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, such as cancer.

Description

AKT1 MODULATORS CROSS REFERENCE

[0001] This application claims the benefit of US Provisional Application No. 63 / 611,004, filedDecember 15, 2023, and US Provisional Application No.63 / 643,058, filed May 6, 2024, both of which are incorporated herein by reference in their entirety. BACKGROUND

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

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

[0004] One embodiment provides a compound having the structure of Formula (I), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof:(I) wherein, Ring A is an optionally substituted 5-membered heteroaryl; w, x, y, and z are each independently N or C-R1; each R1is independently selected from H, D, halogen, or -CN; R2and R3are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R2and R3together form an oxo; or R2and R3join together to form a carbocycle or heterocycle; L is selected from -N(R4)-, -O-, or a divalent radical selected from:, ,, , ,; wherein the asters ( ) n cates t e on to t e ; each R4is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl; each R25are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R25together form an oxo; or two independently selected R25join together to form a carbocycle or heterocycle; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 1, or 2; n is 0 or 1; LCG is a group selected from the group consisting of: (a QQ2is O or S; Q3is a bond, O, S, N-R9a; R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R9is absent and Q3and L join together to form a heterocycle; andR9ais selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R9and R9ajoin together to form a heterocycle; (b)T1is N or C-R10; T2is N or C-R10; T3is N or C-R10; T4is N or C-R10; T5is O, S, or N-R11; each R10is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R11is hydrogen, or optionally substituted C1-C6 alkyl; nd; T6is N or C-R12; T7is N or C-R12; T8is N or C-R12; each R12is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionallysubstituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl; (d wherein each R , R , R , and R is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .

[0005] One embodiment provides a compound having the structure of Formula (I’), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof:) wherein, Ring A is an optionally substituted 5-membered heteroaryl; w, x, y, and z are each independently N or C-R1; each R1is independently selected from H, D, halogen, or -CN; R2and R3are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R2and R3together form an oxo; or R2and R3join together to form a carbocycle or heterocycle; L is selected from -N(R4)-, -O-, or a divalent radical selected from:wherein the asterisk (*) indicates the bond to the LCG; each R4is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl; each R25are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R25together form an oxo; or two independently selected R25join together to form a carbocycle or heterocycle; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 1, or 2; n is 0 or 1; LCG is a group selected from the group consisting of:(a Q Q Q3is a bond, O, S, N-R9a; R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R9is absent and Q3and L join together to form a heterocycle; and R9ais selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R9and R9ajoin together to form a heterocycle;T1is N or C-R10; T2is N or C-R10; T3is N or C-R10; T4is N or C-R10; T5is O, S, or N-R11; each R10is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R11is hydrogen, or optionally substituted C1-C6 alkyl;ndT6is N or C-R12; T7is N or C-R12; T8is N or C-R12; each R12is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl; (dwherein each R13, R14, R15, and R16is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .

[0006] One embodiment provides a compound having the structure of Formula (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof:(III) wherein: a is N, or C; b is N, N-R30, or C-R24;R24is selected from H, D, halogen, -CN, -OH, -SR7, -N(R7)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl- C(O)O-, -CON(R7)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R30is selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, or optionally substituted (carbocyclyl)alkyl; c is N, or C; d is N, NH, O, S, or C-H; e is N, or C; provided that only one or two of a, b, c, d, or e are selected from N or NH; provided that a and e are not N; provided that a and c are not N; provided that e and c are not N; w, x, y, and z are each independently N or C-R1; each R1is independently selected from H, D, halogen, or -CN; R2and R3are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R2and R3together form an oxo; or R2and R3join together to form a carbocycle or heterocycle; u is selected from O, S, C(R5)(R6), or NR7; m is 1 or 2; R5and R6are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R5and R6together form an oxo; or R5and R6join together to form a carbocycle or heterocycle; R7is selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; w1, x1, y1, and z1 are each independently N or C-R8; each R8is selected from H, D, halogen, -CN, -OH, -SR4, -N(R4)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl-C(O)O-, -CON(R4)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; L is selected from -N(R4)-, -O-, or a divalent radical selected from:, ,wherein the asterisk (*) indicates the bond to the LCG; each R4is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl; each R25are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R25together form an oxo; or two independently selected R25join together to form a carbocycle or heterocycle; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4;f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 1, or 2; n is 0 or 1; LCG is a group selected from the group consisting of: (a Q QQ3is a bond, O, S, N-R9a; R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R9is absent and Q3and L join together to form a heterocycle; and R9ais selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R9and R9ajoin together to form a heterocycle; (b)T1is N or C-R10; T2is N or C-R10; T3is N or C-R10; T4is N or C-R10; T5is O S or N R11;each R10is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R11is hydrogen, or optionally substituted C1-C6 alkyl; ndT6is N or C-R12; T7is N or C-R12; T8is N or C-R12; each R12is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl; (dwherein each R13, R14, R15, and R16is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .

[0007] One embodiment provides a compound having the structure of Formula (IV), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein: a is N, N-R30, or C-R24; b is N, N-R30, or C-R24; each R24is independently selected from H, D, halogen, -CN, -OH, -SR7, -N(R7)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl-C(O)O-, -CON(R7)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each R30is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, or optionally substituted (carbocyclyl)alkyl; c is N, or C; d is N, or C; e is N, or C; provided that only one or two of a, b, c, d, or e are selected from N and N-R30; w, x, y, and z are each independently N or C-R1; each R1is independently selected from H, D, halogen, or -CN; R2and R3are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R2and R3together form an oxo; or R2and R3join together to form a carbocycle or heterocycle; u is selected from O, S, C(R5)(R6), or NR7; m is 1 or 2; R5and R6are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R5and R6together form an oxo; or R5and R6join together to form a carbocycle or heterocycle; R7is selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; w1, x1, y1, and z1 are each independently N or C-R8; each R8is selected from H, D, halogen, -CN, -OH, -SR4, -N(R4)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl-C(O)O-, -CON(R4)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; L is selected from -N(R4)-, -O-, or a divalent radical selected from:wherein the asterisk (*) indicates the bond to the LCG; each R4is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl; each R25are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R25together form an oxo; or two independently selected R25join together to form a carbocycle or heterocycle; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4;d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 1, or 2; n is 0 or 1; LCG is a group selected from the group consisting of: (a Q QQ3is a bond, O, S, N-R9a; R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R9is absent and Q3and L join together to form a heterocycle; and R9ais selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R9and R9ajoin together to form a heterocycle; (b)T1is N or C-R10; T2is N or C-R10; T3is N or C R10;T4is N or C-R10; T5is O, S, or N-R11; each R10is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R11is hydrogen, or optionally substituted C1-C6 alkyl; ndT6is N or C-R12; T7is N or C-R12; T8is N or C-R12; each R12is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl; (d) wherein each R13, R14, R15, and R16is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .

[0008] One embodiment provides a compound having the structure of Formula (V), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof:)wherein: a is N, or C; b is N, N-R30, or C-R24; R24is selected from H, D, halogen, -CN, -OH, -SR7, -N(R7)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl- C(O)O-, -CON(R7)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R30is selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, or optionally substituted (carbocyclyl)alkyl; c is N, or C; d is N, NH, O, S, or C-H; e is N, or C; provided that only one or two of a, b, c, d, or e are selected from N or NH; provided that a and e are not N; provided that a and c are not N; provided that e and c are not N; w, x, y, and z are each independently N or C-R1; each R1is independently selected from H, D, halogen, or -CN; R2and R3are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R2and R3together form an oxo; or R2and R3join together to form a carbocycle or heterocycle; R5and R6are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R5and R6together form an oxo; or R5and R6join together to form a carbocycle or heterocycle; R7is selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; w1, x1, y1, and z1 are each independently N or C-R8;each R8is selected from H, D, halogen, -CN, -OH, -SR4, -N(R4)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl-C(O)O-, -CON(R4)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; L is selected from -N(R4)-, -O-, or a divalent radical selected from:, , ,;wherein the asterisk (*) indicates the bond to the LCG; each R4is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl; each R25are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R25together form an oxo; or two independently selected R25join together to form a carbocycle or heterocycle; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 1, or 2; n is 0 or 1; LCG is a group selected from the group consisting of: (a QQ2is O or S; Q3is a bond, O, S, N-R9a;R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R9is absent and Q3and L join together to form a heterocycle; and R9ais selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R9and R9ajoin together to form a heterocycle; (b)T1is N or C-R10; T2is N or C-R10; T3is N or C-R10; T4is N or C-R10; T5is O, S, or N-R11; each R10is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R11is hydrogen, or optionally substituted C1-C6 alkyl; nd; T6is N or C-R12; T7is N or C-R12; T8is N or C-R12;each R12is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl; (dwherein each R13, R14, R15, and R16is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .

[0009] One embodiment provides a pharmaceutical composition comprising a compound of Formula(I), (II), (III), (IV), (V), or (VI), or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and at least one pharmaceutically acceptable excipient.

[0010] One embodiment provides a method of treating a disease or disorder in a patient in needthereof comprising administering to the patient a compound of Formula (I), (II), (III), (IV), (V), or (VI), or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof. Another embodiment provides the method wherein the disease or disorder is cancer. INCORPORATION BY REFERENCE

[0011] All publications, patents, and patent applications mentioned in this specification are hereinincorporated by reference for the specific purposes identified herein. DETAILED DESCRIPTION OF THE INVENTION

[0012] As used herein and in the appended claims, the singular forms "a," "and," and "the" includeplural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, ill b t 1% d 15% f th t t d b i l Th t"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

[0013] As used in the specification and appended claims, unless specified to the contrary, thefollowing terms have the meaning indicated below.

[0014] "Amino" refers to the –NH2 radical.

[0015] "Cyano" refers to the -CN radical.

[0016] "Nitro" refers to the -NO2 radical.

[0017] "Oxa" refers to the -O- radical.

[0018] "Oxo" refers to the =O radical.

[0019] "Thioxo" refers to the =S radical.

[0020] "Imino" refers to the =N-H radical.

[0021] "Oximo" refers to the =N-OH radical.

[0022] "Hydrazino" refers to the =N-NH2 radical.

[0023] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbonand hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C1-C8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8 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-C5alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1- methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso- butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halocyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, - N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). In certain embodiments, an optionally substituted alkyl is a haloalkyl. In other embodiments, an optionally substituted alkyl is a fluoroalkyl. In other embodiments, an optionally substituted alkyl is a -CF3group.

[0024] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula –O-alkyl, wherealkyl is an alkyl chain as defined above.

[0025] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solelyof 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 (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) aralkyl (optionally substituted with halogen hydroxy methoxyor 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] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solelyof carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl comprises two to six carbon atoms. In other embodiments, an alkynyl comprises two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, - C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0027] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chainlinking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and having from one to twelve carbon atoms, for example,methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain In certain embodiments an alkylene comprises one to eight carbon atoms (eg C1-C8alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1- C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1- C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C1 alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C5- C8 alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, - C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0028] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbonchain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkenylene comprises two to eight carbon atoms (e.g., C2-C8alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (e.g., C2-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-C3alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (e.g., C2 alkenylene) In other embodiments an alkenylene comprises five to eight carbon atoms (egC5-C8 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C3-C5alkenylene). Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, - N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0029] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbonchain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C2-C8alkynylene). 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-C3alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C5-C8alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C3-C5 alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, - N(Ra)S(O)tRa(where t is 1 or 2) -S(O)tORa(where t is 1 or 2) -S(O)tRa(where t is 1 or 2)and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (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).

[0030] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbonring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb- OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, - Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen hydroxy methoxy or trifluoromethyl) or heteroarylalkyl (optionally substitutedwith 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.

[0031] "Aralkyl" refers to a radical of the formula -Rc-aryl where Rc is an alkylene chain as definedabove, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0032] "Aralkenyl" refers to a radical of the formula –Rd-aryl where Rd is an alkenylene chain asdefined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0033] "Aralkynyl" refers to a radical of the formula -Re-aryl, where Re is an alkynylene chain asdefined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0034] "Aralkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc-arylwhere Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0035] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radicalconsisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds). A fully saturated carbocyclyl radical is also referred to as "cycloalkyl." Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo

[0221] heptanyl) norbornenyl decalinyl 77-dimethyl-bicyclo

[0221] heptanyl and thelike. 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.

[0036] "Carbocyclylalkyl" refers to a radical of the formula –Rc-carbocyclyl where Rc is an alkylenechain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0037] "Carbocyclylalkynyl" refers to a radical of the formula –Rc-carbocyclyl where Rc is analkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0038] "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.

[0039] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.

[0040] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or morefluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, thealkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0041] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical that comprisestwo to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl,isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb- C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, - Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkyleneor 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.

[0042] "N-heterocyclyl" or “N-attached heterocyclyl” refers to a heterocyclyl radical as definedabove containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1- piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, and imidazolidinyl.

[0043] "C-heterocyclyl" or “C-attached heterocyclyl” refers to a heterocyclyl radical as definedabove 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.

[0044] "Heterocyclylalkyl" refers to a radical of the formula –Rc-heterocyclyl where Rc is analkylene 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.

[0045] "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.

[0046] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical thatcomprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present are optionally quaternized The heteroaryl is attached to the rest of the moleculethrough any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, optionally substituted fluoroalkyl, optionally substituted haloalkenyl, optionally substituted haloalkynyl, oxo, thioxo, cyano, nitro, -Rb- ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb- C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, - Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogenalkyl (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.

[0047] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogenand where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0048] "C-heteroaryl" refers to a heteroaryl radical as defined above and where the point ofattachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0049] "Heteroarylalkyl" refers to a radical of the formula –Rc-heteroaryl, where Rc is an alkylenechain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0050] "Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula –O-Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0051] The compounds disclosed herein, in some embodiments, contain one or more asymmetriccenters and thus give rise to enantiomers diastereomers and other stereoisomeric forms thatare defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic andoptically pure forms, and all tautomeric forms are also intended to be included. The term “geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans) of an alkene doublebond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0052] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule toanother atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include: HHN OH O

[0053] The compounds disclosed herein, in some embodiments, are used in different enrichedisotopic forms, e.g., enriched in the content of2H,3H,11C,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos.5,846,514 and 6,334,997. As described in U.S. Patent Nos.5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0054] Unless otherwise stated, structures depicted herein are intended to include compounds whichdiffer only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0055] The compounds of the present disclosure optionally contain unnatural proportions of atomicisotopes 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,11C,13C,14C,15C,12N,13N,15N,16N, 16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35Cl,37Cl,79Br,81Br,125I are all contemplated. In some embodiments, isotopic substitution with18F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0056] In certain embodiments, the compounds disclosed herein have some or all of the 1H atomsreplaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0057] Deuterium substituted compounds are synthesized using various methods such as describedin: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1- 2), 9-32.

[0058] Deuterated starting materials are readily available and are subjected to the synthetic methodsdescribed herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0059] Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, such asiodomethane-d3 (CD3I), are readily available and may be employed to transfer a deuterium- substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD3I is illustrated, by way of example only, in the reaction schemes below.OH CD3I O D R R D

[0060] Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAlD4), are employed totransfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD4is illustrated, by way of example only, in the reaction schemes below. R LiAlD4 R NHLiAlD D D O ' OH

[0061] Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbonlinkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below. R"R'

[0062] In one embodiment, the compounds disclosed herein contain one deuterium atom. In anotherembodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable1H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.

[0063] "Pharmaceutically acceptable salt" includes both acid and base addition salts. Apharmaceutically acceptable salt of any one of the AKT1 inhibitory compounds describedherein is intended to encompass any and all pharmaceutically suitable salt forms. Preferredpharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0064] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain thebiological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0065] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biologicaleffectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins for example isopropylamine trimethylaminediethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0066] "Pharmaceutically acceptable solvate" refers to a composition of matter that is the solventaddition form. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein exist in either unsolvated or solvated forms.

[0067] The term “subject” or “patient” encompasses mammals. Examples of mammals include, butare not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0068] As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are usedinterchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and / or a prophylactic benefit. By “therapeutic benefit” means eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made. AKT1 Protein and Function

[0069] AKT, also known as protein kinase B (PKB), is a serine / threonine protein kinase with threeisoforms AKT1 AKT2 and AKT3 While the isoforms are encoded by different genes theyare 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).

[0070] 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 (NfκB), which may link AKT signaling to the nucleus of a cell.

[0071] AKT1 is ubiquitously expressed, whereas AKT2 is primarily expressed in insulin-responsivetissues, and AKT3 is primarily expressed in brain and testes. A shared phosphorylation site of AKT in the catalytic domain corresponds to a threonine residue; specifically, Thr308 in AKT1, Thr309 in AKT2, and Thr305 in AKT3. A shared phosphorylation site in the C- terminus of the protein cis a serine residue; specifically, Ser473 in AKT1, Ser474 in AKT2, and Ser472 in AKT3.

[0072] AKT is a key downstream mediator of the phosphoinositide-3-kinase (PI3K) signalingpathway. PI3Ks are activated by different compounds. For example, PI3Kα, PI3Kβ, and PI3Kδ, are activated by extracellular ligands binding to a transmembrane glycoprotein with enzymatic activity, receptor tyrosine kinases (RTKs). In contrast, PI3Kγ is activated by G- protein-compound receptors (GPCRs) and by RAS family of GTPases.

[0073] 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

[0074] 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).

[0075] mTOR is a key component in the AKT signaling pathway, which is a downstream member ofAKT and an important regulator for cell metabolism and growth. mTOR is also an activator which can directly phosphorylate AKT’s regulatory serine residue, Ser473. mTOR forms a complex with rapamycin-insensitive companion of mTOR (RICTOR) (and other proteins) toform mTOR complex 2 (mTORC2), which can directly phosphorylate AKT Ser473. AKT can affect cell survival and growth because it can influence the tuberous sclerosis complex (TSC) 1 / 2 along the mTORC signaling pathway and inhibit pro-apoptotic proteins or signals.

[0076] AKT is known as a survival kinase and mediates cell survival and proliferation by inhibitingpathways including, but not limited to Bcl2 and MDM2, which promotes apoptosis. Studies have shown that the AKT signaling cascade has frequent malfunctions in various cancers, and may be associated with tumor aggressiveness (Nitulescu, G. M. et al., Int J Oncol., 2018; 53(6): 2319-2331). Malfunctions of AKT typically lead to enhanced proliferation, growth, survival, and resistance to apoptosis (Alwhaibi, A. et al., Pharmacol Res., 2019, 145: 104270). Malfunction and mis-regulation of AKT may lead to cancers such as but not limited to breast cancer, gastric carcinoma, glioblastoma, gliosarcomas, head and neck squamous cell carcinoma, ovarian cancer, pancreatic cancer, and prostate cancer.

[0077] Additionally, AKT1 has been found to be involved in invasion and migration of cancerouscells (Alwhaibi, A. et al., Pharmacol Res., 2019, 145: 104270). Researchers found that silencing the AKT1 isoform can abrogate specific types of cancer cell migration. However, there have been other studies which have demonstrated that activated AKT1 resulted in less metastatic propensity for lung metastatic lesion cells and breast cancer cells. AKT1 has also been identified as a key protein involved in angiogenesis, lung cancer, and tumorigenesis.

[0078] Furthermore, overexpression of AKT has been correlated to resistance to chemotherapeuticagents such as cisplatin, methotrexate, and paclitaxel. Thus, there remains a need to find AKT inhibitors given its role in cell survival and cancer proliferation.

[0079] 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.

[0080] The E17K mutation enhances migration of breast cancer cells, and also enhances resistance tochemotherapeutic drugs. However, the E17K mutation can also selectively destroy chemo- resistant tumor-promoting AKT1 quiescent cancer cells, suggesting that the AKT1(E17K) mutation is crucial in the oncogenic / anti-tumor mechanism

[0081] A major pathway that activates PI3K-AKT signaling pathway is somatic cell mutations, withthe E17K mutation being the highest frequency of AKT1 mutations. It is nearly exclusively present in AKT1. The AKT1(E17K) is a recurrent somatic cell mutation predominantly in breast cancer, ovarian cancer, meningioma, and Proteus syndrome.

[0082] AKT1(E17K) mutations mediate the PI3K-AKT signaling cascade by expanding PIP lipidspecificity, which causes conformational changes. This also enhances subcellular localization to accelerate localization of the PH structural domain to the plasma membrane. The E17K mutation increases PIP3 binding specificity by 7-fold and phosphatidylinositol-(4,5)- bisphosphate (PIP2) by 100-fold.

[0083] The AKT1(E17K) mutation also causes rapid conformational changes in the AKT1 PHstructural domain. The conformational changes to this domain result in a 4.5-fold increase in its membrane localization, which can result in excessive phosphorylation. The AKT1(E17K) mutation can also result in enhanced subcellular localization by increasing the transient expression.

[0084] Given the conformational and signaling effects of the AKT1(E17K) mutation, this target maybe useful for targeted treatment of cancers. Prior Art AKT1 Inhibitors

[0085] Most AKT inhibitors targeting the ATP binding site are non-selective against the threeisoforms, as well as having poor to no selectivity against other structurally similar kinases. Thus, there remains a need to develop new and novel AKT inhibitors. These ATP targeting inhibitors are classified as aminofurazans, azepane derivatives, isoquinoline-5-sulfonamides, phenylpyrazole derivatives, thiophene carboxamide derivatives, and thiazole carboxamide derivatives.

[0086] There are also ATP non-competitive AKT inhibitors which are allosteric modulators whichhave greater specificity than the ATP targeting inhibitors. Many of these allosteric modulator inhibitors are classified as purine derivatives, thiourea derivatives, alkylphospholipids, sulfonamides, 2,3-diphenylquinoxaline analogs, and indole-3-carbinol derivatives. Novel AKT1 Inhibitory Compounds

[0087] In one aspect, provided herein is an AKT1 inhibitory compound.

[0088] One embodiment provides a compound having the structure of Formula (I), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof:) wherein,Ring A is an optionally substituted 5-membered heteroaryl; w, x, y, and z are each independently N or C-R1; each R1is independently selected from H, D, halogen, or -CN; R2and R3are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R2and R3together form an oxo; or R2and R3join together to form a carbocycle or heterocycle; L is selected from -N(R4)-, -O-, or a divalent radical selected from:, ,* **; wherein the asterisk (*) indicates the bond to the LCG; each R4is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl; each R25are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R25together form an oxo; or two independently selected R25join together to form a carbocycle or heterocycle; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 1, or 2; n is 0 or 1; LCG is a group selected from the group consisting of:(a Q Q Q3is a bond, O, S, N-R9a; R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R9is absent and Q3and L join together to form a heterocycle; and R9ais selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R9and R9ajoin together to form a heterocycle; (b)T1is N or C-R10; T2is N or C-R10; T3is N or C-R10; T4is N or C-R10; T5is O, S, or N-R11; each R10is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R11is hydrogen, or optionally substituted C1-C6 alkyl;ndT6is N or C-R12; T7is N or C-R12; T8is N or C-R12; each R12is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl; (dwherein each R13, R14, R15, and R16is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .

[0089] One embodiment provides a compound having the structure of Formula (I’), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof:(I’) wherein, Ring A is an optionally substituted 5-membered heteroaryl; w, x, y, and z are each independently N or C-R1; each R1is independently selected from H, D, halogen, or -CN;R2and R3are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R2and R3together form an oxo; or R2and R3join together to form a carbocycle or heterocycle; L is selected from -N(R4)-, -O-, or a divalent radical selected from:wherein the asterisk (*) indicates the bond to the LCG; each R4is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl;each R25are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R25together form an oxo; or two independently selected R25join together to form a carbocycle or heterocycle; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 1, or 2; n is 0 or 1; LCG is a group selected from the group consisting of: (a Q Q; Q3is a bond, O, S, N-R9a; R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R9is absent and Q3and L join together to form a heterocycle; and R9ais selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R9and R9ajoin together to form a heterocycle; (b)T1is N or C-R10; T2is N or C-R10; T3is N or C-R10; T4is N or C-R10; T5is O, S, or N-R11; each R10is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R11is hydrogen, or optionally substituted C1-C6 alkyl; nd; T6is N or C-R12; T7is N or C-R12; T8is N or C-R12; each R12is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionall substituted ar l(d)wherein each R13, R14, R15, and R16is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .

[0090] One embodiment provides a compound having the structure of Formula (I) or (I’), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (Ia)) wherein: a is N, N-R26, or C-R21; b is N, N-R27, or C-R22; c is N, or C; d is N, N-R28, or C-H; e is N, N-R29, or C-R23; provided that only one or two of a, b, c, d, or e are selected from a N-containing group; R21is selected from H, D, halogen, -CN, -OH, -SR4, -N(R4)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl- C(O)O-, -CON(R4)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R22is selected from H, D, halogen, -CN, -OH, -SR4, -N(R4)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl- C(O)O-, -CON(R4)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R23is selected from H, D, halogen, -CN, -OH, -SR4, -N(R4)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl- C(O)O-, -CON(R4)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or optionally R23and R26together with the adjacent atoms to which they are attached, join to form a ring; and R26, R27, R28, and R29 are independently selected from H, optionally substituted C1-C6alkyl optionally substituted carbocyclyl or optionally substituted (carbocyclyl)alkyl

[0091] One embodiment provides a compound having the structure of Formula (Ia), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (Ia-i): ).

[0092] One embodiment provides a compound having the structure of Formula (Ia), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (Ia-ii):).

[0093] One embodiment provides a compound having the structure of Formula (Ia), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (Ia-iii):(Ia-iii).

[0094] One embodiment provides a compound having the structure of Formula (Ia), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (Ia-iv):).

[0095] One embodiment provides a compound having the structure of Formula (Ia), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (Ia-v):).

[0096] One embodiment provides a compound having the structure of Formula (Ia), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (Ia-vi):(Ia-vi).

[0097] One embodiment provides a compound having the structure of Formula (Ia), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (Ia-vii):(Ia-vii).

[0098] One embodiment provides a compound having the structure of Formula (Ia), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (Ia-viii): a-viii).

[0099] One embodiment provides a compound having the structure of Formula (Ia), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (Ia-ix):a-ix).

[0100] One embodiment provides a compound having the structure of Formula (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof:(III) wherein: a is N, or C; b is N, N-R30, or C-R24; R24is selected from H, D, halogen, -CN, -OH, -SR7, -N(R7)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl- C(O)O-, -CON(R7)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;R30is selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, or optionally substituted (carbocyclyl)alkyl; c is N, or C; d is N, NH, O, S, or C-H; e is N, or C; provided that only one or two of a, b, c, d, or e are selected from N or NH; provided that a and e are not N; provided that a and c are not N; provided that e and c are not N; w, x, y, and z are each independently N or C-R1; each R1is independently selected from H, D, halogen, or -CN; R2and R3are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R2and R3together form an oxo; or R2and R3join together to form a carbocycle or heterocycle; u is selected from O, S, C(R5)(R6), or NR7; m is 1, 2, or 3; R5and R6are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R5and R6together form an oxo; or R5and R6join together to form a carbocycle or heterocycle; R7is selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; w1, x1, y1, and z1 are each independently N or C-R8; each R8is selected from H, D, halogen, -CN, -OH, -SR4, -N(R4)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl-C(O)O-, -CON(R4)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; L is selected from -N(R4)-, -O-, or a divalent radical selected from:, ,; wherein the asterisk (*) indicates the bond to the LCG;each R4is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl; each R25are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R25together form an oxo; or two independently selected R25join together to form a carbocycle or heterocycle; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 1, or 2; n is 0 or 1; LCG is a group selected from the group consisting of: (a Q Qs O or S; Q3is a bond, O, S, N-R9a; R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R9is absent and Q3and L join together to form a heterocycle; and R9ais selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R9and R9ajoin together to form a heterocycle; (b)T1is N or C-R10; T2is N or C-R10; T3is N or C-R10; T4is N or C-R10; T5is O, S, or N-R11; each R10is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R11is hydrogen, or optionally substituted C1-C6 alkyl; nd; T6is N or C-R12; T7is N or C-R12; T8is N or C-R12; each R12is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionall substituted ar l(d)wherein each R13, R14, R15, and R16is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .

[0101] One embodiment provides a compound having the structure of Formula (III’), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof:’) wherein: a is N, or C; b is N, N-R30, or C-R24; R24is selected from H, D, halogen, -CN, -OH, -SR7, -N(R7)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl- C(O)O-, -CON(R7)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R30is selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, or optionally substituted (carbocyclyl)alkyl; c is N, or C; d is N, NH, O, S, or C-H; e is N, or C; provided that only one or two of a, b, c, d, or e are selected from N or NH; provided that a and e are not N; provided that a and c are not N; provided that e and c are not N; w, x, y, and z are each independently N or C-R1; each R1is independently selected from H, D, halogen, or -CN; R2and R3are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R2and R3together form an oxo; or R2and R3join together to form a carbocycle or heterocycle; u is selected from O, S, C(R5)(R6), or NR7; i 1 2 3R5and R6are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R5and R6together form an oxo; or R5and R6join together to form a carbocycle or heterocycle; R7is selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; w1, x1, y1, and z1 are each independently N or C-R8; each R8is selected from H, D, halogen, -CN, -OH, -SR4, -N(R4)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl-C(O)O-, -CON(R4)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; L is selected from -N(R4)-, -O-, or a divalent radical selected from:,* **; wherein the asterisk (*) indicates the bond to the LCG; each R4is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl; each R25are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R25together form an oxo; or two independently selected R25join together to form a carbocycle or heterocycle; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 1, or 2; n is 0 or 1; LCG is a group selected from the group consisting of:(a Q Q Q3is a bond, O, S, N-R9a; R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R9is absent and Q3and L join together to form a heterocycle; and R9ais selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R9and R9ajoin together to form a heterocycle; (b)T1is N or C-R10; T2is N or C-R10; T3is N or C-R10; T4is N or C-R10; T5is O, S, or N-R11; each R10is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R11is hydrogen, or optionally substituted C1-C6 alkyl;ndT6is N or C-R12; T7is N or C-R12; T8is N or C-R12; each R12is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl; (dwherein each R13, R14, R15, and R16is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .

