostate cancer.[Embodiment 84] The method of embodiment 83, wherein the cancer is prostate adenocarcinoma.[Embodiment 85] The method of embodiment 83, wherein the cancer is prostate neuroendocrine cancer.[Embodiment 86] The method of embodiment 83, wherein the cancer is prostate small cell neuroendocrine cancer.[Embodiment 87] The method of embodiment 83, wherein the cancer is prostate large cell carcinoma.[Embodiment 88] The method of embodiment 83, wherein the cancer is prostate transitional cell carcinoma.[Embodiment 89] The method of embodiment 83, wherein the cancer is prostate sarcoma. [Embodiment 90] The method of any one of embodiments 1-59, wherein the cancer is bladder cancer.[Embodiment 91] The method of embodiment 90, wherein the cancer is urothelial cancer.[Embodiment 92] The method of embodiment 90, wherein the cancer is squamous cell cancer of the bladder.[Embodiment 93] The method of embodiment 90, wherein the cancer is small cell cancer of the bladder.[Embodiment 94] The method of embodiment 90, wherein the cancer is adenocarcinoma of the bladder.[Embodiment 95] The method of any one of embodiments 1-59, wherein the cancer is lung cancer.[Embodiment 96] The method of any one of embodiments 1-59, wherein the cancer is non-small cell lung cancer.[Embodiment 97] The method of any one of embodiments 1-59, wherein the cancer is non-squamous non-small cell lung cancer.[Embodiment 98] The method of any o < ne of embodiments 1-59, wherein the cancer is squamous non-small cell lung cancer.[Embodiment 99] The method of any one of embodiments 1-59, wherein the cancer is colon cancer.[Embodiment 100] The method of any one of embodiments 1-59, wherein the cancer is anal cancer.[Embodiment 101] The method of any one of embodiments 1-59, wherein the cancer is a meningioma.[Embodiment 102] The method of any one of embodiments 1-59, wherein the cancer is a glioma.[Embodiment 103] The method of any one of embodiments 1-59, wherein the cancer is pancreatic cancer.[Embodiment 104] The method of embodiment 103, wherein the cancer is exocrine pancreatic cancer.[Embodiment 105] The method of embodiment 103, wherein the cancer is neuroendocrine pancreatic cancer.[Embodiment 106] The method of any one of embodiments 1-59, wherein the cancer is thyroid cancer.[Embodiment 107] The method of any one of embodiments 1-59, wherein the cancer is myxofibrosarcoma.[Embodiment 108] The method of any one of embodiments 1-59, wherein the cancer is parotid gland cancer.[Embodiment 109] The method of any one of embodiments 1-59, wherein the cancer is esophageal cancer.[Embodiment 110] The method of any one of embodiments 1-59, wherein the cancer is stomach cancer.[Embodiment 111] The method of any one of embodiments 1-59, wherein the cancer is skin cancer.[Embodiment 112] The method of embodiment 111, wherein the cancer is nonmelanoma skin cancer.[Embodiment 113] The method of embodiment 112, wherein the cancer is squamous nonmelanoma skin cancer.[Embodiment 114] The method of embodiment 112, wherein the cancer is non-squamous nonmelanoma skin cancer.[Embodiment 115] The method of any one of embodiments 1-59, wherein the cancer is ovarian cancer.[Embodiment 116] The method of embodiment 115, wherein the cancer is epithelial ovarian cancer.[Embodiment 117] The method of embodiment 115, wherein the cancer is serous epithelial ovarian cancer.[Embodiment 118] The method of embodiment 115, wherein the cancer is endometrioid ovarian cancer.[Embodiment 119] The method of embodiment 115, wherein the cancer is clear cell ovarian cancer.[Embodiment 120] The method of embodiment 115, wherein the cancer is mucinous ovarian cancer.[Embodiment 121] The method of any one of embodiments 1-59, wherein the cancer is adenoid cystic carcinoma.[Embodiment 122] The method of any one of embodiments 1-59, wherein the cancer is renal cell cancer.[Embodiment 123] The method of any one of embodiments 1-59, wherein the cancer is appendix cancer.[Embodiment 124] The method of any one of embodiments 1-59, wherein the cancer is multiple myeloma.[Embodiment 125] The method of any one of embodiments 1-59, wherein the cancer is acute myeloid leukemia.[Embodiment 126] The method of any one of embodiments 1-59, wherein the cancer is cancer of unknown primary.[Embodiment 127] The method of any one of embodiments 1-59, wherein the cancer is locally advanced.[Embodiment 128] The method of any one of the preceding embodiments, wherein the cancer is metastatic.[Embodiment 129] The method of any one of the preceding embodiments, wherein the method is adjuvant therapy following surgical resection.[Embodiment 130] The method of any one of the preceding embodiments, wherein the method is neo-adjuvant therapy.[Embodiment 131] The method of any one of the preceding embodiments, wherein the method is first-line systemic therapy for locally advanced or metastatic disease.[Embodiment 132] The method of any one of the preceding embodiments, wherein the patient has relapsed after prior therapy.[Embodiment 133] The method of any one of the preceding embodiments, wherein the patient has acquired resistance to prior therapy.[Embodiment 134] The method of any one of the preceding embodiments, wherein the patient is refractory to therapy.[Embodiment 135] The method of any one of embodiments 60-67, wherein the patient has shown progression on at least one CDK4 / 6 inhibitor.[Embodiment 136] The method of any one of embodiments 60-67, wherein the patient has shown progression on at least one endocrine-based regimen.[Embodiment 137] The method of any one of the preceding embodiments, wherein the patient has shown progression on cytotoxic chemotherapy.[Embodiment 138] The method of any one of the preceding embodiments, wherein the cancer is characterized by existence of AKT1-E17K mutation.[Embodiment 139] The method of any one of the preceding embodiments, wherein the cancer exhibits one or more co-occurring alterations selected from a PIK3CA alteration, a PIK3R1 alteration, an AKT1 alteration, and PTEN alteration.[Embodiment 140] The method of any one of the preceding embodiments, wherein the patient exhibits risk factors for hyperglycemia.[Embodiment 141] The method of any one of the preceding embodiments, wherein the patient exhibits risk factors selected from obesity, body mass index greater than or equal to 30, fasting blood glucose over 160 mg / dL, HbAlc greater than 6.0.[Embodiment 142] The method of any one of the preceding embodiments, wherein the patient exhibits Type I diabetes, diabetes requiring insulin, diabetes requiring metformin or another oral hypoglycemic agent, or pre-diabetes treated with metformin or another oral hypoglycemic agent.[Embodiment 143] The method of any one of the preceding embodiments, wherein the compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, is administered orally.[Embodiment 144] The method of any one of the preceding embodiments, wherein the compound of Tables 1-4, or a pharmaceutically acceptable salt or solvate thereof, is administered orally.[Embodiment 145] The method of any one of the preceding embodiments, wherein the compound, or a pharmaceutically acceptable salt or solvate thereof, selected from: 4-((l-((4-(2-(2-aminopyri din-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3- yl)phenyl)methyl-d2)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-((l-(4-(2-(2-aminopyridin-3-yl)-5-(6-ethylpyridin-3-yl)-3H-imidazo[4,5-b]pyri din-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-(4-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3- yl)benzyl)piperazin-l-yl)pyrimidine-2-carbonitrile;4-((l-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)-lH-imidazo[4,5-c]pyridin-l- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-((l-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)-lH-imidazo[4,5-b]pyridin-l- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-(( 1 -(4-(2-(2-aminopyri din-3 -yl)-6-(5 -fluoropyri din-2 -yl)- 1 H-imidazo [4, 5 -c]pyridin- 1 - yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-(( 1 -(4-(2-(2-aminopyri din-3 -yl)-6-(5 -fluoropyri din-2 -yl)- 1 H-imidazo [4, 5 -b]pyridin- 1 - yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-(4-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3- yl)benzyl)-4,7-diazaspiro[2.5]octan-7-yl)pyrimidine-2-carbonitrile;3-((l-(4-(2-(2-aminopyri din-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3- yl)benzyl)piperidin-4-yl)amino)-4-m ethoxy cy cl obut-3-ene- 1,2-dione;N-(l -(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3- yl)benzyl)piperidin-4-yl)ethenesulfonamide;4-((l-((5-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4, 5-b]pyridin-3- yl)pyridin-2-yl)methyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-((l-(4-(8-(2-aminopyridin-3-yl)-2-(4-fluorophenyl)-9H-purin-9-yl)benzyl)piperi din-4- yl)amino)pyrimidine-2-carbonitrile;4-((l-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)-lH-imidazo[4,5-b]pyrazin-l- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;4-(( 1 -(4-(2-(2-aminopyri din-3 -yl)-6-(5 -fluoropyri din-2 -yl)- 1 H-imidazo [4, 5 -b]pyrazin- 1 - yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; and4-((l-(4-(8-(2-aminopyri din-3 -yl)-2-(5 -fluoropyri din-2 -yl)-9H-purin-9-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile, is administered orally.[Embodiment 146] The method of any one of the preceding embodiments, wherein the oral administration occurs once per day, twice per day, three times per day, every other day, or one to six days per week.

[0189] Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way.EXAMPLESI. Chemical Synthesis

[0190] In some embodiments, the AKT1 inhibitory compounds disclosed herein are synthesized according to the following examples. As used below, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:ACN acetonitrile°C degrees Celsius5H chemical shift in parts per million downfield from tetramethylsilaneDCM di chloromethane ( CH2Cl2)DIAD diisopropyl azodicarboxylateDIEA diisopropylethylamineDMF dimethylformamideDMSO dimethylsulfoxideEA ethyl acetateEtOAc ethyl acetateESI electrospray ionizationEt ethyl g gram(s) h hour(s)HPLC high performance liquid chromatographyHz hertzJ coupling constant (in NMR spectrometry)LCMS liquid chromatography mass spectrometry n micro m multiplet (spectral); meter(s); milliM molarM+parent molecular ionMe methylMsCl methanesulfonyl chlorideMHz megahertz min minute(s) mol mole(s); molecular (as in mol wt) mL milliliterMS mass spectrometry nm nanometer(s)NMR nuclear magnetic resonancePE petroleum etherRT room temperature s singlet (spectral) t triplet (spectral)SFC Supercritical fluid chromatographyT temperatureTFA trifluoroacetic acidTHF tetrahydrofuranTPP TriphenylphosphineExperimental Procedures

[0191] Intermediate 1 : Methyl 4-(2-(2-aminopyridin-3-yl)-5-bromo-3H-imidazo[4,5-Z>]pyri din-3 -yl)benzoateStep 1 : Methyl 4-((6-bromo-3-nitropyridin-2-yl)amino)benzoateTo a solution of 2,6-dibromo-3-nitropyridine (5 g, 17.7 mmol) and methyl 4-aminobenzoate (2.68 g, 17.7 mmol) in 1,4-dioxane (50 mL) was added DIEA (4.58 g, 35.5 mmol). The mixture was stirred at 50 °C for 12 hr under N2. The mixture was concentrated under reduced pressure. The crude was triturated with EtOAc (100 mL) at 25 °C for 30 min to give the title compound (4.4 g, yield: 70%) as a red solid. MS: m / z = 351.9, 353.9 [M+H]+.Step 2: Methyl 4-(2-(2-aminopyridin-3-yl)-5-bromo-3H-imidazo[4,5b] pyridin-3-yl)benzoate To a solution of methyl 4-((6-bromo-3-nitropyridin-2-yl)amino)benzoate (2 g, 5.68 mmol) and 2-aminopyridine-3-carbaldehyde (763 mg, 6.25 mmol) in DMSO (20 mL) was added Na2SO4 (2.47 g, 14.2 mmol). The mixture was stirred at 100 °C for 12 hr under N2. The mixture was quenched with sat. NaHCCO3 aq. (50 mL) and extracted with CH2Cl2 / MeOH (10 / 1, 50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered and concentrated. After purification by silica gel flash chromatography (Eluent of 0 ~ 100% EtOAc in petroleum ether), the title compound (Intermediate 1, 1.3 g, yield: 54%) was obtained as a black, brown solid. MS: m / z = 423.9, 425.9 [M+H]+. ' H NMR (400 MHz, Chloroform-d) 5 8.25 - 8.15 (m, 2H), 8.10 - 8.00 (m, 1H), 7.95 (d, J= 8.4 Hz, 1H), 7.55-7.40 (m, 3H), 7.05 - 7.00 (m, 1H), 6.83 (br s, 2H), 6.45-6.30 (m, 1H), 3.97 (s, 3H).

[0192] Intermediate 2: 3-(5-Bromo-3-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-3H- imidazo[4,5-b]pyridin-2-yl)pyridin-2-amineStep 1 : 4-((( / c / 7-Butyldimethylsilyl)oxy)methyl)anilineTo a solution of (4-aminophenyl)methanol (5 g, 40.6 mmol) in (50 mL C) H w2eCrel2 added TBSC1 (8.34 g, 55.4 mmol), TEA (10.3 mL, 73.8 mmol) and DMAP (225 mg, 1.85 mmol). The mixture was degassed, purged with N2 three times, and stirred at 25 °C for 2 hr under N2. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (8.76 g, crude) as a white oil, which was used in the next step without further purfi ci ti on.Step 2: 6-Bromo-A-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-3-nitropyridin-2-amine To a solution of 4-[[ / c / 7-butyl(dimethyl)silyl]oxymethyl]aniline (8.76 g, 36.9 mmol) in 1,4- dioxane (100 mL) were added DIEA (19.3 mL, 111 mmol) and 2, 6-dibromo-3 -nitropyridine (10.4 g, 36.9 mmol). The mixture was degassed, purged with N2 three times, and stirred at 45 °C for 16 hr under N2. The reaction mixture was concentrated under reduced pressure and purified by silica gel flash chromatography (Eluent of 1-10% EtOAc in Petroleum ether) to give the title compound (13.7 g, yield: 72%) as a red solid. MS: m / z = 440.2 [M+H]+.JH NMR (400 MHz, Chloroform-d) 5 10.23 (s, 1H), 8.32 (d, J= 8.4 Hz, 1H), 7.61 (d, J= 8.4 Hz, 2H), 6.95 (d, J= 8.4 Hz, 1H), 4.75 (s, 2H), 0.96 (s, 9H), 0.12 (s, 6H).Step 3 : 6-Bromo-A2-(4-((( / er / -butyldimethylsilyl)oxy)methyl)phenyl)pyridine-2,3-diamine To a solution of 6-bromo-A-(4-((( / er / -butyldimethylsilyl)oxy)methyl)phenyl)-3-nitropyridin- 2-amine (46 g, 105 mmol) in EtOH (500 mL) and H2O (100 mL) were added Fe (17.6 g, 315 mmol) and NH4CI (39.3 g, 735 mmol). The mixture was degassed, purged with N2 three times, and stirred at 80 °C for 2 hr under N2. The reaction mixture was filtered and concentrated under reduced pressure. The title compound (42.9 g, crude) was obtained as a yellow solid, which was used in the next step without further purification. MS: m / z = 408.9, 409.9 [M+H]+.Step 4: 3-(5-Bromo-3-(4-((( / ert-butyldimethylsilyl)oxy)methyl)phenyl)-3H-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amineTo a solution of 6-bromo-A2-(4-((( / er / -butyldimethylsilyl)oxy)methyl)phenyl)pyridine-2,3- diamine (41 g, 100 mmol), 2-aminonicotinaldehyde (9.81 g, 80.3 mmol) in EtOH (500 mL) was added InCh (2.22 g, 10.0 mmol). The mixture was degassed, purged with N2 three times, and stirred at 80 °C for 2 hr under N2. Then Mn02 (52.4 g, 602 mmol) was added. The mixture was stirred at 80 °C for 2 hr under N2. The reaction mixture was filtered and concentrated under reduced pressure. The crude was purified by silica gel flash chromatography (Eluent of 1-50% EtOAc in petroleum ether) to give the title compound (Intermediate 2, 19.5 g, yield: 32%) as a brown solid. MS: m / z = 509.9, 511.9 [M+H]+. 'HNMR (400 MHz, Chloroform-d) 5 8.10 - 8.01 (m, 1H), 7.92 (d, J= 8.4 Hz, 1H), 7.54 - 7.40 (m, 3H), 7.31 (d, J= 8.0 Hz, 2H), 7.07 (d, J= 7.6 Hz, 1H), 6.64 (br s, 2H), 6.41 - 6.27 (m, 1H), 4.83 (s, 2H), 0.97 (s, 9H), 0.14 (s, 6H).

[0193] Intermediate 3: 3-(3-(4-(Chloromethyl)phenyl)-5-(5-fluoropyridin-2-yl)-3H- imidazo[4,5-b]pyridin-2-yl)pyridin-2-amineStep 1 : 3-(3-(4-((( / er / -Butyldimethylsilyl)oxy)methyl)phenyl)-5-(5-fluoropyridin-2-yl)-3H- imidazo[4,5-b]pyridin-2-yl)pyridin-2-amineTo a solution of Intermediate 2 (500 mg, 979 pmol) in 1,4-dioxane (16.5 mL) were added CuBr (105 mg, 734 pmol), CS2CO3 (105 mg, 957 pmol), (5-fluoropyridin-2-yl)boronic acid (690 mg, 957 mmol) and cataCXium A Pd G3 (71 mg, 98 pmol) at 25 °C. The reaction mixture was degassed and purged with N2 three times. The mixture was stirred at 100 °C for 4 hr under N2. The reaction mixture was poured into H2O (50 mL) and extracted with CH2Cl2 (20 mL x 2). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO,4 filtered and concentrated. After purification by silica gel flash chromatography (Eluent of 0-40% EtOAc in petroleum ether), the title compound (450 mg, yield: 85%) was obtained as a brown solid. MS: m / z = 527.2 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) 8 8.67 (d, J= 3.2 Hz, 1H), 8.40 (d, J= 8.4 Hz, 1H), 8.32 (d, J= 8.0 Hz, 1H), 8.25 - 8.17 (m, 1H), 8.04 - 7.98 (m, 1H), 7.87 - 7.78 (m, 1H), 7.55 - 7.45 (m, 4H), 7.25 - 7.16 (m, 1H), 7.11 - 6.88 (m, 2H), 6.43 - 6.35 (m, 1H), 4.83 (s, 2H), 0.95 - 0.92 (m, 9H), 0.13 - 0.11 (m, 6H).Step 2: (4-(2-(2-Aminopyri din-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5b] pyri din-3- yl)phenyl)methanolTo a solution of 3-(3-(4-((( / er / -butyldimethylsilyl)oxy)methyl)phenyl)-5-(5-fluoropyridin-2- yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (450 mg, 854 pmol) in THF (5 mL) was added TBAF (670 mg, 2.5ml, IM) at 25 °C. The mixture was stirred at 25 °C for 1 hr. The reaction mixture was poured into H2O (20 mL). The mixture was extracted with (20 CH2Cl2 mL x 2). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the title compound (300 mg, crude) as ayellow solid. MS: m / z = 413.1 [M + H]+. 'H NMR (400 MHz, Dimethyl sulfoxide-d6) 5 8.66 (d, .7= 2.4 Hz, 1H), 8.40 (d, J= 6.4 Hz, 1H), 8.31 (d, J= 8.4 Hz, 1H), 8.22 (dd, J= 8.8, 4.8 Hz, 1H), 8.01 (dd, J= 4.8, 2.0 Hz, 1H), 7.87 - 7.80 (m, 1H), 7.53 - 7.44 (m, 4H), 7.23 (dd, J = 7.6, 1.6 Hz, 1H), 6.98 (br s, 2H), 6.42 (dd, J= 7.6, 4.8 Hz, 1H), 5.36 (br s, 1H), 4.61 (s, 2H).Step 3 : 3-(3-(4-(Chloromethyl)phenyl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5b] pyridin-2- yl)pyridin-2-amineTo a solution of (4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5- b]pyri din-3 -yl)phenyl)methanol (300 mg, 727 pmol) in (5 mL C)H w2aCsl2 added SOCI2 (433 mg, 3.6 mmol) at 25 °C. The mixture was stirred at 40 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (Intermediate 3, 300 mg, crude) as a yellow solid, which was used in the next step without further purification. MS: m / z = 431.0 [M ]+. 1H NMR (400 MHz, Dimethyl sulfoxide-d6) 5 8.67 (d, J = 2.8 Hz, 1H), 8.41 (d, J = 8.4 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 8.24 (dd, J = 8.8, 4.8 Hz, 1H), 8.01 (dd, J = 4.8, 1.6 Hz, 1H), 7.87 - 7.82 (m, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.25 - 7.21 (m, 1H), 6.90 (br s, 2H), 6.44 (dd, J = 7.6, 4.8 Hz, 1H), 4.88 (s, 2H). 19F NMR (400 MHz, Dimethyl sulfoxide-d6) 5 -127.227.

[0194] Intermediate 4: 4-((Methyl-d3)(piperidin-4-yl)amino)pyrimidine-2-carbonitrileStep 1 : te / 7-Butyl 4-((2-cyanopyrimidin-4-yl)(methyl-d3)amino)piperidine-l -carboxylate To a solution of tert-butyl 4-((2-cyanopyrimidin-4-yl)amino)piperidine-l -carboxylate (refer to Intermediate 5 for detail procedures, 1 g, 3.30 mmol) in THF (10 mL) was added NaH (264 mg, 6.59 mmol, 60% in oil) at 0 °C under N2 atmosphere. The mixture was stirred at 0 °C for 0.5 hr under N2 atmosphere, and CD3I (956 mg, 6.59 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 16 hr under N2 atmosphere. The reaction mixture was quenched with H2O (50 mL) at 25 °C and extracted with (50 mL x C 3H).2Cl2 The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The title compound (1 g, yield: 90%) was obtained as a yellow solid. MS: m / z = 321.3 [M + H]+. D%: 3D% = 100%. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 8 8.25 (d, J= 6.4 Hz, 1H), 7.30 - 6.72 (m, 1H), 4.11 - 4.05 (m, 1H), 2.96 - 2.76 (m, 2H), 2.50 - 2.48 (m, 2H), 1.68 - 1.56 (m, 4H), 1.41 (s, 9H).Step 2: 4-((Methyl-d3)(piperidin-4-yl)amino)pyrimidine-2-carbonitrileTo a solution of terLbutyl 4-((2-cyanopyrimidin-4-yl)(methyl-d3)amino)piperidine-l- carboxylate (90 mg, 281 pmol) in C (2H m2CLl)2 was added TFA (96.1 mg, 843 pmol). The mixture was stirred at 25 °C for 0.5 hr. The reaction was concentrated under reduced pressure to give the title compound (Intermediate 4, 93.9 mg, TFA salt) as a yellow oil. MS: m / z = 221.2 [M + H]+.

[0195] Intermediate 5: 4-(Piperidin-4-ylamino)pyrimidine-2-carbonitrileStep 1 : tert-Butyl 4-((2-cyanopyrimidin-4-yl)amino)piperidine-l -carboxylateTo a solution of tert-butyl 4-aminopiperidine-l -carboxylate (600 mg, 3.0 mmol) and 2- chloropyrimidine-4-carbonitrile (418 mg, 3.0 mmol) in DMF (5 mL) were added K2CO3 (1.24 g, 8.99 mmol) and Nal (89.8 mg, 599 pmol). The mixture was stirred at 80 °C for Ihr. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 2).The combined organic layers were washed with brine (50 mL), dried over Na2SO,4 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.JH NMR (400 MHz, Dimethylsulfoxide-d6) 5 8.13 - 8.01 (m, 2H), 6.66 (d, J= 5.6 Hz, 1H), 4.05 - 3.95 (m, 1H), 3.87 - 3.84 (m, 2H), 2.99 - 2.86 (m, 2H), 1.86 - 1.83 (m, 2H), 1.40 (s, 9H), 1.34 - 1.26 (m, 2H).Step 2: 4-(Piperidin-4-ylamino)pyrimidine-2-carbonitrileTo a solution of tert-Butyl 4-((2-cyanopyrimidin-4-yl)amino)piperidine-l -carboxylate (110 mg, 362 pmol) in DCM (3 mL) was added TFA (767 mg, 6.73 mmol) .The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure. The title compound (Intermediate 5, 120 mg, yield: 100%, TFA salt) was used in the next step without further purification. MS: m / z = 204.0 [M + H]+.

[0196] Intermediate 6: 4-((5'-Fluoro-5-nitro-[2,2'-bipyridin]-6-yl)amino)benzyl acetateStep 1 : (4-((6-Chloro-3-nitropyridin-2-yl)amino)phenyl)methanolTo a solution of 2,6-dichloro-3-nitropyridine (50 g, 259 mmol) and (4-aminophenyl)methanol (32 g, 259 mmol) in 1,4-di oxane (500 mL) was added DIEA (100 g, 777 mmol). The mixture was stirred at 70 °C for 1 hr. The reaction mixture was diluted with H2O (500 mL) and extracted with CH2CI2 (300 mL x 2). The combined organic layers were washed with brine (200 mL), dried over Na2SO,4 filtered and concentrated to give the title compound (67 g, yield: 92%) as an orange solid, which was used in the next step without purification.JH NMR (400 MHz, Dimethylsulfoxide-d6) 8 10.11 (br s, 1H), 8.53 (d, J= 8.4 Hz, 1H), 7.53 (d, J= 8.4 Hz, 2H), 7.33 (d, J= 8.4 Hz, 2H), 6.98 (d, J= 8.8 Hz, 1H), 5.20 (br s, 1H), 4.49 (s, 2H).Step 2: 4-((6-Chl oro-3 -nitropyridin-2-yl)amino)benzyl acetateTo a solution of (4-((6-chloro-3-nitropyridin-2-yl)amino)phenyl)m ethanol (67 g, 239 mmol) in CH2Cl2 (600 mL) were added EtsN (72.7 g, 718 mmol) and DMAP (2.93 g, 23.9 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 min, and then AC2O (24.5 g, 239 mmol) in CH2Cl2 (50 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 16 hr. The reaction mixture was diluted with H2O (500 mL) and extracted with (500 CH2Cl2 mL x 2). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0 ~ 1% MeOH in ), th CeH ti2tlCel2 compound (36 g, yield: 45%) was obtained as an orange solid. MS: m / z = 321.8 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) 6 10.14 (s, 1H), 8.55 (d, J= 8.4 Hz, 1H), 7.61 - 7.58 (m, 2H), 7.39 - 7.37 (m, 1H), 7.08 - 6.97 (m, 2H), 5.07 (s, 2H), 2.07 (s, 3H).Step 3: 4-((5'-Fluoro-5-nitro-[2,2'-bipyridin]-6-yl)amino)benzyl acetateA mixture of 4-((6-chloro-3-nitropyridin-2-yl)amino)benzyl acetate (10 g, 31 mmol), (5- fhioropyridin-2-yl)boronic acid (13 g, 93 mmol), Cata CXium A Pd G3 (2.3 g, 3.1 mmol), CuBr (3.34 g, 23.3 mmol) and CS2CO3 (30 g, 93 mmol) in 1,4-dioxane (350 mL) was degassed and purged with N2 three times. The mixture was stirred at 125 °C for 2.5 hr under N2 atmosphere. The reaction mixture was poured into H2O (500 mL) and extracted with CH2Cl2 (200 mL x 2). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. After trituration (10% EtOAc in petroleum ether, 100 mL) at 25 °C for 1 hr, the title compound (Intermediate 6, 10 g, yield: 72%) was obtained as a yellow solid. MS: m / z = 383.0 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 6 10.10 (s, 1H), 8.77 - 8.74 (m, 1H), 8.69 (d, J= 8.8 Hz, 1H), 8.25 - 8.21 (m, 1H), 7.97 - 7.92 (m, 1H), 7.90 (d, J= 8.4 Hz, 1H), 7.75 (d, J= 8.4 Hz, 2H),7.48 -7.44 (m, 2H), 5.10 (s, 2H), 2.09 (s, 3H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 6 - 124.159.