[0102] One embodiment provides a compound, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, having the structure of Formula (III’’):(III’’) wherein: a is N, or C; b is N, N-R30, or C-R24;R24is selected from H, D, halogen, -CN, -OH, -SR7, -N(R7)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl- C(O)O-, -CON(R7)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R30is selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, or optionally substituted (carbocyclyl)alkyl; c is N, or C; d is N, NH, O, S, or C-H; e is N, or C; provided that only one or two of a, b, c, d, or e are selected from N or NH; provided that a and e are not N; provided that a and c are not N; provided that e and c are not N; w, x, y, and z are each independently N or C-R1; each R1is independently selected from H, D, halogen, or -CN; R2and R3are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R2and R3together form an oxo; or R2and R3join together to form a carbocycle or heterocycle; u is selected from O, S, C(R5)(R6), or NR7; m is 1 or 2; R5and R6are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R5and R6together form an oxo; or R5and R6join together to form a carbocycle or heterocycle; R7is selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; w1, x1, y1, and z1 are each independently N or C-R8; each R8is selected from H, D, halogen, -CN, -OH, -SR4, -N(R4)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl-C(O)O-, -CON(R4)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; L is selected from -N(R4)- -O- or a divalent radical selected from:, ,wherein the asterisk (*) indicates the bond to the LCG; each R4is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl; each R25are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R25together form an oxo; or two independently selected R25join together to form a carbocycle or heterocycle; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4;g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 1, or 2; n is 0 or 1; LCG is a group selected from the group consisting of: (a Q QQ3is a bond, O, S, N-R9a; R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R9is absent and Q3and L join together to form a heterocycle; and R9ais selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R9and R9ajoin together to form a heterocycle; (b)T1is N or C-R10; T2is N or C-R10; T3is N or C-R10; T4is N or C-R10; T5is O, S, or N-R11;each R10is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R11is hydrogen, or optionally substituted C1-C6 alkyl; ndT6is N or C-R12; T7is N or C-R12; T8is N or C-R12; each R12is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl; (dwherein each R13, R14, R15, and R16is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .

[0103] One embodiment provides a compound having the structure of Formula (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (III-i):).

[0104] One embodiment provides a compound having the structure of Formula (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (III-ii):).

[0105] One embodiment provides a compound having the structure of Formula (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (III-iii):(III-iii).

[0106] One embodiment provides a compound having the structure of Formula (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (III-iv):).

[0107] One embodiment provides a compound having the structure of Formula (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (III-v):).

[0108] One embodiment provides a compound having the structure of Formula (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (III-vi):(III-vi).

[0109] One embodiment provides a compound having the structure of Formula (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (III-vii):).

[0110] One embodiment provides a compound having the structure of Formula (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (III-viii):).

[0111] One embodiment provides a compound having the structure of Formula (III), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (III-ix):(III-ix).

[0112] One embodiment provides a compound having the structure of Formula (IV), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof:)wherein: a is N, N-R30, or C-R24; b is N, N-R30, or C-R24; each R24is independently selected from H, D, halogen, -CN, -OH, -SR7, -N(R7)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl-C(O)O-, -CON(R7)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each R30is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, or optionally substituted (carbocyclyl)alkyl; c is N, or C; d is N, or C; e is N, or C; provided that only one or two of a, b, c, d, or e are selected from N and N-R30; w, x, y, and z are each independently N or C-R1; each R1is independently selected from H, D, halogen, or -CN; R2and R3are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R2and R3together form an oxo; or R2and R3join together to form a carbocycle or heterocycle; u is selected from O, S, C(R5)(R6), or NR7; m is 1 or 2; R5and R6are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R5and R6together form an oxo; or R5and R6join together to form a carbocycle or heterocycle; R7is selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; 1 1 1 d 1 h i d d tl N C R8each R8is selected from H, D, halogen, -CN, -OH, -SR4, -N(R4)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl-C(O)O-, -CON(R4)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; L is selected from -N(R4)-, -O-, or a divalent radical selected from:, , ,;wherein the asterisk (*) indicates the bond to the LCG; each R4is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl; each R25are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R25together form an oxo; or two independently selected R25join together to form a carbocycle or heterocycle; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 1, or 2; n is 0 or 1; LCG is a group selected from the group consisting of: (a QQ2is O or S; Q3is a bond, O, S, N-R9a;R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R9is absent and Q3and L join together to form a heterocycle; and R9ais selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R9and R9ajoin together to form a heterocycle; (b)T1is N or C-R10; T2is N or C-R10; T3is N or C-R10; T4is N or C-R10; T5is O, S, or N-R11; each R10is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R11is hydrogen, or optionally substituted C1-C6 alkyl; nd; T6is N or C-R12; T7is N or C-R12; T8is N or C-R12;each R12is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl; (dwherein each R13, R14, R15, and R16is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .

[0113] One embodiment provides the compound, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, having the structure of Formula (IV’):’) wherein: a is N, N-R30, or C-R24; b is N, N-R30, or C-R24; each R24is independently selected from H, D, halogen, -CN, -OH, -SR7, -N(R7)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl-C(O)O-, -CON(R7)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each R30is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, or optionally substituted (carbocyclyl)alkyl; c is N, or C; d is N, or C; e is N, or C; provided that only one or two of a, b, c, d, or e are selected from N and N-R30; 1each R1is independently selected from H, D, halogen, or -CN; R2and R3are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R2and R3together form an oxo; or R2and R3join together to form a carbocycle or heterocycle; u is selected from O, S, C(R5)(R6), or NR7; m is 1 or 2; R5and R6are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R5and R6together form an oxo; or R5and R6join together to form a carbocycle or heterocycle; R7is selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; w1, x1, y1, and z1 are each independently N or C-R8; each R8is selected from H, D, halogen, -CN, -OH, -SR4, -N(R4)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl-C(O)O-, -CON(R4)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; L is selected from -N(R4)-, -O-, or a divalent radical selected from:* ,wherein the asterisk (*) indicates the bond to the LCG; each R4is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl; each R25are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R25together form an oxo; or two independently selected R25join together to form a carbocycle or heterocycle; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 1, or 2; n is 0 or 1; LCG is a roup selected from the group consisting of: (a Q2Q3is a bond, O, S, N-R9a; R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R9is absent and Q3and L join together to form a heterocycle; and R9ais selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R9and R9ajoin together to form a heterocycle; (b)T1is N or C-R10; T2is N or C-R10; T3is N or C-R10; T4is N or C-R10; T5is O, S, or N-R11; each R10is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R11is hydrogen, or optionally substituted C1-C6 alkyl; nd; T6is N or C-R12; T7is N or C-R12;each R12is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl; (dwherein each R13, R14, R15, and R16is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .

[0114] One embodiment provides a compound having the structure of Formula (IV), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (IV-i):).

[0115] One embodiment provides a compound having the structure of Formula (IV), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (IV-ii):(IV-ii).

[0116] One embodiment provides a compound having the structure of Formula (IV), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure ofV-iii).

[0117] One embodiment provides a compound having the structure of Formula (IV), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (IV-iv):V-iv).

[0118] One embodiment provides a compound having the structure of Formula (IV), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (IV-v):(IV-v).

[0119] One embodiment provides a compound having the structure of Formula (IV), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (IV-vi):V-vi).

[0120] One embodiment providesa compound having the structure of Formula (IV), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (IV-vii):V-vii).

[0121] One embodiment provides a compound having the structure of Formula (IV), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (IV-viii):(IV-viii).

[0122] One embodiment provides a compound having the structure of Formula (IV), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (IV-ix):V-ix).

[0123] One embodiment providesa compound having the structure of Formula (IV), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (IV-x):).

[0124] One embodiment provides a compound having the structure of Formula (IV), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (IV-xi):(IV-xi).

[0125] One embodiment provides a compound having the structure of Formula (IV), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (IV-xii):V-xii).

[0126] One embodiment provides a compound having the structure of Formula (IV), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (IV-xiii):V-xiii).

[0127] One embodiment provides a compound having the structure of Formula (V), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof:(V) wherein: a is N, or C; b is N, N-R30, or C-R24; R24is selected from H, D, halogen, -CN, -OH, -SR7, -N(R7)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl- C(O)O-, -CON(R7)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;R30is selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, or optionally substituted (carbocyclyl)alkyl; c is N, or C; d is N, NH, O, S, or C-H; e is N, or C; provided that only one or two of a, b, c, d, or e are selected from N or NH; provided that a and e are not N; provided that a and c are not N; provided that e and c are not N; w, x, y, and z are each independently N or C-R1; each R1is independently selected from H, D, halogen, or -CN; R2and R3are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R2and R3together form an oxo; or R2and R3join together to form a carbocycle or heterocycle; R5and R6are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R5and R6together form an oxo; or R5and R6join together to form a carbocycle or heterocycle; R7is selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; w1, x1, y1, and z1 are each independently N or C-R8; each R8is selected from H, D, halogen, -CN, -OH, -SR4, -N(R4)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl-C(O)O-, -CON(R4)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; L is selected from -N(R4)-, -O-, or a divalent radical selected from:; wherein the asterisk (*) indicates the bond to the LCG; each R4is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl; each R25are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R25together form an oxo; or two independently selected R25join together to form a carbocycle or heterocycle; a1 is 0, 1, 2, 3, or 4; b1 is 0 1 2 3 or 4;c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 1, or 2; n is 0 or 1; LCG is a group selected from the group consisting of: (a) Q1is O or S; Q2is O or S; Q3is a bond, O, S, N-R9a; R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R9is absent and Q3and L join together to form a heterocycle; and R9ais selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R9and R9ajoin together to form a heterocycle; (b)T1is N or C-R10; 210T3is N or C-R10; T4is N or C-R10; T5is O, S, or N-R11; each R10is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R11is hydrogen, or optionally substituted C1-C6 alkyl; ndT6is N or C-R12; T7is N or C-R12; T8is N or C-R12; each R12is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl; (d) wherein each R13, R14, R15, and R16is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .

[0128] One embodiment provides a compound having the structure of Formula (VI), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof:I)wherein: w, x, y, and z are each independently N or C-R1; each R1is independently selected from H, D, halogen, or -CN; R2and R3are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R2and R3together form an oxo; or R2and R3join together to form a carbocycle or heterocycle; u is selected from O, S, C(R5)(R6), or NR7; m is 1 or 2; R5and R6are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R5and R6together form an oxo; or R5and R6join together to form a carbocycle or heterocycle; R7is selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; w1, x1, y1, and z1 are each independently N or C-R8; each R8is selected from H, D, halogen, -CN, -OH, -SR4, -N(R4)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl-C(O)O-, -CON(R4)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R24is independently selected from H, D, halogen, -CN, -OH, -SR7, -N(R7)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl-C(O)O-, -CON(R7)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; L is selected from -N(R4)- -O- or a divalent radical selected from:, ,wherein the asterisk (*) indicates the bond to the LCG; each R4is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl; each R25are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R25together form an oxo; or two independently selected R25join together to form a carbocycle or heterocycle; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4;g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 1, or 2; n is 0 or 1; LCG is a group selected from the group consisting of: (a Q QQ3is a bond, O, S, N-R9a; R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R9is absent and Q3and L join together to form a heterocycle; and R9ais selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R9and R9ajoin together to form a heterocycle; (b)T1is N or C-R10; T2is N or C-R10; T3is N or C-R10; T4is N or C-R10; T5is O, S, or N-R11;each R10is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R11is hydrogen, or optionally substituted C1-C6 alkyl; ndT6is N or C-R12; T7is N or C-R12; T8is N or C-R12; each R12is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl; (dwherein each R13, R14, R15, and R16is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .

[0129] One embodiment provides an AKT1 inhibitory compound, or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, having a structure presented in Table 1. T bl 1 - -carbonitrileSynthetic - -N carbonitrileSynthetic - -SyntheticSynthetic - l-carbonitrileSynthetic - -carbonitrileSynthetic - - -Synthetic e - -carbonitrileSynthetic - - - - 4 - ecarbonitrileSynthetic - - - - - - - -Synthetic - - - - -Synthetic - - - - -carbonitrileSynthetic - - - -2-en-1-oneSynthetic - - - --en--oneSynthetic - - - - -Synthetic - - - -carbonitrile

[0130] Another embodiment provides an AKT1 inhibitory compound, or a pharmaceuticallyacceptable salt, solvate, or deuteroisotope thereof, having a structure presented in Table 2. Table 2N

[0131] Another embodiment provides a compound having the structure of Formula (II), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, as described in Formulae (IIa)-(IIi).

[0132] Another embodiment provides a compound having the structure of Formula (IIa), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof: w :.

[0133] Another embodiment provides a compound having the structure of Formula (IIb), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof: w :.

[0134] Another embodiment provides a compound having the structure of Formula (IIc), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof: )wherein G is a pyridyl group selected from:.

[0135] Another embodiment provides a compound having the structure of Formula (IId), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof:) wherein G is a monofluorophenyl group selected from:.

[0136] Another embodiment provides a compound having the structure of Formula (IIe), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof:(IIe) wherein R is selected from H, D, halogen, -CN, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0137] Another embodiment provides a compound having the structure of Formula (IIf), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof:f) wherein each R is independently selected from H, D, halogen, -OH, -CN, optionally substituted C1-C6 alkyl; or the two R groups together form an oxo; or the two R groups join to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl.

[0138] Another embodiment provides a compound having the structure of Formula (IIg), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof:) wherein R is selected from H, D, halogen, -CN, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0139] Another embodiment provides a compound having the structure of Formula (IIh), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof:(IIh) wherein R is selected from H, D, halogen, -CN, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0140] Another embodiment provides a compound having the structure of Formula (IIi), or apharmaceutically acceptable salt solvate or deuteroisoto e thereof:(IIi)wherein R is selected from H, D, halogen, -CN, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl. Preparation of Compounds

[0141] The compounds used in the synthetic chemistry reactions described herein are madeaccording 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).

[0142] Suitable reference books and treatise that detail the synthesis of reactants useful in thepreparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif.1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3527-29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999)Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[0143] Specific and analogous reactants are optionally identified through the indices of knownchemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (contact the American Chemical Society, Washington, D.C. for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference useful for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H.Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002. Pharmaceutical Compositions

[0144] In certain embodiments, the AKT1 inhibitory compound described herein is administered as apure chemical. In other embodiments, the AKT1 inhibitory compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0145] Provided herein is a pharmaceutical composition comprising at least one AKT1 inhibitorycompound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the otheringredients of the composition and not deleterious to the recipient (i.e., the subject or the patient) of the composition.

[0146] One embodiment provides a pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof.

[0147] One embodiment provides a method of preparing a pharmaceutical composition comprisingmixing a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable carrier.

[0148] In certain embodiments, the AKT1 inhibitory compound as described by Formula (I), (II),(III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0149] One embodiment provides a pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof.

[0150] One embodiment provides a method of preparing a pharmaceutical composition comprisingmixing a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable carrier.

[0151] In certain embodiments, the AKT1 inhibitory compound as described by Table 1, or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0152] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard orsoft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0153] In some embodiments, the AKT1 inhibitory compound as described by Formula (I), (II), (III),(IV), (V), or (VI) or Table 1, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, is formulated for administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a non- aqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like.

[0154] The dose of the composition comprising at least one AKT1 inhibitory compound as describedherein differs depending upon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors.

[0155] Pharmaceutical compositions are administered in a manner appropriate to the disease to betreated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity. Optimal doses 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.

[0156] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more,per day. Methods of Treatment

[0157] One embodiment provides a compound of Formula (I), (II), (III), (IV), (V), or (VI), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treatment of the human or animal body.

[0158] One embodiment provides a compound of Formula (I), (II), (III), (IV), (V), or (VI), or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treatment of cancer or neoplastic disease.

[0159] One embodiment provides a pharmaceutical composition comprising a compound of Formula(I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or neoplastic disease.

[0160] One embodiment provides a use of a compound of Formula (I), (II), (III), (IV), (V), or (VI),or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

[0161] In some embodiments is provided a method of treating cancer, in a patient in need thereof,comprising administering to the patient a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient.

[0162] One embodiment provides the method wherein the cancer is breast cancer. Anotherembodiment provides the method wherein the cancer is a hormone receptor positive (HR+) breast cancer. Another embodiment provides the method wherein the cancer is a human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Another embodiment provides the method wherein the cancer is a HR+ / HER2- breast cancer. Another embodiment provides the method wherein the cancer is a HR+ / HER2-low breast cancer. Another embodiment provides the method wherein the cancer is a HR+ / HER2+ breast cancer.

[0163] Another embodiment provides the method wherein the cancer is a triple negative breastcancer (TNBC). Another embodiment provides the method wherein the cancer is an invasive breast cancer. Another embodiment provides the method wherein the patient has shown progression on at least one CDK4 / 6 inhibitor. Another embodiment provides the method wherein the patient has shown progression on at least one endocrine-based regimen.

[0164] One embodiment provides the method wherein the cancer is uterine cancer. Anotherembodiment provides the method wherein the cancer is uterine sarcoma. Another embodiment provides the method wherein the cancer is endometrial cancer. Another embodiment provides the method wherein the cancer is Type I endometrial cancer.

[0165] One embodiment provides the method wherein the cancer is Type II endometrial cancer.

[0166] Another embodiment provides the method wherein the cancer is Type II endometrialpapillary serous carcinoma. Another embodiment provides the method wherein the cancer is Type II endometrial clear cell carcinoma. Another embodiment provides the method wherein the cancer is Type II endometrial undifferentiated carcinoma. Another embodiment provides the method wherein the cancer is Type II endometrioid carcinoma. Another embodiment provides the method wherein the cancer is microsatellite instability (MSI) high and / or DNA mismatch repair (MMR) deficient Another embodiment provides the method wherein thecancer is tumor mutational burden (TMB) high. Another embodiment provides the method wherein the cancer is HER2-.

[0167] One embodiment provides the method wherein the cancer is cervical cancer. Anotherembodiment provides the method wherein the cancer is a cervical squamous cell carcinoma.

[0168] Another embodiment provides the method wherein the cancer is a cervical adenocarcinoma.

[0169] One embodiment provides the method wherein the cancer is prostate cancer. Anotherembodiment provides the method wherein the cancer is prostate adenocarcinoma.

[0170] Another embodiment provides the method wherein the cancer is prostate neuroendocrinecancer. Another embodiment provides the method wherein the cancer is prostate small cell neuroendocrine cancer. Another embodiment provides the method wherein the cancer is prostate large cell carcinoma. Another embodiment provides the method wherein the cancer is prostate transitional cell carcinoma. Another embodiment provides the method wherein the cancer is prostate sarcoma.

[0171] One embodiment provides the method wherein the cancer is bladder cancer. Anotherembodiment provides the method wherein the cancer is urothelial cancer. Another embodiment provides the method wherein the cancer is squamous cell cancer of the bladder. Another embodiment provides the method wherein the cancer is small cell cancer of the bladder. Another embodiment provides the method wherein the cancer is adenocarcinoma of the bladder.

[0172] One embodiment provides the method wherein the cancer is lung cancer.

[0173] One embodiment provides the method wherein the cancer is non-small cell lung cancer.

[0174] One embodiment provides the method wherein the cancer is non-squamous non-small celllung cancer.

[0175] One embodiment provides the method wherein the cancer is squamous non-small cell lungcancer.

[0176] One embodiment provides the method wherein the cancer is colon cancer.

[0177] One embodiment provides the method wherein the cancer is anal cancer.

[0178] One embodiment provides the method wherein the cancer is a meningioma.

[0179] One embodiment provides the method wherein the cancer is a glioma.

[0180] One embodiment provides the method wherein the cancer is pancreatic cancer. Anotherembodiment provides the method wherein the cancer is exocrine pancreatic cancer. Another embodiment provides the method wherein the cancer is neuroendocrine pancreatic cancer.

[0181] One embodiment provides the method wherein the cancer is thyroid cancer.

[0182] One embodiment provides the method wherein the cancer is myxofibrosarcoma.

[0183] One embodiment provides the method wherein the cancer is parotid gland cancer.

[0184] One embodiment provides the method wherein the cancer is esophageal cancer.

[0185] One embodiment provides the method wherein the cancer is stomach cancer.

[0186] One embodiment provides the method wherein the cancer is skin cancer. Anotherembodiment provides the method wherein the cancer is nonmelanoma skin cancer. Another embodiment provides the method wherein the cancer is squamous nonmelanoma skin cancer. Another embodiment provides the method wherein the cancer is non-squamous nonmelanoma skin cancer.

[0187] One embodiment provides the method wherein the cancer is ovarian cancer. Anotherembodiment provides the method wherein the cancer is epithelial ovarian cancer. Another embodiment provides the method wherein the cancer is serous epithelial ovarian cancer. Another embodiment provides the method wherein the cancer is endometrioid ovarian cancer. Another embodiment provides the method wherein the cancer is clear cell ovarian cancer. Another embodiment provides the method wherein the cancer is mucinous ovarian cancer.

[0188] One embodiment provides the method wherein the cancer is adenoid cystic carcinoma.

[0189] One embodiment provides the method wherein the cancer is renal cell cancer.

[0190] One embodiment provides the method wherein the cancer is appendix cancer.

[0191] One embodiment provides the method wherein the cancer is multiple myeloma.

[0192] One embodiment provides the method wherein the cancer is acute myeloid leukemia.

[0193] One embodiment provides the method wherein the cancer is cancer of unknown primary.

[0194] One embodiment provides the method wherein the cancer is locally advanced.

[0195] One embodiment provides the method wherein the cancer is metastatic.

[0196] One embodiment provides the method wherein the method is adjuvant therapy followingsurgical resection.

[0197] One embodiment provides the method wherein the method is neo-adjuvant therapy.

[0198] One embodiment provides the method wherein the method is first-line systemic therapy forlocally advanced or metastatic disease.

[0199] One embodiment provides the method wherein the patient has relapsed after prior therapy.

[0200] One embodiment provides the method wherein the patient has acquired resistance to priortherapy.

[0201] One embodiment provides the method wherein the patient is refractory to therapy.

[0202] One embodiment provides the method wherein the patient has shown progression oncytotoxic chemotherapy.

[0203] One embodiment provides the method wherein the cancer is characterized by existence ofAKT1-E17K mutation.

[0204] One embodiment provides the method wherein the cancer exhibits one or more co-occurringalterations selected from a PIK3CA alteration, a PIK3R1 alteration, an AKT1 alteration, and PTEN alteration.

[0205] One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, for use in a method of treatment of the human or animal body.

[0206] One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, for use in a method of treatment of cancer or neoplastic disease.

[0207] One embodiment provides a pharmaceutical composition comprising a compound of Table 1,or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or neoplastic disease.

[0208] One embodiment provides a use of a compound of Table 1, or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

[0209] In some embodiments is provided a method of treating cancer, in a patient in need thereof,comprising administering to the patient a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient.

[0210] 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.

[0211] One embodiment provides a method of inhibiting an AKT1 enzyme comprising contactingthe AKT1 enzyme with a compound of Formula (I), (II), (III), (IV), (V), or (VI), or Table 1. Another embodiment provides the method of inhibiting an AKT1 enzyme, wherein the AKT1 enzyme is contacted in an in vivo setting. Another embodiment provides the method of inhibiting an AKT1 enzyme, wherein the AKT1 enzyme is contacted in an in vitro setting.

[0212] Other embodiments and uses will be apparent to one skilled in the art in light of the presentdisclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way. EXAMPLES I. Chemical Synthesis

[0213] In some embodiments, the AKT1 inhibitory compounds disclosed herein are synthesizedaccording to the following examples. As used below, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: ACN acetonitrile oC degrees Celsius δHchemical shift in parts per million downfield from tetramethylsilane DCM dichloromethane (CH2Cl2) DIAD diisopropyl azodicarboxylate DIEA diisopropylethylamine DMF dimethylformamide DMSO dimethylsulfoxide EA ethyl acetate EtOAc ethyl acetate ESI electrospray ionization Et ethyl g gram(s) h hour(s) HPLC high performance liquid chromatography Hz hertz Jcoupling constant (in NMR spectrometry)LCMS liquid chromatography mass spectrometry μmicrom multiplet (spectral); meter(s); milli M molar M+parent molecular ion Me methyl MsCl methanesulfonyl chloridemin minute(s) mol mole(s); molecular (as in mol wt) mL milliliter MS mass spectrometry nm nanometer(s) NMR nuclear magnetic resonance pH potential of hydrogen; a measure of the acidity or basicity of an aqueous solution PE petroleum ether RT room temperature s singlet (spectral) t triplet (spectral) SFC Supercritical fluid chromatography T temperature TFA trifluoroacetic acid THF tetrahydrofuran TPP triphenylphosphineExperimental Procedures

[0214] Intermediate 1: 3-Bromo-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazineStep 1: 4-Hydroxynicotinaldehyde A solution of 4-chloronicotinaldehyde (50 g, 353 mmol) in HCl (3 M, 500 mL) was degassed and purged with N2 three times. H2O2 (2.19 g, 19.3 mmol, 30%) was added dropwise to the above solution in an ice bath. The result mixture was stirred at 100 °C for 6 h under N2. The reaction was quenched with NaHCO3until the reaction became cloudy and many solids precipitated. The mixture was filtered, and the filtered cake was washed with H2O (200 mL x 2) and dried under reduced pressure. The title compound (35 g, yield: 80%) was obtained asa yellow solid.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 12.32 - 11.59 (m, 1H), 10.09 (s, 1H), 8.15 (d, J = 1.6 Hz, 1H), 7.71 (dd, J = 7.2, 1.6 Hz, 1H), 6.36 (d, J = 7.2 Hz, 1H). Step 2: 3-(1H-Imidazol-2-yl)pyridin-4-ol To a solution of 4-hydroxynicotinaldehyde (20 g, 162 mmol) in MeOH (200 mL) were added oxalaldehyde (57.7 g, 398 mmol, 40%) and NH3·H2O (80.1 g, 640 mmol, 28%). The mixture was stirred at 25 °C for 2 h. The reaction was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0 ~ 5% MeOH in CH2Cl2), the title compound (23 g, yield: 90%) was obtained as a yellow solid. MS: m / z = 162.0 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 12.17 - 9.18 (m, 2H), 8.55 (d, J = 1.6 Hz, 1H), 7.79 (dd, J = 7.2, 1.6 Hz, 1H), 7.10 - 7.02 (m, 2H), 6.44 (d, J = 6.8 Hz, 1H). Step 3: 5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazine To a solution of 3-(1H-imidazol-2-yl)pyridin-4-ol (15.0 g, 93.1 mmol, 1 eq) in DMF (200 mL) were added CH2I2(49.9 g, 186 mmol) and NaOH (7.34 g, 186 mmol). The mixture was stirred at 25 °C for 2 h. The reaction was concentrated under reduced pressure. After purification by prep-HPLC (column: Phenomenex luna C18 (250 x 70 mm, 10 µm); mobile phase: [water (NH4HCO3) - ACN]; gradient:1% - 31% B over 22 min), the title compound (3.22 g, yield: 9.8%) was obtained as a light-yellow solid. MS: m / z = 174.0 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.89 (s, 1H), 8.45 (d, J = 6.0 Hz, 1H), 7.34 (d, J = 1.2 Hz, 1H), 7.20 - 7.15 (m, 2H), 6.11 (s, 2H). Step 4: 3-Bromo-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazine To a solution of 5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazine (1.5 g, 8.66 mmol) in CH2Cl2 (75 mL) and EtOH (37.5 mL) was added NBS (1.54 g, 8.66 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with H2O (50 mL) at 25 °C and extracted with CH2Cl2 (50 mL x 2). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0 ~ 2% MeOH in CH2Cl2), the title compound (Intermediate 1, 870 mg, yield: 36%) was obtained as a yellow solid. MS: m / z = 251.7, 253.7 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.89 (s, 1H), 8.48(d, J = 5.6 Hz, 1H), 7.28 (s, 1H), 7.21 (d, J = 5.6 Hz, 1H), 6.08 (s, 2H).

[0215] Int rm di t 2 4 (Pi ridin 4 l min ) rimidin 2 rb nitrileStep 1: tert-Butyl 4-((2-cyanopyrimidin-4-yl)amino)piperidine-1-carboxylateTo a solution of tert-butyl 4-aminopiperidine-1-carboxylate (600 mg, 3.0 mmol) and 2- chloropyrimidine-4-carbonitrile (418 mg, 3.0 mmol) in DMF (5 mL) were added K2CO3(1.24 g, 8.99 mmol) and NaI (89.8 mg, 599 μmol). The mixture was stirred at 80 °C for 1h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0 ~ 50% EtOAc in petroleum ether) to give the title compound (860 mg, yield: 92%) as a white solid.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 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-carbonitrile To a solution of tert-butyl 4-[(2-cyanopyrimidin-4-yl)amino]piperidine-1-carboxylate (110 mg, 362 μmol) in DCM (3 mL) was added TFA (767 mg, 6.73 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The crude title compound (Intermediate 2, 120 mg, yield: 100%, TFA salt) was used in the next step without further purification. MS: m / z = 204.0 [M + H]+.

[0216] Intermediate 3: 4-((1-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileStep 1: 1-Bromo-4-(chloromethyl)benzene To a solution of (4-bromophenyl)methanol (5 g, 26.7 mmol) in CH2Cl2(50 mL) was added SOCl2(9.54 g, 80.2 mmol). The mixture was stirred at 25 °C for 1 h. The reaction was concentrated under reduced pressure to give the title compound (6.47 g, HCl salt) as a light- yellow oil.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 7.58 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 4.74 (s, 2H). Step 2: 4-((1-(4-Bromobenzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile To a solution of 1-bromo-4-(chloromethyl)benzene (6.47 g, 26.7 mmol, HCl salt) and Intermediate 2 (8.48 g, 26.7 mmol, TFA salt) in DMF (70 mL) were added K2CO3 (18.5 g, 134 mmol) and NaI (802 mg, 5.35 mmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with H2O (200 mL) at 25 °C and extracted with EtOAc (250 mL x 2). The combined organic layers were washed with brine (500 mL x 3), dried over anhydrous Na2SO4filtered and concentrated under reduced pressure After purification bysilica gel flash chromatography (Eluent of 0 ~ 5% MeOH in CH2Cl2), the title compound (7.5 g, yield: 74% for two steps) was obtained as an off-white solid. MS: m / z = 371.6, 373.6 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.07 (d, J = 6.0 Hz, 1H), 8.01 (d, J = 7.2 Hz, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 6.66 (d, J = 6.0 Hz, 1H), 3.86 - 3.70 (m, 1H), 3.44 (s, 2H), 2.81 - 2.69 (m, 2H), 2.17 - 2.04 (m, 2H), 1.90 - 1.76 (m, 2H), 1.53 - 1.39 (m, 2H). Step 3: 4-((1-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile A mixture of 4-((1-(4-bromobenzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile (6.7 g, 18.0 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (9.14 g, 36.0 mmol), KOAc (5.30 g, 54.0 mmol), and Pd(dppf)Cl2 (1.32 g, 1.80 mmol) in 1,4-dioxane (70 mL) was degassed, purged with N2three times, and stirred at 90 °C for 2 h under N2. The reaction mixture was quenched with H2O (100 mL) at 25 °C and extracted with CH2Cl2(150 mL x 2). The combined organic layers were washed with brine (300 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0 ~ 5% MeOH in CH2Cl2), the title compound (Intermediate 3, 7.55 g, yield: 90%) was obtained as a black solid. MS: m / z = 420.2 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.08 (d, J = 6.0 Hz, 2H), 7.65 (d, J = 7.2 Hz, 2H), 7.41 -7.28 (m, 2H), 6.67 (d, J = 5.6 Hz, 1H), 3.87 - 3.72 (m, 1H), 3.65 - 3.42 (m, 2H), 2.93 - 2.65 (m, 2H), 2.32 - 1.98 (m, 2H), 1.93 - 1.79 (m, 2H), 1.57 - 1.38 (m, 2H), 1.28 (s, 12H).

[0217] Intermediate 4: 2-Bromo-3-(pyridin-3-yl)-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazineStep 1: 3-(Pyridin-3-yl)-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazine To a solution of Intermediate 1 (300 mg, 1.19 mmol) in 1,4-dioxane (3 mL) and H2O (0.6 mL) were added Pd(dppf)Cl2(87.1 mg, 119 μmol), Cs2CO3(1.16 g, 3.57 mmol) and 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (268 mg, 1.31 mmol). The mixture was degassed, purged with N2 three times, and stirred at 90 °C for 2 h under N2. The reaction mixture was diluted with EtOAc (50 mL), filtered through Celite, dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 6% MeOH in CH2Cl2), the title compound (268 mg, yield: 83%) was obtained as a gray solid MS: m / z = 2510 [M+H]+ 1H NMR (400 MHzDimethylsulfoxide-d6) δ 8.96 (s, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.61 (dd, J = 4.8, 1.6 Hz, 1H), 8.50 (d, J = 5.6 Hz, 1H), 7.93 (td, J = 8.0, 2.0 Hz, 1H), 7.55 - 7.51 (m, 2H), 7.23 (d, J = 5.2 Hz, 1H), 6.26 (s, 2H). Step 2: 2-Bromo-3-(pyridin-3-yl)-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazine To a solution of 3-(pyridin-3-yl)-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazine (248 mg, 99 μmol) in CH2Cl2(10 mL) and EtOH (1 mL) was added NBS (529 mg, 2.97 mmol). The mixture was degassed, purged with N2 three times, and stirred at 25 °C for 1 h under N2. The reaction mixture was diluted with CH2Cl2 (100 mL), washed with brine (120 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (Intermediate 4, 240 mg, yield: 74%) as a yellow solid. MS: m / z = 328.9, 330.9 [M+H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.02 (s, 1H), 8.76 - 8.67 (m, 2H), 8.57 (d, J = 5.6 Hz, 1H), 8.04 - 7.94 (m, 1H), 7.62 (dd, J = 7.6, 4.8 Hz, 1H), 7.33 (d, J = 5.6 Hz, 1H), 6.15 (s, 2H).

[0218] Intermediate 5: 2-Bromo-3-(pyrazin-2-yl)-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazineStep 1: 3-(Pyrazin-2-yl)-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazine A mixture of Intermediate 1 (80 mg, 317 μmol), pyrazin-2-ylboronic acid (78.7 mg, 635 μmol), Cs2CO3(310 mg, 952 μmol), and Pd(PPh3)4(36.7 mg, 31.7 μmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was degassed, purged with N2 three times, and stirred at 90 °C for 16 h under N2. The reaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with CH2Cl2(25 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 6% MeOH in CH2Cl2), the title compound (30 mg, yield: 35%) was obtained as a yellow solid. MS: m / z = 252.0 [M + H]+. 1H NMR (400 MHz, Chloroform-d) δ 9.19 (s, 1H), 8.99 (s, 1H), 8.56 - 8.49 (m, 2H), 8.45 (d, J = 2.4 Hz, 1H), 7.84 (s, 1H), 7.09 (d, J = 5.6 Hz, 1H), 6.56 (s, 2H). Step 2: 2-Bromo-3-(pyrazin-2-yl)-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazine To a solution of 3-(pyrazin-2-yl)-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazine (30 mg, 119 μmol) in DMF (1 mL) was added NBS (42.5 mg, 239 μmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with H2O (25 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. The title compound (Intermediate 5, 50 mg, crude) was obtained as a yellow solid. MS: m / z = 329.9, 331.9 [M + H]+. 1H NMR (400 MHz, Chloroform-d) δ 9.51 (d, J = 1.2 Hz, 1H), 9.17 (s, 1H),8.63 - 8.59 (m, 1H), 8.59 - 8.55 (m, 2H), 7.22 (d, J = 6.0 Hz, 1H), 6.46 (s, 2H).

[0219] Intermediate 6: 3-(2-Bromo-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-3-yl)pyridin-2-amineStep 1: 3-(5H-Imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-3-yl)pyridin-2-amine A mixture of Intermediate 1 (400 mg, 1.59 mmol), (2-aminopyridin-3-yl)boronic acid (263 mg, 1.90 mmol), Cs2CO3 (1.55 g, 4.76 mmol), and Pd(dppf)Cl2 (116 mg, 159 μmol) in 1,4- dioxane (5 mL) and H2O (1 mL) was degassed, purged with N2three times, and stirred at 100 °C for 16 h under N2. The reaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with CH2Cl2 (25 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 8% MeOH in CH2Cl2), the title compound (150 mg, yield: 33%) was obtained as a yellow solid. MS: m / z = 266.1 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.94 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 8.04 (dd, J = 4.8, 1.6 Hz, 1H), 7.39 (dd, J = 7.2, 1.2 Hz, 1H), 7.24 (s, 1H), 7.19 (d, J = 5.6 Hz, 1H), 6.66 (dd, J = 7.6, 5.2 Hz, 1H), 5.93 (br s, 2H), 5.89 (s, 2H). Step 2: tert-Butyl N-tert-butoxycarbonyl-N-[3-(8-oxa-3,6,12-triazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,10,12-pentaen-5-yl)-2-pyridyl]carbamate To a solution of 3-(5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-3-yl)pyridin-2-amine (150 mg, 565 μmol) in CH2Cl2 (3 mL) were added Boc2O (309 mg, 1.41 mmol), DMAP (6.91 mg, 56.6 μmol), and TEA (172 mg, 1.70 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with H2O (25 mL) at 25 °C and extracted with CH2Cl2(25 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The title compoundChloroform-d) δ 9.16 (s, 1H), 8.63 (dd, J = 4.8, 1.6 Hz, 1H), 8.50 (d, J = 5.6 Hz, 1H), 8.16 (d, J = 6.4 Hz, 1H), 7.72 (dd, J = 7.6, 1.6 Hz, 1H), 7.41 (dd, J = 7.6, 4.8 Hz, 1H), 6.99 (d, J = 5.6 Hz, 1H), 5.73 (s, 2H), 1.38 (s, 18H). Step 3: tert-Butyl N-[3-(4-bromo-8-oxa-3,6,12-triazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,10,12-pentaen-5-yl)-2-pyridyl]-N-tert-butoxycarbonyl-carbamate To a solution of tert-butyl N-tert-butoxycarbonyl-N-[3-(8-oxa-3,6,12- triazatricyclo[7.4.0.02,6]trideca-1(9),2,4,10,12-pentaen-5-yl)-2-pyridyl]carbamate (263 mg, 565 μmol) in DMF (3 mL) was added NBS (302 mg, 1.69 mmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with H2O (20 mL) and extracted with CH2Cl2 (25 mL x 2). The combined organic layers were washed with brine (25 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The title compound (307 mg) was obtained as a yellow solid. MS: m / z = 543.8, 545.8 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 9.15 (s, 1H), 8.67 (dd, J = 4.8, 2.0 Hz, 1H), 8.54 (d, J = 5.6 Hz, 1H), 7.84 (dd, J = 7.6, 1.6 Hz, 1H), 7.43 (dd, J = 7.6, 4.8 Hz, 1H), 7.09 (d, J = 5.6 Hz, 1H), 5.88 (d, J = 8.8 Hz, 1H), 5.67 (d, J = 8.8 Hz, 1H), 1.39 (s, 18H). Step 4: 3-(2-Bromo-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-3-yl)pyridin-2-amine To a solution of tert-butyl N-[3-(4-bromo-8-oxa-3,6,12-triazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,10,12-pentaen-5-yl)-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (307 mg, 564 μmol) in 1,4-dioxane (1 mL) was added HCl in 1,4-dioxane (2 M, 4 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with H2O (30 mL) at 25 °C and extracted with CH2Cl2 (25 mL x 2). The aqueous phase was basified with aqueous NaHCO3 (pH~8) and extracted with CH2Cl2(30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The title compound (Intermediate 6, 180 mg) was obtained as a yellow solid. MS: m / z = 343.6, 345.6 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 9.07 - 8.96 (m, 1H), 8.56 - 8.44 (m, 1H), 8.17 - 8.03 (m, 1H), 7.84 - 7.66 (m, 1H), 7.05 (d, J = 5.2 Hz, 1H), 6.99 - 6.92 (m, 1H), 6.84 - 6.12 (m, 2H), 5.87 - 5.77 (m, 1H), 5.63 (d, J = 8.8 Hz, 1H).

[0220] Intermediate 7: 2-Bromo-3-phenyl-5H-imidazo[12-c]pyrido[3,4-e][1,3]oxazineStep 1: 3-Phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazineA mixture of Intermediate 1 (270 mg, 1.07 mmol), phenylboronic acid (196 mg, 1.61 mmol), Cs2CO3(1.05 g, 3.21 mmol), and Pd(dppf)Cl2(78.4 mg, 107 μmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was degassed, purged with N2three times, and stirred at 80 °C for 2 h under N2. The reaction mixture was quenched with H2O (10 mL) and extracted with CH2Cl2 (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 10% ~ 75% EtOAc in petroleum ether), the title compound (210 mg, yield: 66%) was obtained as a yellow solid. MS: m / z = 250.1 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.95 (s, 1H), 8.48 (d, J = 5.6 Hz, 1H), 7.53 - 7.43 (m, 5H), 7.39 (s, 1H), 7.22 (d, J = 5.6 Hz, 1H), 6.22 (s, 2H). Step 2: 2-Bromo-3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazineTo a solution of 3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazine (210 mg, 843 μmol) in DMF (2 mL) was added NBS (225 mg, 1.26 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with H2O (10 mL) and extracted with CH2Cl2 (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The title compound (Intermediate 7, 260 mg, yield: 94%) was obtained as a brown solid. MS: m / z = 327.8, 329.8 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.96 (s, 1H), 8.52 (d, J = 5.6 Hz, 1H), 7.58 - 7.48 (m, 5H), 7.25 (d, J = 5.6 Hz, 1H), 6.08 (s, 2H).

[0221] Intermediate 8: 3-Bromo-2-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazineStep 1: 3-(5-Phenyl-1H-imidazol-2-yl)pyridin-4-ol To a solution of 2-oxo-2-phenylacetaldehyde (8 g, 59.7 mmol) and 4-hydroxynicotinaldehyde (3 g, 24.4 mmol) in MeOH (30 mL) was added NH3.H2O (13.4 mL, 97.5 mmol) at 25 °C. The mixture was stirred at 25 °C for 3 h. The suspension was filtered, and the filter cake was washed with EtOAc (10 mL). The solid was dried under vacuum. After purification by silica gel flash chromatography (Eluent of 50% EtOAc in petroleum ether and 3% ~ 9% MeOH in CH2Cl2), the title compound (4.1 g, yield: 69%) was obtained as a yellow solid. MS: m / z = 237.9 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 12.56 (s, 1H), 11.96 (s, 1H), 8.58 (br s, 1H), 7.88 - 7.72 (m, 3H), 7.56 (s, 1H), 7.397.33 (m, 2H), 7.25 - 7.16 (m, 1H), 6.41 (br s, 1H).To a solution of 3-(5-phenyl-1H-imidazol-2-yl)pyridin-4-ol (4 g, 16.9 mmol) and Cs2CO3 (11 g, 33.7 mmol) in DMF (40 mL) was added CH2I2(2.7 mL, 33.7 mmol) at 25 °C. The mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 10% MeOH in CH2Cl2), the title compound (300 mg, yield: 6%) was obtained as a yellow solid. MS: m / z = 250.0 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.99 - 8.93 (m, 1H), 8.48 (d, J = 5.6 Hz, 1H), 7.85 (d, J = 7.6 Hz, 2H), 7.81 (s, 1H), 7.41 (t, J = 7.6 Hz, 2H), 7.29 - 7.24 (m, 1H), 7.20 (d, J = 5.6 Hz, 1H), 6.15 (s, 2H). Step 3: 3-Bromo-2-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazine To a solution of 2-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazine (280 mg, 1.12 mmol) in DMF (3 mL) was added NBS (200 mg, 1.12 mmol) at 25 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with H2O (10 mL) at 25 °C and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3),dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 10% ~ 40% EtOAc in Petroleum ether), the title compound (Intermediate 8, 120 mg, yield: 32%) was obtained as a yellow solid. MS: m / z = 327.8, 329.8 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 9.19 (s, 1H), 8.51 (d, J = 5.6 Hz, 1H), 8.03 - 7.97 (m, 2H), 7.49 - 7.42 (m, 2H), 7.39 - 7.33 (m, 1H), 7.02 (d, J = 5.6 Hz, 1H), 5.91 (s, 2H).

[0222] Intermediate 9: 3-(4-Bromo-1-methyl-1H-imidazol-5-yl)pyridineStep 1: 3-(1-Methyl-1H-imidazol-5-yl)pyridine To a mixture of 5-bromo-1-methyl-1H-imidazole (650 mg, 4.04 mmol) and 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (911 mg, 4.44 mmol) in 1,4-dioxane (15 mL) and H2O (3 mL) were added Cs2CO3 (3.95 g, 12.1 mmol) and Pd(dppf)Cl2 (295 mg, 404 μmol). The mixture was stirred at 100 °C for 2 h 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 (0 - 10% MeOH in CH2Cl2 (0.1% TEA)), the title compound (780 mg, yield: 92%) was obtained as a brown solid. MS: m / z = 159.9 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.76 - 8.70 (m, 1H), 8.58 - 8.54 (m, 1H), 796 792 (m 1H) 778 (s 1H) 750 747 (m 1H) 718 (s 1H) 371 (s 3H)Step 2: 3-(4-Bromo-1-methyl-1H-imidazol-5-yl)pyridine To a solution of 3-(1-methyl-1H-imidazol-5-yl)pyridine (360 mg, 1.72 mmol) in CH2Cl2(10 mL) was added NBS (336 mg, 1.89 mmol) at 0 °C. The reaction mixture was stirred at 20 °C for 2 h. The resulting mixture was diluted with CH2Cl2 (5 mL), washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. After purification by silica gel flash chromatography (0 - 10% MeOH in CH2Cl2) and by prep- HPLC (column: C18150 × 30 mm; mobile phase: [water (NH3H2O + NH4HCO3) - ACN]; gradient: 23% - 43% B over 7 min), the title compound (Intermediate 9, 140 mg, yield: 34%) was obtained as an off-white solid.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.68 (dd, J = 2.4, 0.8 Hz, 1H), 8.64 (dd, J = 4.8, 1.6 Hz, 1H), 7.96 - 7.92 (m, 1H), 7.84 (s, 1H), 7.58 - 7.52 (m, 1H), 3.61 (s, 3H).

[0223] Intermediate 10: 3-(4-(4-(Chloromethyl)phenyl)-1-methyl-1H-imidazol-5-yl)pyridin-2-amineStep 1: 3-(1-Methyl-1H-imidazol-5-yl)-2-nitropyridine To a solution of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole (5 g, 24.0 mmol), 3-bromo-2-nitropyridine (4.43 g, 21.9 mmol) in 1,4-dioxane (50 mL) and H2O (10 mL) were added Pd(dppf)Cl2(1.60 g, 2.18 mmol) and Cs2CO3(21.4 g, 65.5 mmol). The mixture was degassed, purged with N2three times, and stirred at 90 °C for 2 h under N2. The reaction mixture was quenched with H2O (200 mL) at 25 °C and extracted with CH2Cl2 (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% ~ 7% MeOH in CH2Cl2), the title compound (960 mg, yield: 21%) was obtained as a brown oil. MS: m / z = 205.0 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.66 (dd, J = 4.8, 1.6 Hz, 1H), 8.30 (dd, J = 8.0, 1.6 Hz, 1H), 7.92 (dd, J = 7.6, 4.4 Hz, 1H), 7.84 (s, 1H), 6.97 (s, 1H), 3.93 (s, 3H). Step 2: 3-(4-Bromo-1-methyl-1H-imidazol-5-yl)-2-nitropyridine To a solution of 3-(1-methyl-1H-imidazol-5-yl)-2-nitropyridine (950 mg, 4.65 mmol) in CH2Cl2(10 mL) was added NBS (994 mg, 5.58 mmol) at 0 °C in an ice bath. The mixturereaction mixture was quenched with H2O (20 mL) at 0 °C and extracted with CH2Cl2 (20 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by prep-HPLC (column: CD07-Daisogel SP-100-8-ODS-PK 150 x 25 x 10 µm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 10% - 40% B over 10 min), the title compound (190 mg, yield: 14%) was obtained as a yellow solid.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.78 (dd, J = 4.8, 1.6 Hz, 1H), 8.34 (dd, J = 8.0, 1.6 Hz, 1H), 8.01 (dd, J = 7.6, 4.8 Hz, 1H), 7.89 (s, 1H), 3.52 (s, 3H). Step 3: 3-(4-Bromo-1-methyl-1H-imidazol-5-yl)pyridin-2-amine A mixture of 3-(4-bromo-1-methyl-1H-imidazol-5-yl)-2-nitropyridine (190 mg, 671 μmol), Fe (112 mg, 2.01 mmol) and NH4Cl (251 mg, 4.70 mmol) in EtOH (1 mL) and H2O (0.2 mL) was degassed, purged with N2three times, and stirred at 80 °C for 2 h under N2. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (170 mg, yield: 95%) as a yellow solid. MS: m / z = 252.9, 254.9 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.04 (dd, J = 4.8, 1.6 Hz, 1H), 7.75 (s, 1H), 7.33 (dd, J = 7.2, 1.6 Hz, 1H), 6.64 (dd, J = 7.2, 4.8 Hz, 1H), 5.82 (s, 2H), 3.43 (s, 3H). Step 4: (4-(5-(2-Aminopyridin-3-yl)-1-methyl-1H-imidazol-4-yl)phenyl)methanol A mixture of 3-(4-bromo-1-methyl-1H-imidazol-5-yl)pyridin-2-amine (75 mg, 296 μmol), (4- (hydroxymethyl)phenyl)boronic acid (45.0 mg, 296 μmol), Cs2CO3(290 mg, 889 μmol) and Pd(dppf)Cl2 (21.7 mg, 29.6 μmol) in 1,4-dioxane (1 mL) and H2O (0.2 mL) was degassed, purged with N2 three times, and stirred at 80 °C for 2 h under N2. The reaction mixture was quenched with H2O (10 mL) and extracted with CH2Cl2(10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by prep-TLC (CH2Cl2 : MeOH = 10 : 1), the title compound (20 mg, yield: 22%) was obtained as a yellow solid. MS: m / z = 281.1 [M + H]+. Step 5: 3-(4-(4-(Chloromethyl)phenyl)-1-methyl-1H-imidazol-5-yl)pyridin-2-amine To a solution of (4-(5-(2-aminopyridin-3-yl)-1-methyl-1H-imidazol-4-yl)phenyl)methanol (20 mg, 71.4 μmol) in CH2Cl2 (1 mL) was added SOCl2 (25.4 mg, 214 μmol). The mixture was stirred at 40 °C for 0.5 h. The reaction was concentrated under reduced pressure to give the title compound (Intermediate 10, 23.9 mg, HCl salt) as a yellow solid. MS: m / z = 299.1, 301.1 [M + H]+.

[0224] Intermediate 11: 2-Bromo-3-cyclohexyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazineStep 1: 3-(Cyclohex-1-en-1-yl)-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazine A mixture of Intermediate 1 (250 mg, 992 μmol), cyclohex-1-en-1-ylboronic acid (187 mg, 1.49 mmol), Cs2CO3 (969 mg, 2.98 mmol), and Pd(dppf)Cl2 (72.6 mg, 99.2 μmol) in 1,4- dioxane (5 mL) and H2O (1 mL) was degassed, purged with N2 three times, and stirred at 90 °C for 2 h under N2. The reaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with CH2Cl2(15 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 3% MeOH in CH2Cl2), the title compound (230 mg, yield: 88%) was obtained as a yellow solid. MS: m / z = 254.1 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.88 (s, 1H), 8.44 (d, J = 5.6 Hz, 1H), 7.19 - 7.14 (m, 2H), 6.10 (s, 2H), 5.79 - 5.70 (m, 1H), 2.32 - 2.28 (m, 2H), 2.21 - 2.17 (m, 2H), 1.73 - 1.67 (m, 2H), 1.64 - 1.58 (m, 2H). Step 2: 3-Cyclohexyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazine To a solution of 3-(cyclohex-1-en-1-yl)-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazine (100 mg, 395 μmol) in MeOH (5 mL) was added Pd / C (100 mg, 94.0 μmol, 10%) under N2. The mixture was degassed, purged with H2three times, and stirred at 25 °C under 15 psi H2for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (88 mg, yield: 83%) as a light yellow solid. MS: m / z = 255.9 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 9.11 (d, J = 3.6 Hz, 1H), 8.45 (t, J = 5.2 Hz, 1H), 7.12 (s, 0.5H), 6.99 - 6.94 (m, 1.5H), 5.90 (s, 1H), 5.82 (s, 1H), 5.68 - 5.63 (m, 0.5H), 2.59 - 2.45 (m, 0.5H), 2.38 - 2.29 (m, 1H), 2.27 - 2.21 (m, 1H), 1.96 - 1.85 (m, 2H), 1.80 - 1.74 (m, 2H), 1.72 - 1.67 (m, 1H), 1.48 - 1.37 (m, 2H), 1.33 - 1.24 (m, 1H). Step 3: 2-Bromo-3-cyclohexyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazine To a solution of 3-cyclohexyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazine (88 mg, 345 μmol) in CH2Cl2(3 mL) was added NBS (79.8 mg, 448 μmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with H2O (10 mL) and extracted with CH2Cl2 (15 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 2% MeOH in CH2Cl2), the title compound[M + H]+.1H NMR (400 MHz, Chloroform-d) δ 9.09 (s, 1H), 8.47 (d, J = 5.6 Hz, 1H), 7.03 (d, J = 5.6 Hz, 1H), 5.91 (s, 2H), 2.77 - 2.69 (m, 1H), 1.93 - 1.79 (m, 6H), 1.71 - 1.65 (m, 2H), 1.43 - 1.35 (m, 2H).

[0225] Intermediate 12: 2-Bromo-3-(pyridin-4-yl)-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazineStep 1: 3-(Pyridin-4-yl)-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazine To a solution of Intermediate 1 (150 mg, 595 μmol) and pyridin-4-ylboronic acid (80.5 mg, 655 μmol) in 1,4-dioxane (3 mL) and H2O (0.6 mL) were added Pd(dppf)Cl2 (43.5 mg, 59.5 μmol) and Cs2CO3 (582 mg, 1.79 mmol). The mixture was degassed, purged with N2 three times, and stirred at 90 °C for 2 h under N2. The reaction mixture was quenched with EtOAc (30 mL), washed with brine (30 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 4% MeOH in CH2Cl2), the title compound (143 mg, yield: 91%) was obtained as a gray solid. MS: m / z = 250.9 [M+H]+.1(400 MHz, Dimethylsulfoxide-d6) δ 8.97 (s, 1H), 8.68 - 8.63 (m, 2H), 8.51 (d, J = 5.6 Hz, 1H), 7.67 (s, 1H), 7.53 - 7.51 (m, 2H), 7.24 (d, J = 5.6 Hz, 1H), 6.34 (s, 2H). Step 2: 2-Bromo-3-(pyridin-4-yl)-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazine To a solution of 3-(pyridin-4-yl)-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazine (133 mg, 531 μmol) in DMF (4 mL) was added NBS (189 mg, 1.06 mmol). The mixture was degassed, purged with N2three times, and stirred at 25 °C for 1 h under N2. The reaction mixture was quenched with H2O (50 mL) at 25 °C and extracted with CH2Cl2 (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 12, 133 mg, yield: 68%) was obtained as a yellow solid. MS: m / z = 328.9, 330.9 [M+H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.04 (s, 1H), 8.82 (d, J = 5.6 Hz, 2H), 8.59 (d, J = 5.6 Hz, 1H), 7.69 (d, J = 5.6 Hz, 2H), 7.36 (d, J = 5.6 Hz, 1H), 6.23 (s, 2H).

[0226] Int di 13 2 B 3 2 fl h l 5H i idazo[1,2-c]pyrido[3,4-e][1,3]oxazineIntermediate 13 was prepared in a manner similar to Intermediate 12. MS: m / z =346.0, 348.0 [M + H]+.1H NMR (400 MHz, Dimethysulfoxide-d6) δ 8.97 (s, 1H), 8.53 (d, J = 5.6 Hz, 1H), 7.65 - 7.50 (m, 2H), 7.47 - 7.37 (m, 2H), 7.31 - 7.23 (m, 1H), 6.01 (s, 2H).19F NMR (400 MHz, Dimethysulfoxide-d6) δ -112.911.

[0227] Intermediate 14: 2-Bromo-3-(3-fluorophenyl)-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazineIntermediate 14 was prepared in a manner similar to Intermediate 12. MS: m / z = 346.0, 348.0 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.95 (s, 1H), 8.52 (d, J = 5.6 Hz, 1H), 7.70 - 7.55 (m, 1H), 7.43 - 7.33 (m, 3H), 7.24 (d, J = 5.6 Hz, 1H), 6.09 (s, 2H).19F NMR (400 MHz, Dimethylsulfoxide-d6) δ - 111.876.

[0228] Intermediate 15: 2-Bromo-3-(4-fluorophenyl)-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazineIntermediate 15 was prepared in a manner similar to Intermediate 12. MS: m / z = 345.7, 347.7 [M+H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.95 (s, 1H), 8.52 (d, J = 5.6 Hz, 1H), 7.60 - 7.53 (m, 2H), 7.45 - 7.37 (m, 2H), 7.24 (d, J = 5.6 Hz, 1H), 6.05 (s, 2H).19F NMR (400 MHz, Dimethylsulfoxide-d6) δ -111.913.