[0197] Intermediate 7: 5-Bromo-2-(fluoromethyl)pyridineTo a solution of (5-bromopyridin-2-yl)methanol (2 g, 10.6 mmol) in (20 mL) C iHn2 aCnl2 ice bath was added DAST (3.42 g, 21.2 mmol) in (20 C mHL2C) l d2ropwise. The mixture was degassed, purged with N2 three times, and stirred at 0 °C for 10 min under N2. The reaction mixture was poured into sat. NaHCCh aq. (400mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (300 mL x 3), dried over Na2SO,4 filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 10% EtOAc in petroleum ether), the title compound (Intermediate 7, 488 mg, yield: 24%) was obtained as a yellow liquid. MS: m / z = 189.9, 191.9 [M + H]+. 'HNMR (400 MHz, Dimethylsulfoxide-d6) 8 8.72 (s, 1H), 8.14 (d, J= 8.0 Hz, 1H), 7.49 (d, J= 8.0 Hz, 1H), 5.45 (d, J= 46.8 Hz, 2H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 6 -216.231 ppm.

[0198] Intermediate 8: (5-Bromopyridin-2-yl)methyl acetateTo a solution of (5-bromopyridin-2-yl)methanol (1.3 g, 6.91 mmol) in CH2CI2 (15 mL) were added DMAP (169 mg, 1.38 mmol), Ac2O (779 pL, 8.30 mmol) and TEA (2.89 mL, 20.7 mmol). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was quenched with H2O (30 mL) at 25 °C and extracted with CH2CI2 (25 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO,4 filtered and concentrated. After purification by silica gel flash chromatography (Eluent of 0% ~ 15% EtOAc in petroleum ether), the title compound (Intermediate 8, 1.5 g, yield: 94%) was obtained as a light-yellow oil.XH NMR (400 MHz, Chloroform-d) 5 8.66 (s, 1H), 7.84 (d, J= 8.4, 1H), 7.28 (d, J= 2.8 Hz, 1H), 5.18 (s, 2H), 2.17 (s, 3H).

[0199] Intermediate 9: (6-B romopyri din-3 -yl)methyl acetateTo a solution of (6-brom opyri din-3 -yl)m ethanol (1.3 g, 6.91 mmol) in CH2CI2 (13 mL) were added DMAP (169 mg, 1.38 mmol9), AC2O (847 mg, 8.30 mmol) and TEA (2.10 g, 20.7 mmol). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was quenched with H2O (30 mL) at 25 °C and extracted with CH2CI2 (25 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous , filter Neda2 aSnOd4 concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 15% EtOAc in petroleum ether), the title compound (Intermediate 9, 1.5 g, yield: 92%) was obtained as a light-yellow oil. MS: m / z = 229.9, 231.9 [M + H]+. 'H NMR (400 MHz, Chloroform-d) 5 8.37 (s, 1H), 7.59 - 7.52 (m, 1H), 7.51 - 7.45 (m, 1H), 5.07 (s, 2H), 2.10 (s, 3H).

[0200] Intermediate 10: 2-Bromo-5-(fluoromethoxy-6 / 2)pyridineTo a solution of 6-brom opyri din-3 -ol (422 mg, 2.42 mmol), fluoromethyls / ? 4- methylbenzenesulfonate (500 mg, 2.42 mmol) in DMF (5 mL) was added K2CO3 (1.01 g, 7.27 mmol). The mixture was stirred at 50 °C for 2 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. After purification by silica gel flash chromatography (Eluent of 0% ~ 1% EtOAc in petroleum ether), the title compound (Intermediate 10, 90 mg, yield: 18%) was obtained as a colorless oil. 'H NMR (400 MHz, DimethysulfoxidesL) 5 8.27 (d, J = 3.2 Hz, 1H), 7.66 (d, J= 8.8 Hz, 1H), 7.59 - 7.58 (m, 1H).19F NMR (400 MHz, Dimethysulfoxide- d6) 8 -153.513.

[0201] Intermediate 11 : 4-(Piperazin-l-yl)pyrimidine-2-carbonitrileStep 1 : te / 7-Butyl 4-(2-cyanopyrimidin-4-yl)piperazine-l -carboxylateTo a solution of terLbutyl piperazine- 1 -carboxylate (550 mg, 2.95 mmol) and 2- chloropyrimidine-4-carbonitrile (412 mg, 2.95 mmol) in DMF (5 mL) were added K2CO3 (1.22 g, 8.86 mmol) and Nal (88.5 mg, 590 pmol). The mixture was stirred at 80 °C for 1 hr. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filteredand 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]+. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 8 8.29 (d, J= 6.4 Hz, 1H), 7.10 (d, J= 6.4 Hz, 1H), 3.73 - 3.60 (m, 4H), 3.46 - 3.41 (m, 4H), 1.42 (s, 9H).Step 2: 4-(Piperazin-l-yl)pyrimidine-2-carbonitrileTo a solution of tert-butyl 4-(2-cyanopyrimidin-4-yl)piperazine-l -carboxylate (140 mg, 483 pmol) in CH2Cl2 (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]+.

[0202] Intermediate 12: 4-(l-(Piperidin-4-yl)vinyl)pyrimidine-2-carbonitrileStep 1 : tert-Butyl 4-(l-(((trifluoromethyl)sulfonyl)oxy)vinyl)piperidine-l -carboxylateTo a solution of tert-butyl 4-acetylpiperidine-l -carboxylate (4 g, 17.6 mmol) in THF (80 mL) was added LiHMDS (1 M in THF, 17.6 mL) at -78 °C under N2 atmosphere. The resulting mixture was stirred at -78 °C for 1 hr. 1,1,1-Trifluoro-A-phenyl-A- ((trifluoromethyl)sulfonyl)methanesulfonamide (6.92 g, 19.4 mmol) at 0 °C was added. The mixture was stirred at 0 °C for 3 hr. The reaction mixture was quenched with aqueous NH4CI (20 mL) at 0 °C, diluted with H2O (50 mL), and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 5% EtOAc in petroleum ether), the title compound (5.6 g, yield: 80%) was obtained as a colorless oil. 'H NMR (400 MHz, Chloroform-d) 6 5.14 (d, J = 4.0 Hz, 1H),4.93 (dd, J= 4.0, 1.2 Hz, 1H), 4.27 - 4.13 (m, 2H), 2.82 - 2.65 (m, 2H), 2.44 - 2.29 (m, 1H),1.94 - 1.85 (m, 2H), 1.46 (s, 9H), 1.43 - 1.33 (m, 2H).Step 2: tert-Butyl 4-(l-(trimethylstannyl)vinyl)piperidine-l-carboxylateA mixture of tert-butyl 4-(l-(((trifluoromethyl)sulfonyl)oxy)vinyl)piperidine-l -carboxylate (1 g, 2.78 mmol), LiCl (796 mg, 18. 8 mmol), Pd(PPh3)4(322 mg, 278 pmol) and 1, 1,1, 2,2,2- hexamethyldistannane (1.49 g, 4.55 mmol) in 1,4-dioxane (10 mL) was degassed and purged with N2 three times. The mixture was stirred at 60 °C for 16 hr under N2 atmosphere. The mixture was filtered through Celite at 25 °C and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 3% EtOAc in petroleum ether), the title compound (700 mg, yield: 57%) was obtained as a colorless oil.JH NMR (400 MHz, Chloroform-d) 5 5.70 - 5.64 (m, 1H), 5.18 - 5.12 (m, 1H), 4.25 - 4.01 (m, 2H), 2.78 - 2.63 (m, 2H), 2.37 - 2.19 (m, 1H), 1.65 - 1.59 (m, 2H), 1.46 (s, 9H), 1.38 - 1.27 (m, 2H), 0.36 - 0.01 (m, 9H).Step 3: tert-Butyl 4-(l-(2-cyanopyrimidin-4-yl)vinyl)piperidine-l-carboxylateA mixture of tert-butyl 4-(l-(trimethylstannyl)vinyl)piperidine-l-carboxylate (520 mg, 1.39 mmol), Pd(PPh3)2Ch (195 mg, 278 pmol) and 4-chloropyrimidine-2-carbonitrile (252 mg, 1.81 mmol) in DMF (8 mL) was degassed, purged with N2 three times, and stirred at 90 °C for 16 hr under N2 atmosphere. 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. After purification by silica gel flash chromatography (Eluent of 0% ~ 20% EtOAc in petroleum ether), the title compound (180 mg, yield: 38%) was obtained as a light-yellow oil. MS: m / z = 337.0 [M + Na]+. 'H NMR (400 MHz, Chloroform-d) 5 8.76 (d, J= 5.6 Hz, 1H), 7.62 (d, J= 5.2 Hz, 1H), 5.97 (s, 1H), 5.56 (s, 1H), 4.32 - 4.16 (m, 2H), 3.08 - 2.98 (m, 1H), 2.89 - 2.78 (m, 2H), 1.85 - 1.73 (m, 2H), 1.47 (s, 9H), 1.45 - 1.37 (m, 2H).Step 4: 4-(l-(Piperidin-4-yl)vinyl)pyrimidine-2-carbonitrileTo a solution of terLbutyl 4-(l-(2-cyanopyrimidin-4-yl)vinyl)piperidine-l -carboxylate (44 mg, 140 pmol) in CH2C (3l2 mL) was added TFA (307 mg, 2.69 mmol). The mixture was stirred at 25 °C for 0.5 hr. The reaction was concentrated under reduced pressure to give the title compound (Intermediate 12, 46.0 mg, TFA salt) as a light-yellow oil. MS: m / z = 214.8 [M + H]+.

[0203] Intermediate 13 : 4-(l -(Piped din-4-yl)ethyl)pyrimidine-2-carbonitrileStep 1 : tert-Butyl 4-(l-(2-cyanopyrimidin-4-yl)ethyl)piperidine-l -carboxylateTo a solution of tert-butyl 4-(l-(2-cyanopyrimidin-4-yl)vinyl)piperidine-l -carboxylate (refer to Intermediate 12 for detail procedures, 220 mg, 700 pmol) in EtOH (5 mL) was added Rh(PPh3)3Cl (324 mg, 350 pmol) under N2 atmosphere. The mixture was degassed, purged with H2 three times, and stirred at 65 °C, 15 psi for 4 hr under H2 atmosphere. The reaction was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 20% EtOAc in petroleum ether), the title compound (35 mg, yield: 13%) was obtained as a light yellow solid. MS: m / z = 338.9 [M + Na]+.JH NMR (400 MHz, Chloroform-d) 5 8.70 (d, J= 5.2 Hz, 1H), 7.29 (d, J= 5.2 Hz, 1H), 4.22 - 3.97 (m, 2H), 2.73 - 2.55 (m, 3H), 1.90 - 1.74 (m, 2H), 1.44 (s, 9H), 1.30 - 1.27 (m, 3H), 1.26 - 1.22 (m, 1H), 1.21 - 1.05 (m, 2H).Step 2: 4-(l-(Piperidin-4-yl)ethyl)pyrimidine-2-carbonitrileTo a solution of tert-butyl 4-(l-(2-cyanopyrimidin-4-yl)ethyl)piperidine-l -carboxylate (32 mg, 101 pmol) in CH2C (2l2 mL) was added TFA (34.6 mg, 303 pmol). The mixture was stirred at 25 °C for 0.5 hr. The reaction was concentrated under reduced pressure to give the title compound (Intermediate 13, 33.4 mg) as a light-yellow oil. MS: m / z = 217.2 [M + H]+.

[0204] Intermediate 14: 4-((3aR,6aS)-Dihydro-1H,4H-3a,6a- (methanooxymethano)pyrrolo[3,4-c]pyrrol-2(3H)-yl)pyrimidine-2-carbonitrileIntermediate 14 was prepared in a manner similar to Intermediate 11. MS: m / z = 258.2 [M + H]+.

[0205] Intermediate 15: 4-(l ,2,3 ,6-T etrahydropyridin-4-yl)pyrimidine-2-carbonitrileStep 1: terLButyl 4-(2-cyanopyrimidin-4-yl)-3,6-dihydropyridine-l(2H)-carboxylateA mixture of 4-chloropyrimidine-2-carbonitrile (2 g, 14.3 mmol), (l-(tert-butoxycarbonyl)- l,2,3,6-tetrahydropyridin-4-yl)boronic acid (3.25 g, 14.3 mmol), Pd(dppf)C12 (1.05 g, 1.43 mmol) and CS2CO3 (14 g, 43 mmol) in 1,4-dioxane (20 mL) and H2O (4 mL) was degassed, purged with N2 three times, and stirred at 80 °C for 2 hr under N2 atmosphere. The reaction mixture was quenched with H2O (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography(Eluent of 0% ~ 30% EtOAc in petroleum ether), the title compound (500 mg, yield: 12%) was obtained as a yellow solid. MS: m / z = 231.1 [M - 56 + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) 8 8.93 (d, J= 5.2 Hz, 1H), 7.95 (d, J= 5.6 Hz, 1H), 7.20 - 7.12 (m, 1H), 4.16 - 4.09 (m, 2H), 3.57 - 3.51 (m, 2H), 2.55 - 2.52 (m, 2H), 1.42 (s, 9H).Step 2: 4-(l,2,3,6-Tetrahydropyridin-4-yl)pyrimidine-2-carbonitrileTo a solution of tert-butyl 4-(2-cyanopyrimidin-4-yl)-3,6-dihydropyridine-l(2H)-carboxylate (170 mg, 594 pmol) in CH (22Cl m2L) was added TFA (203 mg, 1.78 mmol). The mixture was stirred at 25 °C for 0.5 hr. The reaction was concentrated under reduced pressure to give the title compound (Intermediate 15, 178 mg, TFA salt) as a yellow oil. MS: m / z = 187.1 [M + H]+.

[0206] Intermediate 16: 4-(2,7-Diazaspiro[3.5]nonan-2-yl)pyrimidine-2-carbonitrileIntermediate 16 was prepared in a manner similar to Intermediate 11. MS: m / z = 230.0 [M + H]+.

[0207] Intermediate 17: 4-(2,6-diazaspiro[3.3]heptan-2-yl)pyrimidine-2-carbonitrileIntermediate 17 was prepared in a manner similar to Intermediate 11.

[0208] Intermediate 18: 4-(2,7-Diazaspiro[3.5]nonan-7-yl)pyrimidine-2-carbonitrileIntermediate 18 was prepared in a manner similar to Intermediate 11. MS: m / z = 230.0 [M + H]+.

[0209] Intermediate 19: (A)-4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidine-2-carbonitrileIntermediate 19 was prepared in a manner similar to Intermediate 11. MS: m / z = 230.2 [M + H]+.

[0210] Intermediate 20: (S)-4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidine-2-carbonitrileIntermediate 20 was prepared in a manner similar to Intermediate 11. MS: m / z = 230.1 [M + H]+.

[0211] Intermediate 21 : 4-(Piperazin-l-ylamino)pyrimidine-2-carbonitrileStep 1 : terLButyl 4-((2-cyanopyrimidin-4-yl)amino)piperazine-l -carboxylateTo a solution of tert-butyl 4-aminopiperazine-l -carboxylate (200 mg, 994 pmol) and 4- chloropyrimidine-2-carbonitrile (139 mg, 994 pmol) in 1,4-dioxane (2 mL) was added TEA (277 pL, 1.99 mmol). The mixture was stirred at 110 °C for 2 hr. The mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous , filter Neda,2 aSnOd4 concentrated. After purification by silica gel flash chromatography (Eluent of 0% ~ 26% EtOAc in Petroleum ether), the title compound (240 mg, yield: 81.6%) was obtained as a white solid. MS: m / z = 305.2 [M + H]+. 'HNMR (400 MHz, Dimethylsulfoxide-d6) 8 9.32 (s, 1H), 8.30 (d, J= 6.0 Hz, 1H), 7.04 (d, J= 6.0 Hz, 1H), 4.06 - 3.42 (m, 4H), 2.90 - 2.55 (m, 4H), 1.41 (s, 9H).Step 2: 4-(Piperazin-l-ylamino)pyrimidine-2-carbonitrileA mixture of tert-butyl 4-((2-cyanopyrimidin-4-yl)amino)piperazine-l -carboxylate (110 mg, 361 pmol) in CH2C (l02.9 mL) and TFA (0.3 mL) was stirred at 20 °C for 1 hr. The mixture was concentrated to give the title compound (Intermediate 21, 73.8 mg) as a yellow oil. MS: m / z = 205.1 [M + H]+.

[0212] Intermediate 22: 5-Bromo-2-(methyl-d3)pyridineStep 1 : terLButyl (6-(methyl-d3)pyridin-3-yl)carbamateTo a solution of ZnCh (2.99 g, 22.0 mmol) in THF (30 mL) was added (methyl- d3)magnesium iodide (1 M, 87.87 mL, 8 eq) dropwise at 25 °C. After addition, the resulting mixture was stirred at 25 °C for 1 hr under N2 atmosphere, and terLbutyl (6-brom opyri din-3 - yl)carbamate (3 g, 11.0 mmol), Pd(PPhs)4 (1.27 g, 1.10 mmol) and 1,4-dioxane (30 mL) wereadded. The mixture was degassed, purged with N2 three times, and stirred at 60 °C for 16 hr under N2 atmosphere. The reaction mixture was poured into H2O (300 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (500 mL x 2), 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 (1.58 g, yield: 65%) was obtained as a yellow solid. MS: m / z = 212.2 [M + H]+. 'HNMR (400 MHz, Dimethyl sulfoxide-d6) 8 9.41 (br s, 1H), 8.47 (d, J= 2.0 Hz, 1H), 7.79 - 7.68 (m, 1H), 7.13 (d, J= 8.4 Hz, 1H), 1.47 (s, 9H).Step 2: 6-(Methyl--d2)pyri din-3 -amineTo a solution of tert-butyl (6-(methyl--d2)pyridin-3-yl)carbamate (1.55 g, 7.34 mmol) in 1,4- dioxane (15 mL) was added HCl / dioxane (2 M, 22.0 mL). The mixture was degassed, purged with N2 three times, and stirred at 25 °C for 2 hr under N2 atmosphere. The reaction mixture was filtered, and the filtered cake was dried under reduced pressure to give the title compound (1.08 g, crude, HC1) as a yellow solid, which was used directly in the next step. 'HNMR (400 MHz, Dimethyl sulfoxide-d6) 6 7.86 (d, J= 2.8 Hz, 1H), 7.60 (dd, J= 8.8, 2.8 Hz, 1H), 7.50 (d, J= 8.8 Hz, 1H).Step 3: 5-Bromo-2-(methyl--d2)pyridineA mixture of 6-(methyl-d3)pyridin-3-amine (1.08 g, 7.32 mmol, HC1) , CuBr (1.15 g, 8.05 mmol,) and HBr (1.99 mL, 40% purity) in H2O (15 mL) was added NaNCL (606 mg, 8.78 mmol). The mixture was degassed and purged with N2 three times. The result mixture was stirred at 0 °C for 2 hr under N2 atmosphere. The reaction mixture was quenched with H2O (50 mL). The pH of the mixture was adjusted to 8 with Sat.NaHCCL. The mixture was extracted with CH2CI2 (30 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The title compound (Intermediate 22, 800 mg, crude) was obtained as a green oil, which was used directly in the next step. MS: m / z = 175.1, 177.1 [M + H]+.

[0213] Intermediate 23 : 4-((Methyl-6?3)(piperazin-l -yl)amino)pyrimidine-2-carbonitrileStep 1 : tert-Butyl 4-((2-cyanopyrimidin-4-yl)(methyl-d3)amino)piperazine-l -carboxylateTo a solution of terLbutyl 4-((2-cyanopyrimidin-4-yl)amino)piperazine-l -carboxylate (refer to Intermediate 21 for detail procedures, 230 mg, 756 pmol) in DMF (3 mL) was added NaH(45.3 mg, 1.13 mmol, 60% purity) at 0 °C under N2. The mixture was stirred at 0 °C for 30 mins, and CD3I (70.6 pL, 1.13 mmol) was added slowly. The mixture was stirred 20 °C for 2.5 hr. The mixture was quenched with H2O (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. The title compound (243 mg) was obtained as a white solid. MS: m / z = 305.2 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) 8 8.29 (d, J= 6.4 Hz, 1H), 7.41 (d, J= 6.4 Hz, 1H), 4.00 - 3.89 (m, 2H), 3.17 - 2.93 (m, 2H), 2.83 - 2.74 (m, 2H), 2.71 - 2.64 (m, 2H), 1.41 (s, 9H).Step 2: 4-((Methyl-d3)(piperazin-l-yl)amino)pyrimidine-2-carbonitrileA mixture of tert-butyl 4-((2-cyanopyrimidin-4-yl)(methyl-d3)amino)piperazine-l- carboxylate (Intermediate 23, 90 mg, 280 pmol) in CH2CI2 (1 mL) and TFA (0.4 mL) was stirred at 20 °C for 1 hr. The mixture was concentrated to give the title compound (62.0 mg) as yellow oil. MS: m / z = 222.1 [M + H]+.

[0214] Intermediate 24: (2-(Difluoromethoxy)pyrimidin-5-yl)boronic acidStep 1 : 5-Bromo-2-(difluoromethoxy)pyrimidineA mixture of 5-bromopyrimidin-2-ol (1.5 g, 8.57 mmol), sodium 2-chloro-2,2-difluoroacetate (2.6 g, 17 mmol) and K2CO3 (2.5 g, 18 mmol) in DMF (10 mL) was degassed, purged with N2 three times, and stirred at 65 °C for 16 hr under N2 atmosphere. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 5), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 4% EtOAc in petroleum ether), the title compound (110 mg, yield: 3%) was obtained as a white oil. 'HNMR (400 MHz, Chloroform-d) 5 8.65 (s, 2H), 7.39 (t, J = 71.6 Hz, 1H).19F NMR (400 MHz, Chloroform-d) 5 -89.947.Step 2: (2-(Difluoromethoxy)pyrimidin-5-yl)boronic acidA mixture of 5-bromo-2-(difhioromethoxy)pyrimidine (1.5 g, 2.9 mmol), 4, 4, 4', 4', 5, 5, 5', 5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.1 g, 4.4 mmol), KO Ac (865 mg, 8.8 mmol) and Pd(dppf)C12 (120 mg, 147 pmol) in 1,4-di oxane (15 mL) was degassed, purged with N2 three times, and stirred at 90 °C for 8 hr under N2 atmosphere. The title compound (Intermediate24) was obtained as a black liquid, which was used directly in the next step and without work-up and purification. MS: m / z = 191.2 [M + H]+.

[0215] Intermediate 25: 4-((l-(4-(2-(2-Aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-Z>]pyridin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileStep 1 : (4-((6-Chloro-3-nitropyridin-2-yl)amino)phenyl)methanolTo a mixture of (4-aminophenyl)methanol (5 g, 40.6 mmol) and 2, 6-di chi oro-3 -nitro-pyridine (7.84 g, 40.6 mmol) in THF (70 mL) was added DIEA (10.5 g, 81.2 mmol, 14.1 mL). The mixture was stirred at 80 °C for 1 hr. The mixture was concentrated to give the title compound (11.36 g, yield: 100%) as yellow oil. MS: m / z = 279.8 [M+H]+.Step 2: A-(4-(((tert-Butyldimethylsilyl)oxy )methyl)phenyl)-6-chl oro-3 -nitropyridin-2-amine To a mixture of (4-((6-chloro-3-nitropyridin-2-yl)amino)phenyl)methanol (1 g, 3.58 mmol) in CH2CI2 (10 mL) were added imidazole (365 mg, 5.36 mmol) and TBSC1 (701 mg, 4.65 mmol). The mixture was stirred at 20 °C for 1 hr. The mixture was diluted with H2O (50 mL) and extracted with CH (52C0l m2 L x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO,4 filtered and concentrated to give the title compound (1.1 g, yield: 78%) as a yellow solid. MS: m / z = 394.0 [M+H]+. ' H NMR (400 MHz, Dimethylsulfoxide-d6) 8 10.12 (s, 1H), 8.54 (d, J= 8.8 Hz, 1H), 7.59 - 7.52 (m, 2H), 7.36 - 7.30 (m, 2H), 7.00 (d, J= 8.4 Hz, 1H), 4.71 (s, 2H), 0.91 (s, 9H), 0.09 (s, 6H).Step 3 : A2-(4-(((terLButyldimethylsilyl)oxy)methyl)phenyl)-6-chloropyridine-2,3-diamine To a solution of A-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-6-chloro-3-nitropyridin- 2-amine (5 g, 12.7 mmol) in EtOH (50 mL) and H2O (10 mL) were added Fe (1.42 g, 25.4 mmol) and NH4CI (3.39 g, 63.5 mmol). The mixture was degassed, purged with N2 threetimes, and stirred at 80 °C for 2 hr under N2. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (4.62 g, crude) as a black solid, which was used in the next step directly. MS: m / z = 364.2 [M+H]+.Step 4: 3-(3-(4-(((tert-Butyldimethylsilyl)oxy)methyl)phenyl)-5-chloro-3H-imidazo[4,5- Z>]pyri din-2 -yl)pyridin-2-amineTo a solution of A2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-6-chloropyridine-2,3- diamine (13.9 g, 38.1 mmol) and 2-aminonicotinaldehyde (4.65 g, 38.1 mmol) in EtOH (150 mL) was added InCl3 (842 mg, 3.81 mmol). The mixture was degassed and purged with N2 three times and stirred at 80 °C for 2 hr under N2. Then MnCL (19.9 g, 228 mmol) was added. The mixture was degassed, purged with N2 three times, and stirred at 80 °C for 2 hr under N2. The reaction mixture was filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 1 ~ 50% EtOAc in petroleum ether), the title compound (6.02 g, 11.8 mmol) was obtained as a gray solid. MS: m / z = 466.3 [M+H]+. 'HNMR (400 MHz, Chloroform-d) 5 8.06 - 8.00 (m, 2H), 7.49 (d, J= 8.0 Hz, 2H), 7.31 (dd, J= 1.8, 8.4 Hz, 3H), 7.09 (dd, J= 7.6, 1.2 Hz, 1H), 6.80 (br s, 2H), 6.36 (dd, J= 7.6, 5.2 Hz, 1H), 4.83 (s, 2H), 0.97 (s, 9H), 0.14 (s, 6H).Step 5: (4-(2-(2-Aminopyridin-3-yl)-5-chloro-3H-imidazo[4, 5- / >]pyri din-3 - yl)phenyl)methanolTo a solution of 3-(3-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-5-chloro-3H- imidazo[4,5b] pyridin-2-yl)pyridin-2-amine (500 mg, 1.07 mmol) in (5 mL) w CaHs 2Cl2 added TBAF (1 M, 1.61 mL). The mixture was degassed, purged with N2 three times, and stirred at 25 °C for 2 hr under N2. The reaction mixture was quenched with sat. NH4CI aq.(20 mL) at 25 °C and extracted with ( C10H m2CLl2 x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The title compound (3H mg, crude) was obtained as a yellow solid. MS: m / z = 352.2 [M+H]+.Step 6: 3-(5-Chloro-3-(4-(chloromethyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)pyri din-2- amineTo a solution of (4-(2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5b] pyridin-3- yl)phenyl)methanol (3H mg, 1.07 mmol) in CH2CI2 (5 mL) was added SOCI2 (1.28 g, 10.7 mmol). The mixture was degassed, purged with N2 three times, and stirred at 25 °C for 4 hr under N2. The reaction mixture was concentrated under reduced pressure to give the title compound (430 mg, crude) as a gray solid. MS: m / z = 370.1 [M+H]+.Step 7: 4-(( l -(4-(2-(2-Aminopyridin-3-yl)-5-chloro-37 / -imidazo[4,5- / i]pyridin-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileTo a solution of Intermediate 5 (165 mg, 810 pmol) and 3-(5-Chloro-3-(4- (chloromethyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (300 mg, 810 pmol) in DMF (3 mL) was added DIEA (314 mg, 2.43 mmol). The mixture was degassed, purged with N2 three times, and stirred at 25 °C for 16 hr under N2. The reaction mixture was quenched with H2O (10 mL) at 25 °C and extracted with (5 mL C xH 32C).l2 The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO,4 filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 1 ~ 8% MeOH in CH2CI2) to give the title compound (Intermediate 25, 226 mg, yield: 52%) as a light-yellow solid. MS: m / z = 537.2 [M+H]+.JH NMR (400 MHz, Dimethylsulfoxide-d6) 8 8.27 (d, J= 8.0 Hz, 1H), 8.14 - 8.02 (m, 2H), 7.99 (dd, J= 4.8, 1.6 Hz, 1H), 7.52 - 7.36 (m, 5H), 7.16 (dd, J= 7.6, 1.6 Hz, 1H), 6.94 (br s, 2H), 6.67 (d, J= 6.0 Hz, 1H), 6.38 (dd, J= 7.6, 4.8 Hz, 1H), 3.88 - 3.74 (m, 1H), 3.57 (s, 2H), 2.86 - 2.75 (m, 2H), 2.20 - 2.07 (m, 2H), 1.94 - 1.79 (m, 2H), 1.57 - 1.40 (m, 2H).