[0229] Intermediate 16: 4-(Piperazin-1-yl)pyrimidine-2-carbonitrileStep 1: tert-Butyl 4-(2-cyanopyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl piperazine-1-carboxylate (550 mg, 2.95 mmol) and 2- chloropyrimidine-4-carbonitrile (412 mg, 2.95 mmol) in DMF (5 mL) were added K2CO3 (1.22 g, 8.86 mmol) and NaI (88.5 mg, 590 μmol). The mixture was stirred at 80 °C for 1 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash(780 mg, yield: 92%) as a white solid. MS: m / z = 290.0 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 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-1-yl)pyrimidine-2-carbonitrile To a solution of tert-butyl 4-(2-cyanopyrimidin-4-yl)piperazine-1-carboxylate (140 mg, 483 μmol) in CH2Cl2(3 mL) was added TFA (767 mg, 6.73 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The title compound (Intermediate 16, 146 mg TFA salt, yield: 100%) was used in the next step without further purification. MS: m / z = 190.0 [M + H]+.

[0230] Intermediate 17: 2-(4-(Chloromethyl)phenyl)-3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazineStep 1: (4-(3-Phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)methanol A mixture of Intermediate 7 (4.4 g, 13.4 mmol), (4-(hydroxymethyl)phenyl)boronic acid (2.04 g, 13.4 mmol), Pd(dppf)Cl2 (981 mg, 1.34 mmol), and Cs2CO3 (13.1 g, 40.2 mmol) in 1,4-dioxane (40 mL) and H2O (8 mL) was degassed, purged with N2 three times, and stirred at 80 °C for 2 h under N2. 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), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 3% MeOH in CH2Cl2), the title compound (3.4 g, yield: 70%) was obtained as a yellow solid. MS: m / z = 356.3 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.02 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 7.53 - 7.49 (m, 3H), 7.45 - 7.40 (m, 4H), 7.24 - 7.20 (m, 3H), 5.95 (s, 2H), 5.15 (t, J = 5.6 Hz, 1H), 4.46 (d, J = 5.6 Hz, 2H). Step 2: 2-(4-(Chloromethyl)phenyl)-3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazine To a solution of (4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2- yl)phenyl)methanol (500 mg, 1.41 mmol) in CH2Cl2(5 mL) was added SOCl2(1 mL). The mixture was degassed, purged with N2three times, and stirred at 25 °C for 1 h under N2. The reaction mixture was concentrated under reduced pressure to give the title compound (Intermediate 17, 577 mg, HCl salt) as a gray solid, which was used in the next step directly. MS: m / z = 3742 3762 [M+H]+

[0231] Intermediate 18: 4-((Methyl-d3)(piperidin-4-yl)amino)pyrimidine-2-carbonitrileStep 1: tert-Butyl 4-((2-cyanopyrimidin-4-yl)(methyl-d3)amino)piperidine-1-carboxylate To a solution of tert-butyl 4-((2-cyanopyrimidin-4-yl)amino)piperidine-1-carboxylate (1 g, 3.30 mmol, refer to Intermediate 2 for detail procedures) in THF (10 mL) was added NaH (264 mg, 6.59 mmol, 60% in oil) at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 h under N2, and CD3I (956 mg, 6.59 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 16 h under N2. The reaction mixture was quenched with H2O (50 mL) at 25 °C and extracted with CH2Cl2 (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The title compound (1 g, yield: 90%) was obtained as a yellow solid. MS: m / z = 321.3 [M + H]+. D%: 3D% = 100%.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 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-carbonitrile To a solution of tert-butyl 4-((2-cyanopyrimidin-4-yl)(methyl-d3)amino)piperidine-1- carboxylate (90 mg, 281 μmol) in CH2Cl2 (2 mL) was added TFA (96.1 mg, 843 ^mol). The mixture was stirred at 25 °C for 0.5 h. The reaction was concentrated under reduced pressure to give the title compound (Intermediate 18, 93.9 mg, TFA salt) as a yellow oil. MS: m / z = 221.2 [M + H]+.

[0232] Intermediate 19: 2-(Piperidin-4-ylamino)pyrimidine-4-carbonitrileIntermediate 19 was prepared in a manner similar to Intermediate 2. MS: m / z = 204.0 [M + H]+.

[0233] Intermediate 20: 6-(Piperidin-4- lamino)p rimidine-4-carbonitrileIntermediate 20 was prepared in a manner similar to Intermediate 2. MS: m / z = 204.0 [M + H]+.Step 1: tert-Butyl 4-(1-(((trifluoromethyl)sulfonyl)oxy)vinyl)piperidine-1-carboxylate To a solution of tert-butyl 4-acetylpiperidine-1-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. The resulting mixture was stirred at -78 °C for 1 h. 1,1,1-Trifluoro-N-phenyl-N- ((trifluoromethyl)sulfonyl)methanesulfonamide (6.92 g, 19.4 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 3 h. The reaction mixture was quenched with aq. NH4Cl (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.1H NMR (400 MHz, Chloroform-d) δ 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-(1-(trimethylstannyl)vinyl)piperidine-1-carboxylate A mixture of tert-butyl 4-(1-(((trifluoromethyl)sulfonyl)oxy)vinyl)piperidine-1-carboxylate (1 g, 2.78 mmol), LiCl (796 mg, 18.8 mmol), Pd(PPh3)4 (322 mg, 278 μmol), and 1,1,1,2,2,2-hexamethyldistannane (1.49 g, 4.55 mmol) in 1,4-dioxane (10 mL) was degassed, purged with N2 three times, and stirred at 60 °C for 16 h under N2. 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.1H NMR (400 MHz, Chloroform-d) δ 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-(1-(2-cyanopyrimidin-4-yl)vinyl)piperidine-1-carboxylate A mixture of tert-butyl 4-(1-(trimethylstannyl)vinyl)piperidine-1-carboxylate (520 mg, 1.39 mmol), Pd(PPh3)2Cl2 (195 mg, 278 μmol), and 4-chloropyrimidine-2-carbonitrile (252 mg, 1.81 mmol) in DMF (8 mL) was degassed, purged with N2three times, and stirred at 90 °Cfor 16 h under N2. 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]+. 1H NMR (400 MHz, Chloroform-d) δ 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-(1-(Piperidin-4-yl)vinyl)pyrimidine-2-carbonitrile To a solution of tert-butyl 4-(1-(2-cyanopyrimidin-4-yl)vinyl)piperidine-1-carboxylate (44 mg, 140 μmol) in CH2Cl2 (3 mL) was added TFA (307 mg, 2.69 mmol). The mixture was stirred at 25 °C for 0.5 h. The reaction was concentrated under reduced pressure to give the title compound (Intermediate 21, 46.0 mg, TFA salt) as a light-yellow oil. MS: m / z = 214.8 [M + H]+.

[0235] Intermediate 22: 4-(1-(Piperidin-4-yl)ethyl)pyrimidine-2-carbonitrileStep 1: tert-Butyl 4-(1-(2-cyanopyrimidin-4-yl)ethyl)piperidine-1-carboxylate To a solution of tert-butyl 4-(1-(2-cyanopyrimidin-4-yl)vinyl)piperidine-1-carboxylate (220 mg, 700 μmol, refer to Intermediate 21 for detail procedures) in EtOH (5 mL) was added Rh(PPh3)3Cl (324 mg, 350 μmol) under N2. The mixture was degassed, purged with H2three times, and stirred at 65 °C for 4 h under H2(15 psi). 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]+.1H NMR (400 MHz, Chloroform-d) δ 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-(1-(Piperidin-4-yl)ethyl)pyrimidine-2-carbonitrile To a solution of tert-butyl 4-(1-(2-cyanopyrimidin-4-yl)ethyl)piperidine-1-carboxylate (32 mg, 101 μmol) in CH2Cl2 (2 mL) was added TFA (34.6 mg, 303 μmol). The mixture was stirred at 25 °C for 0.5 h. The reaction was concentrated under reduced pressure to give the title compound (Intermediate 22, 33.4 mg) as a light-yellow oil. MS: m / z = 217.2 [M + H]+.

[0236] I di 23 4 (1 (Pi idi 4 l) l l) i idi 2 b i ilStep 1: tert-Butyl 4-(1-(2-cyanopyrimidin-4-yl)cyclopropyl)piperidine-1-carboxylate To a 15 mL vial equipped with a stir bar were added tert-butyl 4-(1-(2-cyanopyrimidin-4- yl)vinyl)piperidine-1-carboxylate (150 mg, 477 μmol, refer to Intermediate 21 for detail procedures), Ru(bpz)3(PF6)2(4.13 mg, 4.77 μmol), 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 N2. 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 h. The reaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with CH2Cl2 (25 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 20% EtOAc in petroleum ether), the title compound (70 mg, yield: 44%) was obtained as a light-yellow oil. MS: m / z = 350.9 [M + Na]+.1H NMR (400 MHz, Chloroform-d) δ 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-(1-(Piperidin-4-yl)cyclopropyl)pyrimidine-2-carbonitrile To a solution of tert-butyl 4-(1-(2-cyanopyrimidin-4-yl)cyclopropyl)piperidine-1-carboxylate (70 mg, 213 μmol) in CH2Cl2 (3 mL) was added TFA (72.9 mg, 639 μmol). The mixture was stirred at 25 °C for 0.5 h. The reaction was concentrated under reduced pressure to give the title compound (Intermediate 23, 73 mg, TFA salt) as a light-yellow oil. MS: m / z = 229.2 [M + H]+.

[0237] Intermediate 24: 4-((3aR,6aS)-Dihydro-1H,4H-3a,6a-(methanooxymethano)pyrrolo[3,4-c]pyrrol-2(3H)-yl)pyrimidine-2-carbonitrileIntermediate 24 was prepared in a manner similar to Intermediate 2. MS: m / z = 258.2 [M + H]+.

[0238] Intermediate 25: 4-(Piperidin-4-yloxy)pyrimidine-2-carbonitrileStep 1: tert-Butyl 4-((2-(methylthio)pyrimidin-4-yl)oxy)piperidine-1-carboxylate To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2 g, 9.94 mmol) in THF (50 mL) was added NaH (795 mg, 19.9 mmol, 60%) at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 h 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 h under N2. The mixture was quenched with sat. NH4Cl (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]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 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: tert-Butyl 4-((2-(methylsulfonyl)pyrimidin-4-yl)oxy)piperidine-1-carboxylate To a solution of tert-butyl 4-((2-(methylthio)pyrimidin-4-yl)oxy)piperidine-1-carboxylate (500 mg, 1.54 mmol) in CH2Cl2(6 mL) was added m-CPBA (624 mg, 3.07 mmol, 85%) at 0 °C. The reaction mixture was stirred at 30 °C for 12 h. The reaction mixture was quenched with sat. Na2SO3 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 petroleumether), the title compound (490 mg, yield: 89%) was obtained as a colorless oil. 1H NMR(400 MHz, Dimethylsulfoxide-d6) δ 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: tert-Butyl 4-((2-cyanopyrimidin-4-yl)oxy)piperidine-1-carboxylate To a solution of tert-butyl 4-((2-(methylsulfonyl)pyrimidin-4-yl)oxy)piperidine-1-carboxylate (250 mg, 699 μmol) in CH2Cl2 (5 mL) and H2O (1 mL) were added TBAB (22.6 mg, 69.9 μmol) and NaCN (50 mg, 1.02 mmol) at 15 °C. The mixture was stirred at 30 °C for 10 hextracted with CH2Cl2 (10 mL 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 a 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-carbonitrile A mixture of tert-butyl 4-((2-cyanopyrimidin-4-yl)oxy)piperidine-1-carboxylate (100 mg, 329 μmol) in CH2Cl2 (2 mL) and TFA (3.37 mmol, 250 μL) was stirred at 15 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound (Intermediate 25, 67.1 mg, TFA salt) as brown oil, which was used in the next step directly. MS: m / z = 205 [M + H]+.

[0239] Intermediate 26: 4-(1,2,3,6-Tetrahydropyridin-4-yl)pyrimidine-2-carbonitrileStep 1: tert-Butyl 4-(2-cyanopyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate A mixture of 4-chloropyrimidine-2-carbonitrile (2 g, 14.3 mmol), (1-(tert-butoxycarbonyl)- 1,2,3,6-tetrahydropyridin-4-yl)boronic acid (3.25 g, 14.3 mmol), Pd(dppf)Cl2 (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 N2three times, and stirred at 80 °C for 2 h under N2. 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) δ 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-(1,2,3,6-Tetrahydropyridin-4-yl)pyrimidine-2-carbonitrile To a solution of tert-butyl 4-(2-cyanopyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (170 mg, 594 μmol) in CH2Cl2(2 mL) was added TFA (203 mg, 1.78 mg, 1.78 mmol). The mixture was stirred at 25 °C for 0.5 h. The reaction was concentrated under reduced pressure to give the title compound (Intermediate 26, 178 mg, TFA salt) as a yellow oil. MS: m / z = 187.1 [M + H]+.

[0240] Intermediate 27: 4-(Piperidin-4-yl)pyrimidine-2-carbonitrileStep 1: tert-Butyl 4-(2-(methylthio)pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate A mixture of (1-(tert-butoxycarbonyl)-1,2,3,6-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)Cl2(322 mg, 440 μmol) in 1,4-dioxane (10 mL) and H2O (2 mL) was degassed, purged with N2three times, and stirred at 90 °C for 3 h under N2. The reaction mixture was quenched with H2O (30 mL) at 25 °C and extracted with CH2Cl2 (25 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flashchromatography (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]+.1H NMR (400 MHz, Chloroform-d) δ 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: tert-Butyl 4-(2-(methylthio)pyrimidin-4-yl)piperidine-1-carboxylate To a solution of tert-butyl 4-(2-(methylthio)pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)- carboxylate (850 mg, 2.77 mmol) in MeOH (10 mL) was added 10% Pd / C (198 mg, 186 μmol) under Ar. The suspension was degassed and purged with H2 three times. The mixture was stirred at 40 °C under H2(30 psi) for 48 h. The reaction was filtered and concentrated under reduced pressure to give the title compound (855 mg) as a light-yellow oil. MS: m / z = 310.1 [M + H]+. Step 3: tert-Butyl 4-(2-(methylsulfonyl)pyrimidin-4-yl)piperidine-1-carboxylate To a solution of tert-butyl 4-(2-(methylthio)pyrimidin-4-yl)piperidine-1-carboxylate (300 mg, 970 μmol) 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 h. 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 to give the title compound (280 mg, yield: 84% for two steps) as a yellow oil. MS: m / z = 364.0 [M + Na]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 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: tert-Butyl 4-(2-cyanopyrimidin-4-yl)piperidine-1-carboxylate To a solution of tert-butyl 4-(2-(methylsulfonyl)pyrimidin-4-yl)piperidine-1-carboxylate (280 mg, 820 μmol) in CH2Cl2(5 mL) and H2O (0.5 mL) were added NaCN (48 mg, 984 ^mol) and TBAB (13.2 mg, 41 ^mol). The mixture was stirred at 25 °C for 16 h. 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) δ 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-carbonitrile To a solution of tert-butyl 4-(2-cyanopyrimidin-4-yl)piperidine-1-carboxylate (105 mg, 364 μmol) in CH2Cl2 (2 mL) was added TFA (125 mg, 1.09 mmol). The mixture was stirred at 25 °C for 0.5 h. The reaction was concentrated under reduced pressure to give the title compound (Intermediate 27, 110 mg, TFA salt) as a purple oil. MS: m / z = 189.0 [M + H]+.

[0241] Intermediate 28: 4-(Azetidin-3-ylamino)pyrimidine-2-carbonitrileIntermediate 28 was prepared in a manner similar to Intermediate 2.

[0242] Intermediate 29: 4-(2,6-Diazaspiro[3.3]heptan-2-yl)pyrimidine-2-carbonitrileIntermediate 29 was prepared in a manner similar to Intermediate 2.

[0243] Int rm di t 30 (S) 4 (27 di z ir

[0044] n n n 2 l) rimidin 2-carbonitrileIntermediate 30 was prepared in a manner similar to Intermediate 2. MS: m / z = 230.1 [M + H]+

[0244] Intermediate 31: 2-Bromo-3-phenyl-5H-imidazo[1,2-c]pyrido[3,2-e][1,3]oxazineStep 1: 2-Bromo-3-(1H-imidazol-2-yl)pyridine To a solution of 2-bromonicotinaldehyde (5 g, 26.9 mmol) and oxalaldehyde (9.75 g, 67.2 mmol, 40% in H2O) in MeOH (50 mL) was added NH3·H2O (14.8 mL, 108 mmol , 28%) in an ice bath. The mixture was degassed, purged with N2 three times, and stirred at 0 °C for 2 h under N2 atmophere. The reaction mixture was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 2% MeOH in CH2Cl2), the title compound (2.8 g, yield: 43%) was obtained as a yellow solid. MS: m / z = 223.9, 225.9 [M+H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 12.43 (br s, 1H), 8.42 (dd, J = 4.8, 1.6 Hz, 1H), 8.04 (dd, J = 7.6, 1.6 Hz, 1H), 7.55 (dd, J = 7.6, 4.8 Hz, 1H), 7.32 (s, 1H), 7.10 (s, 1H). Step 2: 5H-Imidazo[1,2-c]pyrido[3,2-e][1,3]oxazine To a solution of 2-bromo-3-(1H-imidazol-2-yl)pyridine (2.5 g, 11.2 mmol) in i-PrOH (250 mL) were added HCHO (11.1 mL, 150 mmol, 37%) and KOH (3.76 g, 70 mmol). The mixture was degassed, purged with N2 three times, and stirred at 80 °C for 16 h under N2. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 / MeOH=10 / 1 (200 mL ), filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 50% ~ 70% EtOAc in petroleum ether), the title compound (1.07 g, yield: 50%) was obtained as a yellow solid. MS: m / z = 173.9 [M+H]+.1H NMR (400 MHz, Chloroform-d) δ 8.28 - 8.24 (m, 2H), 7.25 (s, 1H), 7.16 (dd, J = 7.6, 5.2 Hz, 1H), 6.97 (s, 1H), 6.00 (s, 2H). Step 3: 3-Bromo-5H-imidazo[1,2-c]pyrido[3,2-e][1,3]oxazine To a solution of 5H-imidazo[1,2-c]pyrido[3,2-e][1,3]oxazine (500 mg, 2.89 mmol) in CH2Cl2(5 mL) and EtOH (1 mL) was added NBS (565 mg, 3.18 mmol). The mixture was degassed, purged with N2 three times, and stirred at 0 °C for 1 h under N2. The reaction mixture wasquenched with H2O (30 mL) and extracted with CH2Cl2 (30 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 60% EtOAc in petroleum ether), the title compound (354 mg, yield: 48%) was obtained as a light-yellow solid. MS: m / z = 251.9, 254.0 [M+H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.26 (dd, J = 5.2, 2.0 Hz, 1H), 8.17 (dd, J = 7.6, 2.0Hz, 1H), 7.30 - 7.25 (m, 2H), 6.11 (s, 2H). Step 4: 3-Phenyl-5H-imidazo[1,2-c]pyrido[3,2-e][1,3]oxazine To a solution of 3-bromo-5H-imidazo[1,2-c]pyrido[3,2-e][1,3]oxazine (350 mg, 1.39 mmol), phenylboronic acid (203 mg, 1.67 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) were added Pd(dppf)Cl2 (102 mg, 139 μmol) and Cs2CO3 (1.36 g, 4.17 mmol). The mixture was degassed, purged with N2three times, and stirred at 90 °C for 2 h under N2. The reaction mixture was diluted with EtOAc (50 mL) and stirred for 10 mins. The mixture was filtered through Celite, washed with brine (60 mL x 2), 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 (180 mg, yield: 48%) was obtained as a yellow solid. MS: m / z = 250.0 [M+H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.29 - 8.17 (m, 2H), 7.54 - 7.47 (m, 4H), 7.46 - 7.40 (m, 1H), 7.39 (s, 1H), 7.29 (dd, J = 7.2, 4.8 Hz, 1H), 6.25 (s, 2H). Step 5: 2-Bromo-3-phenyl-5H-imidazo[1,2-c]pyrido[3,2-e][1,3]oxazine To a solution of 3-phenyl-5H-imidazo[1,2-c]pyrido[3,2-e][1,3]oxazine (107 mg, 429 μmol) in DMF (2 mL) was added NBS (84.0 mg, 472 μmol). The mixture was stirred at 25 °C for 1hr. The reaction mixture was quenched with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (Intermediate 31, 140 mg) as a yellow solid. MS: m / z = 328.0, 330.0 [M+H]+.

[0245] Intermediate 32: 2-Bromo-3-phenyl-5H-imidazo[1,2-c]pyrido[4,3-e][1,3]oxazineStep 1: 4-(1H-Imidazol-2-yl)pyridin-3-ol To a solution of 3-hydroxyisonicotinaldehyde (5.0 g, 40.6 mmol) in MeOH (50 mL) was added NH3·H2O (22 mL, 28%) at 0 °C for 10 min. Then oxalaldehyde (14.4 g, 99.5 mmol, 40% in H2O) was added to the mixture, and the mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 3% MeOH in CH2Cl2), the title compound (4.5 g, yield: 69%) was obtained as a yellow solid. MS: m / z =162.0 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 13.68 - 11.82 (m, 2H), 8.32 (s, 1H), 8.14 (d, J = 5.2 Hz, 1H), 7.79 (d, J = 5.2 Hz, 1H), 7.57 - 7.16(m, 2H). Step 2: 5H-Imidazo[1,2-c]pyrido[4,3-e][1,3]oxazine To a solution of 4-(1H-Imidazol-2-yl)pyridin-3-ol (2 g, 12.4 mmol) in DMF (40 mL) were added K2CO3(5.15 g, 37.2 mmol) and CH2I2(6.65 g, 24.8 mmol) at 0°C. The mixture was warmed to 80 °C and stirred at 80 °C for 3 h. The reaction mixture was filtered and concentrated under reduced pressure. After purification by prep-HPLC (column: Phenomenex luna C18 (250 x 70mm,10 μm); mobile phase: [water (NH4HCO3) - ACN]; gradient: 0% - 33% B over 27 min), the title compound (902 mg, yield: 42%) was obtained as a brown solid. MS: m / z =174.0 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.46 (s, 1H), 8.37 (d, J = 4.8 Hz, 1H), 7.69 (d, J = 4.8 Hz, 1H), 7.44 - 7.37 (m, 1H), 7.27 - 7.19 (m, 1H), 6.09 (s, 2H) Step 3: 3-Bromo-5H-imidazo[1,2-c]pyrido[4,3-e][1,3]oxazine To a solution of 5H-imidazo[1,2-c]pyrido[4,3-e][1,3]oxazine (850 mg, 4.91 mmol) in CH2Cl2 (20 mL) and EtOH (10 mL) was added NBS (1.05 g, 5.89 mmol). The mixture was stirred at 0 °C for 4 h. The reaction mixture was poured into H2O (20 mL) and extracted with CH2Cl2(100 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The title compound (510 mg) was obtained as a black brown solid. MS: m / z =251.9, 253.9 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ8.50 (s, 1H), 8.39 (d, J = 5.2 Hz, 1H), 7.71 - 7.66 (m, 1H), 7.35 (s, 1H), 6.06 (s, 2H). Step 4: 3-Phenyl-5H-imidazo[1,2-c]pyrido[4,3-e][1,3]oxazine A mixture of 3-bromo-5H-imidazo[1,2-c]pyrido[4,3-e][1,3]oxazine (300 mg, 1.19 mmol), phenylboronic acid (160 mg, 1.31 mmol), Cs2CO3 (1.16 g, 3.57 mmol), and Pd(dppf)Cl2 (87.1 mg, 119 μmol) in 1,4-dioxane (10 mL) and H2O (2 mL) was degassed, purged with N2 three times, and stirred at 80 °C for 16 h under N2. The reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 65% EtOAc in petroleum ether), the title compound (510 mg, yield: 30% for two steps) was obtained as a brown solid. MS: m / z =250.1 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.50 (s, 1H), 8.39 (d, J = 4.8 Hz, 1H), 7.75(d, J = 5.2 Hz, 1H), 7.53 - 7.50 (m, 4H), 7.47 - 7.43 (m, 2H), 6.20 (s, 2H). Step 5: 2-Bromo-3-phenyl-5H-imidazo[1,2-c]pyrido[4,3-e][1,3]oxazine To a solution of 3-phenyl-5H-imidazo[1,2-c]pyrido[4,3-e][1,3]oxazine (100 mg, 401 μmol) in DMF (2 mL) was added NBS (78.5 mg, 441 μmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (Intermediate 32, 132 mg) as a yellow solid. MS: m / z =328.0, 330.0 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.52 (s, 1H), 8.43 (d, J = 4.8 Hz, 1H), 7.76 (d, J = 5.2 Hz, 1H), 7.59 - 7.49 (m, 5H), 6.05 (s, 2H).

[0246] Intermediate 33: 2-Bromo-3-phenyl-5H-imidazo[1,2-c]pyrido[2,3-e][1,3]oxazineIntermediat3 was prepared in a manner similar to Intermediate 32. MS: m / z =328.1, 330.0 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.41 (d, J = 4.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.59 - 7.49 (m, 5H), 7.43 (dd, J = 8.0, 4.4 Hz, 1H), 6.01 (s, 2H).Step 1: 3-Fluoro-5-methoxyisonicotinaldehyde To a solution of 3-fluoro-5-methoxypyridine (10 g, 78.6 mmol) in THF (100 mL) was added LDA (59.1 mL, 2 M in THF) dropwise at -65 °C under N2. The mixture was stirred at -65 °C for 0.5 h under N2. Then DMF (11.5 g, 157.2 mmol) was added dropwise at -65 °C under N2. The mixture was stirred at -65 °C for 1 h under N2. The reaction mixture was quenched with NH4Cl aq. (200 mL) at 0 °C and extracted with EtOAc (200 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% ~ 30% EtOAc in petroleum ether), the title compound (1.9 g, yield: 16%) was obtained as a yellow solid.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 10.30 (s, 1H), 8.57 (s, 1H), 8.38 (s, 1H), 4.05 (s, 3H).19F NMR (400 MHz, Dimethylsulfoxide-d6) δ -133.807. Step 2: 3-Fluoro-4-(1H-imidazol-2-yl)-5-methoxypyridine To a solution of 3-fluoro-5-methoxyisonicotinaldehyde (1.9 g, 12.3 mmol) and oxalaldehyde (4.44 g, 30.6 mmol, 40% in H2O) in MeOH (60 mL) in an ice bath was added NH3·H2O (6.13 g, 49.0 mmol, 28%) dropwise. The mixture was degassed, purged with N2 three times, and stirred at 25 °C for 2 h under N2. The reaction mixture was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 5% MeOH in CH2Cl2), the title compound (1.3 g, yield: 52%) was obtained as a yellow solid. MS: m / z = 194.1 [M+H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 12.61 - 11.87 (m, 1H), 8.40 (s, 1H), 8.34 (s, 1H), 7.29 - 7.17 (m, 2H), 3.99 (s, 3H).19F NMR (400 MHz, Dimethylsulfoxide- d6) δ -128.734. Step 3: 5-Fluoro-4-(1H-imidazol-2-yl)pyridin-3-ol To a solution of 3-fluoro-4-(1H-imidazol-2-yl)-5-methoxypyridine (1.3 g, 6.73 mmol) in MeCN (20 mL) in an ice bath was added TMSI (4.04 g, 20.2 mmol). The mixture was degassed, purged with N2 three times, and stirred at 80 °C for 16 h under N2. The reaction mixture was concentrated under reduced pressure. After purification by silica gel flashchromatography (Eluent of 0% ~ 5% MeOH in CH2Cl2), the title compound (540 mg, yield: 42%) was obtained as a yellow solid. MS: m / z = 180.1 [M+H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.37 (d, J = 5.2 Hz, 2H), 7.90 (s, 2H).19F NMR (400 MHz, Dimethylsulfoxide-d6) δ -128.434. Step 4: 10-Fluoro-5H-imidazo[1,2-c]pyrido[4,3-e][1,3]oxazine To a solution of 5-fluoro-4-(1H-imidazol-2-yl)pyridin-3-ol (450 mg, 2.51 mmol) and K2CO3(1.04 g, 7.54 mmol) in DMF (5 mL) in an ice bath was added CH2I2 (1.35 g, 5.02 mmol). The mixture was degassed, purged with N2 three times, and stirred at 25 °C for 16 h under N2. The reaction mixture was filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 3% MeOH in CH2Cl2), the title compound (60 mg, yield: 13%) was obtained as a yellow solid. MS: m / z = 192.0 [M+H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.43 (s, 1H), 8.37 (s, 1H), 7.47 (s, 1H), 7.29 (s, 1H), 6.13 (s, 2H).19F NMR (400 MHz, Dimethylsulfoxide-d6) δ -130.616. Step 5: 3-Bromo-10-fluoro-5H-imidazo[1,2-c]pyrido[4,3-e][1,3]oxazine To a solution of 10-fluoro-5H-imidazo[1,2-c]pyrido[4,3-e][1,3]oxazine (60 mg, 314 μmol) in CH2Cl2(2 mL) and EtOH (1 mL) was added NBS (55.7 mg, 314 μmol). The mixture was degassed, purged with N2 three times, and stirred at 0 °C for 1 h under N2. The reaction mixture was quenched with H2O (20 mL) and extracted with CH2Cl2 (10 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% ~ 50% EtOAc in petroleum ether), the title compound (40 mg, yield: 30%) was obtained as a yellow solid. MS: m / z = 269.9, 271.9 [M+H]+.1H NMR (400 MHz, Chloroform-d) δ 8.38 (s, 1H), 8.35 (s, 1H), 7.34 (s, 1H), 5.88 (s, 2H).19F NMR (400 MHz, Chloroform-d) δ -128.936. Step 6: 10-Fluoro-3-phenyl-5H-imidazo[1,2-c]pyrido[4,3-e][1,3]oxazine To a solution of 3-bromo-10-fluoro-5H-imidazo[1,2-c]pyrido[4,3-e][1,3]oxazine (40 mg, 148 μmol) and phenylboronic acid (18.1 mg, 148 μmol) in 1,4-dioxane (3 mL) and H2O (0.6 mL) were added Pd(dppf)Cl2 (10.8 mg, 14.8 μmol) and Cs2CO3 (145 mg, 444 μmol). The mixture was degassed, purged with N2three times, and stirred at 80 °C for 2 h under N2. The reaction mixture was quenched with H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 50% EtOAc in petroleum ether), the title compound (20 mg, yield: 50%) was obtained as a yellow solid MS: m / z = 2679 [M+H]+ 1H NMR (400 MHzChloroform-d) δ 8.38 (s, 1H), 8.34 (s, 1H), 7.56 - 7.42 (m, 4H), 7.41 - 7.35 (m, 2H), 5.96 (s, 2H).19F NMR (400 MHz, Chloroform-d) δ -129.357. Step 7: 2-Bromo-10-fluoro-3-phenyl-5H-imidazo[1,2-c]pyrido[4,3-e][1,3]oxazine To a solution of 10-fluoro-3-phenyl-5H-imidazo[1,2-c]pyrido[4,3-e][1,3]oxazine (20 mg, 74.8 μmol) in DMF (1 mL) was added NBS (20.0 mg, 112 μmol). The mixture was degassed, purged with N2three times, and stirred at 25 °C for 1 h under N2. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (80 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The title comppound (Intermediate 34, 25 mg) was obtained as a brown solid. MS: m / z = 346.0, 348.0 [M+H]+.

[0248] Intermediate 35: 2-Bromo-10-fluoro-3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazineIntermediate 35 was prepared in a manner similar to Intermediate 34. MS: m / z = 346.0, 347.9 [M+H]+.

[0249] Intermediate 36: 2-Bromo-10-fluoro-3-phenyl-5H-benzo[e]imidazo[1,2-c][1,3]oxazineIntermediate6 was prepared in a manner similar to Intermediate 34. MS: m / z = 346.9, 344.9 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 7.60 - 7.39 (m, 6H), 7.13 (t, J = 9.2, 1H), 7.06 (d, J = 8.4 Hz, 1H), 5.95 (s, 2H).19F NMR (400 MHz, Dimethylsulfoxide-d6) δ -

[0250] Interemediate 37: 2-Bromo-10-methoxy-3-phenyl-5H-benzo[e]imidazo[1,2-c][1,3]oxazineIntermediate 37 was prepared in a manner similar to Intermediate 34. MS: m / z = 357.0, 358.6 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 7.60 - 7.45 (m, 5H), 7.35 (t, J = 8.0 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 5.82 (s, 2H), 3.92 (s, 3H).

[0251] Intermediate 38: 2-Bromo-3-phenyl-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepineStep 1: 4-Chloro-3-(1H-imidazol-2-yl)pyridine To a solution of 4-chloronicotinaldehyde (6 g, 42.4 mmol) in MeOH (60 mL) was added oxalaldehyde (15.4 g, 106 mmol, 40%) at 0 °C for 10 min. Then NH3·H2O (21.2 g, 170 mmol, 28%) was added to the mixture. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 3% MeOH in CH2Cl2), the title compound (3 g, yield: 39%) was obtained as a yellow solid. MS: m / z = 180.1, 182.1 [M + H]+. 1H NMR (400 MHz,Dimethysulfoxide-d6) δ 12.50 (br s, 1H), 8.91 (s, 1H), 8.52 (d, J = 5.2 Hz, 1H), 7.97 (d, J = 13.6 Hz, 1H), 7.66 (d, J = 5.6 Hz, 1H), 7.14 (s, 1H). Step 2: 3-(1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1H-imidazol-2-yl)-4-chloropyridine To a solution of 4-chloro-3-(1H-imidazol-2-yl)pyridine (500 mg, 2.78 mmol) and (2- bromoethoxy)(tert-butyl)dimethylsilane (799 mg, 3.34 mmol) in DMF (5 mL) were addedK2CO3 (1.15 g, 8.35 mmol) and NaI (41.7 mg, 278 μmol). The mixture was stirred at 80 °C for 2 h. The reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (20 mL x 3). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 40% EtOAc in petroleum ether), the title compound (280 mg, yield: 30%) was obtained as a yellow oil. MS: m / z = 338.1, 340.0 [M + H]+.1H NMR (400 MHz, Dimethysulfoxide-d6) δ 8.68 - 8.58 (m, 2H), 7.73 (d, J = 5.2 Hz ,1H), 7.49 - 7.35 (m, 1H), 7.15 - 7.00 (m, 1H), 3.89 (t, J = 5.2 Hz, 2H), 3.73 (t, J = 5.2 Hz, 2H), 0.76 (s, 9H), -0.11 (s, 6H). Step 3: 2-(2-(4-Chloropyridin-3-yl)-1H-imidazol-1-yl)ethan-1-ol To a solution of 3-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-imidazol-2-yl)-4- chloropyridine (80 mg, 237 μmol) in THF (4 mL) was added TBAF (1 M, 0.5 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound(53 mg) as a yellow oil. MS: m / z = 224.0, 226.0 [M + H]+. Step 4: 5,6-Dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine A mixture of 2-(2-(4-chloropyridin-3-yl)-1H-imidazol-1-yl)ethan-1-ol (53 mg, 237 μmol) in DMF (2 mL) was degassed and purged with N2 three times. NaH (11.4 mg, 284 μmol, 60% purity) was added to the mixture in an ice bath. The mixture was stirred at 25 °C for 2 h under N2. The reaction mixture was quenched with sat. NH4Cl (20 mL) at 0 °C and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (35 mg ) as a yellow solid. MS: m / z = 188.2 [M + H]+.1H NMR (400 MHz, Chloroform-d) 9.66 (s, 1H), 8.36 (d, J = 6.0 Hz, 1H), 7.20 (s, 1H), 7.02 (s, 1H), 6.91 (d, J = 5.6 Hz, 1H), 4.56 - 4.47 (m, 2H), 4.44 - 4.38 (m, 2H). Step 5: 3-Bromo-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine A mixture of 5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine (80 mg, 427 μmol) in CH2Cl2 (3 mL) was degassed and purged with N2 three times. NBS (76.1 mg, 427 μmol) was added to the mixture at 0 °C, and the mixture was stirred at 0 °C for 1 h under N2. The reaction mixture was poured into H2O (15 mL) and extracted with CH2Cl2 (15 mL x 3). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 3% MeOH in CH2Cl2), the title compound (50 mg, yield :44% for three steps) was obtained as a yellow solid MS: m / z = 2660 2679 [M + H]+ 1H NMR (400 MHzChloroform-d) δ 9.61 (s, 1H), 8.37 (d, J = 5.6 Hz, 1H), 7.19 (s, 1H), 6.92 (d, J = 5.6 Hz, 1H), 4.61 - 4.51 (m, 2H), 4.47 - 4.34 (m, 2H). Step 6: 3-Phenyl-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine A mixture of 3-bromo-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine (50mg, 188 μmol), phenylboronic acid (27.5 mg, 225 μmol), Pd(dppf)Cl2 (13.8 mg, 18.8 μmol), and Cs2CO3(184 mg, 564 μmol) in 1,4-dioxane (4 mL) and H2O (1 mL) was degassed, purged with N2 three times, and stirred at 80 °C for 16 h under N2. The reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (20 mL x 3). The organic phase was 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 (22 mg, yield :45%) was obtained as a yellow solid. MS: m / z = 264.1 [M + H]+. Step 7: 2-Bromo-3-phenyl-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine To a solution of 3-phenyl-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine (22 mg, 83.6 μmol) in CH2Cl2 (4 mL) was added NBS (14.9 mg, 83.6μmol). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was poured into H2O (20 mL) and extracted with CH2Cl2 (20 mL x 3). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (Intermediate 38, 63 mg) as a yellow solid. MS: m / z = 342.0, 344.0[M + H]+.

[0252] Intermediate 39 & 40: 2-(4-(Chloromethyl)phenyl)-3-phenyl-5,6-dihydroimidazo[2,1-a][2,7]naphthyridine & 2-(4-(chloromethyl)phenyl)-3-phenylimidazo[2,1- a][2,7]naphthyridine Br ClN N NIntermediate 39NIntermediate 40Step 1: Methyl 4-(imidazo[2,1-a][2,7]naphthyridin-2-yl)benzoate To a solution of methyl 4-(2-bromoacetyl)benzoate (1.77 g, 6.89 mmol) in EtOH (30 mL) were added NaHCO3(868 mg, 10.3 mmol) and 2,7-naphthyridin-1-amine (1 g, 6.89 mmol). The mixture was stirred at 90 °C for 16 h. The reaction mixture was concentrated underEtOAc in Petroleum ether), the title compound (380 mg, yield:18%) was obtained as a light- yellow solid. MS: m / z =304.0 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 10.03 (s, 1H), 8.74 (d, J = 5.6 Hz, 1H), 8.17 - 8.07 (m, 6H), 7.99 (s, 1H), 7.57 (d, J = 5.6 Hz, 1H), 7.06 (d, J = 7.2 Hz, 1H), 3.95 (s, 2H). Step 2: (4-(Imidazo[2,1-a][2,7]naphthyridin-2-yl)phenyl)methanol To a solution of methyl 4-(imidazo[2,1-a][2,7]naphthyridin-2-yl)benzoate (170 mg, 560 μmol) in THF (5 mL) was added LiAlH4 (448 μL, 2.5 M in THF) dropwise at 0 °C under N2. The mixture was stirred at this temperature for 20 min. The resulting mixture was stirred at 25 °C for 1 h under N2. The reaction mixture was quenched with Na2SO4(10 × H2O ) (2 g) at 0°C, filtered, and concentrated under reduced pressure. The title compound (150 mg) was obtained as a yellow solid. MS: m / z =275.9 , 278.0 [M + H]+. Step 3: (4-(5,6-Dihydroimidazo[2,1-a][2,7]naphthyridin-2-yl)phenyl)methanol To a solution of (4-(imidazo[2,1-a][2,7]naphthyridin-2-yl)phenyl)methanol (150 mg, 545 μmol) in MeOH (5 mL) was added Pd / C (290 mg, 272 μmol, 10%) under N2. The suspension was degassed and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25 °C for 16 h. The reaction mixture was filtered and concentrated to give the title compound (150 mg) as a light-yellow solid. MS: m / z =277.9 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.02 (s, 1H), 8.51 (s, 2H), 7.80 - 7.77 (m, 2H), 7.39 (d, J = 4.8 Hz, 1H), 7.33 (d, J = 7.6 Hz, 2H), 5.25 - 5.21 (m, 1H), 4.51 - 4.48 (m, 2H), 4.28 - 4.23 (m, 2H), 3.20 - 3.17 (m, 2H). Step 4: (4-(3-Bromo-5,6-dihydroimidazo[2,1-a][2,7]naphthyridin-2-yl)phenyl)methanol To a solution of (4-(5,6-Dihydroimidazo[2,1-a][2,7]naphthyridin-2-yl)phenyl)methanol (150 mg, 541 μmol) in CH2Cl2(10 mL) was added NBS (96.3 mg, 541 μmol). The mixture was stirred at 25 °C for 1 h. The mixture was diluted with H2O (10 mL) and extracted with CH2Cl2 (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 5% MeOH in CH2Cl2), the title compound (70 mg, yield: 36% for three steps) was obtained as a yellow solid. MS: m / z =356.1, 358.1 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.03 (s, 1H), 8.50 (d, J = 4.8 Hz, 1H), 7.94 (d, J = 7.6 Hz, 2H), 7.44 - 7.39 (m, 3H), 5.29 - 5.18 (m, 1H), 4.53 (s, 2H), 4.23 - 4.18 (m, 2H), 3.27 - 3.23 (m, 2H). Step 5: (4-(3-Phenyl-5,6-dihydroimidazo[2,1-a][2,7]naphthyridin-2-yl)phenyl)methanol A mixture of (4-(3-bromo-5,6-dihydroimidazo[2,1-a][2,7]naphthyridin-2-yl)phenyl)methanol (70 mg 197 μmol) phenylboronic acid (359 mg 295 μmol) Pd(dppf)Cl2 (144 mg 197μmol) , and Cs2CO3 (128 mg, 393 μmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was degassed, purged with N2three times, and stirred at 100 °C for 16 h under N2. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 5% MeOH in CH2Cl2), the title compound (60 mg, yield: 86%) was obtained as a yellow solid. MS: m / z =354.0 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.16 - 9.05 (m, 1H), 8.56 - 8.47 (m, 1H), 7.54 - 7.49 (m, 3H), 7.45 - 7.41 (m, 5H), 7.20 (d, J = 8.0 Hz, 2H), 5.26 - 5.01 (m, 1H), 4.45 (s, 2H), 4.04 - 3.99 (m, 2H), 3.20 - 3.16 (m, 2H). Step 6: 2-(4-(Chloromethyl)phenyl)-3-phenyl-5,6-dihydroimidazo[2,1-a][2,7]naphthyridine & 2-(4-(chloromethyl)phenyl)-3-phenylimidazo[2,1-a][2,7]naphthyridine To a solution of (4-(3-phenyl-5,6-dihydroimidazo[2,1-a][2,7]naphthyridin-2- yl)phenyl)methanol (60 mg, 170 μmol) in CH2Cl2 (2 mL) and SOCl2 (0.3 mL). The mixture was stirred at 40 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure. Intermediate 39 and Intermediate 40 (60 mg, HCl salt, a mixture) were obtained as a yellow solid. MS: m / z =372.2, 374.2, 370.2, 372.2 [M + H]+.

[0253] Intermediate 41: 2-Bromo-3-phenyl-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepineStep 1: 5,6-Dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine To a solution of 4-(1H-imidazol-2-yl)pyridin-3-ol (1 g, 6.20 mmol, refer to Intermediate 32 for detail procedures) and Cs2CO3 (7.08 g, 21.7 mmol) in DMF (10 mL) was added 1,2- dibromoethane (4.08 g, 21.7 mmol) at 0 °C. The mixture was stirred at 90 °C for 2 h. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (50 mLx 5). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 5%MS: m / z = 188.1 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.34 (s, 1H), 8.25 - 8.17 (m, 2H), 7.45 (d, J = 1.2 Hz, 1H), 7.14 (d, J = 1.2 Hz, 1H), 4.53 - 4.48 (m, 4H). Step 2: 3-Bromo-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine To a solution of 5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine (132 mg, 705 μmol) in DMF (4 mL) was added NBS (126 mg, 705 μmol). The mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched with H2O (20 mL) and extracted with EtOAc (30 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% ~ 3% MeOH in CH2Cl2), the title compound (140 mg, yield: 37 %) was obtained as a yellow solid. MS: m / z = 265.9, 267.9 [M + H]+. 1H NMR (400MHz, Dimethylsulfoxide-d6) 8.36 (s, 1H), 8.25 (d, J = 5.2 Hz, 1H), 8.18 (d, J = 5.2 Hz, 1H), 7.32 (s, 1H), 4.58 - 4.53 (m, 2H), 4.44 - 4.39 (m, 2H). Step 3: 3-Phenyl-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine A mixture of 3-bromo-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine (140 mg, 526 μmol), phenylboronic acid (70.6 mg, 579 μmol), Cs2CO3 (514 mg, 1.58 mmol), and Pd(dppf)Cl2(38.5 mg, 52.6 μmol) in 1,4-dioxane (4 mL) and H2O (1 mL) was degassed, purged with N2 three times, and stirred at 80 °C for 16 h under N2. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (20 mL x 3). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 45% EtOAc in petroleum ether, the title compound (145 mg, yield :91%) was obtained as a brown solid. MS: m / z = 264.0 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.36 (s, 1H), 8.32 - 8.18 (m, 2H), 7.58 - 7.49 (m, 4H), 7.48 - 7.42 (m, 1H), 7.31 (s, 1H), 4.51 - 4.44 (m, 4H). Step 4: 2-Bromo-3-phenyl-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine To a solution of 3-phenyl-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine (145 mg, 551 μmol) in CH2Cl2(6 mL) and EtOH (3 mL) was added NBS (108 mg, 606 μmol). The mixture was stirred at 25 °C for 1 h. 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. The title compound (Intermediate 41, 192 mg) was obtained as a yellow solid. MS: m / z = 342.0, 344.0 [M + H]+.

[0254] Intermediate 42: 2-Bromo-10-fluoro-3-phenyl-5H-imidazo[1,2-c]pyrido[3,2-e][1,3]oxazineStep 1: 4-Bromo-2-fluoro-3-(1H-imidazol-2-yl)pyridine To a solution of 4-bromo-2-fluoronicotinaldehyde (5 g, 24.5 mmol) and oxaldehyde (7.83 mL, 60.1 mmol) in MeOH (50 mL) was added NH3.H2O (13.3 mL, 96.8 mmol, 28% purity) dropwise at 0 °C. The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 45% EtOAc in Petroleum ether), the title compound (1.8 g, yield: 30%) was obtained as a yellow solid. MS: m / z = 241.8, 243.8 [M + H]+.1H NMR (400 MHz, Dimethysulfoxide-d6) δ 12.50 (br s, 1H), 8.22 (d, J = 5.2 Hz, 1H), 7.82 (d, J = 5.6 Hz, 1H), 7.41 - 7.31 (m, 1H), 7.16 - 7.07 (m, 1H). Step 2: 10-Bromo-5H-imidazo[1,2-c]pyrido[3,2-e][1,3]oxazine To a solution of 4-bromo-2-fluoro-3-(1H-imidazol-2-yl)pyridine (2.7 g, 11.2 mmol) in i- PrOH (80 mL) were added HCHO (10.4 mL, 139 mmol, 37% purity) and KOH (2.5 g, 44.6 mmol). The mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 60% EtOAc in Petroleum ether), the title compound (2 g, yield: 71%) was obtained as a yellow solid. MS: m / z = 253.9, 255.9 [M + H]+.1H NMR (400 MHz, Dimethysulfoxide-d6) δ 8.03 (d, J = 5.6 Hz, 1H), 7.55 (d, J = 5.2 Hz, 1H), 7.42 (d, J = 0.8 Hz, 1H), 7.24 (d, J = 1.2 Hz, 1H), 6.15 (s, 2H). Step 3: 10-Fluoro-5H-imidazo[1,2-c]pyrido[3,2-e][1,3]oxazine To a solution of 10-bromo-5H-imidazo[1,2-c]pyrido[3,2-e][1,3]oxazine (700 mg, 2.78 mmol) in DMSO (5 mL) were added CsF (844 mg, 5.55 mmol) and 1,4,7,10,13,16- hexaoxacyclooctadecane (367 mg, 1.39 mmol). The mixture was stirred at 100 °C for 16 h. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (100 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flashmg, yield: 60%) was obtained as a yellow solid. MS: m / z = 192.0 [M + H]+.1H NMR (400 MHz, Dimethysulfoxide-d6) δ 8.23 (dd, J = 8.4, 6.0 Hz, 1H), 7.39 (s, 1H), 7.27 - 7.22 (m, 1H), 7.20 (s, 1H), 6.17 (s, 2H).19F NMR (400 MHz, Dimethysulfoxide-d6) δ -103.246. Step 4: 3-Bromo-10-fluoro-5H-imidazo[1,2-c]pyrido[3,2-e][1,3]oxazine To a solution of 10-fluoro-5H-imidazo[1,2-c]pyrido[3,2-e][1,3]oxazine (300 mg, 1.57 mmol) in CH2Cl2(10 mL) was added NBS (223 mg, 1.26 mmol). The mixture was stirred at 0 °C for 1 h. The mixture was diluted with H2O (20 mL) and extracted with CH2Cl2 (20 mL ×2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 50% EtOAc in Petroleum ether), the title compound (230 mg, yield: 54%) was obtained as a light-yellow solid. MS: m / z = 270.0, 272.0 [M + H]+.1H NMR (400 MHz, Dimethysulfoxide-d6) δ 8.27 (dd, J = 8.4, 6.0 Hz, 1H), 7.32 (s, 1H), 7.30 - 7.24 (m, 1H), 6.13 (s, 2H). Step 5: 10-Fluoro-3-phenyl-5H-imidazo[1,2-c]pyrido[3,2-e][1,3]oxazine A mixture of 3-bromo-10-fluoro-5H-imidazo[1,2-c]pyrido[3,2-e][1,3]oxazine (230 mg, 852 μmol), phenylboronic acid (156 mg, 1.28 mmol), Cs2CO3(555 mg, 1.70 mmol), and Pd(dppf)Cl2(62.3 mg, 85.2 μmol) in 1,4-dioxane (10 mL) and H2O (2 mL) was degassed, purged with N2 three times, and stirred at 80 °C for 16 h under N2. The mixture was diluted with H2O (20 mL) and extracted with CH2Cl2 (20 mL × 2). The combined organic layers were washed with brine (20 mL ), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 50% EtOAc in Petroleum ether), the title compound (130 mg, yield: 57%) was obtained as a light- yellow solid. MS: m / z = 267.9 [M + H]+.1H NMR (400 MHz, Dimethysulfoxide-d6) δ 8.26 (dd, J = 8.0, 6.0 Hz, 1H), 8.02 (s, 1H), 7.79 - 7.76 (m, 1H), 7.51 - 7.42 (m, 5H), 6.26 (s, 2H).19F NMR (400 MHz, Dimethysulfoxide-d6) δ -103.178. Step 6: 2-Bromo-10-fluoro-3-phenyl-5H-imidazo[1,2-c]pyrido[3,2-e][1,3]oxazine To a solution of 10-fluoro-3-phenyl-5H-imidazo[1,2-c]pyrido[3,2-e][1,3]oxazine (130 mg, 486 μmol) in CH2Cl2(5 mL) was added NBS (86.6 mg, 486 μmol). The mixture was stirred at 25 °C for 1 h. The mixture was diluted with H2O (20 mL) and extracted with CH2Cl2 (20 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (Intermediate 42, 160 mg) as a yellow solid. MS: m / z = 346.0, 348.0 [M + H]+.1H NMR (400 MHz, Dimethysulfoxide-d6) δ 8.30 (dd, J = 8.4, 6.0 Hz, 1H), 7.59 - 7.50 (m, 5H), 7.34 - 7.30 (m,

[0255] Intermediate 43: 4-(((3S,4S)-3-Fluoropiperidin-4-yl)amino)pyrimidine-2-carbonitrileStep 1: tert-Butyl (3S,4S)-4-((2-cyanopyrimidin-4-yl)amino)-3-fluoropiperidine-1- carboxylate To a solution of tert-butyl (3S,4S)-4-amino-3-fluoropiperidine-1-carboxylate (250 mg, 1.15 mmol) and 4-chloropyrimidine-2-carbonitrile (160 mg, 1.15 mmol) in MeCN (3 mL) were added K2CO3(792 mg, 5.73 mmol) and NaI (17.2 mg, 115 ^mol). The mixture was stirred at 80 °C for 1 h. The reaction mixture was quenched with H2O (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous 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 (160 mg, yield: 43%) was obtained as a yellow solid. MS: m / z = 322.1 [M + H]+. 1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.25 - 8.12 (m, 2H), 6.74 (d, J = 5.6 Hz, 1H), 4.46 - 4.17 (m, 2H), 3.99 - 3.87 (m, 1H), 3.73 - 3.62 (m, 1H), 3.20 - 2.84 (m, 2H), 1.98 - 1.86 (m, 1H), 1.46 - 1.43 (m, 1H), 1.41 (s, 9H).19F NMR (400 MHz, Dimethylsulfoxide-d6) δ - 187.224. Step 2: 4-(((3S,4S)-3-Fluoropiperidin-4-yl)amino)pyrimidine-2-carbonitrile To a solution of tert-butyl (3S,4S)-4-((2-cyanopyrimidin-4-yl)amino)-3-fluoropiperidine-1- carboxylate (45 mg, 140 μmol) in CH2Cl2 (2 mL) was added TFA (0.2 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction was concentrated under reduced pressure to give the title compound (Intermediate 43, 47 mg, TFA salt) as a yellow oil. MS: m / z = 222.0 [M + H]+.

[0256] Intermediate 44: 3-Chloro-4-phenyl-5H-pyrano[2,3-c:4,5-c']dipyridineStep 1: 6-Chloro-3'-fluoro-[3,4'-bipyridine]-4-carbaldehyde To a solution of (3-fluoropyridin-4-yl)boronic acid (4.0 g, 28.4 mmol) and 5-bromo-2- chloroisonicotinaldehyde (6.26 g, 28.4 mmol) in H2O (10 mL) and DMA (50 mL) were added Pd(dppf)Cl2(2.08 g, 2.84 mmol) and Na2CO3(9.03 g, 85.2 mmol). The mixture was degassed, purged with N2three times, and stirred at 90 °C for 2 h under N2. The reaction was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 10% ~ 35% EtOAc in petroleum ether), the title compound (950 mg, yield: 11%) was obtained as a brown oil. MS: m / z = 237.0, 239.0 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.93 (d, J = 2.0 Hz, 1H), 8.72 (d, J = 1.6 Hz, 1H), 8.69 (s, 1H), 8.60 (dd, J = 4.8, 0.4 Hz, 1H), 8.05 (s, 1H), 7.66 (dd, J = 6.4, 4.8 Hz, 1H).19F NMR (400 MHz, Dimethylsulfoxide-d6) δ -130.993. Step 2: (6-Chloro-3'-fluoro-[3,4'-bipyridin]-4-yl)methanol To a solution of 6-chloro-3'-fluoro-[3,4'-bipyridine]-4-carbaldehyde (950 mg, 4.01 mmol) in EtOH (20 mL) was degassed and purged with N2three times. NaBH4(360 mg, 9.52 mmol) was added to the above solution at 0 °C. The mixture was stirred at 25 °C for 0.5 h under N2. The reaction mixture was quenched with NH4Cl (20 mL) at 0 °C under N2 and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The title compound (950 mg) was obtained as a brown solid. MS: m / z = 239.1, 241.1 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.73 (d, J = 1.2 Hz, 1H), 8.59 - 8.53 (m, 1H), 8.33 (s, 1H), 7.68 (s, 1H), 7.54 (dd, J = 6.4, 4.8 Hz, 1H), 5.62 (t, J = 5.6 Hz, 1H), 4.38 (d, J = 5.6 Hz, 2H). Step 3: 3-Chloro-5H-pyrano[2,3-c:4,5-c']dipyridineA solution of (6-chloro-3'-fluoro-[3,4'-bipyridin]-4-yl)methanol (50 mg, 210 μmol) in DMF (12 mL) was degassed and purged with N2three time. t-BuOK (47 mg, 419 μmol) was added to the above solution at 0 °C. The mixture was stirred at 60 °C for 0.5 h under N2. The reaction was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 45% EtOAc in petroleum ether), the title compound (80 mg, yield: 19% for two steps) was obtained as a yellow solid. MS: m / z = 219.1, 221.0 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 8.76 (s, 1H), 8.39 (s, 1H), 8.35 (d, J = 4.8 Hz, 1H), 7.60 (d, J = 4.8 Hz, 1H), 7.19 (s, 1H), 5.18 (s, 2H). Step 4: 3-Methoxy-5H-pyrano[2,3-c:4,5-c']dipyridine A solution of 3-chloro-5H-pyrano[2,3-c:4,5-c']dipyridine (60 mg, 274 μmol) in MeOH (5 mL) was degassed and purged with N2 three times. NaOMe (44.5 mg, 823 μmol) was added to the above solution at 0 °C. The mixture was stirred at 60 °C for 12 h under N2. The reaction mixture was quenched with H2O (10 mL) and extracted with CH2Cl2(15 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (58.7 mg) as a yellow solid. MS: m / z = 215.2 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.80 (s, 1H), 8.28 (s, 1H), 8.25 (d, J = 5.2 Hz, 1H), 7.89 (d, J = 5.2 Hz, 1H), 6.84 - 6.80 (m, 1H), 5.22 (s, 2H), 3.91 (s, 3H). Step 5: 5H-Pyrano[2,3-c:4,5-c']dipyridin-3-ol A solution of 3-methoxy-5H-pyrano[2,3-c:4,5-c']dipyridine (58 mg, 271 μmol) in MeCN (3 mL) was degassed and purged with N2 three times. TMSI (108 mg, 542 μmol) was added to the above solution at 0 °C. The mixture was stirred at 80 °C for 3 h under N2. The reaction mixture was quenched with H2O (1 mL) at 0 °C and concentrated under reduced pressure to give the title compound (54.9 mg) as a yellow solid. MS: m / z = 201.0 [M + H]+. Step 6: 4-Bromo-5H-pyrano[2,3-c:4,5-c']dipyridin-3-ol To a solution of 5H-pyrano[2,3-c:4,5-c']dipyridin-3-ol (54 mg, 270 μmol) in DMF (2 mL) was added NBS (96.0 mg, 539 μmol). The mixture was stirred at 80 °C for 2 h. The reaction was concentrated under reduced pressure to give the title compound (75.3 mg) as a yellow solid. MS: m / z = 278.9, 280.9 [M + H]+. Step 7: 4-Phenyl-5H-pyrano[2,3-c:4,5-c']dipyridin-3-ol To a solution of 4-bromo-5H-pyrano[2,3-c:4,5-c']dipyridin-3-ol (75 mg, 269 μmol) and phenylboronic acid (36.0 mg, 296 μmol) in 1,4-dioxane (5 mL) and H2O (1 mL) were added Pd(dppf)Cl2 (39.3 mg, 53.8 μmol) and Cs2CO3 (263 mg, 806 μmol). The mixture was degassed purged with N2 three times and stirred at 80 °C for 16 h under N2 The reactionwas concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 10% MeOH in CH2Cl2), the title compound (20 mg) was obtained as a yellow solid. MS: m / z = 277.0 [M + H]+. Step 8: 3-Chloro-4-phenyl-5H-pyrano[2,3-c:4,5-c']dipyridine A solution of 4-phenyl-5H-pyrano[2,3-c:4,5-c']dipyridin-3-ol (20 mg, 72.4 μmol) in POCl3 (1 mL). was stirred at 100 °C for 16 h. The reaction mixture was poured into H2O (20 mL) at 30 °C. The pH of the mixture was adjusted to 8 with sat. Na2CO3. The mixture was extracted with CH2Cl2 (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (Intermediate 44, 21 mg) as a brown solid. MS: m / z = 295.0, 296.9 [M + H]+.