[0216] Intermediate 26: Zc / V-Butyl A-tert-butoxycarbonyl-A-(4-formylisothiazol-3- yl)carbamateStep 1 : 3-Bromo-4-iodoisothiazoleTo a solution of 3-bromoisothiazole (2.5 g, 15.2 mmol) in H2SO4 (25 mL) was added I2 (2.71 g, 10.7 mmol). The mixture was stirred at 25 °C for 30 mins, then NaICU (1.63 g, 7.62 mmol) was added to the mixture slowly. The mixture was degassed, purged with N2 three times, and stirred at 25 °C for 16 hr under N2. The reaction mixture was poured into ice water (100 mL) and then quenched with sat. ISfeSCL aq. (50 mL). The mixture was extracted with CH2Cl2 (80 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO,4 filtered and concentrated under reduced pressure. The title compound (3.23 g, yield: 73%) was obtained as an off white solid.1H NMR (400 MHz, Chloroform-d) 5 8.62 (s, 1H). Step 2: 3-Bromo-4-vinylisothiazoleTo a solution of 3-bromo-4-iodoisothiazole (3.22 g, 11.1 mmol) in 1,4-dioxane (30 mL) and H2O (6 mL) were added Pd(dppf)C12 (813 mg, 1.11 mmol), CS2CO3 (10.9 g, 33.3 mmol) and 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (2.05 g, 13.3 mmol). The mixture was degassed, purged with N2 three times, and stirred at 90 °C for 2 hr under N2. The reaction mixture was diluted with EtOAc (100 mL), 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 (1.80 g, yield: 77%) was obtained as a light yellow liquid. MS: m / z = 189.8, 191.8 [M + H]+. 'HNMR (400 MHz, Chloroform-d) 5 8.57 (s, 1H), 6.70 (dd, J= 17.6, 11.2 Hz, 1H), 5.73 (d, J= 17.6 Hz, 1H), 5.43 (d, J= 11.2 Hz, 1H).Step 3: 4-Vinylisothiazol-3-amineTo a solution of 3-bromo-4-vinylisothiazole (1.75 g, 9.21 mmol) in 2-methoxyethan-l-ol (18 mL) saturated with NH3 H2O (12.7 mL, 92.1 mmol, 28% purity) was added CU2O (264 mg, 1.84 mmol). The mixture was stirred at 100 °C in a 100 mL of sealed tube for 16 hr. The reaction mixture was diluted with EtOAc (100 mL), 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% ~ 10% EtOAc in petroleum ether), the title compound (530 mg, yield: 45%) was obtained as a yellow oil. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 8 8.77 (s, 1H), 6.64 ( dd, J= 17.6, 11.2 Hz, 1H), 6.12 (br s, 2H), 5.65 (d, J= 17.6 Hz, 1H), 5.21 (d, J = 11.2 Hz, 1H)Step 4: / c / V-Butyl A-te / 7-butoxy carbonyl -A-(4-vinylisothiazol-3-yl)carbamateTo a solution of 4-vinylisothiazol-3-amine (530 mg, 4.20 mmol) in (8 mL) C wHer2eCl2 added Boc2O (2.02 g, 9.24 mmol), DMAP (51.3 mg, 420 pmol), and TEA (2.34 mL, 16.80 mmol). The mixture was degassed, purged with N2 three times, and stirred at 25 °C for 1 hr under N2. The reaction mixture was diluted with (30 C mHL2)C aln2 d 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% ~ 10% EtOAc in petroleum ether), the title compound (1.24 g, yield: 90 %) was obtained as a yellow solid. 'H NMR (400 MHz, Chloroform-d) 5 8.56 (s, 1H), 6.47 (dd, J= 17.6, 11.2 Hz, 1H), 5.65 (d, J= 17.6 Hz, 1H), 5.35 (d, J= 11.2 Hz, 1H), 1.39 (s, 18H).Step 5: tert-Butyl A-tert-butoxycarbonyl -A-(4-formylisothiazol-3-yl)carbamate To a solution of te / 7-butyl A- / er / -butoxycarbonyl-A-(4-vinylisothiazol-3-yl)carbamate (1.24 g, 3.80 mmol) in THF (20 mL) and H2O (2 mL) were added NaKL (1.63 g, 7.60 mmol) andK2OSO4. 2H2O (140 mg, 380 pmol). The mixture was degassed, purged with N2 three times, and stirred at 0 °C for 1 hr under N2. The reaction mixture was quenched with .« / / . Na2SO? aq. (100 mL) and extracted with EtOAc (60 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 20% EtOAc in petroleum ether), the title compound (Intermediate 26, 320 mg, yield: 26%) was obtained as a yellow solid.1H NMR (400 MHz, Chloroform-d) 5 9.92 (s, 1H), 9.31 (s, 1H), 1.42 (s, 18H).

[0217] Intermediate 27: 2-Hydroxy-4-(piperazin-l-yl)benzaldehydeStep 1 : tert-Butyl 4-(4-formyl-3-hydroxyphenyl)piperazine-l -carboxylateTo a solution of 5-fluoro-2-hydroxy -benzaldehyde (200 mg, 1.43 mmol) and tert-butyl piperazine- 1 -carboxylate (266 mg, 1.43 mmol) in DMSO (2 mL) was added DIEA (746 pL, 4.28 mmol). The mixture was degassed and purged with N2 three times and stirred at 100 °C for 16 hr under N2. The reaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (25 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 1-25% EtOAc in petroleum ether) to give the title compound (197 mg, yield: 45%) as a white solid. MS: m / z = 307.1 [M+H]+.XH NMR (400 MHz, Chloroform-d) 11.48 (s, 1H), 9.58 (s, 1H), 7.34 (d, J= 8.8 Hz, 1H), 6.44 (dd, J= 8.8, 2.4 Hz, 1H), 6.25 (d, J= 2.4 Hz, 1H), 3.60 - 3.53 (m, 4H), 3.44 - 3.37 (m, 4H), 1.48 (s, 9H).Step 2: 2-Hydroxy-4-(piperazin-l-yl)benzaldehydeTo a solution of tert-butyl 4-(3-formyl-4-hydroxy-phenyl)piperazine-l-carboxylate (190 mg, 621 pmol) in 1,4-dioxane (1 mL) was added HC1 in 1,4-dioxane (4M, 2 mL). The mixture was degassed, purged with N2 three times, and stirred at 25 °C for 2 hr under N2. The reaction mixture was concentrated under reduced pressure to give the title compound (Intermediate 27, 146 mg HC1 salt, yield: 98%) as a gray solid, which was used in the next step without further purification. MS: m / z = 207.0 [M+H]+.

[0218] Intermediate 28: 3-(5-(5-Fluoropyridin-2-yl)-3-(4-(piperazin-l-ylmethyl)phenyl)-3H- imidazo[4,5-b]pyridin-2-yl)pyridin-2-amineStep 1 : tert-Butyl 4-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-37 / -imidazo[4,5- Z>]pyridin-3-yl)benzyl)piperazine-l -carboxylateTo a solution of Intermediate 3 (500 mg, 1.07 mmol, HC1 salt), tert-butyl piperazine-1- carboxylate (219 mg, 1.18 mmol) in DMF (6 mL) were added Nal (32.1 mg, 214 pmol) and K2CO3 (444 mg, 3.21 mmol). The mixture was degassed and purged with N2 three times and stirred at 25 °C for 16 hr under N2. The reaction mixture was diluted with CH2CI2 (20 mL) and stirred for 10 mins. The mixture was washed with sat. NaHCCh aq. (20 mL x 2), brine (20 mL x 2), dried over Na2SO,4 filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 4% MeOH in ), the CH2Cl2 title compound (404 mg, yield: 63%) was obtained as a brown solid. MS: m / z = 581.4 [M+H]+. 'HNMR (400 MHz, Dimethylsulfoxide-d6) 8 8.67 (d, J= 2.8 Hz, 1H), 8.43 - 8.38 (m, 1H), 8.34 - 8.29 (m, 1H), 8.23 (dd, J= 8.8, 4.4 Hz, 1H), 8.01 (dd, J= 4.8, 2.0 Hz, 1H), 7.88 - 7.79 (m, 1H), 7.52 - 7.44 (m, 4H), 7.17 (dd, J= 7.6, 1.6 Hz, 1H), 7.01 (br s, 2H), 6.39 (dd, J= 7.6, 4.8 Hz, 1H), 3.60 (s, 2H), 3.38 - 3.33 (m, 4H), 2.40 - 2.33 (m, 4H), 1.40 (s, 9H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 6 -127.824.Step 2 : 3 -(5 -(5 -Fluoropyri din-2 -yl)-3 -(4-(piperazin- 1 -ylmethyl)phenyl)-3 J / -imidazo[4, 5 - Z>]pyri din-2 -yl)pyridin-2-amineTo a solution of tert-butyl 4-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperazine-l-carboxylate (404 mg, 696 pmol) in 1,4- di oxane (3 mL) was added HC1 in 1,4-di oxane (8 mL, 2M). The mixture was degassed, purged with N2 three times, and stirred at 25 °C for 2 hr under N2. The reaction mixture was concentrated under reduced pressure, the title compound (Intermediate 28, 340 mg, HC1 salt) was obtained as a yellow solid, which was used in the next step directly. MS: m / z = 481.2 [M+H]+.

[0219] Intermediate 29: 3-(3-(4-((4-Aminopiperidin-l-yl)methyl)phenyl)-5-(5-fluoropyridin- 2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amineStep 1 : tert-Butyl ( l -(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-37 / -imidazo[4,5- b]pyridin-3-yl)benzyl)piperidin-4-yl)carbamateTo a solution of Intermediate 3 (373 mg, 866 pmol) and tert-butyl piperidin-4-ylcarbamate (191 mg, 952 pmol) in DMF (5 mL) were added K2CO3 (598 mg, 4.33 mmol) and Nal (13 mg, 86.6 pmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with (25 m CLH x22C)l.2 The combined organic layers were washed with brine (50 mL x 5), dried over anhydrous Na2SO,4 filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 5% MeOH in ), t CheH t2iCtlel2 compound (410 mg, yield: 76%) was obtained as a yellow solid. MS: m / z = 595.8 [M + H]+.JH NMR (400 MHz, Chloroform-d) 5 8.55 - 8.42 (m, 2H), 8.33 (dd, J= 8.8, 4.8 Hz, 1H), 8.17 (d, J= 8.4 Hz, 1H), 8.08 (dd, J= 5.2, 1.6 Hz, 1H), 7.65 - 7.50 (m, 2H), 7.48 - 7.37 (m, 3H), 7.09 (dd, J= 7.6, 1.2 Hz, 1H), 6.63 (br s, 2H), 6.36 (dd, J= 8.0, 4.8 Hz, 1H), 4.62 - 4.39 (m, 1H), 3.82 - 3.49 (m, 3H), 3.13 - 2.81 (m, 2H), 2.43 - 2.16 (m, 2H), 2.05 - 1.98 (m, 2H), 1.67 - 1.57 (m, 2H), 1.45 (s, 9H).19F NMR (400 MHz, Chloroform-d) -127.728.Step 2 : 3 -(3 -(4-((4- Aminopiperidin- 1 -yl)methyl)phenyl)-5 -(5 -fluoropyridin-2-yl)-37 / - imidazo[4,5-b]pyridin-2-yl)pyridin-2-amineTo a solution of tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)carbamate (410 mg, 689 pmol) in 1,4- dioxane (2 mL) was added 2 M HC1 in 1,4-dioxane (2 M, 1.03 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was quenched with NaHCCL (20 mL, PH ~ 8) at 25 °C and extracted with CH (225C ml2L x 2). The combined organic layers were washed with brine (50mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (Intermediate 29, 330 mg) was obtained as a yellow solid. MS: m / z = 495.3 [M + H]+.

[0220] Intermediate 30: 4-(l-(Piperidin-4-yl)cyclopropyl)pyrimidine-2-carbonitrileStep 1 : tert-Butyl 4-(l-(2-cyanopyrimidin-4-yl)cyclopropyl)piperidine-l -carboxylate To an 15 mL vial equipped with a stir bar were added tert-butyl 4-(l-(2-cyanopyrimidin-4- yl)vinyl)piperidine-l -carboxylate (150 mg, 477 pmol), Ru(bpz)3(PFe)2(4.13 mg, 4.77 pmol), DIEA (308 mg, 2.39 mmol), and Na2S2O3-5H2O (1.33 M, 1.79 mL) in ACN (2 mL). The vial was sealed and placed under nitrogen. Then diiodomethane (319 mg, 1.19 mmol) was added. The reaction was stirred and irradiated with a blue 10 W LED lamp (3 cm away), with cooling water to keep the reaction temperature at 25 °C for 14 hr. The reaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with CH2C12(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% ~ 20% EtOAc in petroleum ether), the title compound (Intermediate 30, 70 mg, yield: 44%) was obtained as a light-yellow oil. MS: m / z = 350.9 [M + Na]+.JH NMR (400 MHz, Chloroform-d) 5 8.64 (d, J= 5.2 Hz, 1H), 7.32 (d, J= 5.6 Hz, 1H), 4.23 - 4.13 (m, 2H), 2.74 - 2.67 (m, 2H), 2.16 - 2.05 (m, 1H), 1.67 - 1.61 (m, 2H), 1.45 (s, 9H), 1.21 - 1.15 (m, 2H), 1.13 - 1.09 (m, 4H).Step 2: 4-(l-(Piperidin-4-yl)cyclopropyl)pyrimidine-2-carbonitrileTo a solution of tert-butyl 4-(l-(2-cyanopyrimidin-4-yl)cyclopropyl)piperidine-l -carboxylate (70 mg, 213 pmol) in CH2C12(3 mL) was added TFA (72.9 mg, 639 pmol). The mixture was stirred at 25 °C for 0.5 hr. The reaction was concentrated under reduced pressure to give the title compound (Intermediate 30, 73 mg, TFA salt) as a light-yellow oil. MS: m / z = 229.2 [M + H]+.

[0221] Intermediate 31 : 4-(Piperidin-4-yloxy)pyrimidine-2-carbonitrileStep 1 : tert-Butyl 4-((2-(methylthio)pyrimidin-4-yl)oxy)piperidine-l -carboxylateTo a solution of tert-butyl 4-hydroxypiperidine-l -carboxylate (2 g, 9.94 mmol) in THF (50mL) was added NaH (795 mg, 19.9 mmol, 60% purity) at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 hr under N2. Then 4-chloro-2-(methylthio)pyrimidine (1.21 mL, 10.4 mmol) was added. The mixture was stirred at 20 °C for 12 hr under N2. The mixture was quenched with sat. NH4CI (50 mL) under N2 and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4, filtered and concentrated. After purification by silica gel flash chromatography (Eluent of 10 - 55% EtOAc in petroleum ether), the title compound (2.48 g, yield: 77%) was obtained as a colorless oil. MS: m / z = 326 [M + H]+. 'H NMR (400 MHz, Dimethyl sulfoxide-d6) 5 8.33 (d, J= 5.6 Hz, 1H), 6.59 (d, J= 5.6 Hz, 1H), 5.29 - 5.19 (m, 1H), 3.70 - 3.61 (m, 2H), 3.27 - 3.13 (m, 2H), 2.48 (s, 3H), 2.02 - 1.90 (m, 2H), 1.62 - 1.51 (m, 2H), 1.40 (s, 9H).Step 2: terLButyl 4-((2-(methylsulfonyl)pyrimidin-4-yl)oxy)piperidine-l-carboxylate To a solution of terLbutyl 4-((2-(methylthio)pyrimidin-4-yl)oxy)piperidine-l -carboxylate (500 mg, 1.54 mmol) in CH2CI2 (6 mL) was added m-CPBA (624 mg, 3.07 mmol, 85% purity) at 0 °C. The reaction mixture was stirred at 30 °C for 12 hr. The reaction mixture was quenched with sat. Na2SOs aq. (10 mL). The organic layer was washed with sat. Na2CO3 aq. (10 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated. After purification by silica gel flash chromatography (Eluent of 20 - 55% EtOAc in petroleum ether), the title compound (490 mg, yield: 89%) was obtained as a colorless oil. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 5 8.74 (d, J= 6.0 Hz, 1H), 7.22 (d, J= 6.0 Hz, 1H), 5.36 - 5.27 (m, 1H), 3.69 - 3.61 (m, 2H), 3.39 (s, 3H), 3.29 - 3.18 (m, 2H), 2.03 - 1.99 (m, 1H), 1.99 - 1.95 (m, 1H), 1.71 - 1.58 (m, 2H), 1.41 (s, 9H).Step 3: terLButyl 4-((2-cyanopyrimidin-4-yl)oxy)piperidine-l -carboxylate To a solution of terLbutyl 4-((2-(methylsulfonyl)pyrimidin-4-yl)oxy)piperidine-l- carboxylate (250 mg, 699 pmol) in ( C5H m2CLl)2 and H2O (1 mL) were added TBAB (22.6 mg, 69.9 pmol) and NaCN (50 mg, 1.02 mmol) at 15 °C. The mixture was stirred at 30 °C for 10 hr under N2. The mixture was diluted with H2O (10 mL) under N2. The aqueous phase was extracted with C (H102C ml2L x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the title compound (200 mg, yield: 94%) as brown oil, which was used in the next step without purification. MS: m / z = 249 [M - C4H8 + H]+.Step 4: 4-(Piperidin-4-yloxy)pyrimidine-2-carbonitrileA mixture of tert-butyl 4-((2-cyanopyrimidin-4-yl)oxy)piperidine-l -carboxylate (100 mg, 329 pmol) in CH2C (l22 mL) and TFA (3.37 mmol, 250 pL) was stirred at 15 °C for 1 hr.The reaction mixture was concentrated under reduced pressure to give the title compound (Intermediate 31, 67.1 mg, TFA salt) as brown oil, which was used in the next step directly. MS: m / z = 205 [M + H]+.

[0222] Intermediate 32: 4-(Piperidin-4-yl)pyrimidine-2-carbonitrileStep 1 : terLButyl 4-(2-(methylthio)pyrimidin-4-yl)-3,6-dihydropyridine-l(2H)-carboxylate A mixture of (l-(terLbutoxycarbonyl)-l,2,3,6-tetrahydropyridin-4-yl)boronic acid (1.0 g, 4.40 mmol), 4-chloro-2-(methylthio)pyrimidine (707 mg, 4.40 mmol), CS2CO3 (4.30 g, 13.2 mmol), and Pd(dppf)C12 (322 mg, 440 pmol) in 1,4-di oxane (10 mL) and H2O (2 mL) was degassed, purged with N2 three times, and stirred at 90 °C for 3 hr under N2 atmosphere. The reaction mixture was quenched with H2O (30 mL) at 25 °C and extracted with (25 CH2Cl2 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 (1.1 g, yield: 73%) was obtained as a yellow solid. MS: m / z = 308.0 [M + H]+.JH NMR (400 MHz, Chloroform-d) 5 8.44 (d, J= 5.2 Hz, 1H), 6.96 (d, J= 5.6 Hz, 1H), 6.93 - 6.89 (m, 1H), 4.20 - 4.12 (m, 2H), 3.66 - 3.59 (m, 2H), 2.60 - 2.54 (m, 5H), 1.48 (s, 9H).Step 2: te / 7-Butyl 4-(2-(methylthio)pyrimidin-4-yl)piperidine-l -carboxylate To a solution of tert-butyl 4-(2-(methylthio)pyrimidin-4-yl)-3,6-dihydropyridine- 1(277)- carboxylate (850 mg, 2.77 mmol) in MeOH (10 mL) was added Pd / C (198 mg, 186 pmol, purity: 10%) under Ar atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred at 40 °C for 48 hr under H2 (30 psi). The reaction was filtered and concentrated under reduced pressure to give the title compound (855 mg) as a lightyellow oil. MS: m / z = 310.1 [M + H]+.Step 3: terLButyl 4-(2-(methylsulfonyl)pyrimidin-4-yl)piperidine-l -carboxylate To a solution of terLbutyl 4-(2-(m ethylthio)pyrimidin-4-yl)piperi dine- 1 -carboxylate (300 mg, 970 pmol) in THF (3 mL) and MeOH (3 mL) was added oxone (590 mg, 3.88 mmol) in H2O (3 mL). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was diluted withH2O (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 (280 mg, yield: 84% for two steps) as a yellow oil. MS: m / z = 364.0 [M + Na]+. 'H NMR (400 MHz, Dimethyl sulfoxide-d6) 8 9.00 - 8.95 (m, 1H), 7.81 - 7.76 (m, 1H), 4.10 - 4.02 (m, 2H), 3.40 (s, 3H), 3.07 - 2.98 (m, 1H), 2.92 - 2.79 (m, 2H), 1.93 - 1.90 (m, 2H), 1.66 - 1.55 (m, 2H), 1.41 (s, 9H).Step 4: / c / V-Butyl 4-(2-cyanopyrimidin-4-yl)piperidine-l -carboxylateTo a solution of terLbutyl 4-(2-(methylsulfonyl)pyrimidin-4-yl)piperidine-l -carboxylate (280 mg, 820 pmol) in CH2C (5l2 mL) and H2O (0.5 mL) were added NaCN (48 mg, 984 pmol) and TBAB (13.2 mg, 41 pmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was diluted 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% ~ 35% EtOAc in petroleum ether), the title compound (105 mg, yield: 44%) was obtained as an off white solid. MS: m / z = 311.1 [M + Na]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) 6 8.92 (d, J= 5.2 Hz, 1H), 7.82 (d, J= 5.6 Hz, 1H), 4.13 - 4.03 (m, 2H), 3.05 - 2.96 (m, 1H), 2.92 - 2.75 (m, 2H), 1.91 - 1.82 (m, 2H), 1.59 - 1.50 (m, 2H), 1.41 (s, 9H).Step 5: 4-(Piperidin-4-yl)pyrimidine-2-carbonitrileTo a solution of terLbutyl 4-(2-cyanopyrimidin-4-yl)piperidine-l -carboxylate (105 mg, 364 pmol) in CH2Cl2 (2 mL) was added TFA (125 mg, 1.09 mmol). The mixture was stirred at 25 °C for 0.5 hr. The reaction was concentrated under reduced pressure, the title compound (Intermediate 32, 110 mg, TFA salt) was obtained as a purple oil. MS: m / z = 189.0 [M + H]+.

[0223] Intermediate 33: 4-(4,7-Diazaspiro[2.5]octan-7-yl)pyrimidine-2-carbonitrileStep 1 : / c / V-Butyl 7-(2-cyanopyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylateTo a solution of terLbutyl 4,7-diazaspiro[2.5]octane-4-carboxylate (500 mg, 2.36 mmol) in DMF (15 mL) were added 4-chloropyrimidine-2-carbonitrile (329 mg, 2.36 mmol), K2CO3 (977 mg, 7.07 mmol), and Nal (70.6 mg, 471 pmol). The mixture was stirred at 50 °C for 1 hr under N2. The reaction mixture was diluted with water (80 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (100 mL), dried overanhydrous 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 (671 mg, yield: 90%) was obtained as a white solid. MS: m / z = 316.2 [M + H]+. 'HNMR (400 MHz, Dimethyl sulfoxide-d6) 8 8.27 (d, J= 6.0 Hz, 1H), 7.09 (d, J= 6.0 Hz, 1H), 3.67 (br s, 2H), 3.56 - 3.42 (m, 4H), 1.42 (s, 9H), 0.94 - 0.80 (m, 4H).Step 2: 4-(4,7-Diazaspiro[2.5]octan-7-yl)pyrimidine-2-carbonitrileTo a solution of tert-butyl 7-(2-cyanopyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate (90 mg, 285 pmol) in C (1H.52C ml2L) was added TFA (0.5 mL), and the mixture was stirred at 20 °C for 2 hr. The residue was concentrated to give the title compound (Intermediate 33, 61.4 mg) as a brown oil, which was used in the next step without further purification. MS: m / z = 216.1 [M + H]+.

[0224] Intermediate 34: 3-(l-(4-(Chloromethyl)phenyl)-6-(5-fluoropyridin-2-yl)-UT- imidazo[4,5b] pyridin-2-yl)pyridin-2-amineStep 1 : 4-(2-(2-Aminopyridin-3-yl)-6-bromo-1H-imidazo[4,5b] pyridin-l-yl)benzyl acetate To a solution of 4-((5-bromo-2-nitropyridin-3-yl)amino)benzyl acetate (3 g, 8.19 mmol) in DMSO (30 mL) and MeOH (3 mL) were added 2-aminonicotinaldehyde (1.10 g, 9.01 mmol) and Na2SO4 (4.28 g, 24.6 mmol, 85% purity). The mixture was stirred at 100 °C for 12 hr. The mixture was quenched with saturated NaHCCL (30 mL) under N2, filtered, and extracted with EtOAc (40 mL x 3). The organic phase was washed with H2O (30 mL x 4) and brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. After purification by silica gel flash chromatography (Eluent of 0% ~ 82% EtOAc in Petroleum ether), the title compound (1.1 g, yield: 31%) was obtained as a yellow solid. MS: m / z = 438.0, 440.0 [M + H]+. ‘H NMR (400 MHz, Dimethylsulfoxide-d6) 6 8.55 (s, 1H), 8.05 - 7.98 (m, 1H), 7.90 -7.83 (m, 1H), 7.58 -7.53 (m, 2H), 7.51 - 7.47 (m, 2H), 7.23 (dd, J= 7.6, 1.6 Hz, 1H), 6.88 (br s, 2H), 6.47 - 6.37 (m, 1H), 5.17 (s, 2H), 2.11 (s, 3H).Step 2: (l-(4-(Acetoxymethyl)phenyl)-2-(2-aminopyridin-3-yl)-1H-imidazo[4,5b] pyridin-6- yl)boronic acidTo a mixture of 4-(2-(2-aminopyridin-3-yl)-6-bromo-17 / -imidazo[4,5b] pyridin-l-yl)benzyl acetate (550 mg, 1.25 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (478 mg, 1.88 mmol) in 1,4-dioxane (5.5 mL) were added KOAc (370 mg, 3.76 mmol) and Pd(dppf)C12 (91.8 mg, 126 pmol), and the mixture was stirred at 110 °C for 12 hr. The title compound (506 mg) was obtained as black liquid, which was used in the next step directly. MS: m / z = 404.1 [M + H]+.Step 3: 4-(2-(2-Aminopyridin-3-yl)-6-(5-fluoropyridin-2-yl)-lJH-imidazo[4,5b] pyridin-l- yl)benzyl acetateTo a solution of (l-(4-(acetoxymethyl)phenyl)-2-(2-aminopyridin-3-yl)-1H-imidazo[4,5- Z>]pyridin-6-yl)boronic acid (506 mg, 1.25 mmol) in 1,4-dioxane (3 mL) and H2O (0.3 mL) were added 2-bromo-5-fluoropyridine (221 mg, 1.25 mmol), CS2CO3 (1.23 g, 3.76 mmol) and Pd(PPhs)4 (145 mg, 126 pmol). The mixture was stirred at 100 °C for 2 hr. The mixture was diluted with H2O (40 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. After purification by silica gel flash chromatography (Eluent of 0% ~ 95% EtOAc in Petroleum ether), the title compound (280 mg, yield: 49% for two steps) was obtained as a white solid. MS: m / z = 455.1 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) 8 9.23 (d, J= 2.0 Hz, 1H), 6.67 (d, J= 2.8 Hz, 1H), 8.25 (dd, J= 8.8, 4.0 Hz, 1H), 8.18 (d, .7= 2.0 Hz, 1H), 8.07 - 7.00 (m, 1H), 7.89 - 7.80 (m, 1H), 7.62 - 7.52 (m, 4H), 7.25 (dd, J= 7.6, 1.6 Hz, 1H), 7.00 (br s, 2H), 6.48 - 6.40 (m, 1H), 5.20 (s, 2H), 2.13 (s, 3H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 6 -129.194.Step 4: (4-(2-(2-Aminopyri din-3 -yl)-6-(5-fluoropyri din-2 -yl)-1H-imidazo[4,5b] pyri din-1- yl)phenyl)methanolTo a solution of 4-(2-(2-aminopyridin-3-yl)-6-(5-fluoropyridin-2-yl)-1H-imidazo[4,5- Z>]pyridin-l-yl)benzyl acetate (250 mg, 550 pmol) in THF (0.2 mL) and MeOH (0.2 mL) and H2O (0.1 mL) was added K2CO3 (228 mg, 1.65 mmol), and the mixture was stirred at 20 °C for 1 hr. The mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4,filtered and concentrated to give the title compound (227 mg) was obtained as a yellow solid, which was used in the next step directly. MS: m / z = 413.1 [M + H]+.Step 5: 3-(l-(4-(Chloromethyl)phenyl)-6-(5-fluoropyridin-2-yl)-1H-imidazo[4,5b] pyridin-2- yl)pyridin-2-amineTo a solution of (4-(2-(2-aminopyridin-3-yl)-6-(5-fluoropyridin-2-yl)-1H-imidazo[4,5- Z>]pyridin-l-yl)phenyl)methanol (227 mg, 550 pmol) in CH2CI2 (3 mL) was added SOCI2 (196 mg, 1.65 mmol), and the mixture was stirred at 20 °C for 1 hr. The mixture was concentrated to give the title compound (Intermediate 34, 237 mg, HC1 salt) was obtained as a yellow solid, which was used in the next step directly. MS: m / z = 431.1, 433.1 [M + H]+.