[0257] Intermediate 45: 4-(4-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazin-1-yl)pyrimidine-2-carbonitrileStep 1: 4-(4-(4-Bromobenzyl)piperazin-1-yl)pyrimidine-2-carbonitrile To a solution of 1-bromo-4-(chloromethyl)benzene (9.95 g, 48.4 mmol) and Intermediate 16 (7.34 g, 24.2 mmol, TFA salt) in DMF (100 mL) were added K2CO3 (16.7 g, 121 mmol) and NaI (363 mg, 2.42 mmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with H2O (200 mL) and extracted with EtOAc (250 mL x 2). The combined organic layers were washed with brine (500 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0 ~ 5% MeOH in CH2Cl2), the title compound (8 g, yield: 74%) was obtained as an off-white solid. MS: m / z = 358.0, 359.9 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 8.17 (d, J = 6.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 6.57 (d, J = 6.4 Hz, 1H), 3.78 - 3.59 (m, 4H), 3.50 (s, 2H), 2.55 - 2.43 (m, 4H). Step 2: 4-(4-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazin-1- yl)pyrimidine-2-carbonitrile A mixture of 4-(4-(4-bromobenzyl)piperazin-1-yl)pyrimidine-2-carbonitrile (8 g, 22.3 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (11.3 g, 44.7 mmol), KOAc (6.57 g, 67.0 mmol), and Pd(dppf)Cl2 (1.63 g, 2.23 mmol) in 1,4-dioxane (100 mL) was degassed, purged with N2three times, and stirred at 80 °C for 2 h under N2. The reaction mixture was quenched with H2O (100 mL) at 25 °C and extracted with CH2Cl2(150 mL x 2). The combined organic layers were washed with brine (300 mL x 3), dried over anhydrousflash chromatography (Eluent of 0 ~ 30% EtOAc in petroleum ether), the title compound (Intermediate 45, 6.5 g, yield: 67%) was obtained as a yellow solid. MS: m / z = 406.1 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 8.17 (d, J = 6.4 Hz, 1H), 7.79 (d, J = 7.6 Hz, 2H),7.34 (d, J = 8.0 Hz, 2H), 6.56 (d, J = 6.4 Hz, 1H), 3.80 - 3.61 (m, 4H), 3.57 (s, 2H), 2.55 - 2.47 (m, 4H), 1.35 (s, 12H).

[0258] Intermediate 46: 2-(4-(Chloromethyl)phenyl)-3-phenyl-5H-imidazo[1,2-c]pyrido[4,3-e][1,3]oxazine Cl O N InteIntermediate 46 was prepared in a similar manner to Intermediate 17. MS: m / z = 374.0, 376.0 [M + H]+.

[0259] Intermediate 47: 2-Bromo-10-methoxy-3-phenyl-5H-imidazo[1,2-c]pyrido[3,2-e][1,3]oxazineStep 1: 10-Methoxy-5H-imidazo[1,2-c]pyrido[3,2-e][1,3]oxazine To a solution of 2-fluoro-3-(1H-imidazol-2-yl)-4-methoxypyridine (300 mg, 1.55 mmol, refer to Intermediate 35 for detail procedures) in i-PrOH (20 mL) were added HCHO (1.58 g, 19.4 mmol, 37% purity in water) and KOH (349 mg, 6.21 mmol). The mixture was degassed, purged with N2three times, and stirred at 80 °C for 16 h under N2. The reaction mixture was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 3% MeOH in CH2Cl2), the title compound (230 mg, yield: 72%) was obtained as a light-yellow solid. MS: m / z = 204.0 [M + H]+.1H NMR (400 MHz, Dimethysulfoxide-d6) δ 8.10 (d, J = 6.0 Hz, 1H), 7.28 (s, 1H), 7.10 (s, 1H), 7.00 (d, J = 6.0 Hz, 1H), 6.02 (s, 2H), 3.96 (s, 3H). Step 2: 3-Bromo-10-methoxy-5H-imidazo[1,2-c]pyrido[3,2-e][1,3]oxazineμmol) in CH2Cl2 (5 mL) was added NBS (158 mg, 886 μmol). The mixture was stirred at 0 °C for 1 h. The mixture was diluted with H2O (20 mL) and extracted with CH2Cl2 (20 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 90% EtOAc in Petroleum ether), the title compound (90 mg, yield: 36%) was obtained as a white solid. MS: m / z = 281.9, 283.9 [M + H]+.1H NMR (400 MHz, Dimethysulfoxide-d6) δ 8.14 (d, J = 6.0 Hz, 1H), 7.21 (s, 1H), 7.03 (d, J = 6.0 Hz, 1H), 5.98 (s, 2H), 3.97 (s, 3H). Step 3: 10-Methoxy-3-phenyl-5H-imidazo[1,2-c]pyrido[3,2-e][1,3]oxazine A mixture of 3-bromo-10-methoxy-5H-imidazo[1,2-c]pyrido[3,2-e][1,3]oxazine (90 mg, 319 μmol), phenylboronic acid (46.7 mg, 383 μmol), Cs2CO3(208 mg, 638 μmol), and Pd(dppf)Cl2 (23.3 mg, 31.9 μmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was degassed, purged with N2 three times, and stirred at 100 °C for 2 h under N2. The mixture was diluted with H2O (10 mL) and extracted with CH2Cl2 (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 100% EtOAc in Petroleum ether), the title compound (73 mg, yield: 81%) was obtained as a light-yellow solid. MS: m / z = 280.0 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 8.15 (d, J = 6.0 Hz, 1H), 7.51 - 7.45 (m, 2H), 7.43 - 7.39 (m, 1H), 7.39 - 7.34 (m, 3H), 6.79 (d, J = 6.0 Hz, 1H), 5.96 (s, 2H), 4.12 (s, 3H). Step 4: 2-Bromo-10-methoxy-3-phenyl-5H-imidazo[1,2-c]pyrido[3,2-e][1,3]oxazine To a solution of 10-methoxy-3-phenyl-5H-imidazo[1,2-c]pyrido[3,2-e][1,3]oxazine (70 mg, 251 μmol) in CH2Cl2 (3 mL) was added NBS (44.6 mg, 251 μmol). The mixture was stirred at 25 °C for 1 h. The mixture was diluted with H2O (10 mL) and extracted with CH2Cl2 (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The title compound (Intermediate 47, 90 mg) was obtained as a light-yellow solid. MS: m / z = 357.8, 359.8 [M + H]+.

[0260] Intermediate 48: 2-Bromo-3-phenyl-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepineStep 1: 2-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-3-(1H-imidazol-2-yl)pyridine To a solution of 3-(1H-imidazol-2-yl)pyridin-2-ol (1 g, 6.20 mmol, refer to Intermediate 1 for similar procedures), 2-((tert-butyldimethylsilyl)oxy)ethan-1-ol (1.37 g, 7.76 mmol), and PPh3 (2.44 g, 9.31 mmol) in THF (10 mL) was added slowly DEAD (1.62 g, 9.31 mmol) at 0 °C. The mixture was degassed, purged with N2 three times, and stirred at 25 °C for 2 h under N2. The reaction mixture was concentrated under reduced pressure. After purification by prep- HPLC (column: XPT C18250 x 70 x 7 µm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 38% - 78% B over 27 min), the title compound (607 mg, yield: 31%) was obtained as a yellow oil. MS: m / z = 320.6 [M+H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 11.61 (br s, 1H), 8.38 (dd, J = 7.2, 2.0 Hz, 1H), 8.14 (dd, J = 4.8, 2.0 Hz, 1H), 7.22 - 7.00 (m, 3H), 4.56 (t, J = 5.2 Hz, 2H), 4.01 (t, J = 5.2 Hz, 2H), 0.80 (s, 9H), -0.03 (s, 6H). Step 2: 2-((3-(1H-Imidazol-2-yl)pyridin-2-yl)oxy)ethan-1-ol To a solution of 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-3-(1H-imidazol-2-yl)pyridine (4.42 g, 13.8 mmol) in THF (40 mL) was added TBAF (20.8 mL, 1 M in THF). The mixture was degassed, purged with N2 three times, and stirred at 25 °C for 1 h under N2. The reaction mixture was diluted with EtOAc (200 mL), washed with brine (200 mL x 4), 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 (2.79 g, yield: 97%) was obtained as a colorless oil. MS: m / z = 206.1 [M+H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 12.03 - 11.41 (m, 1H), 8.39 (dd, J = 7.6, 1.6 Hz, 1H), 8.15 (dd, J = 4.4, 1.6 Hz, 1H), 7.24 - 7.14 (m, 2H), 7.11 (dd, J = 7.6, 4.4 Hz, 1H), 5.27 - 5.06 (m, 1H), 4.47 (t, J = 4.8 Hz, 2H), 3.82 (t, J = 4.8 Hz, 2H). Step 3: 5,6-Dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine A solution of 2-((3-(1H-imidazol-2-yl)pyridin-2-yl)oxy)ethan-1-ol (1.5 g, 7.31 mmol), 2- (tributyl-λ5-phosphaneylidene)acetonitrile (17.6 g, 73.1 mmol) in toluene (150 mL) was degassed, purged with N2 three times, and stirred at 115 °C for 16 h under N2. The reactionflash chromatography (Eluent of 0% ~ 85% EtOAc in petroleum ether), the title compound (1.6 g, yield: 82%) was obtained as a brown oil. MS: m / z = 188.1 [M+H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.79 (dd, J = 8.0, 2.0 Hz, 1H), 8.19 (dd, J = 4.4, 2.0 Hz, 1H), 7.36 (d, J = 1.2 Hz, 1H), 7.20 (dd, J = 8.0, 4.4 Hz, 1H), 7.08 (d, J = 1.2 Hz, 1H), 4.55 - 4.52 (m, 2H), 4.48 - 4.45 (m, 2H). Step 4: 3-Bromo-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine To a solution of 5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine (500 mg, 2.67 mmol) in CH2Cl2 (15 mL) and EtOH (3 mL) was added NBS (238 mg, 1.34 mmol). The mixture was degassed, purged with N2three times, and stirred at 0 °C for 0.5 h under N2. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 45% EtOAc in petroleum ether), the title compound (150 mg, yield: 21%) was obtained as an off-white solid. MS: m / z = 265.8, 267.8 [M+H]+.1H NMR (400 MHz, Chloroform-d) δ 8.86 (dd, J = 8.0, 2.0 Hz, 1H), 8.26 (dd, J = 4.4, 2.0 Hz, 1H), 7.19 (s, 1H), 7.15 (dd, J = 8.0, 4.4 Hz, 1H), 4.66 - 4.58 (m, 2H), 4.41 - 4.35 (m, 2H). Step 5: 3-Phenyl-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine To a solution of 3-bromo-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine (150 mg, 564 μmol) and phenylboronic acid (82.5 mg, 676 μmol) in 1,4-dioxane (3 mL) and H2O (0.6 mL) were added Pd(dppf)Cl2 (41.3 mg, 56.4 μmol) and Cs2CO3 (551 mg, 1.69 mmol). The mixture was degassed, purged with N2 three times, and stirred at 90 °C for 2 h under N2. The reaction mixture was quenched with EtOAc (30 mL) and washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 45% EtOAc in petroleum ether), the title compound (40 mg, yield: 27%) was obtained as an off-white solid, which was used directly in the next step. MS: m / z = 264.1 [M+H]+. Step 6: 2-Bromo-3-phenyl-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine To a solution of 3-phenyl-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine (40 mg, 152 μmol) in EtOH (1 mL) and CH2Cl2(5 mL) was added NBS (32.5 mg, 182 μmol). The mixture was degassed, purged with N2 three times, and stirred at 25 °C for 1 h under N2. The reaction mixture was diluted with CH2Cl2 (20 mL) and stirred for 10 mins. The mixture was washed with brine (20 mL x 4), dried over Na2SO4, filtered, and concentrated under reduced pressure. The title compound (Intermediate 48, 52.0 mg) was obtained as a yellow solid, which was used directly in the next step MS: m / z = 3418 3439 [M+H]+

[0261] Intermediate 49: 2-Bromo-3-phenyl-6,7-dihydro-5H-imidazo[1,2-a]pyrido[3,4-c]azepineStep 1: 4-Chloro-3-(1H-imidazol-2-yl) pyridine To a solution of 4-chloronicotinaldehyde (10 g, 70.6 mmol) and oxalaldehyde (22.6 mL, 173 mmol, 40% purity in water) in MeOH (100 mL) was added dropwise NH3.H2O (38.3 mL, 278 mmol, 28% purity) at 0 °C. The resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 3% MeOH in CH2Cl2), the title compound (8.3 g, yield: 65%) was obtained as a yellow solid. MS: m / z = 180.1, 182.1 [M + H]+.1H NMR (400 MHz, Dimethysulfoxide-d6) δ 12.69 - 12.22 (m, 1H), 8.91 (s, 1H), 8.52 (d, J = 5.6 Hz, 1H), 7.66 - 7.64 (m, 1H), 7.26 (br s, 1H), 7.02 (s, 1H). Step 2: 3-(1-Allyl-1H-imidazol-2-yl)-4-chloropyridine To a solution of 4-chloro-3-(1H-imidazol-2-yl) pyridine (4 g, 22.3 mmol) in DMF (50 mL) were added Cs2CO3 (14.5 g, 44.5 mmol) and 3-bromoprop-1-ene (4.04 g, 33.4 mmol). The mixture was stirred at 80 °C for 2 h. The mixture was diluted with H2O (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL×3), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 3% MeOH in CH2Cl2), the title compound (4 g, yield: 82%) was obtained as a yellow oil. MS: m / z = 220.0, 221.9 [M + H]+.1H NMR (400 MHz, Dimethysulfoxide-d6) δ 8.65 (d, J = 5.2 Hz, 1H), 8.59 (s, 1H), 7.72 (d, J = 5.2 Hz, 1H), 7.35 (s, 1H), 7.12 - 7.10 (m, 1H), 6.07 - 5.74 (m, 2H), 5.08 - 5.05 (m, 1H), 4.47 (br d, J = 5.2 Hz, 2H). Step 3: 3-(1-Allyl-1H-imidazol-2-yl)-4-vinylpyridine A mixture of 3-(1-allyl-1H-imidazol-2-yl)-4-chloropyridine (3.4 g, 15.5 mmol), 4,4,5,5- tetramethyl-2-vinyl-1,3,2-dioxaborolane (3.58 g, 23.2 mmol), Pd(dppf)Cl2 (1.13 g, 1.55 mmol), and Cs2CO3(10.1 g, 31.0 mmol) in 1,4-dioxane (30 mL) and H2O (6 mL) was degassed, purged with N2three times, and stirred at 80 °C for 16 h under N2. The mixturewas diluted with H2O (100 mL) and extracted with EtOAc (200 mL × 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 3% MeOH in CH2Cl2), the title compound (2.3 g, yield: 70%) was obtained as a brown oil. MS: m / z = 212.1 [M + H]+.1H NMR (400 MHz, Dimethysulfoxide-d6) δ 8.62 (d, J = 5.2 Hz, 1H), 8.51 (s, 1H), 7.75 (d, J = 5.2 Hz, 1H), 7.36 - 7.29 (m, 1H), 7.14 - 7.07 (m, 1H), 6.57 - 6.46 (m, 1H), 6.08 - 6.01 (m, 1H), 5.88 - 5.77 (m, 1H), 5.56 - 5.47 (m, 1H), 5.10 - 5.05 (m, 10.2 Hz, 1H), 4.85 - 4.76 (m, 1H), 4.45 - 4.38 (m, 2H). Step 4: 5H-imidazo[1,2-a]pyrido[3,4-c]azepine A mixture of 3-(1-allyl-1H-imidazol-2-yl)-4-vinylpyridine (0.5 g, 2.37 mmol) benzylidene- [1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro ruthenium;tricyclohexylphosphane (1.00 g, 1.18 mmol) in CH2Cl2(150 mL) was degassed, purged with N2three times, and stirred at 40 °C for 16 h under N2. The mixture was diluted with H2O (100 mL) and extracted with CH2Cl2 (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by prep-HPLC (column: CD24-XPT C18150 × 25 × 7μm; mobile phase: [water (NH4HCO3)-ACN]; gradient:4%-34% B over 10 min), the title compound (20 mg, yield: 10%) was obtained as a light-yellow oil. MS: m / z = 184.0 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 9.36 (s, 1H), 8.57 (d, J = 5.2 Hz, 1H), 7.24 - 7.22 (m, 1H), 7.14 (d, J = 5.2 Hz, 1H), 6.99 - 6.97 (m, 1H), 6.74 (d, J = 10.8 Hz, 1H), 6.36 - 6.28 (m, 1H), 4.50 (d,6.4 Hz, 2H). Step 5: 6,7-Dihydro-5H-imidazo[1,2-a]pyrido[3,4-c]azepine To a solution of 5H-imidazo[1,2-a]pyrido[3,4-c]azepine (150 mg, 819 μmol) in MeOH (5 mL) was added Pd / C (100 mg, 94.0 μmol, 10% purity) under Ar. The suspension was degassed and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25 °C for 5 h. The reaction mixture was filtered and concentrated. The title compound (140 mg) was obtained as a yellow solid. MS: m / z = 186.1 [M + H]+. Step 6: 3-Bromo-6,7-dihydro-5H-imidazo[1,2-a]pyrido[3,4-c]azepine To a solution of 6,7-Dihydro-5H-imidazo[1,2-a]pyrido[3,4-c]azepine (20 mg, 108.0 μmol) in CH2Cl2 (2 mL) was added NBS (19.2 mg, 108.0 μmol). The mixture was stirred at 0 °C for 0.5 h. The mixture was diluted with H2O (10 mL) and extracted with CH2Cl2 (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The title compound (30 mg) was obtained as a light-yellow solid MS: m / z = 2639 2659 [M + H]+ 1H NMR (400 MHz Chloroform-d) δ9.04 (s, 1H), 8.56 (d, J = 4.8 Hz, 1H), 7.22 (br d, J = 4.4 Hz, 1H), 7.18 (s, 1H), 3.97 (t, J = 6.8 Hz, 2H), 2.80 - 2.77 (m, 2H), 2.39 - 2.34 (m, 2H). Step 7: 3-Phenyl-6,7-dihydro-5H-imidazo[1,2-a]pyrido[3,4-c]azepine A mixture of 3-Bromo-6,7-dihydro-5H-imidazo[1,2-a]pyrido[3,4-c]azepine (50 mg, 189 μmol), phenylboronic acid (34.6 mg, 284.0 μmol), Cs2CO3 (123 mg, 379 μmol), and Pd(dppf)Cl2(13.9 mg, 18.9 μmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was degassed, purged with N2 three times, and stirred at 80 °C for 16 h under N2. The mixture was diluted with H2O (10 mL) and extracted with CH2Cl2 (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 100% Ethyl acetate / Petroleum ether), the title compound (30 mg, yield: 61%) was obtained as a light- yellow solid. MS: m / z = 262.0 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 9.07 (s, 1H), 8.57 (d, J = 4.8 Hz, 1H), 7.51 - 7.46 (m, 2H), 7.44 - 7.40 (m, 3H), 7.29 (s, 1H), 7.24 (d, J = 4.8 Hz, 1H), 3.89 (t, J = 6.8 Hz, 2H), 2.92 - 2.88 (m, 2H), 2.50 - 2.44 (m, 2H). Step 8: 2-Bromo-3-phenyl-6,7-dihydro-5H-imidazo[1,2-a]pyrido[3,4-c]azepine To a solution of 3-phenyl-6,7-dihydro-5H-imidazo[1,2-a]pyrido[3,4-c]azepine (30 mg, 115 μmol) in CH2Cl2 (3 mL) was added NBS (20.4 mg, 115 μmol). The mixture was stirred at 25 °C for 0.5 h. The mixture was diluted with H2O (10 mL) and extracted with CH2Cl2 (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The title compound (Intermediate 49, 30 mg) was obtained as a light-yellow solid. MS: m / z = 339.9, 341.9 [M + H]+.

[0262] Intermediate 50: 2-(4-(Chloromethyl)phenyl)-3-phenyl-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepineStep 1: (4-(3-Phenyl-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin-2- yl)phenyl)methanol A mixture of Intermediate 48 (300 mg, 877 μmol), (4-(hydroxymethyl)phenyl)boronic acid (160 mg, 1.05 mmol), Pd(dppf)Cl2(64.2 mg, 87.7 μmol), and Cs2CO3(857 mg, 2.63 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) was degassed, purged with N2 three times, and stirred at 80 °C for 16 h under N2. The reaction mixture was quenched with H2O (20 mL) d t t d ith EtOA (20 L 3) Th bi d i l h d ith b i(20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 1% MeOH in CH2Cl2), the title compound (265 mg, yield: 82%) was obtained as a light-yellow solid. MS: m / z = 370.1 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.98 (dd, J = 8.0, 2.0 Hz, 1H), 8.24 (dd, J = 4.4, 2.0 Hz, 1H), 7.57 - 7.50 (m, 3H), 7.47 - 7.43 (m, 2H), 7.42 - 7.38 (m, 2H), 7.27 (dd, J = 7.6, 4.4 Hz, 1H), 7.21 - 7.15 (m, 2H), 5.10 (t, J = 5.6 Hz, 1H), 4.56 - 4.53 (m, 2H), 4.43 (d, J = 6.0 Hz, 2H), 4.20 - 4.12 (m, 2H). Step 2: 2-(4-(Chloromethyl)phenyl)-3-phenyl-5,6-dihydroimidazo[1,2-d]pyrido[3,2- f][1,4]oxazepine To a solution of (4-(3-phenyl-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin-2- yl)phenyl)methanol (265 mg, 717 μmol) in CH2Cl2 (8 mL) was added SOCl2 (3 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give the title compound (Interemdiate 50, 270 mg, HCl salt) as a yellow solid. MS: m / z = 388.0, 390.1 [M + H]+.

[0263] Example 1: 4-((1-(4-(1-Methyl-5-phenyl-1H-imidazol-4-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileStep 1: 1-Methyl-5-phenyl-1H-imidazole To a solution of 5-bromo-1-methyl-1H-imidazole (1 g, 6.21 mmol) and phenylboronic acid (909 mg, 7.45 mmol) in 1,4-dioxane (12 mL) and H2O (3 mL) were added Pd(dppf)Cl2 (454 mg, 621 μmol) and Cs2CO3 (6.07 g, 18.6 mmol). The mixture was stirred at 100 °C for 1 h under N2. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. After purification by silica gel flash chromatography (EtOAc in Petroleum ether = 0 - 30%), the title compound (420 mg, yield: 43%) was obtained as a light-yellow solid. MS: m / z = 159.2 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) 7.70 (s, 1H), 7.51 - 7.43 (m, 4H), 7.39 - 7.34 (m, 1H), 7.05 (s, 1H), 3.68 (s, 3 H). Step 2: 4-Bromo-1-methyl-5-phenyl-1H-imidazole To a solution of 1-methyl-5-phenyl-1H-imidazole (100 mg, 632 μmol) in MeCN (1 mL) was added NBS (118, 664 μmol). The mixture was stirred at 25 °C for 2 h under N2. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were dried over anhydrous Na2SO4filtered and concentrated Afterpurification by silica gel flash chromatography (Ethyl acetate in Petroleum ether = 0 - 25%), the title compound (100 mg, yield: 67%) was obtained as light-yellow oil.1H NMR (400 MHz, Dimethylsulfoxide-d6) 7.76 (s, 1H), 7.55 - 7.42 (m, 5H), 3.57 (s, 3H). Step 3: 4-((1-(4-(1-Methyl-5-phenyl-1H-imidazol-4-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile To a solution of 4-bromo-1-methyl-5-phenyl-1H-imidazole (80 mg, 337 μmol) in 1,4-dioxane (3.5 mL) and H2O (0.7 mL) were added Intermediate 3 (156 mg, 371 μmo), Pd(dppf)Cl2 (24.7 mg, 33.7 μmol) and Cs2CO3 (330 mg, 1.01 mmol). The mixture was stirred at 100 °C for 12 h under N2. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. After purification by prep-HPLC (column: C18150 x 30 mm; mobile phase: [water (NH3H2O + NH4HCO3)- ACN]; gradient: 44% - 74% B over 7 min), the title compound (Example 1, 28.3 mg, yield:19%) was obtained. MS: m / z = 450.3 [M+H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.07 (d, J = 6.4 Hz, 1H), 8.04 - 7.98 (m, 1H), 7.77 (s, 1H), 7.54 - 7.46 (m, 3H), 7.39 - 7.37 (m, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.11 d, J = 8.0 Hz, 2H), 6.65 (d, J = 6.0 Hz, 1H), 3.81 - 3.71 (m, 1H), 3.44 (s, 3H), 2.77 - 2.71 (m, 2H), 2.49 - 2.47 (m, 2H), 2.10 - 2.00 (m, 2H), 1.86 - 1.75 (m, 2H), 1.49 - 1.38 (m, 2H).

[0264] Example 2: 4-((1-(4-(3-(Pyridin-3-yl)-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileTo a solution of Intermediate 4 (76 mg, 231 μmol) in 1,4-dioxane (2 mL) and H2O (0.4 mL) were added Pd(dppf)Cl2 (16.9 mg, 23.1 μmol), Cs2CO3 (226 mg, 693 μmol) and Intermediate 3 (96.8 mg, 231 μmol). The mixture was degassed, purged with N2three times, and stirred at 90 °C under N2for 2 h. The reaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with CH2Cl2 (20 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 9% MeOH in CH2Cl2), the title compound (Example 2, 26.2 mg, yield: 20%) was obtained. MS: m / z = 542.2 [M+H]+. 1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.03 (s, 1H), 8.68 (dd, J = 4.8, 1.2 Hz, 1H), 860 (d J = 20 Hz 1H) 851 (d J = 56 Hz 1H) 811 800 (m 2H) 792 787 (m 1H)7.56 (dd, J = 8.0, 4.8 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.26 - 7.22 (m, 3H), 6.66 (br d, J = 6.0 Hz, 1H), 6.01 (s, 2H), 3.85 - 3.72 (m, 1H), 3.45 (s, 2H), 2.80 - 2.74 (m, 2H), 2.14 - 2.05 (m, 2H), 1.89 - 1.81 (m, 2H), 1.49 - 1.42 (m, 2H).

[0265] Example 3: 4-((1-(4-(3-(Pyrazin-2-yl)-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 3 was prepared in a manner similar to Example 2. MS: m / z = 543.2 [M + H]+.1H NMR (400 MHz, Methanol-d4) δ 9.11 (s, 1H), 8.73 (d, J = 1.6 Hz, 1H), 8.52 - 8.42 (m, 3H), 8.04 - 7.98 (m, 1H), 7.58 - 7.51 (m, 2H), 7.50 - 7.44 (m, 2H), 7.23 (d, J = 5.6 Hz, 1H), 6.64 - 6.54 (m, 1H), 6.41 (s, 2H), 4.11 - 3.86 (m, 1H), 3.63 (s, 2H), 3.03 - 2.93 (m, 2H), 2.35 - 2.21 (m, 2H), 2.04 - 1.97 (m, 2H), 1.65 - 1.57 (m, 2H).