[0225] Intermediate 35: 3-(l-(4-(Chloromethyl)phenyl)-6-(4-fluorophenyl)-1H-imidazo[4,5- Z>]pyri din-2 -yl)pyridin-2-amineStep 1 : (4-((5-Bromo-2-nitropyridin-3-yl)amino)phenyl)methanolTo a solution of 5-bromo-3-fluoro-2-nitropyridine (9.5 g, 43.0 mmol) and (4- aminophenyl)methanol (5.29 g, 43.0 mmol) in DMF (95 mL) was added TEA (17.6 mL, 129 mmol). The mixture was stirred at 100 °C for 12 hr. The mixture was diluted with H2O (100 mL) and extracted with EtOAc (100 mL x 3). The organic phase was washed with H2O (100 mL x 4) and brine (100 mL), dried over anhydrous Na2SO,4 filtered, and concentrated to give the title compound (13.9 g) as brown oil, which was used in the next step directly.JH NMR (400 MHz, Dimethylsulfoxide-d6) 8 9.34 (s, 1H), 8.02 (d, J= 2.0 Hz, 1H), 7.62 (d, J= 1.6 Hz, 1H), 7.40 (d, J= 8.0 Hz, 2H), 7.31 (d, J= 8.0 Hz, 2H), 5.23 (t, J= 6.0 Hz, 1H), 4.52 (d, J = 5.2 Hz, 2H).Step 2: 4-((5-Bromo-2-nitropyridin-3-yl)amino)benzyl acetateTo a solution of (4-((5-bromo-2-nitropyri din-3 -yl)amino)phenyl)m ethanol (13.9 g, 43.0 mmol) in CH2CI2 (130 mL) were added DMAP (525 mg, 4.30 mmol), TEA (18.0 mL, 129mmol) and AC2O (6.05 mL, 64.5 mmol). The mixture was stirred at 20 °C for 1 hr. The mixture was diluted with H2O (100 mL) and extracted with CH2CI2 (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous , Na2SO4 filtered and concentrated. After purification by silica gel flash chromatography (Eluent of 0% ~ 25% EtOAc in Petroleum ether), the title compound (8 g, yield: 51% for two steps) was obtained as a light yellow solid. MS: m / z = 366.0, 368.0 [M + H]+.JH NMR (400 MHz, Dimethylsulfoxide-d6) 8 9.33 (s, 1H), 8.06 (d, J= 2.0 Hz, 1H), 7.73 (d, J= 2.0 Hz, 1H), 7.44 (d, J= 8.8 Hz, 2H), 7.35 (d, J= 8.4 Hz, 2H), 5.09 (s, 2H), 2.08 (s, 3H).Step 3: 4-((5-(4-Fluorophenyl)-2-nitropyridin-3-yl)amino)benzyl acetateTo a solution of 4-((5-bromo-2-nitropyridin-3-yl)amino)benzyl acetate (500 mg, 1.37 mmol) in 1,4-dioxane (5 mL) and H2O (0.5 mL) were added (4-fluorophenyl)boronic acid (229 mg, 1.64 mmol), CS2CO3 (1.33 g, 4.10 mmol) and Pd(PPhs)4 (158 mg, 137 pmol). The reaction mixture was degassed and purged with N2 three times. The mixture was stirred at 100 °C for 2 hr. The mixture was combined with another batch (500 mg). The mixture was diluted with H2O (40 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. After purification by silica gel flash chromatography (Eluent of 0% ~ 20% EtOAc in Petroleum ether), the title compound (630 mg, yield: 61%) was obtained as a light yellow solid. MS: m / z = 404.0 [M + Na]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) 6 9.27 (s, 1H), 8.30 (d, J = 2.0 Hz, 1H), 7.85 (d, J= 2.0 Hz, 1H), 7.79 - 7.72 (m, 2H), 7.45 - 7.30 (m, 6H), 5.07 (s, 2H), 2.07 (s, 3H).19F NMR (400 MHz, Dimethyl sulfoxide-d6) 6 -112.149.Step 4 : 4-(2-(2-Aminopyri din-3 -yl)-6-(4-fluorophenyl)- 1H-imidazo[4, 5b] pyridin- 1 - yl)benzyl acetateTo a solution of 4-((5-(4-fluorophenyl)-2-nitropyridin-3-yl)amino)benzyl acetate (570 mg, 1.49 mmol) in DMSO (6 mL) and MeOH (0.6 mL) were added 2-aminonicotinaldehyde (201 mg, 1.64 mmol) and Na2SO4 (781 mg, 4.48 mmol, 85% purity). The mixture was stirred at 100 °C for 12 hr. The mixture was quenched with NaHCCh (20 mL) under N2 and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with H2O (30 mL x 4) and brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. After purification by silica gel flash chromatography (Eluent of 0% ~ 72% EtOAc in Petroleum ether), the title compound (350 mg, yield: 52%) was obtained as yellow oil. MS: m / z = 454.1 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 6 8.81 (d, J= 2.4 Hz, 1H), 8.03 - 8.00 (m, 1H), 7.78 - 7.74 (m, 2H), 7.59 - 7.50 (m, 4H), 7.37 - 7.26 (m, 3H), 7.21 (dd, J= 8.0, 2.0Hz, 1H), 6.95 (br s, 2H), 6.45 - 6.40 (m, 1H), 5.17 (s, 2H), 2.11 (s, 3H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 5 -115.108.Step 5 : (4-(2-(2-Aminopyridin-3-yl)-6-(4-fluorophenyl)-1H-imidazo[4,5b] pyridin-l- yl)phenyl)methanolTo a mixture of 4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)-lJ / -imidazo[4,5b] pyridin-l- yl)benzyl acetate (300 mg, 662 pmol) in THF (1.5 mL), MeOH (1.5 mL) and H2O (0.75 mL) was added K2CO3 (274 mg, 1.98 mmol). The mixture was stirred at 20°C for 1 hr. The mixture was diluted with H2O (30 mL). The aqueous layer was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated, the title compound (170 mg, yield: 63%) was obtained as a yellow solid, which was used in the next step directly. MS: m / z = 412.1 [M + H]+.Step 6: 3-(l-(4-(Chloromethyl)phenyl)-6-(4-fluorophenyl)-1H-imidazo[4,5b] pyridin-2- yl)pyridin-2-amineTo a solution of (4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)- l 7 / -imidazo[4,5-A]pyridin- l - yl)phenyl)methanol (170 mg, 413 pmol) in CH2CI2 (2.5 mL) was added SOCI2 (120 pL, 1.65 mmol). Then the mixture was stirred at 20 °C for 1 hr. The mixture was concentrated to give the title compound (Intermediate 35, 178 mg, HC1 salt) as a yellow solid, which was used in the next step directly. MS: m / z = 430.1, 432.1 [M + H]+.

[0226] Intermediate 36: 4-(2-(2-Aminopyridin-3-yl)-6-bromo-1H-imidazo[4,5-c]pyridin-l- yl)benzyl acetateStep 1 : (4-((2-Bromo-5-nitropyridin-4-yl)amino)phenyl)methanolTo a mixture of 2-bromo-4-chloro-5-nitropyridine (4.5 g, 19.0 mmol) and (4- aminophenyl)methanol (2.57 g, 20.9 mmol) in THF (50 mL) was added DIE A (6.60 mL, 37.9 mmol), and the mixture was stirred at 80 °C for 1 hr. The mixture was concentrated to give the title compound (6.14 g) as yellow solid. MS: m / z = 323.9, 325.9 [M + H]+.Step 2: 4-((2-Bromo-5-nitropyridin-4-yl)amino)benzyl acetateTo a mixture of (4-((2-bromo-5-nitropyridin-4-yl)amino)phenyl)methanol (6.14 g, 18.9 mmol) in CH2CI2 (50 mL) were added DMAP (231 mg, 1.89 mmol), TEA (7.91 mL, 56.8mmol) and AC2O (2.67 mL, 28.4 mmol), and the mixture was stirred at 20 °C for 1 hr. The mixture was diluted with H2O (50 mL) and extracted with CH2CI2 (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous , Na2SO4 filtered and concentrated. After purification by silica gel flash chromatography (Eluent of 0% ~ 20% EtOAc in petroleum ether), the title compound (6.4 g, yield: 92% for two steps) was obtained as yellow oil. MS: m / z = 365.9, 367.9 [M + H]+.JH NMR (400 MHz, Dimethylsulfoxide-d6) 8 9.95 (s, 1H), 8.91 (s, 1H), 7.55 - 7.41 (m, 2H), 7.41 - 7.31 (m, 2H), 6.89 (s, 1H), 5.11 (s, 2H) 2.09 (s, 3H).Step 3: 4-(2-(2-Aminopyridin-3-yl)-6-bromo-1H-imidazo[4,5-c]pyridin-l-yl)benzyl acetate To a mixture of 4-((2-bromo-5-nitropyridin-4-yl)amino)benzyl acetate (2 g, 5.46 mmol) and 2-aminonicotinaldehyde (734 mg, 6.01 mmol) in DMSO (10 mL) was added sat. Na2SO4 (2.38 g, 13.7 mmol), and the mixture was stirred at 100 °C for 12 hr. The mixture was quenched with NaHCCL aq. (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. After purification by silica gel flash chromatography (Eluent of 0% ~ 10% Methanol in CH2C),l2 the title compound (Intermediate 36, 560 mg, yield: 23%) was obtained as yellow oil. MS: m / z = 438.0, 439.8 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 5 8.90 (s, 1H), 8.02 (dd, J= 4.4, 1.6 Hz, 1H), 7.57 - 7.54 (m, 2H), 7.50 - 7.47 (m, 2H), 7.41 (s, 1H), 7.25 (dd, J= 7.6, 2.0 Hz, 1H), 6.81 (br s, 2H), 6.44 (dd, J= 7.6, 4.8 Hz, 1H), 5.16 (s, 2H), 2.11 (s, 3H).

[0227] Intermediate 37: 3-(l-(4-(Chloromethyl)phenyl)-6-(4-fluorophenyl)-1H-imidazo[4,5- c]pyri din-2 -yl)pyridin-2-amineStep 1 : 4-(2-(2-Aminopyridin-3-yl)-6-(4-fluorophenyl)-1H-imidazo[4,5-c]pyridin-l- yl)benzyl acetateTo a mixture of Intermediate 36 (460 mg, 1.05 mmol) and (4-fluorophenyl)boronic acid (220 mg, 1.57 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) were added Pd(dppf)C12 (76.8 mg, 105 pmol) and CS2CO3 (1.03 g, 3.15 mmol), and the mixture was stirred at 100 °C for 1 hr under N2. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. After purification by silica gel flash chromatography (Eluent of 0% ~ 10% Methanol in CH2Cl2), the title compound (450 mg, yield: 95%) was obtained as a brown solid. MS: m / z = 454.1 [M + H]+.JH NMR (400 MHz, Dimethylsulfoxide-d6) 8 9.15 (s, 1H), 8.14 (dd, J= 8.4, 5.6 Hz, 2H), 8.01 (dd, J= 4.8, 1.6 Hz, 1H), 7.67 (s, 1H), 7.57 - 7.51 (m, 4H), 7.29 - 7.24 (m, 2H), 7.22 (dd, J= 7.6, 1.6 Hz, 1H), 6.86 (br s, 2H), 6.38 - 6.47 (dd, J= 7.6, 4.8 Hz, 1H), 5.18 (s, 2H), 1.99 (s, 3H).Step 2: (4-(2-(2-Aminopyridin-3-yl)-6-(4-fluorophenyl)- 1H-imidazo[4,5-c]pyridin-l- yl)phenyl)methanolTo a mixture of 4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)- 1H-imidazo[4,5-c]pyridin-l- yl)benzyl acetate (400 mg, 882 pmol) in THF (2 mL), MeOH (2 mL) and H2O (1 mL) was added K2CO3 (366 mg, 2.65 mmol), and the mixture was stirred at 20 °C for 0.5 hr. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the title compound (363 mg) as a brown solid. MS: m / z = 412.0 [M + H]+.XH NMR (400 MHz, Dimethylsulfoxide-d6) 6 9.14 (s, 1H), 8.16 - 8.10 (dd, J = 8.8, 5.6, 2H), 8.00 (dd, J= 4.8, 2.0, 1H), 7.63 (s, 1H), 7.52 - 7.45 (m, 4H), 7.29 - 7.24 (m, 2H), 7.22 (dd, J= 7.6, 1.6 Hz, 1H), 6.93 (s, 2H), 6.41 (dd, J= 7.2, 4.8, 1H), 5.38 (t, J= 5.6 Hz, 1H), 4.61 (d, J= 5.6 Hz, 2H).Step 3 : 3-(l-(4-(Chloromethyl)phenyl)-6-(4-fluorophenyl)- 1H-imidazo[4,5-c]pyridin-2- yl)pyridin-2-amineTo a mixture of (4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)- 1H-imidazo[4,5-c]pyridin-l- yl)phenyl)methanol (363 mg, 882 pmol) in CH2Cl2 (4 mL) was added SOCI2 (192 pL, 2.65 mmol), the mixture was stirred at 20 °C for 0.5 hr. The mixture was concentrated to give the title compound (Intermediate 37, 379 mg, HC1 salt) was obtained as a brown solid. MS: m / z = 430.0, 432.0 [M + H]+.

[0228] Intermediate 38: 2-Amino-3-(3-(4-(chloromethyl)phenyl)-5-(5-fluoropyridin-2-yl)- 3H-imidazo[4,5-b]pyridin-2-yl)pyridine 1 -oxideStep 1 : 4-(2-(2-Aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-37 / -imidazo[4,5-b]pyridin-3- yl)benzyl acetateTo a solution of (4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5- b]pyri din-3 -yl)phenyl)methanol (refer to Intermediate 3 for detail procedures, 1 g, 2.42 mmol), acetic anhydride (371 mg, 3.64 mmol) in (20 C mHL2)C wl2ere added DMAP (29.6 mg, 243 pmol) and TEA (736 mg, 7.27 mmol). The mixture was stirred at 25 °C for 2 hr. The residue was diluted with H2O (20 mL) and extracted with (10 mL C xH 32)C. l2 The combined organic layers were washed with brine (5 mL x 3), dried over Na2SO,4 filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 5 ~ 8% Ethyl acetate in petroleum ether), 4-(2-(2-aminopyri din-3 - yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl acetate (700 mg, yield: 63%) was obtained as a yellow solid. MS: m / z = 455.1 [M + H]+.JH NMR (400 MHz, Chloroform-d) 5 8.51 (d, J= 2.8 Hz, 1H), 8.48 (d, J= 8.4 Hz, 1H), 8.35 (dd, J= 8.8, 4.4 Hz, 1H), 8.21 - 8.15 (m, 1H), 8.10 (dd, J= 4.8, 1.6 Hz, 1H), 7.58 - 7.52 (m, 2H), 7.49 - 7.43 (m, 3H), 7.12 (dd, J= 7.6, 1.6 Hz, 1H), 6.63 (br s, 2H), 6.44 - 6.39 (m, 1H), 5.25 (s, 2H), 2.20 (s, 3H).Step 2: 3-(3-(4-(Acetoxymethyl)phenyl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyridin- 2-yl)-2-aminopyridine 1 -oxideTo a solution of 4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5- b]pyri din-3 -yl)benzyl acetate (600 mg, 1.32 mmol) in (6 mL C) wH2aCs l a2dded m-CPBA (268 mg, 1.32 mmol, 85% purity). The mixture was stirred at 0 °C for 0.5 hr. The reaction mixture was filtered and concentrated under reduced pressure. After purification by prep- HPLC (column: Phenomenex Cis 150 x 25 mm x 10 pm; mobile phase: [water (NH4HCO3) -ACN]; gradient: 25% - 55% B over 11 min), the title compound (260 mg, yield: 40%) was obtained as a yellow lyophilized powder. MS: m / z = 471.0 [M + H]+.1H NMR (400 MHz, Chloroform-d) 5 8.54 - 8.49 (m, 2H), 8.33 (dd, J= 8.8, 4.4 Hz, 1H), 8.25 - 8.21 (m, 1H), 8.16 (d, J= 6.0 Hz, 1H), 8.05 (br s, 2H), 7.60 - 7.56 (m, 2H), 7.50 - 7.43 (m, 3H), 6.88 - 6.80 (m, 1H), 6.40 - 6.35 (m, 1H), 5.27 (s, 2H), 2.21 (s, 3H).19F NMR (400 MHz, Chloroform-d) 5 - 127.28.Step 3 : 2-Amino-3-(5-(5-fluoropyridin-2-yl)-3-(4-(hydroxymethyl)phenyl)-3H-imidazo[4,5- b]pyri din-2 -yl)pyri dine 1 -oxideTo a solution of 3-(3-(4-(acetoxymethyl)phenyl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5- b]pyridin-2-yl)-2-aminopyridine 1 -oxide (50 mg, 106 pmol) in THF (2 mL), H2O (0.5 mL) and MeOH (2 mL) was added K2CO3 (44.1 mg, 319 pmol). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (5 mL) and extracted with (5 C mHL2C xl 32). The combined organic layers were washed with brine (5 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The title compound (40 mg, yield: 69%) was obtained as a yellow solid. MS: m / z = 429.1 [M + H]+.Step 4: 2-Amino-3-(3-(4-(chloromethyl)phenyl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5- b]pyri din-2 -yl)pyri dine 1 -oxideTo a solution of 2-amino-3-(5-(5-fluoropyridin-2-yl)-3-(4-(hydroxymethyl)phenyl)-3H- imidazo[4,5-b]pyridin-2-yl)pyridine 1-oxide (130 mg, 303 pmol) in CH2CI2 (5 mL) was added SOCI2 (72.2 mg, 607 pmol). The mixture was stirred at 40 °C for 0.5 hr. The reaction was concentrated under reduced pressure, the title compound (Intermediate 38, 130 mg, HC1 salt) was obtained as an off white solid. MS: m / z = 447.1, 449.1 [M + H]+.

[0229] Intermediate 39: 3-(3-(4-((4-Aminopiperidin-l-yl)methyl)phenyl)-5-phenyl-3H- imidazo[4,5b] pyridin-2-yl)pyridin-2-amineStep 1 : tert-Butyl (l-(4-((6-chloro-3-nitropyridin-2-yl)amino)benzyl)piperidin-4- yl)carbamateTo a solution of 2,6-dichloro-3-nitro-pyridine (3.0 g, 15.5 mmol) and tert-butyl (l-(4-((6- chloro-3-nitropyridin-2-yl)amino)benzyl)piperidin-4-yl)carbamate (100 mL) was added DIEA (6.0 g, 46.6 mmol). The mixture was stirred at 50 °C for 12 hr. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO,4 filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0~5% MeOH in CH2)C tol2 give the title compound (4.6 g, yield: 64%) as an orange solid. MS: m / z = 462.1 [M + H]+. 'HNMR (400 MHz, Chloroform-d) 5 10.26 (s, 1H), 8.46 (d, J= 8.8 Hz, 1H), 7.60 (d, J= 8.8 Hz, 2H), 7.34 (d, J= 8.4 Hz, 2H), 6.79 (d, J= 8.4 Hz, 1H), 4.42 (br s, 1H), 3.48 (s, 2H), 3.48 - 3.39 (m, 1H), 2.82 (br d, J= 10.8 Hz, 2H), 2.10 (br t, J= 10.8 Hz, 2H), 1.92 (br d, J= 10.8 Hz, 2H), 1.50-1.40 (m, 2H).1.44 (s, 9H).Step 2: tert-Butyl (l-(4-((3-nitro-6-phenylpyridin-2-yl)amino)benzyl)piperidin-4- yl)carbamateA mixture of tert-Butyl (l-(4-((6-chl oro-3 -nitropyri din-2 -yl)amino)benzyl)piperidin-4- yl)carbamate (1.0 g, 2.20 mmol), phenylboronic acid (528 mg, 4.30 mmol), Pd(dppf)C12 (158 mg, 0.216 mmol) and K2CO3 (898 mg, 6.50 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) was degassed, purged with N2 three times, and stirred at 100 °C for 12 hr under N2 atmosphere. The mixture was cooled to 25 °C. The mixture was diluted with H2O and extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2S, O fil4tered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0~7% MeOH in CH2CI2) to give the title compound (1.1 g, yield: 96%) as a yellow solid. MS: m / z = 504.1 [M + H]+. 'H NMR (400 MHz, Chloroform-d) 5 10.31 (s, 1H), 8.59 (d, J= 8.8 Hz, 1H), 8.09 - 8.02 (m, 2H), 7.72 (d, J= 8.4 Hz, 2H), 7.51 - 7.47 (m, 3H), 7.36 (d, J= 8.8 Hz, 1H), 7.30 (d, J= 8.8 Hz, 1H), 4.52 - 4.37 (m, 1H), 3.52 (s, 2H), 3.51 - 3.42 (m, 1H), 2.85 (br d, J= 11.2 Hz, 2H), 2.12 (br t, J= 10.8 Hz, 2H), 1.93 (br d, J= 11.0 Hz, 2H), 1.50 - 1.40 (m, 2H). 1.44 (s, 9H).Step 3: tert-Butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5b] pyridin-3- yl)benzyl)piperidin-4-yl)carbamateA solution of tert-Butyl (l-(4-((3-nitro-6-phenylpyridin-2-yl)amino)benzyl)piperidin-4- yl)carbamate (200 mg, 0.397 mmol), 2-aminopyridine-3-carbaldehyde (53.4 mg, 0.437 mmol), and Na2S2O4 (207 mg, 1.2 mmol) in DMSO (6 mL) was stirred at 100 °C for 18 hr.The reaction mixture was cooled to 25 °C and diluted with DCM (40 mL). The organic layers were separated, washed with H2O (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0~7% MeOH in ) t CoH gi2vCel2 the title compound (100 mg, yield: 40%) as a yellow solid. MS: m / z = 576.2 [M + H]+.Step 4: 3-(3-(4-((4-Aminopiperidin-l-yl)methyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amineA solution of tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5b] pyridin-3-yl)benzyl)piperidin-4-yl)carbamate (200 mg, 0.347 mmol) in HC1 in 1,4-dioxane (4 M, 2 mL) was stirred at 25 °C for 2 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters xbridge 150*25mm lOum; mobile phase: [water (NH4HCO3) - ACN]; B%: 24% - 54%, 8 min) to give the title compound (Intermediate 39, 120 mg, yield: 72 %) as a light-yellow solid. MS: m / z = 476.2 [M + H]+. 'HNMR (400 MHz, Chloroform-d) 5 8.12 (d, J= 8.4 Hz, 1H), 8.05 (dd, J= 5.2, 1.6 Hz, 1H), 8.01 (d, J= 7.2 Hz, 2H), 7.79 (d, J= 8.4 Hz, 1H), 7.50 - 7.35 (m, 7H), 7.09 (dd, J= 7.6, 1.2 Hz, 1H), 6.61 (br s, 2H), 6.35 (dd, J= 7.6, 4.8 Hz, 1H), 3.58 (s, 2H), 2.88 (br d, J = 11.6 Hz, 2H), 2.75 - 2.65 (m, 1H), 2.09 (br t, J= 11.6 Hz, 2H), 1.83 (br d, J= 11.6 Hz, 2H), 1.49 - 1.38 (m, 2H).