[0266] Example 4: 4-((1-(4-(3-(2-Aminopyridin-3-yl)-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 4 was prepared in a manner similar to Example 2. MS: m / z = 557.1 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.01 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.11 (dd, J = 5.2, 2.0 Hz, 1H), 8.09 - 7.99 (m, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.41 (dd, J = 7.2, 1.6 Hz, 1H), 7.23 - 7.19 (m, 3H), 6.69 - 6.63 (m, 2H), 5.97 (s, 2H), 5.81 - 5.75 (m, 2H), 3.88 - 3.70 (m, 1H), 3.43 (s, 2H), 2.80 - 2.73 (m, 2H), 2.13 - 2.03 (m, 2H), 1.88 - 1.78 (m, 2H), 1.51 - 1.39 (m, 2H).

[0267] Example 5: 4-((1-(4-(3-Phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)benz l) i eridin-4- l)amino) rimidine-2-carbonitrileA mixture of Intermediate 7 (260 mg, 792 μmol), Intermediate 3 (365 mg, 872 μmol),H2O (1 mL) was degassed, purged with N2 three times, and stirred at 80 °C under N2 for 2 h. The reaction mixture was quenched with H2O (10 mL) and extracted with CH2Cl2(10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 5% MeOH in CH2Cl2), the title compound (Example 5, 217.1 mg, yield: 50%) was obtained. MS: m / z = 541.7 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.02 (s, 1H), 8.50 (d, J = 5.6 Hz, 1H), 8.10 - 8.00 (m, 2H), 7.55 - 7.51 (m, 3H), 7.47 - 7.43 (m, 4H), 7.23 - 7.19 (m, 3H), 6.66 (d, J = 5.6 Hz, 1H), 5.95 (s, 2H), 3.85 - 3.71 (m, 1H), 3.43 (s, 2H), 2.80 - 2.74 (m, 2H), 2.12 - 2.05 (m, 2H), 1.88 - 1.80 (m, 2H), 1.50 - 1.42 (m, 2H).

[0268] Example 6: 4-((1-(4-(2-Phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 6 was prepared in a manner similar to Example 5. MS: m / z = 541.1 [M + H]+.1H NMR (400 MHz, Methanol-d4) δ 9.14 (s, 1H), 8.46 (d, J = 5.6 Hz, 1H), 8.09 - 7.90 (m, 1H), 7.53 - 7.46 (m, 4H), 7.37 (d, J = 8.0 Hz, 2H), 7.31 - 7.24 (m, 3H), 7.20 (d, J = 5.2 Hz, 1H), 6.60 (br d, J = 4.4 Hz, 1H), 5.96 (s, 2H), 4.09 - 3.83 (m, 1H), 3.64 (s, 2H), 3.01 - 2.93 (m, 2H), 2.27 (br t, J = 11.2 Hz, 2H), 2.05 - 1.95 (m, 2H), 1.66 - 1.56 (m, 2H).

[0269] Example 7: 4-((1-(4-(1-Methyl-5-(pyridin-3-yl)-1H-imidazol-4-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 7 was prepared in a manner similar to Example 2. MS: m / z = 451.1 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.68 - 8.62 (m, 1H), 8.55 (s, 1H), 8.10 - 7.97 (m, 2H), 7.90 - 7.81 (m, 2H), 7.57 - 7.51 (m, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 6.65 (d, J = 6.0 Hz, 1H), 3.83 - 3.69 (m, 1H), 3.49 (s, 3H), 3.40 (s, 2H), 2.78 - 2.71 (m, 2H), 2.11 - 2.01 (m, 2H), 1.88 - 1.78 (m, 2H), 1.48 - 1.37 (m, 2H).

[0270] Example 8: 4-((1-(4-(5-(2-Aminopyridin-3-yl)-1-methyl-1H-imidazol-4-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileTo a solution of Intermediate 10 (23.9 mg, 71.3 μmol, HCl salt) and Intermediate 2 (22.6 mg, 71.3 μmol, TFA salt) in DMF (1 mL) were added K2CO3 (49.3 mg, 356 μmol) and NaI (1.07 mg, 7.13 μmol). The mixture was stirred at 50 °C for 1 h. 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 over Na2SO4, filtered, and concentrated under reduced pressure. After purification by prep-TLC (CH2Cl2 : MeOH = 10 : 1), the title compound (Example 8, 10.2 mg, yield: 30% for two steps) was obtained. MS: m / z = 466.3 [M + H]+.1H NMR (400 MHz, Methanol - d4) δ 8.08 (dd, J = 5.2, 1.6 Hz, 1H), 8.01 - 7.94 (m, 1H), 7.84 (s, 1H), 7.46 - 7.41 (m, 3H), 7.23 (d, J = 8.0 Hz, 2H), 6.75 (dd, J = 7.2, 5.2 Hz, 1H), 6.62 - 6.55 (m, 1H), 3.96 - 3.86 (m, 1H), 3.51 (s, 5H), 2.92 - 2.85 (m, 2H), 2.23 - 2.16 (m, 2H), 2.00 - 1.93 (m, 2H), 1.63 - 1.53 (m, 2H).

[0271] Example 9: 4-((1-(4-(3-(3-Fluorophenyl)-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 9 was prepared in a manner similar to Example 2. MS: m / z = 559.4 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.02 (s, 1H), 8.51 (d, J = 5.6 Hz, 1H), 8.11 - 7.96 (m, 2H), 7.58 - 7.51 (m, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.35 - 7.22 (m, 6H), 6.66 (d, J = 6.0 Hz, 1H), 5.99 (s, 2H), 3.91 - 3.72 (m, 1H), 3.45 (s, 2H), 2.80 - 2.72 (m, 2H), 2.14 - 2.05 (m, 2H), 1.90 - 1.80 (m, 2H), 1.52 - 1.42 (m, 2H).19F NMR (400 MHz, Dimethylsulfoxide-d6) δ - 111.756.

[0272] Example 10 : 4-((1-(4-(3-(2-Fluorophenyl)-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)b nz l) i ridin 4 l) min ) rimidin 2 arbonitrileExample 10 was prepared in a manner similar to Example 2. MS: m / z = 559.3 [M + H]+.1H NMR (400 MHz, Dimethysulfoxide-d6) δ 9.03 (s, 1H), 8.51 (d, J = 5.6 Hz, 1H), 8.16 - 7.94 (m, 2H), 7.65 - 7.58 (m, 1H), 7.51 - 7.36 (m, 5H), 7.26 - 7.19 (m, 3H), 6.66 (d, J = 5.6 Hz, 1H), 5.92 (s, 2H), 3.93 - 3.66 (m, 1H), 3.44 (br s, 2H), 2.75 - 2.79 (m, 2H), 2.14 - 2.03 (m, 2H), 1.89 - 1.78 (m, 2H), 1.50 - 1.39 (m, 2H).19F NMR (400 MHz, Dimethysulfoxide-d6) δ - 112.725.

[0273] Example 11: 4-((1-(4-(3-Cyclohexyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 11 was prepared in a manner similar to Example 2. MS: m / z = 547.3 [M + H]+.1H NMR (400 MHz, Methanol-d4) δ 9.02 (s, 1H), 8.43 (d, J = 5.6 Hz, 1H), 8.09 - 8.00 (m, 1H), 7.50 - 7.46 (m, 4H), 7.19 (d, J = 5.6 Hz, 1H), 6.63 - 6.58 (m, 1H), 6.19 (s, 2H), 5.37 - 5.32 (m, 1H), 4.02 - 3.92 (m, 1H), 3.64 (s, 2H), 2.99 - 2.96 (m, 2H), 2.31 - 2.25 (m, 2H), 2.22 - 2.14 (m, 2H), 2.05 - 1.99 (m, 4H), 1.90 - 1.85 (m, 4H), 1.64 - 1.60 (m, 4H).

[0274] Example 12: 4-((1-(4-(3-(pyridin-4-yl)-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 12 was prepared in a manner similar to Example 2. MS: m / z = 542.3 [M+H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.02 (s, 1H), 8.69 (d, J = 6.0 Hz, 2H), 8.52 (d, J = 5.6 Hz, 1H), 8.11 - 7.99 (m, 2H), 7.45 - 7.40 (m, 4H), 7.28 - 7.23 (m, 3H), 6.66 (d, J = 6.4 Hz, 1H), 6.07 (s, 2H), 3.86 - 3.71 (m, 1H), 3.46 (s, 2H), 2.81 - 2.75 (m, 2H), 2.13 - 2.05 (m, 2H), 1.91 - 1.81 (m, 2H), 1.51 - 1.40 (m, 2H).

[0275] Example 13: 4-((1-(4-(3-(4-Fluorophenyl)-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 13 was prepared in a manner similar to Example 2. MS: m / z = 559.2 [M+H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.01 (s, 1H), 8.50 (d, J = 5.6 Hz, 1H), 8.10 - 8.01 (m, 2H), 7.52 - 7.47 (m, 2H), 7.45 - 7.42 (m, 2H), 7.40 - 7.35 (m, 2H), 7.24 - 7.20 (m, 3H), 6.66 (br d, J = 6.0 Hz, 1H), 5.94 (s, 2H), 3.84 - 3.73 (m, 1H), 3.44 (s, 2H), 2.79 - 2.74 (m, 2H), 2.12 - 2.05 (m, 2H), 1.89 - 1.81 (m, 2H), 1.50 - 1.41 (m, 2H).19F NMR (400 MHz, Dimethylsulfoxide-d6) δ -112.214.

[0276] Example 14: 4-(6-(4-(3-Phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)benzyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidine-2-carbonitrileTo a solution of Intermediate 17 (105 mg, 281 μmol) in DMF (2 mL) were added Intermediate 29 (73.61 mg, 366 μmol), K2CO3 (194 mg, 1.41 mmol), and NaI (16.9 mg, 113 μmol). The mixture was stirred at 20 °C for 1 h. The mixture was diluted with H2O (30 mL) and extracted with EtOAc (20 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: C18150 x 30 mm; mobile phase: [water (NH3H2O + NH4HCO3) - ACN]; gradient: 50% - 80% B over 7 min), the title compound (Example 14, 34.4 mg, yield: 23%) was obtained as a white solid. MS: m / z = 539.2 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.02 (s, 1H), 8.50 (d, J = 5.2 Hz, 1H), 8.21 (d, J = 6.0 Hz, 1H), 7.58 - 7.49 (m, 3H), 7.45 - 7.37 (m, 4H), 7.22 (d, J = 5.6 Hz, 1H), 7.16 (d, J = 8.4 Hz, 2H), 6.61 (d, J = 6.0 Hz, 1H), 5.94 (s, 2H), 4.16 (s, 4H), 3.49 (s, 2H), 3.31 (s, 4H).

[0277] Example 15: 4-(4-(4-(3-Phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)b l i i 1 l i idi 2 b i ilμmol) in DMF (3 mL) were added K2CO3 (194 mg, 1.41 mmol) and NaI (16.9 mg, 113 μmol). The reaction mixture was stirred at 20 °C for 12 h. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20mL), dried over anhydrous Na2SO4, filtered and concentrated. After purification by prep-HPLC (column: C18150 × 30 mm; mobile phase: [water (NH3H2O + NH4HCO3) - ACN]; gradient: 57% - 87% B over 7 min), the title compound (Example 15, 47.4 mg, yield: 32%) was obtained as an off-white solid. MS: m / z = 527.2 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.02 (s, 1H), 8.50 (d, J = 6.0 Hz, 1H), 8.25 (d, J = 6.4 Hz, 1H), 7.57 - 7.42 (m, 7H), 7.27 - 7.20 (m, 3H), 7.08 (d, J = 6.4 Hz, 1H), 5.95 (s, 2H), 3.73 - 3.56 (m, 4H), 3.49 (s, 2H), 2.46 - 2.40 (m, 4H).

[0278] Example 16: 2-((1-(4-(3-Phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-4-carbonitrile N OTo a solution of Intermediate 17 (105 mg, 281 μmol) and Intermediate 19 (68.6 mg, 338μmol) in DMF (6 mL) were added K2CO3 (194 mg, 1.41 mmol) and NaI (16.9 mg, 113 μmol). The reaction mixture was stirred at 20 °C for 12 h. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20mL), dried over anhydrous Na2SO4, filtered, and concentrated. After purification by prep-HPLC (column: C18150 × 30 mm; mobile phase: [water (NH3H2O + NH4HCO3) - ACN]; gradient:61% - 91% B over 7 min), the title compound (Example 16, 86.0 mg, 54% yield) was obtained as a light-yellow solid. MS: m / z = 541.2 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.02 (s, 1H), 8.58 - 8.48 (m, 2H), 7.85 - 7.79 (m, 1H), 7.55 - 7.42 (m, 7H), 7.24 - 7.17 (m, 3H), 7.06 (d, J = 4.4 Hz, 1H), 5.95 (s, 2H), 3.77 - 3.56 (m, 1H), 3.42 (s, 2H), 2.82 - 2.74 (m, 2H), 2.06 - 1.94 (m, 2H), 1.84 - 1.75 (m, 2H), 1.56 - 1.43 (m, 2H).

[0279] Example 17: 6-((1-(4-(3-Phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)b l i idi 4 l i i idi 4 b itrileExample 17 was prepared in a manner similar to Example 16. MS: m / z = 541.1 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.02 (s, 1H), 8.53 - 8.45 (m, 2H), 8.04 (d, J = 7.2 Hz, 1H), 7.55 - 7.50 (m, 3H),7.47 - 7.42 (m, 4H),7.23 - 7.18 (m, 3H), 6.91 (s, 1H), 5.95 (s, 2H), 3.94 - 3.74 (m, 1H), 3.43 (s, 2H), 2.83 - 2.70 (m, 2H), 2.13 - 1.99 (m, 2H), 1.90 - 1.78 (m, 2H), 1.53 - 1.39 (m, 2H).

[0280] Example 22: 4-((1-(4-(3-Phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)benzyl)azetidin-3-yl)amino)pyrimidine-2-carbonitrileExample 22 was prepared in a manner similar to Example 16. MS: m / z =513.2 [M + H]+.1H NMR (400 MHz, Dimethysulfoxide-d6) δ 9.02 (s, 1H), 8.58 (d, J = 6.4 Hz, 1H), 8.50 (d, J = 5.2 Hz, 1H), 8.29 - 8.03 (m, 1H), 7.57 - 7.48 (m, 3H), 7.43 (d, J = 7.2 Hz, 4H), 7.25 - 7.14 (m, 3H), 6.69 (d, J = 6.0 Hz, 1H), 5.94 (s, 2H), 4.54 - 4.11 (m, 1H), 3.56 (s, 4H), 2.99 - 2.90 (m, 2H). Example 25: 4-((Methyl-d3)(1-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileTo a solution of Intermediate 17 (115 mg, 280 μmol, HCl salt) and Intermediate 18 (93.7 mg, 280 μmol, TFA salt) in DMF (2 mL) were added K2CO3 (194 mg, 1.4 mmol) and NaI (4.2 mg, 28 μmol). The mixture was stirred at 25 °C for 16 h. 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 over Na2SO4, filtered, and concentrated under reduced pressure. After purification by prep-HPLC (column: CD07- Daisogel SP-100-8-ODS-PK 150 x 25 x 10 ^m; mobile phase: [water (NH4HCO3) - ACN]; gradient: 40% - 70% B over 10 min), the title compound (Example 25, 31.2 mg, yield: 20% for two steps) was obtained as an off-white solid. MS: m / z = 558.3 [M + H]+. D%: 3D% = 100%.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.02 (s, 1H), 8.50 (d, J = 5.6 Hz, 1H), 8.22 (d, J = 6.0 Hz, 1H), 7.56 - 7.42 (m, 7H), 7.24 - 7.19 (m, 3H), 7.07 - 6.66 (m, 1H), 5.95(s, 2H), 3.46 (s, 2H), 3.36 - 3.34 (m, 1H), 2.92 - 2.85 (m, 2H), 2.14 - 2.03 (m, 2H), 1.83 - 1.71 (m, 2H), 1.63 - 1.50 (m, 2H).

[0281] Example 28: (S)-4-(7-(4-(3-Phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)benzyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidine-2-carbonitrileExample 28 was prepared in a manner similar to Example 16. MS: m / z = 567.1 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.01 (s, 1H), 8.50 (d, J = 5.2 Hz, 1H), 8.20 (t, J = 6.4 Hz, 1H), 7.55 - 7.49 (m, 3H), 7.46 - 7.39 (m, 4H), 7.22 (d, J = 6 Hz, 3H), 6.74 (dd, J = 13.2, 6.8 Hz, 1H), 5.94 (s, 2H), 3.55 (s, 2H), 3.47 - 3.35 (m, 4H), 2.70 - 2.55 (m, 2H), 2.47 - 2.27 (m, 2H), 2.05 - 1.89 (m, 2H), 1.78 (t, J = 6.4, 2H).

[0282] Example 30: 4-((1-(4-(3-Bromo-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileStep 1: 3-Bromo-2-iodo-5H-imidazo [1,2-c]pyrido[3,4-e][1,3]oxazine To a solution of Intermediate 1 (200 mg, 793.4 μmol) in DMF (5 mL) was added NIS (535 mg, 2.38 mmol). The mixture was stirred at 80 °C for 16 h. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 50% EtOAc in petroleum ether), the title compound (130 mg, yield: 43%) was obtained as a yellow solid. MS: m / z =377.8, 379.8 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 9.11 (s, 1H), 8.51 (d, J = 5.6 Hz, 1H), 7.02 (d, J = 5.6 Hz, 1H), 5.86 (s, 2H). Step 2: 4-((1-(4-(3-Bromo-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)benzyl)piperidin- 4-yl)amino)pyrimidine-2-carbonitrile A mixture of 3-bromo-2-iodo-5H-imidazo [1,2-c]pyrido[3,4-e][1,3]oxazine (120 mg, 317 μmol), Intermediate 3 (66.6 mg, 159 μmol), Pd(PPh3)4 (73.4 mg, 63.5 μmol), and Cs2CO3 (207 mg, 635 μmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was degassed, purged with N2three times and stirred at 100 °C for 2 h under N2 The mixture was diluted with H2O (10mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 7% MeOH in CH2Cl2), the title compound (Example 30, 35.9 mg, yield: 20%) was obtained as a light-yellow solid. MS: m / z =543.1, 545.1 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 9.19 (s, 1H), 8.51 (d, J = 5.2 Hz, 1H), 8.19 - 8.09 (m, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 5.6 Hz, 1H), 6.42 (d, J = 6.0 Hz, 1H), 5.92 (s, 2H), 4.32 - 3.75 (m, 1H), 3.62 (s, 2H), 2.97 - 2.88 (m, 2H), 2.29 - 2.22 (m, 2H), 2.05 - 2.01 (m, 2H), 1.64 - 1.60 (m, 2H).

[0283] Example 31: 4-((Methyl-d3)(1-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)benzyl)azetidin-3-yl)amino)pyrimidine-2-carbonitrileTo a solution of Example 22 (190 mg, 371 μmol) in THF (5 mL) was added NaH (95 mg, 2.38 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, and iodomethane-d3 (107 mg, 741 μmol) was added dropwise at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with NH4Cl (10 mL) at 0 °C and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by prep-HPLC (column: CD07-Daisogel SP-100-8-ODS-PK 150 x 25 x 10 μm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 32% - 62% B over 10 min), the title compound (Example 31, 10.2 mg, yield: 5%) was obtained as an off-white lyophilized powder. MS: m / z =530.3 [M + H]+.1H NMR (400 MHz, Methanol-d4) δ 9.14 (s, 1H), 8.47 (d, J = 5.8 Hz, 1H), 8.20 (d, J = 6.4 Hz, 1H), 7.53 - 7.46 (m, 5H), 7.43 - 7.38 (m, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 5.6 Hz, 1H), 6.81 (d, J = 6.4 Hz, 1H), 5.95 (s, 2H), 3.74 - 3.71 (m, 1H), 3.70 (s, 2H), 3.34 - 3.32 (m, 4H).

[0284] Example 35: 4-((1-(4-(3-Phenyl-5H-imidazo[1,2-c]pyrido[4,3-e][1,3]oxazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileA mixture of Intermediate 32 (132 mg, 402 μmol), Intermediate 3 (169 mg, 402 μmol), Pd(dppf)Cl2(29.4 mg, 40.2 μmol), and Cs2CO3(393 mg, 1.21 mmol) in 1,4-dioxane (4 mL) and H2O (1 mL) was degassed, purged with N2three times, and stirred at 80 °C for 16 h under N2. The reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. After purification by prep-HPLC (column: CD02- Waters Xbidge BEH C18150 x 25 x 10 μm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 37% - 67% B over 10 min), the title compound (Example 35, 91.8 mg, yield: 42% for two steps) was obtained as an off-white lyophilized powder. MS: m / z = 541.2 [M + H]+. 1H NMR (400 MHz, Dimethysulfoxide-d6) 8.50 (s, 1H), 8.43 (d, J = 5.2 Hz, 1H), 7.15 - 7.96 (m, 2H), 7.82 (d, J = 4.8 Hz, 1H), 7.58 - 7.50 (m, 3H), 7.47 - 7.39 (m, 4H), 7.21 (d, J = 8.0 Hz, 2H), 6.66 (d, J = 6.0 Hz, 1H), 5.93 (s, 2H), 3.91 - 3.71 (m, 1H), 3.44 (s, 2H), 2.82 - 2.73 (m, 2H), 2.13- 1.99 (m, 2H), 1.91 - 1.74 (m, 2H), 1.58 - 1.39 (m, 2H).

[0285] Example 37: 4-((1-(4-(3-Chloro-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileStep 1: 3-Chloro-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazine To a solution of Intermediate 1 (200 mg, 1.15 mmol) in DMF (3 mL) was added NCS (170 mg, 1.27 mmol). The mixture was stirred at 90 °C for 16 h. The reaction mixture was quenched with H2O (30 mL) at 25 °C and extracted with CH2Cl2(30 mL x 2). The combined organic layers were washed with brine (50 mL x 5), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The title compound (180 mg) was obtained as a yellow solid. MS: m / z = 208.0, 210.0 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.95 - 8.81 (m, 1H), 8.49 (d, J = 5.6 Hz, 1H), 7.31 - 7.13 (m, 2H), 6.10 (s, 2H). Step 2: 3-Chloro-2-iodo-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazine To a solution of 3-chloro-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazine (180 mg, 867 μmol) in DMF (2 mL) was added NIS (390 mg, 1.73 mmol). The mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with H2O (30 mL) at 25 °C and extracted with CH2Cl2 (30 mL x 2). The combined organic layers were washed with brine (50 mL x 5), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The title compoundMHz, Chloroform-d) δ 9.10 (s, 1H), 8.50 (d, J = 5.6 Hz, 1H), 7.03 (d, J = 6.0 Hz, 1H), 5.88 (s, 2H). Step 3: 4-((1-(4-(3-Chloro-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)benzyl)piperidin- 4-yl)amino)pyrimidine-2-carbonitrile A mixture of 3-chloro-2-iodo-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazine (270 mg, 810 μmol), Intermediate 3 (339 mg, 810 μmol), Cs2CO3(791 mg, 2.43 mmol), and Pd(PPh3)4(93.6 mg, 81.0 μmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was degassed and purged with N2 three times, and stirred at 90 °C for 16 h under N2. The reaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with CH2Cl2(15 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by prep-HPLC (column: CD07-Daisogel SP-100-8- ODS-PK 150 x 25 x 10 µm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 30% - 60% B over 15 min), the title compound (Example 37, 70 mg, yield: 17% for three steps) was obtained as a gray lyophilized powder. MS: m / z = 499.1, 501.1 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.97 (s, 1H), 8.52 (d, J = 5.6 Hz, 1H), 8.20 - 7.99 (m, 2H), 7.91 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 5.6 Hz, 1H), 6.67 (d, J = 6.4 Hz, 1H), 6.17 (s, 2H), 3.91 - 3.70 (m, 1H), 3.52 (s, 2H), 2.85 - 2.76 (m, 2H), 2.18 - 2.07 (m, 2H), 1.91 - 1.80 (m, 2H), 1.54 - 1.42 (m, 2H).

[0286] Example 39: 4-((1-(4-(3-Phenyl-5H-imidazo[1,2-c]pyrido[2,3-e][1,3]oxazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 39 was prepared in a manner similar to Example 35. MS: m / z = 541.3 [M + H]+.1H NMR (400 MHz, Dimethysulfoxide-d6) 8.42 (d, J = 4.0 Hz, 1H), 8.26 - 7.94 (m, 2H), 7.60 (dd, J = 8.4, 1.2 Hz, 1H), 7.57 - 7.50 (m, 3H), 7.49 - 7.37 (m, 5H), 7.20 (d, J = 8.0 Hz, 2H), 6.66 (d, J = 5.6 Hz, 1H), 5.88 (s, 2H), 3.91 - 3.66 (m, 1H), 3.43 (s, 2H), 2.83 - 2.71 (m, 2H), 2.15 - 2.00 (m, 2H), 1.91 - 1.74 (m, 2H), 1.51 - 1.37 (m, 2H).

[0287] Example 40: 4-((1-(4-(10-Fluoro-3-phenyl-5H-benzo[e]imidazo[1,2-c][1,3]oxazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 40 was prepared in a manner similar to Example 35. MS: m / z = 558.1 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.07 (d, J = 6.0 Hz, 2H), 7.56 - 7.49 (m, 3H), 7.46 - 7.37 (m, 5H), 7.20 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 9.2 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.66 (d, J = 6.0 Hz, 1H), 5.82 (s, 2H), 3.86 - 3.70 (m, 1H), 3.43 (s, 2H), 2.82 - 2.72 (m, 2H), 2.14 - 2.01 (m, 2H), 1.89 - 1.75 (m, 2H), 1.54 - 1.37 (m, 2H).19F NMR (400 MHz, Dimethylsulfoxide-d6) δ -112.913.

[0288] Example 44: 4-((1-(4-(3-Phenyl-5H-imidazo[1,2-c]pyrido[3,2-e][1,3]oxazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 44 was prepared in a manner similar to Example 35. MS: m / z = 541.2 [M+H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.34 - 8.22 (m, 2H), 8.13 - 7.97 (m, 2H), 7.56 - 7.49 (m, 3H), 7.47 - 7.40 (m, 4H), 7.32 (dd, J =7.6, 5.2 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 6.66 (d, J = 6.4 Hz, 1H), 5.98 (s, 2H), 3.87 - 3.70 (m, 1H), 3.43 (s, 2H), 2.83 - 2.71 (m, 2H), 2.13 - 2.02 (m, 2H), 1.90 - 1.75 (m, 2H), 1.54 - 1.36 (m, 2H).

[0289] Example 45: 4-((1-(4-(3-Cyclopropyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileA mixture of Example 30 (100 mg, 184 μmol), cyclopropylboronic acid (31.6 mg, 368 μmol), Cs2CO3(180 mg, 552 μmol), and Pd(dppf)Cl2(13.5 mg, 18.4 μmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was degassed, purged with N2 three times, and stirred at 90 °C for 2 h under N2. The reaction mixture was quenched with H2O (20 mL) at 25 °C and extracted with CH2Cl2(15 mL x 2). The combined organic layers were washed with brine (30 mL), dried h d N SO filt d d t t d d d d Aft ifi tiby prep-HPLC (column: CD07-Daisogel SP-100-8-ODS-PK 150 x 25 x 10 µm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 28% - 58% B over 15 min), the title compound (Example 45, 3.3 mg, yield: 3.5%) was obtained as a light-yellow solid. MS: m / z = 505.2 [M + H]+.1H NMR (400 MHz, Methanol-d6) δ 9.05 (s, 1H), 8.43 (d, J = 5.6 Hz, 1H), 8.04 - 7.95 (m, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 5.6 Hz, 1H), 6.63 - 6.56 (m, 1H), 6.19 (s, 2H), 4.07 - 3.84 (m, 1H), 3.62 (s, 2H), 3.01 - 2.93 (m, 2H), 2.32 - 2.23 (m, 2H), 2.04 - 1.98 (m, 3H), 1.65 - 1.55 (m, 2H), 1.11 - 1.03 (m, 2H), 0.50 - 0.41 (m, 2H).

[0290] Example 48: 4-(1-(1-(4-(3-Phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)benzyl)piperidin-4-yl)vinyl)pyrimidine-2-carbonitrileExample 48 was prepared in a manner similar to Example 16. MS: m / z = 552.2 [M + H]+.1H NMR (400 MHz, Methanol-d4) δ 9.14 (s, 1H), 8.81 (d, J = 5.6 Hz, 1H), 8.47 (d, J = 5.6 Hz, 1H), 7.88 (d, J = 5.2 Hz, 1H), 7.54 - 7.46 (m, 5H), 7.43 - 7.37 (m, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 5.6 Hz, 1H), 6.12 (s, 1H), 5.94 (s, 2H), 5.63 (s, 1H), 3.57 (s, 2H), 3.05 - 2.96 (m, 2H), 2.95 - 2.85 (m, 1H), 2.28 - 2.14 (m, 2H), 1.90 - 1.73 (m, 2H), 1.66 - 1.52 (m, 2H).