[0230] Intermediate 40: 3-(3-(6-(Chloromethyl)pyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H- imidazo[4,5-b]pyridin-2-yl)pyridin-2-amineStep 1 : Methyl 5-((6-chloro-3-nitropyridin-2-yl)amino)picolinateTo a solution of 2,6-dichloro-3-nitropyridine (4.06 g, 21 mmol) in THF (40 mL) were added methyl 5-aminopicolinate (4 g, 26.3 mmol) and DIEA (10.2 g, 78.9 mmol). The mixture wasstirred at 80 °C for 12 hr under N2. The residue was filtered and concentrated. After purification by silica gel flash chromatography (Eluent of 0-30% EtOAc in petroleum ether), the title compound (1.8 g, yield: 22%) was obtained as a yellow solid. MS: m / z = 308.9, 310.9 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) 8 10.34 (s, 1H), 8.95 (d, J= 2.4 Hz, 1H), 8.60 (d, J= 8.4 Hz, 1H), 8.26 (dd, J= 8.4, 2.4 Hz, 1 H), 8.10 (d, J= 8.4 Hz, 1H), 7.18 (d, J= 8.4 Hz, 1H), 3.88 (s, 3H).Step 2: Methyl 5-((5'-fluoro-5-nitro-[2,2'-bipyridin]-6-yl)amino)picolinateTo a solution of methyl 5-((6-chloro-3-nitropyridin-2-yl)amino)picolinate (1.27 g, 4.11 mmol) in 1,4-dioxane (30 mL) were added (5-fluoropyridin-2-yl)boronic acid (2.03 g, 14.4 mmol), CS2CO3 (4.02 g, 12.3 mmol), catacxium(A) A Pd G3 (300 mg, 411 pmol), and CuBr (443 mg, 3.09 mmol). The mixture was stirred at 110 °C for 2 hr under N2. The mixture was diluted with H2O (100 mL) and extracted with (30 C mHL2C xl23). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated. After purification by silica gel flash chromatography (Eluent of 0~l% MeOH in CH2Cl2), the title compound (1 g, yield: 66%) was obtained as a yellow solid. MS: m / z = 370.0 [M + H]+. ‘HNMR (400 MHz, Dimethylsulfoxide-d6) 6 10.30 (s, 1H), 9.08 (s, 1H), 8.78 - 8.71 (m, 2H), 8.41 - 8.39 (m, 1H), 8.25 - 8.23 (m, 1H), 8.20 - 8.14 (m, 1H), 8.06 - 7.97 (m, 2H), 3.89 (s, 3H).Step 3: Methyl 5-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5- Z>]pyri din-3 -yl)picolinateTo a solution of methyl 5-((5'-fluoro-5-nitro-[2,2'-bipyridin]-6-yl)amino)picolinate (1.16 g, 3.14 mmol) in DMSO (15 mL) were added 2-aminonicotinaldehyde (422 mg, 3.46 mmol) and Na2SO4 (1.64 g, 9.42 mmol). The mixture was stirred at 100 °C for 12 hr under N2. After purification by silica gel flash chromatography (Eluent of 0~3% MeOH in ), the CH2Cl2 title compound (308 mg, yield: 31%) was obtained as a yellow solid.1H NMR (400 MHz, Dimethylsulfoxide-d6) 68.89 (d, J= 2.4 Hz, 1H), 8.68 (d, J= 2.8 Hz, 1H), 8.47 (d, J= 8.4 Hz, 1H), 8.38 (d, J= 8.4 Hz, 1H), 8.34 - 8.28 (m, 1H), 8.25 (d, J= 8.4 Hz, 1H), 8.18 - 8.15 (m, 1H), 8.06 (dd, J= 4.8, 1.6 Hz, 1H), 7.87 - 8.83 (m, 1H), 7.42 (dd, J= 7.6, 1.6 Hz, 1H), 6.67 (s, 2H), 6.55 (dd, J= 8.0, 5.2 Hz, 1H), 3.92 (s, 3H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 5 -127.504.Step 4: (5-(2-(2-Aminopyri din-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5b] pyri din-3- yl)pyridin-2-yl)methanolTo a solution of methyl 5-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5- Z>]pyri din-3 -yl)picolinate (250 mg, 566 pmol) in THF (8 mL) was added LiAITU ( 2.5 M in THF, 362 pL) at 0 °C. The mixture was stirred at 0 °C for 2 hr under N2. The mixture was quenched with Na2SO4 IOH2O that was added in portions until no bubbles were formed. The mixture was stirred at 25 °C for 20 mins and filtered. The filter cake was washed with THF (10 mL x 5), and the combined filtrate was concentrated under reduced pressure to give the title compound (234 mg) as a yellow solid, which was used in the next step directly. MS: m / z = 414.2 [M + H]+.Step 5: 3-(3-(6-(Chloromethyl)pyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5-Z>]pyri din-2 -yl)pyridin-2-amineTo a solution of (5-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5- Z>]pyridin-3-yl)pyridin-2-yl)methanol (234 mg, 566 pmol) in CH2CI2 (8 mL) was added SOCI2 (202 mg, 1.70 mmol). The mixture was stirred at 25 °C for 2 hr under N2. The residue was concentrated under reduce pressure, the title compound (Intermediate 40, 245 mg, HC1 salt) was obtained as a yellow solid which was used in the next step directly. MS: m / z = 432.1, 434.1 [M + H]+.

[0231] Intermediate 41 : 3-(9-(4-(Chloromethyl)phenyl)-2-(4-fluorophenyl)-9H-purin-8- yl)pyridin-2-amineStep 1 : Methyl 4-((2-chloro-5-nitropyrimidin-4-yl)amino)benzoateTo a mixture of 2,4-dichloro-5-nitropyrimidine (10.0 g, 51.7 mmol) and methyl 4- aminobenzoate (7.1 g, 47.0 mmol) in THF (150 mL) was added TEA (7.19 mL, 51.7 mmol). The mixture was stirred at 0 °C for 2 hr. The mixture was concentrated and triturated with EtOAc (150 mL) at 25 °C for 30 min. The title compound (14.5 g) was obtained as a yellow solid. 'HNMR (400 MHz, Dimethylsulfoxide-d6) 8 10.57 (s, 1H), 9.20 (s, 1H), 8.02 (d, J= 8.4 Hz, 2H), 7.74 (d, J= 8.8 Hz, 2H), 3.86 (s, 3H).Step 2: Methyl 4-((5-amino-2-chloropyrimidin-4-yl)amino)benzoateTo a solution of methyl 4-((2-chloro-5-nitropyrimidin-4-yl)amino)benzoate (8 g, 25.9 mmol) in EtOH (80 mL) and H2O (16 mL) were added Fe (4.34 mg, 77.8 mmol) and NH4CI (9.7 g, 181 mmol). The mixture was stirred at 80 °C for 2 hr. The residue was filtered and concentrated. The title compound (4.56 g, yield: 63% for two steps) was obtained as a yellow solid and used in the next step without further purification. MS: m / z = 279.0 [M + H]+. 'HNMR (400 MHz, Dimethylsulfoxide-d6) 8 8.99 (s, 1H), 7.95 (d, J= 8.8, 2H), 7.85 (d, J= 8.8 Hz, 2H), 7.75 (s, 1H), 5.45 (s, 2H), 3.83 (s, 3H).Step 3: Methyl 4-(8-(2-aminopyridin-3-yl)-2-chloro-7,8-dihydro-9J / -purin-9-yl)benzoate To a solution of methyl 4-((5-amino-2-chloropyrimidin-4-yl)amino)benzoate (4.56 g, 16.4 mmol) in CH3COOH (60 mL) were added 2-aminonicotinaldehyde (1.8 g, 14.7 mmol) and CU(OAC)2 (594 mg, 3.27 mmol). The mixture was stirred at 60 °C for 16 hr under N2. The reaction mixture was neutralized with NH3 H2O (adjusted pH to 7 ~ 8). The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The title compound (1.4 g, yield: 22%) was obtained as a black-brown solid and used in the next step without further purification.1H NMR (400 MHz, Dimethylsulfoxide-d6) 6 8.72 (s, 1H), 8.16 (s, 1H), 8.02 - 7.81 (m, 7H), 7.79 - 7.64 (m, 2H), 6.71 (dd, J= 7.6, 4.8 Hz, 1H), 3.84 (s, 3H).Step 4: Methyl 4-(8-(2-aminopyri din-3 -yl)-2-chloro-9H-purin-9-yl)benzoateTo a solution of methyl 4-(8-(2-aminopyridin-3-yl)-2-chloro-7,8-dihydro-9J / -purin-9- yl)benzoate (700 mg, 1.83 mmol) in EtOH (10 mL) was added Mn02 (1.59 g, 18.3 mmol). The mixture was stirred at 80 °C for 24 hr. The residue was filtered and concentrated. After purification by silica gel flash chromatography (Eluent of 0 ~ 56% EtOAc in Petroleum ether), the title compound (53.5 mg, yield: 7.7%) was obtained as a yellow solid. MS: m / z = 381.0 [M + H]+. 'HNMR (400 MHz, Dimethylsulfoxide-d6) 6 9.21 (s, 1H), 8.11 (d, J= 8.8 Hz, 2H), 8.04 (dd, J= 4.8, 1.6 Hz, 1H), 7.61 (d, J= 8.4 Hz, 2H), 7.34 - 7.29 (m, 1H), 6.70 (s, 2H), 6.48 (dd, J= 7.6, 4.4 Hz, 1H), 3.89 (s, 3H).Step 5: Methyl 4-(8-(2-aminopyridin-3-yl)-2-(4-fluorophenyl)-9H-purin-9-yl)benzoate To a solution of methyl 4-(8-(2-aminopyridin-3-yl)-2-chloro-9J / -purin-9-yl)benzoate (53.5 mg, 140 pmol) in 1,4-dioxane (2.8 mL) were added (4-fluorophenyl)boronic acid (68.8 mg, 492 pmol), CS2CO3 (137 mg, 422 pmol), CuBr (15.1 mg, 105 pmol), and catacxium A Pd G3 (10.2 mg, 14.1 pmol). The mixture was stirred at 110 °C for 2 hr under N2. The mixture wasdiluted with H2O (30 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. After purification by silica gel flash chromatography (Eluent of 0 ~ 83% EtOAc in Petroluem ether), the title compound (34 mg, yield: 44%) was obtained as a yellow solid. MS: m / z = 441.2 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 8 9.35 (s, 1H), 8.43 - 8.38 (m, 2H), 8.14 (d, J= 8.0 Hz, 2H), 7.68 (d, J= 8.4 Hz, 2H), 7. 36 - 7. 27 (m, 4H), 6.78 (d, J= 1.2 Hz, 2H), 6. 56 - 6. 45 (m, 1H), 3.90 (s, 3H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 6 -111.205.Step 6: (4-(8-(2- Aminopyri din-3 -yl)-2-(4-fluorophenyl)-9H-purin-9-yl)phenyl)methanol To a solution of methyl 4-(8-(2-aminopyri din-3 -yl)-2-(4-fluorophenyl)-9H-purin-9- yl)benzoate (34 mg, 77.2 pmol) in THF (0.1 mL) was added LiAlH4 (46.3 pL, 2.5 M in THF). The mixture was stirred at 20 °C for 0.5 hr under N2. Na2SO4 IOH2O was added in portions until no bubbles were formed. The resulting mixture was stirred at 25 °C for 20 mins and filtered. The filter cake was washed with THF (10 mL x 2), and the combined filtrate was concentrated to give the title compound (31.8 mg) as a yellow solid and used in the next step without further purification. MS: m / z = 413.1 [M + H]+.Step 7 : 3-(9-(4-(Chloromethyl)phenyl)-2-(4-fluorophenyl)-9H-purin-8-yl)pyridin-2-amine To a solution of (4-(8-(2-aminopyri din-3 -yl)-2-(4-fluorophenyl)-9H-purin-9- yl)phenyl)methanol (31.8 mg, 77.2 pmol) in CH2CI2 (0.3 mL) was added SOCI2 (27.6 mg, 232 pmol). The mixture was stirred at 20 °C for 1 hr. The residue was concentrated to give the title compound (Intermediate 41, 33.3 mg) a yellow solid and used for the next step without further purification. MS: m / z = 431.1 [M + H]+.

[0232] Intermediate 42: 3-(l-(4-(Chloromethyl)phenyl)-6-(4-fluorophenyl)-lH-imidazo[4,5- b]pyrazin-2-yl)pyridin-2-amineStep 1 : 3-Chloro-5-(4-fluorophenyl)pyrazin-2-amineTo a solution of 5-bromo-3-chloropyrazin-2-amine (10 g, 48.0 mmol), (4- fluorophenyl)boronic acid (6.04 g, 43.2 mmol) in 1,4-dioxane (100 mL) and H2O (20 mL) were added Pd(dppf)C12 (3.51 g, 4.80 mmol) and CS2CO3 (46.9 g, 144 mmol). The mixture was degassed, purged with N2 three times, and stirred at 80 °C for 2 hr under N2. The reaction mixture was quenched with H2O (200 mL) at 25 °C and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 11% EtOAc in petroleum ether), the title compound (3.65 g, yield: 36%) was obtained as a yellow solid. MS: m / z = 2A.\ [M + H]+. 'H NMR (400 MHz, Chloroform-d) 5 8.34 (s, 1H), 7.83 - 7.86 (m, 2H), 7.11 - 7.26 (m, 2H), 5.07 (s, 2H).19F NMR (400 MHz, Chloroform-d) 5 -113.228.Step 2: Methyl 4-((3-amino-6-(4-fluorophenyl)pyrazin-2-yl)amino)benzoateTo a solution of 3-chloro-5-(4-fluorophenyl)pyrazin-2-amine (3 g, 9.39 mmol) and methyl 4- aminobenzoate (1.42 g, 9.39 mmol) in 1,4-dioxane (50 mL) were added XPhos-Pd-G4 (808 mg, 939 pmol) and CS2CO3 (9.18 g, 28.2 mmol). The mixture was degassed and purged with N2 three times and stirred at 100 °C for 4 hr under N2. The reaction mixture was quenched with H2O (100 mL) at 25 °C and extracted with (10 C0H m2LCl x2 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% ~ 65% EtOAc in petroleum ether), the title compound (1.7 g, yield: 49%) was obtained as a brown solid. MS: m / z = 339.0 [M + H]+. ' H NMR (400 MHz, DimethylsulfoxidesL) 5 8.70(s, 1H), 8.12 (s, 1H), 8.02 - 7.90 (m, 6H), 7.30 - 7.17 (m, 2H), 6.58 (s, 2H), 3.82 (s, 3H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 5 -115.448.Step 3: Methyl 4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)-177-imidazo[4,5-b]pyrazin-l- yl)benzoateTo a solution of methyl 4-((3-amino-6-(4-fluorophenyl)pyrazin-2-yl)amino)benzoate (1.7 g, 5.02 mmol) and 2-aminonicotinaldehyde (675 mg, 5.53 mmol) in AcOH (40 mL) was added CU(OAC)2 (183 mg, 1.00 mmol). The mixture was stirred at 80 °C for 16 hr. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (100 mL) and extracted with CH (21C00l2 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 purificatoin by silica gel flash chromatography (Eluent of 0% ~ 7% MeOH in CH2Cl2), the title compound (700 mg, yield: 26%) was obtained as a yellow solid. MS: m / z = 441.0 [M + H]+.XH NMR (400 MHz, Dimethylsulfoxide-d6) 8 9.23 (s, 1H), 8.23 - 8.02 (m, 5H), 7.69 (d, J= 8.4 Hz, 2H), 7.40 - 7.28 (m, 3H), 6.86 (br s, 2H), 6.53 - 6.47 (m, 1H), 3.89 (s, 3H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 6 -112.364.Step 4: (4-(2-(2-Aminopyridin-3-yl)-6-(4-fluorophenyl)-1H-imidazo[4,5-b]pyrazin-l- yl)phenyl)methanolTo a solution of methyl 4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)-1H-imidazo[4,5- b]pyrazin-l-yl)benzoate (300 mg, 681 mol) in THF (5 mL) was added LiAlH4 (409pL, 2.5 M in THF) at 0 °C dropwise. The resulting mixture was stirred at 25 °C for 1 hr under N2 atmosphere. The reaction mixture was quenched with Na2SO4 IOH2O (500 mg) at 0 °C, filtered and concentrated under reduced pressure. The title compound (280 mg) was obtained as a yellow solid. MS: m / z = 413.2 [M + H]+.Step 5: 3-(l-(4-(Chloromethyl)phenyl)-6-(4-fluorophenyl)-1H-imidazo[4,5-b]pyrazin-2- yl)pyridin-2-amineTo a solution of (4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)-1H-imidazo[4,5-b]pyrazin-l- yl)phenyl)methanol (280 mg, 679 pmol) in (3 C mHL2C) l w2 as added SOCI2 (242 mg, 214 pmol). The mixture was stirred at 40 °C for 0.5 hr. The reaction was concentrated under reduced pressure to give the title compound (Intermediate 42, 317 mg, HC1 salt) as a yellow solid. MS: m / z = 431.1, 433.1 [M + H]+.

[0233] Intermediate 43: 3-(9-(4-(Chloromethyl)phenyl)-2-(5-fluoropyridin-2-yl)-9H-purin-8- yl)pyridin-2-amineIntermediate 43 was prepared in a manner similar to Intermediate 41. MS: m / z =432.1, 434.1[M + H]+.

[0234] Intermediate 44: 3-(l-(4-(Chloromethyl)phenyl)-6-(5-fluoropyridin-2-yl)-lH-Intermediate 44 was prepared in a manner similar to Intermediate 42. MS: m / z = 432.0, 434.0 [M+H]+.

[0235] Intermediate 45: 3-(l-(4-(Chloromethyl)phenyl)-6-(5-fluoropyridin-2-yl)-lH- imidazo[4,5-c]pyri din-2 -yl)pyridin-2-amineStep 1 : 4-(2-(2-Aminopyridin-3-yl)-6-(5-fluoropyridin-2-yl)-l 7 / -imidazo[4,5-c]pyridin- l - yl)benzyl acetateTo a mixture of Intermediate 36 (200 mg, 456 pmol) and (5-fluoropyridin-2-yl)boronic acid (129 mg, 913 pmol) in DME (5 mL) and H2O (0.5 mL) were added CS2CO3 (446 mg, 1.37 mmol) and Pd(dppf)C12-CH2C12 (37.3 mg, 45.6 pmol). The mixture was stirred at 110 °C for 12 hr under N2. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated. After purification by silica gel flash chromatography (Eluent of 0% ~ 10% Methanol in ), the C tHitl2eC cl2ompound (80 mg, yield: 39%) was obtained as a brown solid. MS: m / z = 455.2 [M + H]+.Step 2: (4-(2-(2-Aminopyri din-3 -yl)-6-(5-fluoropyri din-2 -yl)-1H-imidazo[4,5-c]pyri din-1- yl)phenyl)methanolTo a mixture of 4-(2-(2-aminopyridin-3-yl)-6-(5-fluoropyridin-2-yl)-1H-imidazo[4,5- c]pyridin-l-yl)benzyl acetate (70 mg, 154 pmol) in THF (1 mL), MeOH (1 mL) and H2O (0.5 mL) was added K2CO3 (63.9 mg, 462 pmol). The mixture was stirred at 20 °C for 1 hr. The mixture was diluted with H2O (5 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the title compound (63.5 mg) as a brown solid. MS: m / z = 413.1 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 8 9.17 (s, 1H), 8.59 (d, J= 2.8 Hz, 1H) 8.53 (dd, J= 9.2, 4.8 Hz, 1H) 8.10 (s, 1H), 8.01 (dd, J= 4.8, 1.6 Hz, 1H), 7.88 - 7.83 (m, 1H), 7.54 - 7.50 (m, 4H), 7.27 (dd, J= 8.0, 2.0 Hz, 1H), 7.01 (br s, 2H), 6.43 (dd, J= 8.0, 4.8 Hz, 1H), 5.38 (t, J= 5.6 Hz, 1H), 4.62 (d, J= 5.6 Hz, 2H).Step 3 : 3-(l-(4-(Chloromethyl)phenyl)-6-(5-fluoropyridin-2-yl)-1H-imidazo[4,5-c]pyridin-2- yl)pyridin-2-amineTo a mixture of (4-(2-(2-aminopyridin-3-yl)-6-(5-fluoropyridin-2-yl)-1H-imidazo[4,5- c]pyri din- l-yl)phenyl)m ethanol (63.5 mg, 154 pmol) in CH2CI2 (2 mL) was added SOCI2 (33.6 pL, 462 pmol). The mixture was stirred at 20 °C for 1 hr. The mixture wasconcentrated to give the title compound (Intermediate 45, 66.4 mg, HC1 salt) was obtained as a brown solid. MS: m / z = 431.0, 432.3 [M + H]+.

[0236] Intermediate 46: 3-(3-(4-(Chloromethyl)phenyl)-5-(4-fluorophenyl)-3H-imidazo[4,5-Z>]pyri din-2 -yl)pyridin-2-amineStep 1 : Methyl 4-((6-chloro-3-nitropyridin-2-yl)amino)benzoateTo a solution of methyl 4-aminobenzoate (5 g, 33.1 mmol) in DMSO (50 mL) were added 2,6-dichloro-3-nitro-pyridine (7.66 g, 39.7 mmol) and DIEA (12.82 g, 99.2 mmol). The mixture was stirred at 80 °C for 16 hr. The reaction mixture was cooled to 20 °C, poured into H2O (100 mL), and extracted with ( C1H002C ml2L x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous Na2SO,4 filtered and concentrated. The crude was triturated with EtOAc at 25 °C for 30 min to give the title compound (8 g, yield: 51%). MS: m / z = 307.8 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 8 10.25 (s, 1H), 8.57 (d, J= 8.4 Hz, 1H), 7.97 (d, J= 8.8 Hz, 2H), 7.79 (d, J= 8.8 Hz, 2H), 7.12 (d, J = 8.4 Hz, 1H), 3.85 (s, 3H).Step 2: Methyl 4-((6-(4-fluorophenyl)-3-nitropyridin-2-yl)amino)benzoateA mixture of methyl 4-((6-chloro-3-nitropyridin-2-yl)amino)benzoate (5.0 g, 16.3 mmol), (4- fluorophenyl)boronic acid (3.0 g, 21.1 mmol), Pd(dppf)C12 (1.2 g, 1.63 mmol), and CS2CO3 (15.9 g, 48.8 mmol) in 1,4-dioxane (50 mL) and H2O (5 mL) was degassed, purged with N2 three times, and stirred at 100 °C for 16 hr under N2. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0 ~ 10% MeOH in ) to give C thHe2Cl2 title compound (2.5 g, yield: 34%). MS: m / z = 340.3 [M + H]+. 'H NMR (400 MHz,Dimethylsulfoxide-d6) 6 10.45 (s, 1H), 8.62 (d, J= 8.6 Hz, 1H), 8.15 - 8.04 (m, 4H), 7.85 (d, J= 8.4 Hz, 2H), 7.34 (d, J= 8.6 Hz, 1H), 7.24 - 7.18 (m, 2H), 3.95 (s, 3H).Step 3: Methyl 4-(2-(2-aminopyridin-3-yl)-5-(4-fluorophenyl)-3H-imidazo[4,5b] pyridin-3- yl)benzoateTo a solution of methyl 4-((6-(4-fluorophenyl)-3-nitropyridin-2-yl)amino)benzoate (2.5 g, 6.81 mmol) and 2-aminopyridine-3-carbaldehyde (914 mg, 7.49 mmol) in DMSO (100 mL) was added Na2SO4 (4.74 g, 7.49 mmol). The mixture was stirred at 100 °C for 12 hr. The reaction mixture was diluted with H2O (100 mL) and extracted with (300 mL C xH 22)C. l2 The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0 ~ 100% EtOAc in petroleum ether) to give the title compound (1.3 g, yield: 40%). MS: m / z = 440.0 [M + H]+. *H NMR (400 MHz, Chloroform-d) 5 8.26 - 8.21 (m, 2H), 8.15 (d, J= 8.4 Hz, 1H), 8.08 (dd, J= 5.2, 1.6 Hz, 1H), 8.03 - 7.98 (m, 2H), 7.79 (d, J= 8.4 Hz, 1H), 7.56 (d, J= 8.4 Hz, 2H), 7.17 - 7.08 (m, 3H), 6.82 (br s, 2H), 6.42 (dd, J= 7.6, 4.8 Hz, 1H), 3.99 (s, 3H).Step 4: (4-(2-(2-Aminopyridin-3-yl)-5-(4-fluorophenyl)-3H-imidazo[4,5b] pyridin-3- yl)phenyl)methanolTo a solution of methyl 4-(2-(2-aminopyridin-3-yl)-5-(4-fluorophenyl)-3H-imidazo[4,5- Z>]pyri din-3 -yl)benzoate (1.3 g, 2.92mmol) in THF (100 mL) was added LiAlH4 (2.5 M, 4.44 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 hr. The reaction mixture was quenched with Na2SO4 10H2O (203 mg) at 0 °C and filtered. The filtrate was concentrated under reduced pressure. The crude (1.2 g) was used in the next step without further purification. MS: m / z = 412.0 [M + H]+.Step 5: 3-(3-(4-(Chloromethyl)phenyl)-5-(4-fluorophenyl)-3H-imidazo[4,5b] pyridin-2- yl)pyridin-2-amineTo a solution of (4-(2-(2-aminopyridin-3-yl)-5-(4-fluorophenyl)-3H-imidazo[4,5b] pyridin-3- yl)phenyl)methanol (1.2 g, 2.91mmol) in CH2CI2 (20 mL) was added SOCI2 (2.1 g, 17.5 mmol). The mixture was stirred at 40 °C for 2 hr. The mixture was concentrated under reduced pressure to give the title compound (Intermediate 46, 1.25 g HC1 salt, yield: 89%). MS: m / z = 429.9 [M + H]+.

[0237] Example 1 : 4-((l-((4-(2-(2-Aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H- imidazo[4,5-b]pyridin-3-yl)phenyl)methyl--d2)piperidin-4-yl)amino)pyrimidine-2-carbonitrileStep 1 : (2-(2-Aminopyridin-3-yl)-3-(4-(methoxycarbonyl)phenyl)-37 / -imidazo[4,5-b]pyridin- 5-yl)boronic acidA mixture of methyl 4-(2-(2-aminopyridin-3-yl)-5-bromo-3H-imidazo[4,5-b]pyridin-3- yl)benzoate (1.8 g, 4.24 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (2.15 g, 8.49 mmol), Pd(dppf)C12 (310 mg, 424 pmol) and KOAc (1.25 g, 12.7 mmol) in 1,4- dioxane (20 mL) was degassed and purged with N2 three times, and the mixture was stirred at 80 °C for 2 hr under N2 atmosphere. The title compound was obtained as a black liquid, which was used in the next step without work-up and purification. MS: m / z = 390.0 [M + H]+.Step 2: Methyl 4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5- b]pyri din-3 -yl)benzoateA mixture of (2-(2-aminopyridin-3-yl)-3-(4-(methoxycarbonyl)phenyl)-3H-imidazo[4,5- b]pyridin-5-yl)boronic acid (1.65 g, 4.24 mmol), 2-bromo-5-fhioropyridine (746 mg, 4.24 mmol), CS2CO3 (4.14 g, 12.7 mmol), and Pd(dppf)C12 (310 mg, 424 pmol) in 1,4-dioxane (20 mL) and H2O (4 mL) was degassed, purged with N2 three times, and stirred at 80 °C for 2 hr under N2 atmosphere. The reaction mixture was quenched with H2O (100 mL) and extracted with CH2Cl2 (100 mL x 2). The combined organic layers were washed with brine (100 mL), driedoverNa2SO4 and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 10% ~ 45% EtOAc in petroleum ether), the title compound (1.45 g, yield: 74% for two steps) was obtained as a yellow solid. MS: m / z = 441.0 [M + H]+. ‘HNMR (400 MHz, Dimethylsulfoxide-d6) 8 8.66 (d, J= 2.4 Hz, 1H), 8.47 - 8.30 (m, 2H), 8.27 (dd, J= 8.8, 4.8 Hz, 1H), 8.13 (d, J= 8.4 Hz, 2H), 8.03 (dd, J = 4.8, 1.6 Hz, 1H), 7.85 - 7.78 (m, 1H), 7.68 (d, J= 8.4 Hz, 2H), 7.26 (dd, J= 7.6, 1.6 Hz, 1H), 6.88 (brs, 2H), 6.46 (dd, J= 7.6, 4.8 Hz, 1H), 3.90 (s, 3H).19F NMR (400 MHz, Dimethylsulfoxide- d6) 8 -127.676.Step 3 : (4-(2-(2-Aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)methan--d2-olTo a solution of methyl 4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5- b]pyri din-3 -yl)benzoate (2.7 g, 6.13 mmol) in THF (50 mL) was added LiAlD4 (465 mg, 12.3 mmol). The mixture was degassed, purged with N2 three times, and stirred at 0 °C for 1 hr under N2 atmosphere. The reaction mixture was quenched with Na2SO4' IOH2O (5 g) at 0 °C, filtered and concentrated under reduced pressure. The title compound (2.5 g) was obtained as a yellow solid, which was used in the next step directly. MS: m / z = 415.1 [M + H]+.Step 4: 3-(3-(4-(Chloromethyl--d2)phenyl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amineTo a solution of (4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5- b]pyridin-3-yl)phenyl)methan--d2-ol (2.5 g, 6.03 mmol) in CH2CI2 (50 mL) was added SOCI2 (2.15 g, 18.1 mmol). The mixture was stirred at 40 °C for 0.5 hr. The pH of the reaction mixture was adjusted to 9 with NaHCCh. The mixture was extracted with (100 mL x CH2Cl2 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. After trituration with EtOAc (50 mL), the title compound (1.7 g, yield: 61% for two steps) was obtained as a yellow solid. MS: m / z = 433.1, 435.1 [M + H]+. 'HNMR (400 MHz, Dimethylsulfoxide-d6) 6 8.67 (d, J= 2.4 Hz, 1H), 8.43 - 8.28 (m, 2H), 8.24 (dd, J= 8.8, 4.8 Hz, 1H), 8.02 (d, J= 4.4 Hz, 1H), 7.88 - 7.80 (m, 1H), 7.69 - 7.51 (m, 4H), 7.23 (d, J= 7.6 Hz, 1H), 6.90 (br s, 2H), 6.44 (dd, J= 7.6, 4.8 Hz, 1H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 6 -127.757.Step 5: 4-((l-((4-(2-(2-Aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5- b]pyridin-3-yl)phenyl)methyl--d2)piperidin-4-yl)amino)pyrimidine-2-carbonitrileTo a solution of 3-(3-(4-(chloromethyl--d2)phenyl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine (1.7 g, 3.93 mmol) and Intermediate 5 (1.25 g, 3.93 mmol, TFA) in DMF (10 mL) were added K2CO3 (2.71 g, 19.6 mmol) and Nal (58.9 mg, 393 pmol). The mixture was stirred at 50 °C for 1 hr. The reaction mixture was quenched with H2O (100 mL) at 25 °C and extracted with C (1H020C ml2L x 2). The combined organic layers were washed with brine (100 mL x3), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 1% ~ 6% MeOH in CH2Cl2), the title compound (Example 1, 1.33 g, yield: 56%) was obtained as a yellow solid.MS: m / z = 600.3 [M + H]+. D%: 2D% = 96.6%. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 5 8.66 (d, J= 2.8 Hz, 1H), 8.45 - 8.28 (m, 2H), 8.23 (dd, J= 8.8, 4.8 Hz, 1H), 8.15 - 7.95 (m, 3H), 7.86 - 7.78 (m, 1H), 7.55 - 7.44 (m, 4H), 7.19 - 7.14 (m, 1H), 7.03 (br s, 2H), 6.68 (d, J = 6.0 Hz, 1H), 6.38 (dd, J= 7.6, 4.8 Hz, 1H), 3.90 - 3.73 (m, 1H), 2.89 - 2.76 (m, 2H), 2.23 - 2.09 (m, 2H), 1.95 - 1.81 (m, 2H), 1.58 - 1.44 (m, 2H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 5 -127.809.

[0238] Example 2: 4-((l-(4-(2-(2-Aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)(methyl-d3)amino)pyrimidine-2- carbonitrileTo a solution of Intermediate 3 (115 mg, 246 pmol, HC1 salt) and Intermediate 4 (82.3 mg, 246 pmol, TFA salt) in DMF (2 mL) were added K2CO3 (170 mg, 1.23 mmol) and Nal (3.69 mg, 24.6 pmol). The mixture was stirred at 25 °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 (10 mL x 3), dried overNA2SO4 , filtered and concentrated under reduced pressure. After purification by prep-HPLC (column: CD02- Waters Xbidge BEH C18 150 x 25 x 10 pm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 38% - 68% B over 10 min), the title compound (Example 2, 14.9 mg, yield: 9.9%) was obtained as an off white solid. MS: m / z = 615.2 [M + H]+. D%: 3D% = 100%. ' H NMR (400 MHz, Dimethylsulfoxide-d6) 8 8.67 (d, J= 2.8 Hz, 1H), 8.42 - 8.30 (m, 2H), 8.27 - 8.21 (m, 2H), 8.01 (dd, J= 4.8, 2.0 Hz, 1H), 7.87 - 7.80 (m, 1H), 7.53 - 7.46 (m, 4H), 7.17 (dd, J= 8.0, 1.6 Hz, 1H), 7.02 (br s, 2H), 6.98 - 6.76 (m, 1H), 6.39 (dd, J= 7.6, 4.8 Hz, 1H), 3.63 (s, 2H), 3.41 - 3.33 (m, 1H), 3.02 - 2.89 (m, 2H), 2.24 - 2.13 (m, 2H), 1.91 - 1.80 (m, 2H), 1.66 - 1.57 (m, 2H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 6 -127.817.

[0239] Example 3: 4-((l-((4-(2-(2-Aminopyridin-3-yl)-5-(5-(difluoromethoxy)pyridin-2-yl)- 3H-imidazo[4,5-b]pyridin-3-yl)phenyl)methyl--d2)piperidin-4-yl)amino)pyrimidine-2- carbonitrileExample 3 was prepared in a manner similar to Example 1. MS: m / z = 648.2 [M + H]+. D%: 2D% = 98.6%. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 8 8.57 (d, J= 2.0 Hz, 1H), 8.43 - 8.30 (m, 2H), 8.22 (d, J= 8.8 Hz, 1H), 8.13 - 7.97 (m, 3H), 7.80 - 7.74 (m, 1H), 7.52 - 7.33 (m, 5H), 7.18 - 7.14 (m, 1H), 7.00 (s, 2H), 6.68 (d, J= 5.6 Hz, 1H), 6.38 (dd, J= 7.6, 4.8 Hz, 1H), 3.91 - 3.65 (m, 1H), 2.87 - 2.80 (m, 2H), 2.21 - 2.11 (m, 2H), 1.94 - 1.83 (m, 2H), 1.56 - 1.45 (m, 2H).19F NMR (400 MHz, Dimethyl sulfoxide-d6) 6 - 82.457.

[0240] Example 4: 4-((l-(4-(2-(2-Aminopyridin-3-yl)-5-(5-isopropylpyridin-2-yl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileStep 1 : (2-(2-Aminopyridin-3-yl)-3-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-3H- imidazo[4,5b] pyridin-5-yl)boronic acidTo a mixture of 3-(3-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-5-chloro-3H-imidazo[4,5b] pyridin-2-yl)pyridin-2-amine (refer to Intermediate 25 for detail procedures, 500 mg, 1.07 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (545 mg, 2.15 mmol) in 1,4-dioxane (10 mL) were added KOAc (316 mg, 3.22 mmol) and Pd(dppf)C12 (78.5 mg, 107 pmol), and the mixture was stirred at 100 °C for 1 hr. The title compound was obtained as black liquid, which was used in the next step directly. MS: m / z = 476.2 [M + H]+.Step 2: 3-(3-(4-((( / c / 7-Butyldimethylsilyl)oxy)methyl)phenyl)-5-(5-isopropylpyridin-2-yl)- 3H-imidazo[4,5b] pyridin-2-yl)pyridin-2-amineTo a mixture of (2-(2-aminopyridin-3-yl)-3-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)- 3H-imidazo[4,5b] pyridin-5-yl)boronic acid (510 mg, 1.07 mmol) and 2-bromo-5- isopropylpyridine (236 mg, 1.18 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) were added CS2CO3 (1.05 g, 3.22 mmol) and Pd(dppf)C12 (78.5 mg, 107 pmol), and the mixture was stirred at 100 °C for 2 hr under N2. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO,4 filtered and concentrated. After purification by silica gel flash chromatography (EtOAc in petroleum ether = 0 - 50 %), the title compound (370 mg, yield: 62% for two steps) was obtained as a yellow solid. MS: m / z = 551.3 [M + H]+.JH NMR (400 MHz, Dimethylsulfoxide-d6) 8 8.56 (d, J= 2.0 Hz, 1H), 8.42 (d, J= 8.4 Hz, 1H), 8.29 (d, J= 8.4 Hz, 1H), 8.09 (d, J= 8.0 Hz, 1H), 8.00 (dd, J= 4.8, 1.6 Hz, 1H), 7.76 (dd, J= 8.0, 2.0 Hz, 1H), 7.39 - 7.34 (m, 4H), 7.20 (dd, J =7.6, 1.6 Hz, 1H), 7.01 (br s, 2H), 6.39 (dd, J= 7.6, 4.8 Hz, 1H), 4.83 (s, 2H), 2.93 - 2.79 (m, 1H), 1.14 - 1.11 (m, 6H), 0.93 (s, 9H), 0.12 (s, 6H). Step 3 : (4-(2-(2-Aminopyridin-3-yl)-5-(5-isopropylpyridin-2-yl)-3H-imidazo[4,5b] pyridin- 3 -yl)phenyl)m ethanolTo a mixture of 3-(3-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-5-(5-isopropylpyridin- 2-yl)-3H-imidazo[4,5b] pyridin-2-yl)pyridin-2-amine (370 mg, 672 pmol) in THF (4 mL) was added TBAF (IM in THF, 1.01 mL), and the mixture was stirred at 20 °C for 1 hr. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the title compound (293 mg) as a yellow solid. MS: m / z = 437.2 [M + H]+Step 4: 3-(3-(4-(Chloromethyl)phenyl)-5-(5-isopropylpyridin-2-yl)-3H-imidazo[4,5- Z>]pyri din-2 -yl)pyridin-2-amineTo a mixture of (4-(2-(2-aminopyridin-3-yl)-5-(5-isopropylpyridin-2-yl)-3H-imidazo[4,5-Z>]pyri din-3 -yl)phenyl)methanol (293 mg, 672 pmol) in CH2CI2 (4 mL) was added SOCh (146 pL, 2.02 mmol,), and the mixture was stirred at 20 °C for 0.5 hr. The mixture was concentrated to give the title compound (306 mg) as a yellow solid. MS: m / z = 455.2, 457.1 [M + H]+.Step 5: 4-((l-(4-(2-(2-Aminopyridin-3-yl)-5-(5-isopropylpyridin-2-yl)-3H-imidazo[4,5- Z>]pyridin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileTo a mixture of 3-(3-(4-(chloromethyl)phenyl)-5-(5-isopropylpyridin-2-yl)-3H-imidazo[4,5- Z>]pyridin-2-yl)pyridin-2-amine (306 mg, 672 pmol) and Intermediate 5 (150 mg, 739 pmol) in DMF (4 mL) were added Nal (20.1 mg, 134 pmol) and K2CO3 (464 mg, 3.36 mmol), and the mixture was stirred at 80 °C for 12 hr. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated. After purification by prep- HPLC (column: C18 150 * 30 mm; mobile phase: [water (NH3H2O + NH4HCO3) - ACN]; gradient: 53% - 83% B over 7 min), the title compound (Example 4, 80.1 mg, yield: 19% for three steps) was obtained as a yellow solid. MS: m / z = 622.3 [M + H]+.JH NMR (400 MHz, Dimethylsulfoxide-d6) 8 8.58 (d, J= 2.0 Hz, 1H), 8.43 (d, J= 8.4 Hz, 1H), 8.30 (d, J= 8.4 Hz, 1H), 8.17 - 8.04 (m, 3H), 8.01 (dd, J= 4.8, 1.6 Hz, 1H), 7.78 (dd, J= 8.4, 2.4 Hz, 1H), 7.53 - 7.44 (m, 4H), 7.18 (dd, J= 7.6, 1.6 Hz, 1H) 7.02 (br s, 2H), 6.69 (d, J= 6.0 Hz, 1H), 6.39 (dd, J= 7.6, 4.8 Hz, 1H), 3.90 - 3.76 (m, 1H), 3.61 (s, 2H), 3.03 - 2.95 (m, 1H), 2.90 - 2.75 (m, 2H), 2.22 - 2.12 (m, 2H), 1.99 - 1. 77 (m, 2H), 1.60 - 1.42 (m, 2H), 1.25 (d, J= 6.8 Hz, 6H).

[0241] Example 5: 4-((l-(4-(2-(2-Aminopyridin-3-yl)-5-(6-ethylpyridin-3-yl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 5 was prepared in a manner similar to Example 4. MS: m / z = 608.1 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) 8 9.11 (s, 1H), 8.32 - 8.24 (m, 2H), 8.11 - 7.98 (m, 4H), 7.51 - 7.43 (m, 4H), 7.35 (d, J= 8.0 Hz, 1H), 7.17 d, J= 7.2 Hz, 1H), 7.03 (br s, 2H), 6.72 - 6.61 (m, 1H), 6.44 - 6.33 (m, 1H), 3.89 - 3.75 (m, 1H), 3.59 (s, 2H), 2.86 - 2.74 (m, 4H), 2.22 - 2.10 (m, 2H), 1.94 - 1.84 (m, 2H), 1.56 - 1.45 (m, 2H), 1.23 (t, J= 7.6 Hz, 3H).

[0242] Example 6: 4-((l-(4-(2-(2-Aminopyridin-3-yl)-5-(6-(fluoromethyl)pyridin-3-yl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 6 was prepared in a manner similar to Example 4. MS: m / z = 612.2 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 6 9.23 (d, J= 1.6 Hz, 1H), 8.46 (dd, J= 8.0, 1.2 Hz, 1H), 8.33 (d, .7= 8.4 Hz, 1H), 8.13 - 8.04 (m, 3H), 8.01 (dd, J= 4.4, 1.6 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.51 - 7.45 (m, 4H), 7.20 - 7.15 (m, 1H), 7.03 (br s, 2H), 6.67 (br d, J= 6.0 Hz, 1H), 6.39 (dd, J= 7.6, 4.8 Hz, 1H), 5.51 (d, J= 46.8 Hz, 2H), 3.87 - 3.76 (m, 1H), 3.59 (s,2H), 3.21 - 3.12 (m, 2H), 2.87 - 2.79 (m, 2H), 2.20 - 2.11 (m, 2H), 1.94 - 1.84 (m, 2H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 8 -215.886.

[0243] Example 7: 4-((l-(4-(2-(2-Aminopyridin-3-yl)-5-(6-(hydroxymethyl)pyridin-3-yl)- 3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileStep 1 to 5: refer to Example 4 for detail procedures.Step 6: 4-((l-(4-(2-(2-Aminopyridin-3-yl)-5-(6-(hydroxymethyl)pyridin-3-yl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile To a solution of (5-(2-(2-aminopyridin-3-yl)-3-(4-((4-((2-cyanopyrimidin-4- yl)amino)piperidin-l-yl)methyl)phenyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyridin-2-yl)methyl acetate (170 mg, 260.85 pmol) in THF (10 mL), MeOH (10 mL) and H2O (3 mL) was added K2CO3 (108.2 mg, 782.55 pmol). The mixture was stirred at 25 °C for 1 hr. The mixture was diluted with H2O (10 mL) and extracted with (20 C mHL2C xl22). The combined organic layers were washed with brine (20 mL), dried over Na2SO,4 filtered and concentrated. After purification by silica gel flash chromatography (Eluent of 0% ~ 7% MeOH in ), the CH2Cl2 title compound (Example 7, 51.9 mg, yield: 32% for two steps) was obtained as a light yellow solid. MS: m / z = 610.0 [M + H]+. 'H NMR (400 MHz, Dimethyl sulfoxide-d6) 5 9.12 (s, 1H), 8.40 - 8.28 (m, 2H), 8.10 - 7.98 (m, 4H), 7.57 - 7.45 (m, 5H), 7.20 - 7.14 (m, 1H), 7.03 (br s, 2H), 6.73 - 6.61 (m, 1H), 6.44 - 6.35 (m, 1H), 5.51 - 5.42 (m, 1H), 4.63 - 4.56 (m, 2H), 3.89 - 3.76 (m, 1H), 3.67 - 3.54 (m, 2H), 2.88 - 2.77 (m, 2H), 2.22 - 2.10 (m, 2H), 1.94 - 1.84 (m, 2H), 1.56 - 1.46 (m, 2H).

[0244] Example 8: 4-((l-(4-(2-(2-Aminopyridin-3-yl)-5-(5-(hydroxymethyl)pyridin-2-yl)- 3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 8 was prepared in a manner similar to Example 7. MS: m / z = 610.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 8 8.61 (d, J= 1.6 Hz, 1H), 8.46 (d, J= 8.4 Hz, 1H), 8.30 (d, J= 8.4 Hz, 1H), 8.15 (d, J= 8.0 Hz, 1H), 8.13 - 8.03 (m, 2H), 8.00 (dd, J= 4.8, 1.6 Hz, 1H), 7.81 (dd, J= 8.4, 2.4 Hz, 1H), 7.57 - 7.41 (m, 4H), 7.17 (dd, J= 7.6, 2.0 Hz, 1H), 7.02 (br s, 2H), 6.68 (d, J= 6.0 Hz, 1H), 6.38 (dd, J= 7.6, 4.4 Hz, 1H), 5.36 (br t, J= 5.6 Hz, 1H), 4.57 (d, J= 5.6 Hz, 2H), 3.91 - 3.73 (m, 1H), 3.60 (s, 2H), 2.92 - 2.79 (m, 2H), 2.24 - 2.09 (m, 2H), 1.98 - 1.79 (m, 2H), 1.62 - 1.42 (m, 2H).

[0245] Example 9: 4-((l-(4-(2-(2-Aminopyridin-3-yl)-5-(5-(fluoromethoxy--d2)pyridin-2-yl)- 3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 9 was prepared in a manner similar to Example 4. MS: m / z = 630.5 [M + H]+.D%:2D = 98.1%.1H NMR (400 MHz, Dimethylsulfoxide-d6) 6 8.57 - 8.45 (m, 1H), 8.40 (d,J =8.0, Hz, 1H), 8.30 (d, J= 8.8 Hz, 1H), 8.19 (d, J= 8.4 Hz, 1H), 8.13 - 7.93 (m, 3H), 7.74 -7.62 (m, 1H), 7.53 - 7.44 (m, 4H), 7.17 (d, J= 8.0 Hz, 1H), 7.01 (br s, 2H), 6.75 - 6.58 (m, 1H), 6.47 - 6.29 (m, 1H), 3.92 - 3.74 (m, 1H), 3.60 (br s, 2H), 2.89 - 2.79 (m, 2H), 2.23 - 2.12 (m, 2H), 1.97 - 1.85 (m, 2H), 1.56 - 1.47 (m, 2H).19F NMR (400 MHz, Dimethysulfoxide- de) 8 -152.590.

[0246] Example 10: 4-((l-(4-(2-(2-Aminopyridin-3-yl)-5-(5-(difluoromethoxy)pyrazin-2-yl)- 3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 10 was prepared in a manner similar to Example 4. MS: m / z = 647.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 8 8.98 (d, J= 0.8 Hz, 1H), 8.65 (d, J= 1.2 Hz, 1H), 8.39 - 8.34 (m, 1H), 8.32 - 8.27 (m, 1H), 8.15 - 7.96 (m, 3H), 7.92 - 7.53 (m, 1H), 7.52 - 7.43 (m, 4H), 7.21 (dd, J= 7.6, 1.6 Hz, 1H), 7.03 (br s, 2H), 6.67 (d, J= 6.0 Hz, 1H), 6.41 (dd, J= 7.6, 4.8 Hz, 1H), 3.90 - 3.71 (m, 1H), 3.60 (s, 2H), 2.90 - 2.78 (m, 2H), 2.23 - 2.11 (m, 2H), 1.96 - 1.81 (m, 2H), 1.58 - 1.44 (m, 2H).19F NMR (400 MHz, Dimethyl sulfoxide-d6) 5 - 87.110.

[0247] Example 11 : 4-((l-(4-(2-(2-Aminopyridin-3-yl)-5-(6-(difluoromethoxy)pyridazin-3- yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 10 was prepared in a manner similar to Example 4. MS: m / z = 647.0 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 8 8.54 (d, J= 8.4 Hz, 1H), 8.44 - 8.38 (m, 2H), 8.11 - 8.00 (m, 3H), 7.98 - 7.77 (m, 1H), 7.63 (d, J= 92 Hz, 1H), 7.51 - 7.47 (m, 4H), 7.22 - 7.16(m, 1H), 7.02 (br s, 2H), 6.73 - 6.64 (m, 1H), 6.40 (dd, J= 7.6, 4.8 Hz, 1H), 3.88 - 3.77 (m, 1H), 3.60 (s, 2H), 2.86 - 2.80 (m, 2H), 2.20 - 2.12 (m, 2H), 1.95 - 1.86 (m, 2H), 1.55 - 1.46 (m, 2H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 5 -86.92.

[0248] Example 12: 4-((l-(4-(2-(2-Aminopyridin-3-yl)-5-(5-(difluoromethoxy)pyrimidin-2- yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 12 was prepared in a manner similar to Example 4. MS: m / z = 647.2 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 8 8.89 (s, 2H), 8.45 (d, J= 8.4 Hz, 1H), 8.35 (d, J= 8.4 Hz, 1H), 8.16 - 8.02 (m, 2H), 8.00 (dd, J=4.4, 1.6 Hz, 1H), 7.63 - 7.23(m, 5H), 7.15 (dd, J= 7.6, 1.6 Hz, 1H), 7.00 (br s, 2H), 6.68 (d, J= 5.2 Hz, 1H), 6.37 (dd, J =7.6, 4.8 Hz, 1H), 3.92 - 3.72 (m, 1H), 3.59 (br s, 2H), 2.92 - 2.77 (m, 2H), 2.23 - 2.10 (m, 2H), 1.97 - 1.82 (m, 2H), 1.60 - 1.43 (m, 2H).19F NMR (400 MHz, Dimethysulfoxide-d6) 6 -82.660.

[0249] Example 13: 4-((l-(4-(2-(2-Aminopyridin-3-yl)-5-(5-chloropyridin-2-yl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 13 was prepared in a manner similar to Example 4. MS: m / z = 614.1, 616.1 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 8 8.72 (d, J= 2.4 Hz, 1H), 8.43 (d, J= 8.4 Hz, 1H), 8.32 (d, J= 8.4 Hz, 1H), 8.19 (d, J= 8.4 Hz, 1H), 8.15 - 7.94 (m, 4H), 7.54 - 7.42 (m, 4H), 7.22 - 7.13 (m, 1H), 7.02 (br s, 2H), 6.68 (d, J= 6.0 Hz, 1H), 6.38 (dd, J =8.0, 5.2 Hz, 1H), 3.94 - 3.71 (m, 1H), 3.60 (s, 2H), 2.89 - 2.78 (m, 2H), 2.23 - 2.10 (m, 2H), 1.98 - 1.80 (m, 2H), 1.59 - 1.43 (m, 2H).

[0250] Example 14: 4-(4-(4-(2-(2-Aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H- imidazo[4,5b] pyridin-3-yl)benzyl)piperazin-l-yl)pyrimidine-2-carbonitrileTo a mixture of Intermediate 3 (156 mg, 363 pmol) and Intermediate 11 (82.6 mg, 436 pmol) in DMF (2 mL) were added K2CO3 (301 mg, 2.18 mmol) and Nal (10.9 mg, 72.7 pmol). The mixture was stirred at 20 °C for 12 hr. The mixture was diluted with H2O (5 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated. After purification by silica gel flash chromatography (Eluent of 0% ~ 10% Methanol in ), the t CitHle2C col2mpound (Example 14, 87.3 mg, yield: 41%) was obtained as a yellow solid. MS: m / z = 584.2 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 8 8.67 (d, J= 2.8 Hz, 1H), 8.40 (d, J= 8.4 Hz, 1H), 8.32 (d, J= 8.4 Hz, 1H), 8.29 - 8.22 (m, 2H), 8.01 (dd, J= 4.8, 1.2 Hz, 1H), 7.83 (td, J= 8.8, 2.4 Hz, 1H), 7.56 - 7.46 (m, 4H) 7.17 (dd, J= 7.6, 1.2 Hz, 1H), 7.12 (d, J= 6.4 Hz, 1H), 7.01 (br s, 2H), 6.38 (dd, J= 7.6, 4.8 Hz, 1H), 3.75 - 3.60 (m, 6H), 2.55 - 2.51 (m, 4H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 6 -127.812.

[0251] Example 15: 4-(l-(l-(4-(2-(2-Aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)vinyl)pyrimidine-2-carbonitrileExample 15 was prepared in a manner similar to Example 14. MS: m / z = 609.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 6 8.95 (d, J= 5.2 Hz, 1H), 8.67 (d, J= 2.4 Hz, 1H), 8.44 - 8.37 (m, 1H), 8.34 - 8.28 (m, 1H), 8.26 - 8.20 (m, 1H), 8.08 (d, J= 5.2 Hz, 1H), 8.00 (d, J= 3.2 Hz, 1H), 7.87 - 7.76 (m, 1H), 7.52 - 7.45 (m, 4H), 7.17 (d, J= 6.8 Hz, 1H), 7.02 (br s, 2H), 6.38 (dd, J= 7.2, 4.8 Hz, 1H), 6.19 (s, 1H), 5.67 (s, 1H), 3.61 (s, 2H), 2.99 - 2.91 (m, 2H), 2.87 - 2.75 (m, 1H), 2.18 - 2.09 (m, 2H), 1.79 - 1.72 (m, 2H), 1.59 - 1.48 (m, 2H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 8 -127.826.

[0252] Example 16: 4-(l-(l-(4-(2-(2-Aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)ethyl)pyrimidine-2-carbonitrileExample 16 was prepared in a manner similar to Example 14. MS: m / z = 611.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 88.89 (d, J= 5.2 Hz, 1H), 8.66 (d, J= 2.8 Hz, 1H), 8.44 - 8.36 (m, 1H), 8.34 - 8.29 (m, 1H), 8.22 (dd, J= 8.8, 4.4 Hz, 1H), 8.00 (dd, J= 4.8, 2.0 Hz, 1H), 7.85 - 7.79 (m, 1H), 7.76 (d, J= 5.2 Hz, 1H), 7.49 - 7.41 (m, 4H), 7.15 (dd, J= 8.0, 2.0 Hz, 1H), 7.01 (br s, 2H), 6.37 (dd, J= 7.6, 4.8 Hz, 1H), 3.52 (s, 2H), 2.93 - 2.85 (m, 1H), 2.82 - 2.72 (m, 2H), 2.01 - 1.84 (m, 2H), 1.79 - 1.72 (m, 1H), 1.67 - 1.58 (m, 1H), 1.27 - 1.16 (m, 6H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 6 -127.818.

[0253] Example 17: 4-((3a7?,6a5)-5-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H- imidazo[4,5b] pyridin-3-yl)benzyl)dihydro-1H,4H-3a,6a-(methanooxymethano)pyrrolo[3,4- c]pyrrol-2(3H)-yl)pyrimidine-2-carbonitrileExample 17 was prepared in a manner similar to Example 14. MS: m / z = 652.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 6 8.67 (d, J= 2.8 Hz, 1H), 8.42 - 8.38 (m, 1H), 8.34 - 8.26 (m, 2H), 8.22 (dd, J= 9.2, 4.8 Hz, 1H), 8.03 - 7.98 (m, 1H), 7.85 - 7.78 (m, 1H), 7.53 - 7.43 (m, 4H), 7.15 (dd, J= 7.6, 2.0 Hz, 1H), 7.03 (br s, 2H), 6.90 - 6.84 (m, 1H), 6.37 (dd, J = 7.6, 4.8 Hz, 1H), 3.76 - 3.53 (m, 10H), 2.67 - 2.55 (m, 4H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 5 -127.778.

[0254] Example 18: 4-(l-(4-(2-(2-Aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl)pyrimidine-2-carbonitrileExample 18 was prepared in a manner similar to Example 14. MS: m / z = 581.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 8 8.92 (d, J= 5.6 Hz, 1H), 8.67 (d, J= 2.8 Hz, 1H), 8.44 - 8.31 (m, 2H), 8.24 (dd, J= 8.8, 4.8 Hz, 1H), 8.02 (dd, J= 4.8, 1.6 Hz, 1H), 7.95 (d, J= 5.6 Hz, 1H), 7.87 - 7.81 (m, 1H), 7.57 - 7.47 (m, 4H), 7.22 - 7.17 (m, 2H), 7.01 (s, 2H), 6.42 (dd, J= 7.6, 4.8 Hz, 1H), 3.75 (s, 2H), 3.28 - 3.24 (m, 2H), 2.78 - 2.71 (m, 2H), 2.61 - 2.56 (m, 2H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 6 -127.811.

[0255] Example 19: 4-((l-(4-(2-(2-Aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)(cyclopropyl)amino)pyrimidine-2- carbonitrileStep 1 : tert-Butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperidin-4-yl)(cyclopropyl)carbamateTo a solution of Intermediate 3 (226 mg, 484 pmol, HC1 salt) and tert-butyl cyclopropyl(piperidin-4-yl)carbamate (232 mg, 967 pmol) in DMF (5 mL) were added K2CO3 (334 mg, 2.42 mmol) and Nal (7.25 mg, 48.4 pmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with 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 to give the title compound (307 mg) as a brown solid. MS: m / z = 635.3 [M + H]+.Step 2: 3-(3-(4-((4-(Cyclopropylamino)piperidin-l-yl)methyl)phenyl)-5-(5-fluoropyridin-2- yl)-37 / -imidazo[4,5-b]pyri din-2 -yl)pyridin-2-amineTo a solution of tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)(cyclopropyl)carbamate (306 mg, 482 pmol) in CH2Cl2 (3 mL) was added TFA (1.54 g, 13.5 mmol). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was basified with aqueous NaHCCh (pH~8) and extracted with CH2Cl2 (50 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO,4 filtered and concentrated under reduced pressure to give the title compound (257 mg) as a brown solid. MS: m / z = 535.3 [M + H]+.JH NMR (400 MHz, Chloroform-d) 5 8.54 - 8.44 (m, 2H), 8.34 (dd, J= 8.8, 4.4 Hz, 1H), 8.21 - 8.13 (m, 1H), 8.07 (dd, J= 4.8, 2.0 Hz, 1H), 7.57 - 7.49 (m, 2H), 7.47 - 7.42 (m, 1H), 7.39 (d, J= 8.4 Hz, 2H), 7.10 (dd, J= 7.6, 1.6 Hz, 1H), 6.63 (br s, 2H), 6.35 (dd, J= 7.6, 4.8 Hz, 1H), 3.63 (s, 2H), 3.01 - 2.88 (m, 2H), 2.76 - 2.62 (m, 1H), 2.21 - 2.13 (m, 2H), 2.04 - 1.96 (m, 2H), 1.86 - 1.65 (m, 2H), 1.55 - 1.46 (m, 2H), 0.54 - 0.33 (m, 4H).Step 3 : 4-((l-(4-(2-(2-Aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperidin-4-yl)(cyclopropyl)amino)pyrimidine-2-carbonitrile To a solution of 3-(3-(4-((4-(cyclopropylamino)piperidin-l-yl)methyl)phenyl)-5-(5- fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (257 mg, 481 pmol) and 4-chloropyrimidine-2-carbonitrile (101 mg, 721 pmol) in DMF (5 mL) were added K2CO3 (332 mg, 2.40 mmol) and Nal (7.21 mg, 48.1 pmol). The mixture was stirred at 50 °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 x 5), dried over Na2S,O fi4ltered and concentrated under reduced pressure. After purification by prep-HPLC (column: CD07-Daisogel SP-100-8-ODS-PK 150 x 25 x 10 pm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 48% - 78% B over 10 min), the title compound (Example 19, 98.1 mg, yield: 31% for three steps) was obtained as a brown lyophilized powder. MS: m / z = 638.3 [M + H]+. ' H NMR (400 MHz, DimethylsulfoxidesL) 5 8.67 (d, J = 2.8 Hz, 1H), 8.43 - 8.37 (m, 1H), 8.35 - 8.29 (m, 2H), 8.24 (dd, J= 8.8, 4.8 Hz, 1H), 8.01 (dd, J= 4.8, 2.0 Hz, 1H), 7.87 - 7.79 (m, 1H), 7.53 - 7.44 (m, 4H), 7.21 - 7.14 (m, 2H), 7.03 (br s, 2H), 6.39 (dd, J= 7.6, 4.8 Hz, 1H), 4.26 - 4.06 (m, 1H), 3.62 (s, 2H), 3.05 - 2.91 (m, 2H), 2.59 - 2.55 (m, 1H), 2.17 - 2.04 (m, 4H), 1.85 - 1.73 (m, 2H), 1.07 - 0.97 (m, 2H), 0.77 - 0.69 (m, 2H).19F NMR (400 MHz, DimethylsulfoxidesL) 8 -127.833.

[0256] Example 20: 4-(7-(4-(2-(2-Aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H- imidazo[4,5b] pyridin-3-yl)benzyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidine-2-carbonitrileExample 20 was prepared in a manner similar to Example 14. MS: m / z = 624.3 [M+H]+. 'H NMR (400 MHz, Chloroform-d) 5 8.50 (d, J= 2.8 Hz, 1H), 8.46 (d, J= 8.8 Hz, 1H), 8.33 (dd, J= 8.8, 4.8 Hz, 1H), 8.22 - 8.12 (m, 2H), 8.08 (dd, J= 4.8, 1.6 Hz, 1H), 7.54 - 7.48 (m, 2H), 7.47 - 7.38 (m, 3H), 7.10 (dd, J= 7.6, 1.6 Hz, 1H), 6.63 (br s, 2H), 6.36 (dd, J= 7.6, 4.8 Hz, 1H), 6.26 (d, J= 6.0 Hz, 1H), 3.97 - 3.71 (m, 4H), 3.61 (s, 2H), 2.77 - 2.15 (m, 4H), 1.95 - 1.86 (m, 4H).19F NMR (400 MHz, Chloroform-d) 5 -127.748.

[0257] Example 21 : 4-(6-(4-(2-(2-Aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H- imidazo[4,5b] pyridin-3-yl)benzyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidine-2-carbonitrileExample 21 was prepared in a manner similar to Example 14. MS: m / z = 596.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 8 8.66 (d, J= 2.8 Hz, 1H), 8.40 (d, J= 8.4 Hz, 1H), 8.30 (d, J= 8.4 Hz, 1H), 8.25 - 8.19 (m, 2H), 8.01 (dd, J= 4.8, 2.0 Hz, 1H), 7.83 (td, J= 8.8, 2.8 Hz, 1H), 7.49 - 7.39 (m, 4H), 7.17 (dd, J= 7.6, 2.0 Hz, 1H), 6.99 (br s, 2H), 6.63 (d, J= 6.4 Hz, 1H), 6.41 (dd, J= 7.6, 4.8 Hz, 1H), 4.21 (s, 4H) 3.65 (s, 2H), 3.40 (s, 4H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 6 -127.823.

[0258] Example 22: 4-(2-(4-(2-(2-Aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H- imidazo[4,5b] pyridin-3-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidine-2-carbonitrileExample 22 was prepared in a manner similar to Example 14. MS: m / z = 624.3 [M + H]+. 'H NMR (400 MHz, Dimethysulfoxide-d6) 8 8.71 - 8.63 (m, 1H), 8.46 - 8.36 (m, 1H), 8.34 -8.29 (m, 1H), 8.26 - 8.19 (m, 2H), 8.05 - 7.98 (m, 1H), 7.89 - 7.79 (m, 1H), 7.50 - 7.43 (m, 4H), 7.18 (d, J = 7.6 Hz, 1H), 7.12 (d, J= 6.0 Hz, 1H), 6.98 (s, 2H), 6.48 - 6.32 (m, 1H), 3.71 (s, 2H), 3.69 - 3.53 (m, 4H), 3.11 - 3.05 (m, 4H), 1.79 - 1.70 (m, 4H).19FNMR(400 MHz, Dimethysulfoxide-d6) 5 -127.817.

[0259] Example 23: (7?)-4-(7-(4-(2-(2-Aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H- imidazo[4,5b] pyridin-3-yl)benzyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidine-2-carbonitrileExample 23 was prepared in a manner similar to Example 14. MS: m / z = 624.3 [M + H]+. 'HNMR (400 MHz, Dimethyl sulfoxide-d6) 6 8.66 (d, J= 2.8 Hz, 1H), 8.40 (d, J= 8.4 Hz, 1H), 8.31 (d, .7= 8.4 Hz, 1H), 8.26 - 8.17 (m, 2H), 7.96 (d, J = 4.8 Hz, 1H), 7.81 (td, J= 8.8, 3.2 Hz, 1H), 7.55 - 7.43 (m, 4H), 7.15 (d, J= 7.6 Hz, 1H), 7.02 (s, 2H), 6.77 (t, J= 6.8 Hz,1H), 6.31 (dd, J= 8.0, 4.8 Hz, 1H), 3.71 (s, 2H), 3.60 - 3.37 (m, 4H), 2.75 - 2.55 (m, 3H), 2.47 - 2.43 (m, 1H), 2.10 - 1.90 (m, 2H), 1.87 - 1.77 (m, 2H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 5 -127.776.

[0260] Example 24: (5)-4-(7-(4-(2-(2-Aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H- imidazo[4,5b] pyridin-3-yl)benzyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidine-2-carbonitrileExample 24 was prepared in a manner similar to Example 14. MS: m / z = 624.1 [M + H]+. 'HNMR (400 MHz, Dimethyl sulfoxide-d6) 8 8.67 (d, J= 3.2 Hz, 1H), 8. 40 (d, J= 8.4 Hz, 1H), 8.31 (d, J= 8.4 Hz, 1H), 8.25 - 8.18 (m, 2H), 7.96 (d, J= 4.8 Hz, 1H), 7.81 (td, J = 9.2, 3.2 Hz, 1H), 7.54 - 7.49 (m, 2H), 7.48 - 7.43 (m, 2H), 7.17 - 7.12 (m, 1H), 7.02 (s, 2H), 6.77 (t, J= 6.8 Hz, 1H), 6.31 (dd, J= 7.6, 4.8 Hz, 1H), 3.71 (s, 2H), 3.63 - 3.40 (m, 4H), 2.77 - 2.55 (m, 4H), 2.06 - 1.90 (m, 2H), 1.89 - 1.78 (m, 2H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 6 -127.819.

[0261] Example 25: 4-((4-(4-(2-(2-Aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H- imidazo[4,5b] pyridin-3-yl)benzyl)piperazin-l-yl)amino)pyrimidine-2-carbonitrileExample 25 was prepared in a manner similar to Example 14. MS: m / z = 599.1 [M + H]+. 'HNMR (400 MHz, Dimethyl sulfoxide-d6) 6 9.33 (s, 1H), 8.67 (d, J= 2.8 Hz, 1H), 8.45 - 8.20 (m, 4H), 8.01 (dd, J= 4.8, 1.6 Hz, 1H), 7.83 (td, J= 8.8, 3.2 Hz, 1H), 7.53 - 7.45 (m, 4H), 7.17 (dd, J= 7.6, 1.6 Hz, 1H), 7.05 - 6.92 (m, 3H), 6.39 (dd, J= 8.0, 4.8 Hz, 1H), 3.62 (s, 2H), 3.30 - 3.25 (m, 4H), 2.87 - 2.74 (m, 4H).19F NMR (400 MHz, Dimethylsulfoxide- d / ) 5 -127.822.

[0262] Example 26: 4-((l-((4-(2-(2-Aminopyridin-3-yl)-5-(5-cyclopropoxypyridin-2-yl)-3H- imidazo[4,5-b]pyridin-3-yl)phenyl)methyl-d2)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 26 was prepared in a manner similar to Example 1. MS: m / z = 638.4 [M + H]+. D%: 2D% = 98.6%. 'HNMR (400 MHz, Dimethylsulfoxide-d6) 5 8.45 (d, J= 2.4 Hz, 1H), 8.40 - 8.34 (m, 1H), 8.27 (d, J= 8.4 Hz, 1H), 8.15 (d, J= 8.8 Hz, 1H), 8.13 - 8.02 (m, 2H), 8.00 (dd, J= 4.8, 2.0 Hz, 1H), 7.61 (dd, J= 8.8, 2.8 Hz, 1H), 7.51 - 7.44 (m, 4H), 7.16 (dd, J = 7.6, 1.6 Hz, 1H), 7.02 (br s, 2H), 6.68 (d, J= 6.0 Hz, 1H), 6.38 (dd, J= 7.6, 4.8 Hz, 1H), 4.04 - 3.95 (m, 1H), 3.89 - 3.73 (m, 1H), 2.91 - 2.78 (m, 2H), 2.24 - 2.09 (m, 2H), 1.96 - 1.83 (m, 2H), 1.58 - 1.43 (m, 2H), 0.86 - 0.81 (m, 2H), 0.74 - 0.70 (m, 2H).

[0263] Example 27: 4-((l-(4-(2-(2-Aminopyri din-3 -yl)-5-(6-(methyl-d3)pyri din-3 -yl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 27 was prepared in a manner similar to Example 4. MS: m / z = 597.3 [M + H]+. 3D%= 99%. 'HNMR (400 MHz, Dimethylsulfoxide-d6) 8 9.15 - 9.05 (m, 1H), 8.32 - 8.23 (m, 2H), 8.11 - 7.99 (m, 4H), 7.51 - 7.43 (m, 4H), 7.34 (d, J= 8.0 Hz, 1H), 7.17 (dd, J = 7.6, 1.6 Hz, 1H), 7.03 (br s, 2H), 6.67 (br d, J= 5.6 Hz, 1H), 6.39 (dd, J= 7.6, 4.8 Hz, 1H), 3.90 - 3.75 (m, 1H), 3.59 (s, 2H), 2.87 - 2.79 (m, 2H), 2.21 - 2.12 (m, 2H), 1.95 - 1.86 (m, 2H), 1.56 - 1.44 (m, 2H).

[0264] Example 28: 4-((4-(4-(2-(2-Aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H- imidazo[4,5b] pyridin-3-yl)benzyl)piperazin-l-yl)(methyl-d3)amino)pyrimidine-2- carbonitrileExample 28 was prepared in a manner similar to Example 14. MS: m / z = 616.2 [M + H]+. 'HNMR (400 MHz, Dimethyl sulfoxide-d6) 8 8.66 (d, J= 2.8 Hz, 1H), 8.40 (d, J= 8.4 Hz, 1H), 8.34 - 8.18 (m, 3H), 8.00 (dd, J= 4.4, 1.6 Hz, 1H), 7.83 (td, J= 8.8, 2.8 Hz, 1H), 7.56 - 7.45 (m, 4H), 7.34 (d, J= 6.0 Hz, 1H), 7.17 (dd, J= 7.6, 1.6 Hz, 1H), 7.00 (br s, 2H), 6.38 (dd, J= 7.6, 4.8 Hz, 1H), 3.65 (s, 2H), 3.03 - 2.93 (m, 2H), 2.92 - 2.86 (m, 2H), 2.74 - 2.65 (m, 2H), 2.41 - 2.30 (m, 2H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 6 -127.803.

[0265] Example 29: 4-((l-(4-(2-(2-Aminopyridin-3-yl)-5-(2-(difluoromethoxy)pyrimidin-5- yl)-3H-imidazo[4,5b] pyridin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileA mixture of Intermediate 25 (192 mg, 358 pmol), Intermediate 24 (68 mg, 358 pmol), CS2CO3 (350 mg, 1.1 mmol), and Pd(dppf)C12 (26 mg, 36 pmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was degassed, purged with N2 three times, and stirred at 80 °C for 16 hr under N2 atmosphere. The reaction mixture was quenched with H2O (5 mL) at 25 °C and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over Na2S,O fi4ltered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 8% Methanol in Dichloromethane) and prep- HPLC (column: CD07-Daisogel SP-100-8-ODS-PK 150 x 25 x 10 pm; mobile phase: [water( NH4HCO3)-ACN]; gradient: 40% - 60% B over 10 min), the title compound (Example 29, 31.4 mg, yield: 14% for two steps) was obtained as a brown powder. MS: m / z = 647.2 [M + H]+.XH NMR (400 MHz, Dimethylsulfoxide-d6) 6 9.33 (s, 2H), 8.37 (d, J= 8.4 Hz, 1H), 8.15 - 7.99 (m, 4H), 7.94 - 7.59 (m, 1H), 7.52 - 7.42 (m, 4H), 7.19 (dd, J= 7.6, 1.6 Hz, 1H), 7.04 (br s, 2H), 6.67 (d, J= 6.0 Hz, 1H), 6.40 (dd, J= 7.6, 4.8 Hz, 1H), 3.91 - 3.73 (m, 1H), 3.59 (s, 2H), 2.90 - 2.79 (m, 2H), 2.23 - 2.11 (m, 2H), 1.96 - 1.81 (m, 2H), 1.58 - 1.44 (m, 2H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 5 -88.461.

[0266] Example 30: 4-((l-(4-(2-(2-Aminopyridin-3-yl)-5-(5-hydroxypyridin-2-yl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 30 was prepared in a manner similar to Example 4. MS: m / z = 596.3 [M + H]+. 'H NMR (400 MHz, Dimethyl sulfoxide-d6) 5 11.03 - 9.44 (m, 1H), 8.33 (d, J = 8.4 Hz, 1H), 8.25 - 8.19 (m, 2H), 8.12 - 7.96 (m, 4H), 7.51 - 7.43 (m, 4H), 7.28 - 7.21 (m, 1H), 7.17 - 7.11 (m, 1H), 7.02 (br s, 2H), 6.82 - 6.60 (m, 1H), 6.37 (dd, J= 7.6, 4.8 Hz, 1H), 3.91 - 3.75 (m, 1H), 3.60 (s, 2H), 2.87 - 2.80 (m, 2H), 2.23 - 2.12 (m, 2H), 1.98 - 1.85 (m, 2H), 1.57 - 1.45 (m, 2H).

[0267] Example 31 : 2-Amino-3-(3-(4-((4-((2-cyanopyrimidin-4-yl)amino)piperidin-l- yl)methyl)phenyl)-5-(5-(difluoromethoxy)pyridin-2-yl)-3H-imidazo[4,5-b]pyridin-2- yl)pyridine 1 -oxideStep 1 : (2-(2-Aminopyridin-3-yl)-3-(4-(((terLbutyldimethylsilyl)oxy)methyl)phenyl)-3H- imidazo[4,5b] pyridin-5-yl)boronic acidA mixture of Intermediate 2 (1 g, 1.96 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (995 mg, 3.92 mmol), KOAc (577 mg, 5.88 mmol) and Pd(dppf)C12 (143 mg, 196 mmol) in 1,4-di oxane (5 mL) was degassed, purged with N2 three times, and stirred at 90 °C for 16 hr under N2 atmosphere. The title compound was obtained as a black liquid, which was used in the next step without work-up and purification. MS: m / z = 476.2 [M + H]+.Step 2 : 3 -(3 -(4-((( / m-Butyl di m ethyl silyl)oxy)methyl)phenyl)-5 -(5 - (difluoromethoxy)pyri din-2 -yl)-3H-imidazo[4,5b] pyri din-2 -yl)pyridin-2-amine A mixture of (2-(2-aminopyridin-3-yl)-3-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)- 3H-imidazo[4,5-b]pyridin-5-yl)boronic acid (470 mg, 989 pmol), 2-bromo-5- (difluoromethoxy)pyridine (266 mg, 1.19 mmol), Pd(dppf)C12 (72.3 mg, 98.9 pmol) and CS2CO3 (966 mg, 2.97 mmol) in 1,4-dioxane (4 mL) and H2O (1 mL) was degassed, purged with N2 three times, and stirred at 90 °C for 16 hr under N2 atmosphere. The reaction mixture was poured into H2O (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 56% EtOAc in petroleum ether), the title compound (210 mg, yield: 37% for two steps) was obtained as a brown solid. MS: m / z = 575.2 [M + H]+. 'H NMR (400 MHz, Dimethysulfoxide-d6) 5 8.57 (d, .7= 8.4 Hz, 1H), 8.40 (d, J= 8.4 Hz, 1H), 8.31 (d, J= 8.4 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 8.00 (dd, J= 4.8, 2.0 Hz, 1H), 7.76 (dd, J= 8.4, 2.4 Hz, 1H), 7.54 - 7.45 (m, 4H), 7.41 - 7.27 (m, 1H), 7.22 - 7.16 (m, 1H), 7.00 (s, 2H), 6.34 (dd, J= 7.6, 4.8 Hz, 1H), 4.82 (s, 2H), 0.93 (s, 9H), 0.12 (s, 6H).19F NMR (400 MHz, Dimethysulfoxide-d6) 8 -82.487.Step 3 : 2-Amino-3-(3-(4-((( / c / 7-butyldimethylsilyl)oxy)methyl)phenyl)-5-(5- (difluoromethoxy)pyridin-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridine 1 -oxide To a solution of 3-(3-(4-(((terLbutyldimethylsilyl)oxy)methyl)phenyl)-5-(5- (difluoromethoxy)pyridin-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (1 g, 1.74 mmol) in CH2CI2 (50 mL) was added m-CPBA (353 mg, 1.74 mmol, 85% purity) at 0 °C. The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was filtered and concentrated under reduced pressure. After purification by prep-HPLC (column: Phenomenex luna Cis (250 x 70 mm x 10 pm); mobile phase: [water (NH4HCO3) - ACN]; gradient: 55% - 85% B over 22 min), the title compound (580 mg, yield: 49%) was obtainedas a yellow solid. MS: m / z = 591.3 [M + H]+. 'HNMR (400 MHz, Dimethylsulfoxide-d6) 5 8.58 (d, J= 2.8 Hz, 1H), 8.48 - 8.34 (m, 2H), 8.22 (d, J= 8.8 Hz, 1H), 8.17 (dd, J= 6.4, 1.2 Hz, 1H), 7.77 (dd, J= 8.8, 2.8 Hz, 1H), 7.61 (s, 2H), 7.56 - 7.50 (m, 4H), 7.46 - 7.18 (m, 1H), 6.98 (dd, J= 8.0, 1.2 Hz, 1H), 6.51 (dd, J= 8.0, 6.4 Hz, 1H), 4.83 (s, 2H), 0.93 (s, 9H), 0.11 (s, 6H).19F NMR (400 MHz, Di methyl sulfoxide-d6) 8 -82.504.Step 4 : 2- Amino-3 -(5 -(5 -(difluoromethoxy)pyridin-2-yl)-3 -(4-(hy droxym ethyl (phenyl (-37 / - imidazo[4,5-b]pyridin-2-yl)pyridine 1-oxideTo a solution of 2-amino-3-(3-(4-(((terLbutyldimethylsilyl)oxy)methyl)phenyl)-5-(5- (difluoromethoxy)pyridin-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridine 1-oxide (580 mg, 982 pmol) in THF (5 mL) was added TBAF (1.96 mL, 1 M in THF). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with CH2CI2 (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over ISfeSCL, filtered and concentrated under reduced pressure to give the title compound (430 mg, yield: 86%) as a yellow solid. MS: m / z = 477.1 [M + H]+. ' H NMR (400 MHz, Dimethylsulfoxide-d6) 6 8.58 (d, J= 2.8 Hz, 1H), 8.46 - 8.33 (m, 2H), 8.23 (d, J= 8.8 Hz, 1H), 8.18 - 8.15 (m, 1H), 7.78 (dd, J= 8.8, 2.8 Hz, 1H), 7.58 (s, 2H), 7.52 - 7.18 (m, 5H), 7.03 - 6.99 (m, 1H), 6.58 - 6.53 (m, 1H), 5.38 (t, J= 6.0 Hz, 1H), 4.61 (d, J= 6.0 Hz, 2H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 6 -82.464.Step 5 : 2-Amino-3-(3-(4-(chloromethyl)phenyl)-5-(5-(difluoromethoxy)pyridin-2-yl)-3H- imidazo[4,5-b]pyridin-2-yl)pyridine 1-oxideTo a solution of 2-amino-3-(5-(5-(difluoromethoxy)pyridin-2-yl)-3-(4- (hydroxymethyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridine 1-oxide (430 mg, 903 pmol) in CH2Cl2 (5 mL) was added SOCI2 (323 mg, 2.71 mmol). The mixture was stirred at 40 °C for 0.5 hr. The reaction was concentrated under reduced pressure to give the title compound (479 mg, HC1 salt) as a yellow solid. MS: m / z = 495.0, 496.7 [M + H]+.Step 6: 2-Amino-3-(3-(4-((4-((2-cyanopyrimidin-4-yl)amino)piperidin-l-yl)methyl)phenyl)- 5-(5-(difluoromethoxy)pyridin-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridine 1-oxideTo a solution of 2-amino-3-(3-(4-(chloromethyl)phenyl)-5-(5-(difluoromethoxy)pyridin-2- yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridine 1-oxide (479 mg, 901 pmol, HC1 salt) and Intermediate 5 (286 mg, 901 pmol, TFA salt) in DMF (5 mL) were added K2CO3 (623 mg, 4.51 mmol) and Nal (13.5 mg, 90.1 pmol). The mixture was stirred at 50 °C for 1 hr. The reaction mixture was quenched with H2O (50 mL) at 25 °C and extracted with (50 CH2Cl2 mL x 2). The combined organic layers were washed with brine (50 mL x 3), dried overNa2SO4, filtered and concentrated under reduced pressure. After purification by prep-HPLC (column: CD07-Daisogel SP-100-8-ODS-PK 150 x 25 x 10 pm; mobile phase: [water(NH4HCO3) - ACN]; gradient: 30% - 60% B over 10 min), the title compound (Example 31, 64.7 mg, yield: 11% for two steps) was obtained as a yellow lyophilized powder. MS: m / z = 662.3 [M + H]+. 'HNMR (400 MHz, Dimethylsulfoxide-d6) 8 8.58 (d, J= 2.4 Hz, 1H), 8.49 - 8.31 (m, 2H), 8.27 - 8.15 (m, 2H), 8.14 - 7.93 (m, 2H), 7.78 (dd, J= 8.8, 2.8 Hz, 1H), 7.61 (br s, 2H), 7.54 - 7.17 (m, 5H), 6.97 - 6.91 (m, 1H), 6.75 - 6.63 (m, 1H), 6.52 (dd, J= 8.0, 6.8 Hz, 1H), 3.92 - 3.73 (m, 1H), 3.60 (s, 2H), 2.88 - 2.78 (m, 2H), 2.22 - 2.10 (m, 2H), 1.95 - 1.81 (m, 2H), 1.57 - 1.42 (m, 2H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 6 -82.495.

[0268] Example 32: 4-((l-(4-(2-(3-Aminoisothiazol-4-yl)-5-(5-fluoropyridin-2-yl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileStep 1 : 4-(2-(3-Aminoisothiazol-4-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3- yl)benzyl acetateTo a solution of Intermediate 6 (574 mg, 1.50 mmol) and Intermediate 26 (320 mg, 974 pmol) in DMSO (10 mL) was added Na2SO4 (1.04 g, 6.00 mmol). The mixture was degassed, purged with N2 three times, and stirred at 100 °C for 3 hr under N2. The reaction mixture was quenched with H2O (20 mL) and extracted with (10 mL C xH 42)C.l2 The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in (10 mL), an CdH2Cl2 TFA (2 mL) was added to the mixture. The mixture was degassed, purged with N2 three times, and stirred at 25 °C for 2 hr under N2. The reaction mixture was quenched with H2O (50 mL). The pH of the mixture was adjusted to 8 with sat. NaHCCL aq.. The mixture wasextracted with CH2CI2 (30 mL x 5). The combined organic layers were washed with brine (100 mL x 3), dried over Na2SO,4 filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 30% EtOAc in petroleum ether), the title compound (223 mg, yield: 30%) was obtained as a red solid. MS: m / z = 461.1 [M+H]+. 'H NMR (400 MHz, Chloroform-d) 5 8.49 (d, J= 2.8 Hz, 1H), 8.45 (d, J= 8.4 Hz, 1H), 8.27 (dd, J= 8.8, 4.4 Hz, 1H), 8.16 (d, J= 8.0 Hz, 1H), 7.81 (s, 1H), 7.64 (d, J= 8.0 Hz, 2H), 7.51 (d, J= 8.0 Hz, 2H), 7.42 (td, J= 8.4, 2.8 Hz, 1H), 6.70 (br s, 2H), 5. 31 (s, 2H), 2.22 (s, 3H).19F NMR(400 MHZ, Chloroform-d) 5 -127.725.Step 2: (4-(2-(3-Aminoisothiazol-4-yl)-5-(5-fluoropyridin-2-yl)-37 / -imidazo[4,5-b]pyridin-3- yl)phenyl)methanolTo a solution of 4-(2-(3-aminoisothiazol-4-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5- b]pyri din-3 -yl)benzyl acetate (223 mg, 484 pmol) in THF (2 mL), MeOH (2 mL), and H2O (2 mL) was added K2CO3 (134 mg, 969 pmol). The mixture was degassed, purged with N2 three times, and stirred at 25 °C for 1 hr under N2. The reaction mixture was quenched with H2O (20 mL) and extracted with EtOAc (20 mL x 5). The combined organic layers were washed with brine (100 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (165 mg, yield: 74%) as a red solid. MS: m / z = 419.1 [M+H]+.Step 3 : 4-(3-(4-(Chloromethyl)phenyl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyridin-2- yl)isothiazol-3 -amineTo a solution of (4-(2-(3-aminoisothiazol-4-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5- b]pyri din-3 -yl)phenyl)methanol (163 mg, 390 pmol) in CH2CI2 (2 mL) was added SOCI2 (0.3 mL). The mixture was degassed, purged with N2 three times, and stirred at 25 °C for 0.5 hr under N2. The reaction mixture was concentrated under reduced pressure to give the title compound (184.39 mg, crude, HC1 salt) as a red solid. MS: m / z = 437.0, 439.0 [M+H]+.Step 4: 4-((l-(4-(2-(3-Aminoisothiazol-4-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileTo a solution of 4-(3-(4-(chloromethyl)phenyl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5- b]pyridin-2-yl)isothiazol-3-amine (184 mg, 390 pmol, HC1 salt), Intermediate 5 (124 mg, 390 pmol, TFA salt) in DMF (3 mL) were added K2CO3 (215 mg, 1.56 mmol) and Nal (58 mg, 390 pmol). The mixture was degassed, purged with N2 three times, and stirred at 50 °C for 2 hr under N2. The reaction mixture was quenched with H2O (20 mL) and extracted with CH2Cl2 (10 mL x 4). 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% ~ 4% MeOH in CH2Cl2 ), the title compound (Example 32, 50.3 mg, yield: 20% for two steps) was obtained as an orange solid. MS: m / z = 604.3 [M+H]+. 'HNMR (400 MHz, Dimethylsulfoxide-d6) 8 8.66 (d, J= 3.2 Hz, 1H), 8.41 - 8.36 (m, 1H), 8.34 - 8.30 (m, 1H), 8.15 (dd, J= 8.8, 4.8 Hz, 1H), 8.12 - 8.04 (m, 2H), 7.98 (s, 1H), 7.80 (td, J= 8.8, 3.2 Hz, 1H), 7.63 - 7.55 (m, 4H), 7.38 (s, 2H), 6.69 (br d, J= 6.0 Hz, 1H), 3.91 - 3.78 (m, 1H), 3.68 (s, 2H), 2.94 - 2.90 (m, 2H), 2.27 - 2.19 (m, 2H), 1.98 - 1.89 (m, 2H), 1.57 - 1.51 (m, 2H).19F NMR(400 MHz, Dimethylsulfoxide-d6) 6 -127.791.

[0269] Example 33: 4-((l-(4-(2-(3-Aminopyrazin-2-yl)-5-(5-(difluoromethoxy)pyridin-2-yl)- 3H-imidazo[4,5b] pyridin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 33 was prepared in a manner similar to Example 4. MS: m / z = 647.7 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 6 8.58 (d, J= 2.8 Hz, 1H), 8.47 - 8.42 (m, 1H), 8.40 - 8.36 (m, 1H), 8.19 (d, J= 8.8 Hz, 1H), 8.13 - 8.04 (m, 2H), 8.02 (d, J= 2.0 Hz, 1H), 7.86 - 7.70 (m, 3H), 7.54 - 7.17 (m, 6H), 6.68 (d, J= 5.6 Hz, 1H), 3.91 - 3.76 (m, 1H), 3.61 (s, 2H), 2.94 - 2.84 (m, 2H), 2.23 - 2.13 (m, 2H), 1.96 - 1.86 (m, 2H), 1.57 - 1.45 (m, 2H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 5 -82.527.

[0270] Example 34: 4-(l-(l-(4-(2-(2-Aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)cyclopropyl)pyrimidine-2-carbonitrileTo a solution of Intermediate 30 (82.8 mg, 242 pmol, TFA salt) and Intermediate 3 (113 mg, 242 pmol, HC1 salt) in DMF (5 mL) were added K2CO3 (167 mg, 1.21 mmol) and Nal (3.62 mg, 24.2 pmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with (25 m CLH x22C)l.2 The combined organic layers were washed with brine (50 mL x 5), dried over anhydrous Na2SO,4 filtered and concentrated under reduced pressure. After purification by prep-HPLC (column: CD07- Daisogel SP-100-8-ODS-PK 150 x 25 x 10 pm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 55% - 75% B over 15 min), the title compound (Example 34, 21.2 mg, yield: 14% for two steps) was obtained as an off-white lyophilized powder. MS: m / z = 623.3 [M + H]+. 'HNMR (400 MHz, Dimethyl sulfoxide-d6) 8 8.81 (d, J= 5.6 Hz, 1H), 8.67 (d, J= 2.8 Hz, 1H), 8.42 - 8.38 (m, 1H), 8.33 - 8.29 (m, 1H), 8.22 (dd, J= 8.8, 4.4 Hz, 1H), 8.00 (dd, J= 4.8, 1.6 Hz, 1H), 7.86 - 7.80 (m, 1H), 7.77 (d, J= 5.6 Hz, 1H), 7.50 - 7.40 (m, 4H), 7.16 (dd, J= 7.6, 1.6 Hz, 1H), 7.00 (br s, 2H), 6.38 (dd, J= 8.0, 5.2 Hz, 1H), 3.56 (s, 2H), 2.93 - 2.85 (m, 2H), 2.10 - 1.99 (m, 3H), 1.65 - 1.56 (m, 2H), 1.28 - 1.20 (m, 2H), 1.15 - 1.10 (m, 2H), 1.09 - 1.05 (m, 2H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 6 -127.823.

[0271] Example 35: 4-((l-(4-(2-(2-Aminopyridin-3-yl)-6-(4-fluorophenyl)-1H-imidazo[4,5- c]pyridin-l-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileTo a mixture of Intermediate 37 (379 mg, 882 pmol, HC1 salt) and Intermediate 5 (215 mg, 1.06 mmol) in DMF (5 mL) were added K2CO3 (731 mg, 5.29 mmol) and Nal (26.4 mg, 176 pmol), and the mixture was stirred at 20 °C for 12 hr. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. After purification bysilica gel flash chromatography (Eluent of 0% ~ 5% Methanol in CH2Cl2 ) and prep-HPLC (column: Welch Xtimate Cl 8 150 x 25 mm x 5 pm; mobile phase: [water (NH3H2O + NH4HCO3) - ACN]; gradient: 42% - 72% B over 8 min), the title compound (Example 35, 24.3 mg, yield: 4.6% for three steps) was obtained as a white solid. MS: m / z = 597.1 [M + H]+. ‘H NMR (400 MHz, Dimethylsulfoxide-d6) 8 9.15 (s, 1H), 8.16 - 8.11 (m, 2H), 8.10 - 8.03 (m, 2H), 8.00 (dd, J= 4.8, 2.0 Hz 1H), 7.68 (s, 1H), 7.53 - 7.49 (m, 2H), 7.48 - 7.43 (m, 2H), 7.31 - 7.23 (m, 2H), 7.15 (dd, J= 7.6, 1.6 Hz, 1H), 6.97 (br s, 2H), 6.67 (d, J= 6.0 Hz, 1H), 6.38 (dd, J= 7.6, 4.8 Hz, 1H), 3.87 - 3.76 (m, 1H), 3.60 (s, 2H), 2.88 - 2.81 (m, 2H), 2.21 - 2.12 (m, 2H), 1.93 - 1.86 (m, 2H), 1.53 - 1.42 (m, 2H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 6 -114.282.

[0272] Example 36: 2-Amino-3-(3-(4-((4-(2-cyanopyrimidin-4-yl)piperazin-l- yl)methyl)phenyl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridine 1-oxideTo a solution of Intermediate 38 (169 mg, 350 pmol, HC1 salt) and Intermediate 11 (106 mg, 350 pmol, TFA salt) in DMF (2 mL) were added K2CO3 (242 mg, 1.75 mmol) and Nal (5.24 mg, 35 pmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was filtered. After purification by / i / tyi-HPLC (column: CD07-Daisogel SP-100-8-ODS-PK 150 x 25 x 10 pm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 32% - 62% B over 15 min), the title compound (Example 36, 59.1 mg, yield: 28%) was obtained as a yellow lyophilized powder. MS: m / z = 600.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 6 8.68 (d, J= 2.8 Hz, 1H), 8.47 - 8.35 (m, 2H), 8.30 - 8.22 (m, 2H), 8.17 (dd, J= 6.4, 1.2 Hz, 1H), 7.88 - 7.81 (m, 1H), 7.62 (s, 2H), 7.56 - 7.50 (m, 4H), 7.12 (d, J= 6.4 Hz, 1H), 6.95 (dd, J= 8.0, 1.2 Hz, 1H), 6.52 (dd, J= 8.0, 6.8 Hz, 1H), 3.76 - 3.65 (m, 4H), 3.65 (s, 2H), 2.54 - 2.51 (m, 4H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 8 -127.577.

[0273] Example 38: l-(4-(2-(2-Aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5- b]pyri din-3 -yl)benzyl)-4-(2-cyanopyrimidin-4-yl)piperazine 1-oxideTo a solution of Example 14 (260 mg, 446 pmol) in CH2Cl2 (20 mL) was added m-CPBA (90.4 mg, 446 pmol, 85% purity) at 0°C. The mixture was stirred at 0 °C for 0.5 hr. The reaction mixture was quenched with ISfeSCL (5mL) at 0 °C, diluted with H2O (10 mL), and extracted with CH2CI2 (20 mL x 2). The combined organic layers were washed with brine(20 mL ), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by / i / tyi-HPLC (column: CD07-Daisogel SP-100-8-ODS-PK 150^25x 10 pm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 18%-48% B over 11 min), the title compound (Example 38, 110.9 mg, yield: 41%) was obtained as a yellow lyophilized powder. MS: m / z =600.3 [M + H]+. 'HNMR (400 MHz, Dimethylsulfoxide-d6) 8 8.66 (d, J= 2.8 Hz, 1H), 8.42 - 8.38 (m, 1H), 8.35 - 8.30 (m, 2H), 8.27 - 8.22 (m, 1H), 8.01 (dd, J= 4.8, 1.6 Hz, 1H), 7.86 - 7.81 (m, 1H), 7.81 - 7.77 (m, 2H), 7.53 (d, J= 8.4 Hz, 2H), 7.21 - 7.16 (m, 2H), 7.00 (s, 2H), 6.38 (dd, J= 7.6, 4.8 Hz, 1H), 4.46 (s, 2H), 3.80 - 3.70 (m, 2H), 3.51 - 3.43 (m, 4H), 2.93 - 2.87 (m, 2H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 6 -127.734

[0274] Example 39: 4-((l-(4-(2-(2-Aminopyridin-3-yl)-6-(4-fluorophenyl)-1H-imidazo[4,5- Z>]pyridin-l-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileTo a solution of Intermediate 35 (178 mg, 413 pmol, HC1 salt) in DMF (2 mL) were added Intermediate 5 (92.4 mg, 455 pmol), K2CO3 (171 mg, 1.24 mmol) and Nal (12.4 mg, 82.6 pmol). The mixture was stirred at 60 °C for 2.5 hr. The mixture was diluted with H2O (40 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. After purification by prep-HPLC (column: Welch Xtimate C18 150 x 30 mm x 5pm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 50% - 80% B over 7 min) and / i / c / i-HPLC (column: C18 150x 30 mm; mobile phase: [water (NH3H2O + NH4HCO3) - ACN]; gradient: 45% - 75% B over 7 min), the title compound (Example 39, 20.1 mg, yield: 8.2% for two steps) was obtained as a white solid. MS: m / z = 597.2 [M + H]+.1H NMR (400 MHz, Methanol-d6) 8 8.73 (d, J = 2.0 Hz, 1H), 8.05 - 7.95 (m, 2H), 7.83 (d, J= 2.0 Hz, 1H), 7.73 - 7.63 (m, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.44 (d, J= 8.4 Hz, 2H), 7.33 - 7.10 (m, 3H), 6.65 - 6.51 (m, 1H), 6.48 - 6.40 (m, 1H), 4.05 - 3.70 (m, 1H), 3.66 (s, 2H), 3.00 - 2.85 (m, 2H), 2.33 - 2.19 (m, 2H), 2.03 - 1.95 (m, 2H), 1.66 - 1.50 (m, 2H).19F NMR (400 MHz, Methanol-d6) 5 -116.833.

[0275] Example 42: 4-((l-(4-(2-(2-Aminopyridin-3-yl)-6-(5-fluoropyridin-2-yl)-1H- imidazo[4,5-c]pyridin-l-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 42 was prepared in a manner similar to Example 35. MS: m / z = 598.1 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 6 9.18 (s, 1H), 8.60 (d, J= 2.8 Hz, 1H), 8.53 (dd, J = 8.8, 4.8 Hz, 1H), 8.13 (s, 1H), 8.11 - 8.04 (m, 2H), 8.01 (dd, J= 4.8, 1.6 Hz, 1H), 7.88 - 7.83 (m, 1H), 7.56 - 7.53 (m, 2H), 7.49 - 7.46 (m, 2H), 7.20 (dd, J= 7.2, 1.6 Hz, 1H), 7.02 (br s, 2H), 6.68 (d, J= 5.6 Hz, 1H), 6.39 (dd, J= 7.2, 4.4 Hz, 1H), 3.88 - 3.77 (m, 1H), 3.61 (s, 2H), 2.89 - 2.81 (m, 2H), 2.21 - 2.12 (m, 2H), 1.95 - 1.85 (m, 2H), 1.55 - 1.45 (m, 2H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 8 -128.209.

[0276] Example 43: 4-((l-(4-(2-(2-Aminopyridin-3-yl)-6-(5-fluoropyridin-2-yl)- 1H- imidazo[4,5b] pyridin-l-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 43 was prepared in a manner similar to Example 14. MS: m / z = 598.2 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d6) 6 9.22 (d, J= 2.0 Hz, 1H), 8.65 (d, J= 2.8 Hz, 1H), 8.28 - 8.16 (m, 2H), 8.12 - 7.95 (m, 3H), 7.88 - 7.80 (m, 1H), 7.57 - 7.43 (m, 4H),7.18 (dd, J = 7.6, 1.6 Hz, 1H), 7.08 (br s, 2H), 6.68 (d, J= 6.0 Hz, 1H), 6.39 (dd, J= 7.2, 4.8 Hz, 1H),3.95 - 3.73 (m, 1H), 3.60 (s, 2H), 2.91 - 2.76 (m, 2H), 2.25 - 2.05 (m, 2H), 1.95 - 1.78 (m, 2H), 1.60 - 1.40 (m, 2H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 6 -129.194.

[0277] Example 45: 4-(4-(4-(2-(2-Aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H- imidazo[4,5b] pyridin-3-yl)benzyl)-4,7-diazaspiro[2.5]octan-7-yl)pyrimidine-2-carbonitrileTo a solution of Intermediate 3 (80 mg, 186 pmol) in DMF (3.5 mL) were added Intermediate 33 (48.0 mg, 222 pmol), K2CO3 (128 mg, 928 pmol), and Nal (5.57 mg, 37.1 pmol). The mixture was stirred at 80 °C for 3 hr. The mixture was diluted with H2O (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated. After purification by prep- HPLC (column: Welch Xtimate C18 150 x 25 mm x 5 pm; mobile phase: [water (NH3H2O + NH4HCO3) - ACN]; gradient: 48% - 78% B over 8 min), the title compound (Example 45, 13.8 mg, yield: 12% for 2 steps) was obtained as a white solid. MS: m / z = 610.2 [M + H]+. 'HNMR (400 MHz, Dimethyl sulfoxide-d6) 8 8.66 (d, J= 2.8 Hz, 1H), 8.40 (d, J= 8.4 Hz, 1H), 8.31 (d, .7= 8.4 Hz, 1H), 8.27 - 8.19 (m, 2H), 8.01 (dd, J= 4.8, 1.6 Hz, 1H), 7.90 - 7.78 (m, 1H), 7.54 - 7.43 (m, 4H), 7.18 (dd, J= 7.6, 1.6 Hz, 1H), 7.10 (d, J = 6.4 Hz, 1H), 7.01 (s, 2H), 6.39 (dd, J= 7.6, 4.8 Hz, 1H), 4.03 (s, 2H), 3.77 - 3.59 (m, 4H), 2.90 - 2.80 (m, 2H), 0.70 - 0.58 (m, 4H).19F NMR (400 MHz, Dimethylsulfoxide-d6) 6 -127.812.

[0278] Example 46: l-(4-(4-(2-(2-Aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H- imidazo[4,5b] pyridin-3-yl)benzyl)piperazin-l-yl)prop-2-en-l-oneTo...

Claims

CLAIMSWe claim:

1. A compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:wherein:A is C-H and B is C-H; or A is C-H, and B is N; or A is N, and B is C-H; or A is N, and B is N;Z1is N, C-H, or C-R3;Z2is N, C-H, or C-R4;Z3is N, C-OH, or C-R9;R1is selected from optionally substituted aryl, or optionally substituted heteroaryl;R2is selected from hydrogen, halogen, -OH, -CN, -N(R9)2, -OR9, -SR9, -SO2R9, - CO2R9, -CON(R9)2, -SR9, -S(O)R9, - S(O)2R9, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 4-membered to 6- membered heterocyclyl, optionally substituted aryl, aryl substituted with an optionally substituted 4-membered to 6-membered heterocyclyl, optionally substituted heteroaryl or heteroaryl substituted with an optionally substituted 3-membered to 6-membered carbocyclyl;R3is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl;R4is selected from halogen, -CN, optionally substituted C1-C6 alkyl, or optionally substituted aryl;R5and R6are each independently hydrogen, deuterium, halogen, -OH, or optionally substituted C1-C6 alkyl; or R5and R6together form an oxo; or R5and R6join together to form a carbocycle or heterocycle;LCG is a group selected from the group consisting of:Q2is O or S;Q3is a bond, O, S, or N-R22;R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; andR22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle;(b)T1is N or C-R23;T2is N or C-R23;T3is N or C-R23;T4is N or C-R23;T5is O, S, or N-R24; each R23is 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 R24is hydrogen, or optionally substituted C1-C6 alkyl;T6is N or C-R25;T7is N or C-R25;T8is N or C-R25; each R25is 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 R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and(e) -C=N ;L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the -(CO)q-Ar group;R8is optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, or optionally substituted heterocyclyl; each R9is hydrogen, or optionally substituted C1-C6 alkyl; m is 0, 1, or 2; n is 1, 2, or 3; and q is 0 or 1.

2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof,; wherein the asterisk (*) indicates the bond to the -(CO)q-Ar group.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein LCG is:, whereinQ1is O or S;Q2is O or S;Q3is a bond, O, S, or N-R22;R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; andR22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle.

4. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein LCG is:; whereinT6is N or C-R25;T7is N or C-R25;T8is N or C-R25; each R25is 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.

5. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein LCG is :wherein, each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy.

6. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein LCG is -C=N.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt or solvate thereof, wherein A is C-H, and B is N.

8. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt or solvate thereof, wherein A is N, and B is C-H.

9. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt or solvate thereof, wherein A is N, and B is N.

10. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt or solvate thereof, wherein A is C-H and B is C-H.

11. A compound having the structure of Formula (la), or a pharmaceutically acceptable salt or solvate thereof:X1is N or C-R7;X2is N or C-R7;X3is N or C-R7;X4is N or C-R7;Y is O, S, or N-R9;R1is selected from optionally substituted aryl, or optionally substituted heteroaryl;R2is selected from hydrogen, halogen, -OH, -CN, -N(R9)2, -OR9, -SR9, -SO2R9, - CO2R9, -CON(R9)2, -SR9, -S(O)R9, - S(O)2R9, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 4-membered to 6- membered heterocyclyl, optionally substituted aryl, aryl substituted with an optionally substituted 4-membered to 6-membered heterocyclyl, optionally substituted heteroaryl or heteroaryl substituted with an optionally substituted 3-membered to 6-membered carbocyclyl;R3is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl;R4is selected from halogen, -CN, optionally substituted C1-C6 alkyl, or optionally substituted aryl;R5and R6are each independently hydrogen, deuterium, halogen, -OH, or optionally substituted C1-C6 alkyl; or R5and R6together form an oxo; or R5and R6join together to form a carbocycle or heterocycle; each R7is 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;L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the -(CO)q-Ar group;R8is optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, or optionally substituted heterocyclyl; each R9is hydrogen, or optionally substituted C1-C6 alkyl; m is 0, 1, or 2; n is 1, 2, or 3; and q is 0 or 1.

12. The compound of claim 11, or a pharmaceutically acceptable salt or solvate thereof, wherein L is a divalent radical selected from:; wherein the asterisk (*) indicates the bond to the -(CO)q-Ar group.

13. The compound of any one of claims 1-12, or pharmaceutically acceptable salt or solvate thereof, wherein Z1is N.

14. The compound of any one of claims 1-13, or pharmaceutically acceptable salt or solvate thereof, wherein Z2is C-H.

15. The compound of any one of claims 1-13, or pharmaceutically acceptable salt or solvate thereof, wherein Z2is C-R4.

16. The compound of any one of claims 1-15, or pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted heteroaryl.

17. The compound of claim 16, or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heteroaryl is an optionally substituted pyridinyl or optionally substituted pyridinyl N-oxide.

18. The compound of any one of claims 1-17, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted aryl.

19. The compound of claim 18, or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted aryl is an optionally substituted phenyl.

20. The compound of any one of claims 1-17, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted heteroaryl.

21. The compound of claim 20, or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heteroaryl is an optionally substituted pyridinyl.

22. The compound of any one of claims 1-21, or pharmaceutically acceptable salt or solvate thereof, wherein R5is hydrogen.

23. The compound of any one of claims 1-21, or pharmaceutically acceptable salt or solvate thereof, wherein R6is hydrogen.

24. The compound of any one of claims 1-21, or pharmaceutically acceptable salt or solvate thereof, wherein R5and R6together form an oxo.

25. The compound of any one of claims 1-22, or pharmaceutically acceptable salt or solvate thereof, wherein R6is optionally substituted C1-C6 alkyl.

26. The compound of any one of claims 1-21, or pharmaceutically acceptable salt or solvate thereof, wherein R5and R6join together to form a carbocycle or heterocycle.

27. The compound of any one of claims 1-26, or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:wherein the asterisk (*) indicates the bond to the -(CO)q-Ar group.

28. The compound of any one of claims 1-26, or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:wherein the asterisk (*) indicates the bond to the -(CO)q-Ar group.

29. The compound of any one of claims 1-26, or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:asterisk (*) indicates the bond to the -(CO)q-Ar group.

30. The compound of any one of claims 1-26, or pharmaceutically acceptable salt orsolvate thereof, wherein L is selected from:wherein the asterisk(*) indicates the bond to the -(CO)q-Ar group.

31. The compound of any one of claims 1-26, or pharmaceutically acceptable salt orsolvate thereof, wherein L is selected from: , , and; wherein the asterisk (*) indicates the bond to the -(CO)q-Ar group.

32. The compound of any one of claims 1-31, or pharmaceutically acceptable salt or solvate thereof, wherein R8is optionally substituted C1-C6 alkyl.

33. The compound of any one of claims 1-32, or pharmaceutically acceptable salt or solvate thereof, wherein q is 0.

34. The compound of any one of claims 1-32, or pharmaceutically acceptable salt or solvate thereof, wherein q is 1.

35. The compound of any one of claims 1, 2, 11, or 12, or pharmaceutically acceptable salt or solvate thereof, wherein36. The compound of any one of claims 1, 2, 11, or 12, or pharmaceutically acceptable37. The compound of any one of claims 1, 2, 11, or 12, or pharmaceutically acceptable salt or solvate thereof, wherein Ar is38. The compound of any one of claims 35-37, or pharmaceutically acceptable salt or solvate thereof, wherein X1, X2, and X3are C-H.

39. The compound of any one of claims 35-37, or pharmaceutically acceptable salt or solvate thereof, wherein X1is N; and X2, and X3are C-H.

40. The compound of any one of claims 35-37, or pharmaceutically acceptable salt or solvate thereof, wherein X2is N; and X1, and X3are C-H.

41. The compound of any one of claims 35-37, or pharmaceutically acceptable salt or solvate thereof, wherein X3is N; and X1, and X2are C-H.

42. The compound of any one of claims 35-37, or pharmaceutically acceptable salt or solvate thereof, wherein X1is N; and X2, and X3are C-H.

43. The compound of any one of claims 35-37, or pharmaceutically acceptable salt or solvate thereof, wherein Y is O.

44. The compound of any one of claims 35-37, or pharmaceutically acceptable salt or solvate thereof, wherein Y is S.

45. The compound of any one of claims 35-37, or pharmaceutically acceptable salt or solvate thereof, wherein Y is N-H.

46. The compound of any one of claims 35-37, or pharmaceutically acceptable salt or solvate thereof, wherein Y is N-R9, wherein R9is optionally substituted C1-C6 alkyl.

47. The compound of any one of claims 1, 2, 11, or 12, or pharmaceutically acceptablexf. - x2orxk salt or solvate thereof, wherein’x xfCN.

48. The compound of claim 47, or pharmaceutically acceptable salt or solvate thereof, wherein X1is N.

49. The compound of claim 47, or pharmaceutically acceptable salt or solvate thereof, wherein X2is N.

50. The compound of claim 47, or pharmaceutically acceptable salt or solvate thereof, wherein X3is N.

51. The compound of claim 47, or pharmaceutically acceptable salt or solvate thereof, wherein X4is N.

52. The compound of claim 47, or pharmaceutically acceptable salt or solvate thereof, wherein X1is C-H.

53. The compound of claim 47, or pharmaceutically acceptable salt or solvate thereof, wherein X2is C-H.

54. The compound of claim 47, or pharmaceutically acceptable salt or solvate thereof, wherein X3is C-H.

55. The compound of claim 47, or pharmaceutically acceptable salt or solvate thereof, wherein X4is C-H.

56. The compound of any one of claims 1-55, or pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted C1-C6 alkyl.

57. The compound of any one of claims 1-55, or pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted aryl.

58. The compound of any one of claims 1-57, or pharmaceutically acceptable salt or solvate thereof, wherein R4is optionally substituted C1-C6 alkyl.

59. The compound of any one of claims 1-57, or pharmaceutically acceptable salt or solvate thereof, wherein R4is optionally substituted aryl.

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

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

62. A compound, or pharmaceutically acceptable salt or solvate thereof, as described in Table 3.

63. A compound, or pharmaceutically acceptable salt or solvate thereof, as described in Table 4.

64. A compound, or pharmaceutically acceptable salt or solvate thereof, as described in Table 5.

65. A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt or solvate thereof, as described in any one of claims 1-64 and a pharmaceutically acceptable excipient.

66. A method of preparing a pharmaceutical composition comprising mixing a compound, or pharmaceutically acceptable salt or solvate thereof, of any one of claims 1-64, and a pharmaceutically acceptable carrier.

67. A compound of any one of claims 1-64, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

68. A compound of any one of claims 1-64, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.

69. Use of a compound of any one of claims 1-64, or pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

70. A method of treating cancer in a patient in need thereof, comprising administering to the patient a compound as described in any one of claims 1-64, or pharmaceutically acceptable salt or solvate thereof.

71. A method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound as described in any one of claims 1-64, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

72. A method of inhibiting a AKT1 enzyme comprising contacting the enzyme with a compound of any one of claims 1-64, wherein the AKT1 enzyme is contacted in an in vitro setting.

73. A method of inhibiting a AKT1 enzyme comprising contacting the enzyme with a compound of any one of claims 1-64, wherein the AKT1 enzyme is contacted in an in vivo setting.