[0291] Example 58: 4-((3aR,6aS)-5-(4-(3-Phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)benzyl)dihydro-1H,4H-3a,6a-(methanooxymethano)pyrrolo[3,4-c]pyrrol-2(3H)- yl)pyrimidine-2-carbonitrileExample 58 was prepared in a manner similar to Example 16. MS: m / z = 595.3 [M + H]+.1H NMR (400 MHz, Dimethysulfoxide-d6) δ 9.01 (s, 1H), 8.50 (d, J = 5.6 Hz, 1H), 8.26 (d, J = 6.0 Hz, 1H), 7.54 - 7.49 (m, 3H), 7.45 - 7.41 (m, 4H), 7.23 - 7.19 (m, 3H), 6.83 (d, J = 6.4 Hz, 1H), 5.94 (s, 2H), 3.72 - 3.55 (m, 8H), 3.54 (s, 2H), 2.60 - 2.56 (m, 2H), 2.49 - 2.47 (m, 2H).

[0292] Example 59: 4-(1-(4-(3-Phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)benzyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-2-carbonitrileN OExample 59 was prepared in a manner similar to Example 16. MS: m / z = 524.2 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.02 (s, 1H), 8.90 (d, J = 5.6 Hz, 1H), 8.50 (d, J = 5.6 Hz, 1H), 7.91 (d, J = 5.6 Hz, 1H), 7.54 - 7.43 (m, 7H), 7.28 - 7.20 (m, 3H), 7.18 - 7.12 (m, 1H), 5.95 (s, 2H), 3.59 (s, 2H), 3.21 - 3.14 (m, 2H), 2.69 - 2.62 (m, 2H), 2.56 - 2.52 (m, 2H).

[0293] Example 60: 4-(1-(1-(4-(3-Phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)benzyl)piperidin-4-yl)ethyl)pyrimidine-2-carbonitrileExample 60 was prepared in a manner similar to Example 16. MS: m / z = 554.3 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.01 (s, 1H), 8.88 (d, J = 5.6 Hz, 1H), 8.49 (d, J = 5.6 Hz, 1H), 7.74 (d, J = 5.2 Hz, 1H), 7.54 - 7.50 (m, 3H), 7.44 - 7.40 (m, 4H), 7.22 (d, J = 6.0 Hz, 1H), 7.18 - 7.14 (m, 2H), 5.94 (s, 2H), 3.36 (s, 2H), 2.85 - 2.79 (m, 1H), 2.77 - 2.68 (m, 2H), 1.90 - 1.83 (m, 1H), 1.79 - 1.68 (m, 2H), 1.62 - 1.54 (m, 1H), 1.27 - 1.22 (m, 1H), 1.21 - 1.19 (m, 3H), 1.18 - 1.12 (m, 2H).

[0294] Example 62: 4-((1-(4-(3-Phenyl-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 62 was prepared in a manner similar to Example 35. MS: m / z = 555.2 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.43 - 8.33 (m, 2H), 8.28 (d, J = 5.6 Hz, 1H), 8.16 - 7.91 (m, 2H), 7.59 - 7.50 (m, 3H), 7.50 - 7.44 (m, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 6.66 (d, J = 6.0 Hz, 1H), 4.56 - 4.45 (m , 2H), 4.24 - 4.09 (m, 2H), 3.91 - 3.66 (m, 1H), 3.41 (s, 2H), 2.81 - 2.69 (m, 2H), 2.13 - 1.98 (m, 2H), 1.89 - 1.74 (m, 2H), 1.53 - 1.35 (m, 2H).

[0295] Example 66 and 67: 4-((1-(4-(3-Phenyl-5,6-dihydroimidazo[2,1-a][2,7]naphthyridin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile & 4-((1-(4-(3-phenylimidazo[2,1- a][2,7]naphthyridin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile N N NTo a solution of Intermediate 39 & 40 (a mixture, 60 mg, 147 μmol, HCl salt) and Intermediate 2 (46.6 mg, 147 μmol, TFA salt) in DMF (1 mL) were added K2CO3(101.54 mg, 735 μmol) and NaI (2.2 mg, 14.67 μmol). The mixture was stirred at 25 °C for 16 h. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by prep-HPLC (column: CD07- Daisogel SP-100-8-ODS-PK 150 × 25 × 10 ^m; mobile phase: [water (NH4HCO3) - ACN]; gradient: 46% - 66% B over 15 min), the title comopound (Intermediate 66, 1.9 mg, yield: 2.4%, for two steps) and the other title compound (Intermediate 67, 2.9 mg, yield: 3.6%, for two steps) were obtained as a light yellow soild. Spectra for Intermediate 66: MS: m / z =539.2 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 9.35 (s, 1H), 8.52 (d, J = 4.8 Hz, 1H), 8.13 - 8.06 (m, 1H), 7.62 (d, J = 7.6 Hz, 2H), 7.53 - 7.44 (m, 4H), 7.40 - 7.35 (m, 3H), 7.34 - 7.32 (m, 1H), 7.19 (d, J = 4.8 Hz, 1H), 6.56 - 6.49 (m, 1H), 4.03 - 3.99 (m, 2H), 3.92 - 3.85 (m, 1H), 3.39 - 3.18 (m, 2H), 3.15 - 3.11 (m, 2H), 2.65 - 2.48 (m, 2H), 2.17 - 2.05 (m, 4H), 1.85 - 1.80 (m, 2H). Spectra for Intermediate 67: MS: m / z =537.3 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 10.07 (s, 1H), 8.73 (d, J = 5.6 Hz, 1H), 8.17 - 8.09 (m, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.60 - 7.52 (m, 5H), 7.51 - 7.48 (m, 2H), 7.30 7.27 (m, 2H), 6.97 (d, J = 7.2 Hz, 1H), 6.42 (d, J = 6.0 Hz, 1H), 4.22 - 3.75 (m, 1H), 3.62 - 3.54 (m, 2H), 2.99 - 2.85 (m, 2H), 2.29 - 2.20 (m, 2H), 2.04 - 2.00 (m, 2H), 1.79 - 1.71 (m, 2H).

[0296] Example 72: 4-(1-(4-(3-Phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)b l i idi 4 l i idi 2 b i ilTo a solution of Intermediate 17 (50 mg, 121 μmol, HCl salt) and Intermediate 27 (36.8 mg, 122 μmol, TFA salt) in DMF (1 mL) were added K2CO3(84.2 mg, 609 ^mol) and NaI (1.83 mg, 12.2 μmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered. After purification by prep-HPLC (column: CD07-Daisogel SP-100-8-ODS-PK 150 x 25 x 10 ^m; mobile phase: [water (NH4HCO3) - ACN]; gradient: 38% - 68% B over 11 min), the title compound (Example 72, 10.1 mg, yield: 16%) was obtained as an off-white lyophilized powder. MS: m / z = 526.2 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.02 (s, 1H), 8.89 (d, J = 5.2 Hz, 1H), 8.50 (d, J = 5.6 Hz, 1H), 7.81 (d, J = 5.6 Hz, 1H), 7.53 - 7.42 (m, 7H), 7.24 - 7.21 (m, 3H), 5.95 (s, 2H), 3.46 (s, 2H), 2.94 - 2.89 (m, 2H), 2.82 - 2.74 (m, 1H), 2.09 - 2.01 (m, 2H), 1.88 - 1.82 (m, 2H), 1.78 - 1.69 (m, 2H).

[0297] Example 73: 4-((1-(4-(3-Phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)benzyl)piperidin-4-yl)oxy)pyrimidine-2-carbonitrile N N OExample 73 was prepared in a manner similar to Example 16. MS: m / z = 542 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ = 9.27 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.46 (d, J = 5.6 Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.50 - 7.45 (m, 3H), 7.39 - 7.35 (m, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 5.6 Hz, 1H), 6.86 (d, J = 5.6 Hz, 1H), 5.76 (s, 2H), 5.22 - 5.13 (m, 1H), 3.50 (s, 2H), 2.77 - 2.68 (m, 2H), 2.36 - 2.26 (m, 2H), 2.06 - 1.98 (m, 2H), 1.87 - 1.75 (m, 2H).

[0298] Example 74: 4-((1-(4-(10-Methoxy-3-phenyl-5H-benzo[e]imidazo[1,2-c][1,3]oxazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 74 was prepared in a manner similar to Example 35. MS: m / z = 570.2 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.20 - 7.95 (m, 2H), 7.55 - 7.37 (m, 7H), 7.33 (t, J = 8.4 Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 6.8 Hz, 1H), 5.70 (s, 2H), 3.94 (s, 3H), 3.85 - 3.65 (m, 1H), 3.44 (s, 2H), 2.82 - 272 (m 2H) 214 - 200 (m 2H) 188 - 176 (m 2H) 153 - 133 (m 2H)

[0299] Example 81: 4-((1-(4-(10-Fluoro-3-phenyl-5H-imidazo[1,2-c]pyrido[4,3-e][1,3]oxazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileTo a solution of Intermediate 34 (25 mg, 72.2 μmol), Intermediate 3 (30.3 mg, 72.2 μmol) in 1,4-dioxane (2 mL) and H2O (0.4 mL) were added Pd(dppf)Cl2 (5.28 mg, 7.22 μmol) and Cs2CO3(70.6 mg, 217 μmol). The mixture was degassed, purged with N2three times, and stirred at 80 °C under N2 for 2 h. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (80 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by prep-TLC (SiO2, CH2Cl2: MeOH = 10:1), the title compound (Example 81, 1.8 mg, yield: 4.3% for two steps) was obtained as a yellow solid. MS: m / z = 559.2 [M+H]+. 1H NMR (400 MHz, Chloroform-d) δ 8.39 (s, 1H), 8.32 (s, 1H), 8.18 - 8.09 (m, 1H), 7.55 - 7.49 (m, 5H), 7.39 - 7.34 (m, 2H), 7.21 (d, J = 8.4 Hz, 2H), 6.40 (d, J = 6.4 Hz, 1H), 5.76 (s, 2H), 5.45 - 5.30 (m, 1H), 3.50 (s, 2H), 2.89 - 2.80 (m, 2H), 2.20 - 2.14 (m, 2H), 2.00 - 1.93 (m, 2H), 1.34 - 1.31 (m, 2H).19F NMR (400 MHz, Chloroform-d) δ -128.243.

[0300] Example 82: 4-((1-(4-(3-Phenyl-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileA mixture of Intermediate 38 (63 mg, 184 μmol), Intermediate 3 (77.2 mg, 184 μmol), Cs2CO3 (180 mg, 552 μmol), and Pd(dppf)Cl2 (13.5 mg, 18.4 μmol) in 1,4-dioxane (4 mL) and H2O (1 mL) was degassed, purged with N2 three times, and stirred at 80 °C under N2 for 16 h. The reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. After purification by prep-HPLC (column: CD24-XPT C18150 x 25 x 7 μm; mobile phase: [water (NH4HCO3) - ACN]; gradient:35% - 65% B over 10 min), the title compound (Example 82, 8.6 mg, yield: 8% for two steps) was obtained as a yellow solid. MS: m / z = 555.2 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 9.83 (s, 1H),7.19 (m, 2H), 6.91(d, J = 5.2 Hz, 1H), 6.40 (d, J = 6.0 Hz, 1H), 5.35 - 4.81 (m, 1H), 4.52 - 4.44 (m, 2H), 4.19 - 4.11 (m, 2H), 3.53 (br s, 2H), 2.97 - 2.78 (m, 2H), 2.27 - 2.14 (m, 2H), 2.04 - 1.95 (m, 2H), 1.58 - 1.54 (m, 2H).

[0301] Example 83: 4-((1-(4-(10-Fluoro-3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileExample 83 was prepared in a manner similar to Example 81. MS: m / z = 559.1 [M+H]+.1H NMR (400 MHz, Chloroform-d) δ 8.18 - 8.06 (m, 3H), 7.55 (d, J = 7.6 Hz, 2H), 7.52 - 7.47 (m, 3H), 7.41 - 7.33 (m, 2H), 7.22 (d, J = 7.6 Hz, 2H), 6.99 - 6.90 (m, 1H), 6.41 (d, J = 6.0 Hz, 1H), 5.78 (s, 2H), 5.40 - 5.27 (m, 2H), 4.25 - 4.10 (m, 1H), 3.61 - 3.50 (m, 2H), 2.98 - 2.82 (m, 2H), 2.25 - 2.21 (m, 2H), 2.03 - 2.00 (m, 2H).19F NMR (400 MHz, Chloroform-d) δ -63.874.

[0302] Example 87: 4-((1-(4-(3-Phenyl-6,7-dihydro-5H-imidazo[1,2-a]pyrido[3,4-c]azepin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileA mixture of Intermediate 49 (30 mg, 88.2 μmol), Intermediate 3 (37.0 mg, 88.2 μmol), Cs2CO3 (57.5 mg, 176 μmol), and Pd(dppf)Cl2 (6.45 mg, 8.82 μmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was degassed, purged with N2 three times, and stirred at 100 °C under N2 for 16 h. The mixture was diluted with H2O (10 mL) and extracted with CH2Cl2(10mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by prep-HPLC (column: CD24- XPT C18150 × 25 × 7μm; mobile phase: [water (NH4HCO3)-ACN]; gradient:35%-65% B over 10 min), the title compound (Example 87, 8.3 mg, yield: 16% for two steps) was obtained as a light-yellow solid. MS: m / z = 553.2 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 9.15 (s, 1H), 8.61 - 8.51 (m, 1H), 8.20 - 8.05 (m, 1H), 7.72 - 7.52 (m, 3H), 7.49 - 7.39 (m, 5H), 7.24 - 7.17 (m, 3H), 6.40 (s, 1H), 5.37 - 5.17 (m, 1H), 3.75 - 3.69 (m,2H), 3.51 (s, 2H), 2.92 - 2.82 (m, 4H), 2.38 - 2.31 (m, 2H), 2.22 - 2.14 (m, 2H), 2.01 - 1.94 (m, 2H), 1.60 - 1.51 (m, 2H).

[0303] Example 88: 4-((1-(4-(3-Phenyl-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileTo a solution of Intermediate 48 (52.0 mg, 152 μmol) and Intermediate 3 (66.9 mg, 160 μmol) in 1,4-dioxane (3 mL) and H2O (0.6 mL) were added Pd(dppf)Cl2(11.1 mg, 15.2 μmol) and Cs2CO3 (149 mg, 458 μmol). The mixture was degassed, and purged with N2 three times, and stirred at 90 °C for 3 h under N2. The reaction mixture was diluted with EtOAc (30 mL) and stirred for 10 mins. The mixture was washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by prep-TLC (SiO2, CH2Cl2 : MeOH = 10 : 1), the title compound (Example 88, 23.6 mg, yield: 26 % for two steps) was obtained as an off-white solid. MS: m / z = 555.1 [M+H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.00 - 8.94 (m, 1H), 8.24 (d, J = 2.8 Hz, 1H), 8.11 - 7.96 (m, 2H), 7.57 - 7.51 (m, 3H), 7.49 - 7.45 (m, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.27 (dd, J = 8.0, 4.4 Hz, 1H), 7.16 (d, J = 8.4 Hz, 2H), 6.66 (d, J = 6.0 Hz, 1H), 4.58 - 4.52 (m, 2H), 4.18 - 4.11 (m, 2H), 3.83 - 3.73 (m, 1H), 3.41 (s, 2H), 2.79 - 2.72 (m, 2H), 2.10 - 2.03 (m, 2H), 1.88 - 1.78 (m, 2H), 1.49 - 1.38 (m, 2H).

[0304] Example 89: 1-(2-(4-(3-Phenyl-5H-imidazo[1,2-c]pyrido[4,3-e][1,3]oxazin-2-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)prop-2-en-1-oneStep 1: tert-butyl 2-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[4,3-e][1,3]oxazin-2-yl)benzyl)-27-diazaspiro

[0035] nonane-7-carboxylateTo a solution of Intermediate 46 (192 mg, 468 μmol, HCl salt), tert-butyl 2,7- diazaspiro[3.5]nonane-7-carboxylate (123 mg, 468 μmol, HCl salt) in DMF (2 mL) were added K2CO3(323 mg, 2.34 mmol) and NaI (7.01 mg, 46.8 μmol). The mixture was stirred at 30 °C for 16 h. 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% ~ 6% MeOH in CH2Cl2), the title compound (137 mg, yield: 52%) was obtained as a yellow solid. MS: m / z = 564.2 [M + H]+.1H NMR (400 MHz, Dimethysulfoxide-d6) δ 8.50 (s, 1H), 8.43 (d, J = 4.8 Hz, 1H), 7.82 (d, J = 4.4 Hz, 1H), 7.56 - 7.50 (m, 3H), 7.45 - 7.39 (m, 4H), 7.19 - 7.13 (m, 2H), 5.91 (br s, 2H), 3.53 (br s, 2H), 3.51 - 3.48 (m, 4H), 2.94 - 2.91 (m, 4H), 1.60 - 1.55 (m, 4H), 1.37 (s, 9H). Step 2: 2-(4-((2,7-Diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-3-phenyl-5H-imidazo[1,2- c]pyrido[4,3-e][1,3]oxazine To a solution of tert-butyl 2-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[4,3-e][1,3]oxazin-2- yl)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (137 mg, 243 μmol) in 1,4-dioxane (5 mL) was added HCl in 1,4-dioxane (20 mL, 2 M). The mixture was stirred at 25 °C for 4 h. The reaction mixture was quenched with NaHCO3 (20 mL, adjusted pH to ~ 8) at 25 °C and extracted with CH2Cl2 (25 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The title compound (113 mg) was obtained as a yellow solid. MS: m / z = 464.1 [M + H]+. Step 3: 1-(2-(4-(3-Phenyl-5H-imidazo[1,2-c]pyrido[4,3-e][1,3]oxazin-2-yl)benzyl)-2,7- diazaspiro[3.5]nonan-7-yl)prop-2-en-1-one To a solution of 2-(4-((2,7-diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-3-phenyl-5H- imidazo[1,2-c]pyrido[4,3-e][1,3]oxazine (113 mg, 244 μmol) in CH2Cl2 (10 mL) was added TEA (123 mg, 1.22 mmol). The mixture was degassed and purged with N2 three times. Acryloyl chloride (22.06 mg, 244 μmol) was added to the above mixture at 0 °C. The mixture was stirred at 0 °C for 0.5 h under N2. The reaction mixture was quenched with MeOH (0.2 mL) at 0 °C and concentrated under reduced pressure. After purification by prep- TLC (SiO2, MeOH : CH2Cl2= 1:10), the title compound (Example 89, 42.6 mg, yield : 34% for two steps) was obtained as a yellow solid. MS: m / z = 518.4 [M + H]+.1H NMR (400 MHz, Dimethysulfoxide-d6) δ 8.50 (s, 1H), 8.43 (d, J = 4.8 Hz, 1H), 7.82 (d, J = 5.2 Hz, 1H), 7.61 - 7.51 (m, 3H), 7.48 - 7.38 (m, 4H), 7.17 (d, J = 8.0 Hz, 2H), 6.77 (dd, J =16.8, 10.4 Hz, 1H), 6.12 - 5.99 (m, 1H),5.92 (s, 2H), 5.67 - 5.60 (m, 1H), 3.54 (br s, 2H), 3.49 - 3.40 (m, 4H) 300 - 291(m 4H) 167 - 155 (m 4H)

[0305] Example 90: 4-((1-(4-(10-Methoxy-3-phenyl-5H-imidazo[1,2-c]pyrido[3,2-e][1,3]oxazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileA mixture of Intermediate 47 (90 mg, 251 μmol), Intermediate 3 (116 mg, 276 μmol), Cs2CO3(164 mg, 502 μmol), and Pd(dppf)Cl2(18.4 mg, 25.1 μmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was degassed, purged with N2 three times, and stirred at 100 °C under N2 for 16 h. The mixture was diluted with H2O (20 mL) and extracted with CH2Cl2 (20 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0% ~ 5% MeOH in CH2Cl2), the title compound (Example 90, 45.3 mg, yield: 31%, for two steps) was obtained as a brown solid. MS: m / z = 571.1 [M + H]+.1H NMR (400 MHz, Dimethysulfoxide-d6) δ 8.15 (d, J = 6.0 Hz, 1H), 8.07 (d, J = 5.6 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.53 - 7.48 (m, 3H), 7.42 - 7.37 (m, 4H), 7.20 (d, J = 7.6 Hz, 2H), 7.07 (d, J = 6.0 Hz, 1H), 6.66 (d, J = 6.0 Hz, 1H), 5.85 (s, 2H), 4.03 (s, 3H), 3.84 - 3.73 (m, 1H), 3.43 (s, 2H), 2.81 - 2.72 (m,, 2H), 2.14 - 2.01 (m, 2H), 1.89 - 1.78 (m, 2H), 1.50 - 1.38 (m, 2H).

[0306] Example 91: 6-(4-(3-Phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)benzyl)-2,6-diazaspiro[3.3]heptane-2-carbonitrileStep 1: tert-Butyl 6-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)benzyl)- 2,6-diazaspiro[3.3]heptane-2-carboxylate To a solution of Intermediate 17 (94 mg, 251 ^mol) and tert-butyl 2,6-were added K2CO3 (174 mg, 1.26 mmol) and NaI (3.77 mg, 25.1 μmol). The mixture was stirred at 25 °C for 16 h. 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. After purification by silica gel flash chromatography (Eluent of 0% ~ 5% MeOH in CH2Cl2), the title compound (75 mg, yield: 47%) was obtained as an off-white solid. MS: m / z = 536.2 [M + H]+. 1H NMR (400 MHz, Chloroform -d) δ 9.26 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 7.54 -7.46 (m, 5H), 7.36 - 7.33 (m, 2H), 7.15 (d, J = 8.0 Hz, 2H), 6.99 (d, J = 5.6 Hz, 1H), 5.76 (s, 2H), 3.97 (s, 4H), 3.53 (s, 2H), 3.32 (s, 4H), 1.42 (s, 9H). Step 2: 2-(4-((2,6-Diazaspiro[3.3]heptan-2-yl)methyl)phenyl)-3-phenyl-5H-imidazo[1,2- c]pyrido[3,4-e][1,3]oxazine To a solution of tert-butyl 6-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2- yl)benzyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (75 mg, 140 μmol) i...

Claims

CLAIMS We claim:

1. A compound having the structure of Formula (I), or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof: )wherein, Ring A is an optionally substituted 5-membered heteroaryl; w, x, y, and z are each independently N or C-R1; each R1is independently selected from H, D, halogen, or -CN; R2and R3are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R2and R3together form an oxo; or R2and R3join together to form a carbocycle or heterocycle; L is selected from -N(R4)-, -O-, or a divalent radical selected from:* ,; wherein the asterisk (*) indicates the bond to the LCG; each R4is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl; each R25are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R25together form an oxo; or two independently selected R25join together to form a carbocycle or heterocycle; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0;h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 1, or 2; n is 0 or 1; LCG is a group selected from the group consisting of: (a Q QQ3is a bond, O, S, N-R9a; R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R9is absent and Q3and L join together to form a heterocycle; and R9ais selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R9and R9ajoin together to form a heterocycle; (b)T1is N or C-R10; T2is N or C-R10; T3is N or C-R10; T4is N or C-R10; T5is O, S, or N-R11;each R10is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R11is hydrogen, or optionally substituted C1-C6 alkyl; ndT6is N or C-R12; T7is N or C-R12; T8is N or C-R12; each R12is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl; (dwherein each R13, R14, R15, and R16is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, having the structure of Formula (I’):(I’) wherein, Ring A is an optionally substituted 5-membered heteroaryl;w, x, y, and z are each independently N or C-R1; each R1is independently selected from H, D, halogen, or -CN; R2and R3are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R2and R3together form an oxo; or R2and R3join together to form a carbocycle or heterocycle; L is selected from -N(R4)-, -O-, or a divalent radical selected from:wherein the asterisk (*) indicates the bond to the LCG; each R4is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl;each R25are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R25together form an oxo; or two independently selected R25join together to form a carbocycle or heterocycle; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 1, or 2; n is 0 or 1; LCG is a group selected from the group consisting of: (a Q Q; Q3is a bond, O, S, N-R9a; R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R9is absent and Q3and L join together to form a heterocycle; and R9ais selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R9and R9ajoin together to form a heterocycle; (b)T1is N or C-R10; T2is N or C-R10; T3is N or C-R10; T4is N or C-R10; T5is O, S, or N-R11; each R10is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R11is hydrogen, or optionally substituted C1-C6 alkyl; nd; T6is N or C-R12; T7is N or C-R12; T8is N or C-R12; each R12is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionall substituted ar l(d)wherein each R13, R14, R15, and R16is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein Ring A is an optionally substituted furanyl or optionally substituted thiophenyl.

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein Ring A is an optionally substituted oxazolyl or optionally substituted thiazolyl.

5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein Ring A is an optionally substituted isoxazolyl or optionally substituted isothiazolyl.

6. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, having the structure of Formula (Ia)a) wherein: a is N, N-R26, or C-R21; b is N, N-R27, or C-R22; c is N, or C; d is N, N-R28, or C-H; e is N, N-R29, or C-R23; provided that only one or two of a, b, c, d, or e are selected from a N-containing group; R21is selected from H, D, halogen, -CN, -OH, -SR4, -N(R4)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl- C(O)O-, -CON(R4)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R22is selected from H, D, halogen, -CN, -OH, -SR4, -N(R4)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl-C(O)O-, -CON(R4)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R23is selected from H, D, halogen, -CN, -OH, -SR4, -N(R4)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl- C(O)O-, -CON(R4)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or optionally R23and R26together with the adjacent atoms to which they are attached, join to form a ring; and R26, R27, R28, and R29 are independently selected from H, optionally substituted C1-C6alkyl, optionally substituted carbocyclyl, or optionally substituted (carbocyclyl)alkyl.

7. The compound of claim 6, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, having the structure of Formula (Ia-i):).

8. The compound of claim 6, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, having the structure of Formula (Ia-ii):(Ia-ii).

9. The compound of claim 6, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, having the structure of Formula (Ia-iii):(Ia-iii).

10. The compound of claim 6, or a pharmaceutically acceptable salt, solvate, or deuteroisotope-iv).

11. The compound of claim 6, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, having the structure of Formula (Ia-v):).

12. The compound of any one of claims 6-11, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R21is selected from H, D, optionally substituted C1-C6 alkyl, or optionally substituted carbocyclyl.

13. The compound of any one of claims 6-12, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R22is selected from H, D, optionally substituted C1-C6 alkyl, or optionally substituted carbocyclyl.

14. The compound of any one of claims 6-13, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R23is selected from H, D, optionally substituted C1-C6 alkyl, or optionally substituted carbocyclyl.

15. The compound of any one of claims 6-14, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R26is selected from H, optionally substituted C1-C6 alkyl, or optionally substituted carbocyclyl.

16. The compound of any one of claims 6-15, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R27is selected from H, optionally substituted C1-C6 alkyl, or optionally substituted carbocyclyl.

17. The compound of any one of claims 6-16, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R28is selected from H, optionally substituted C1-C6 alkyl, or optionally substituted carbocyclyl.

18. The compound of any one of claims 6-17, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R29is selected from H, optionally substituted C1-C6 alkyl, or optionally substituted carbocyclyl.

19. The compound of claim 6, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, having the structure of Formula (Ia-vi): -vi).

20. The compound of claim 6, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, having the structure of Formula (Ia-vii):).

21. The compound of claim 6, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, having the structure of Formula (Ia-viii):(Ia-viii).

22. The compound of claim 6, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, having the structure of Formula (Ia-ix):

23. The compound of any one of claims 19-22, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R21is selected from H, D, optionally substituted C1-C6 alkyl, or optionally substituted carbocyclyl.

24. The compound of any one of claims 19-22, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R22is selected from H, D, optionally substituted C1-C6 alkyl, or optionally substituted carbocyclyl.

25. The compound of any one of claims 19-22, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R23is selected from H, D, optionally substituted C1-C6 alkyl, or optionally substituted carbocyclyl.

26. The compound of any one of claims 19-22, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R26is selected from H, optionally substituted C1-C6 alkyl, or optionally substituted carbocyclyl.

27. The compound of any one of claims 19-22, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R27is selected from H, optionally substituted C1-C6 alkyl, or optionally substituted carbocyclyl.

28. The compound of any one of claims 19-22, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R29is selected from H, optionally substituted C1-C6 alkyl, or optionally substituted carbocyclyl.

29. A compound having the structure of Formula (III), or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof:(III) wherein: a is N, or C; b is N, N-R30, or C-R24; R24is selected from H, D, halogen, -CN, -OH, -SR7, -N(R7)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl- C(O)O-, -CON(R7)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, ti ll b tit t d l ti ll b tit t d h t lR30is selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, or optionally substituted (carbocyclyl)alkyl; c is N, or C; d is N, NH, O, S, or C-H; e is N, or C; provided that only one or two of a, b, c, d, or e are selected from N or NH; provided that a and e are not N; provided that a and c are not N; provided that e and c are not N; w, x, y, and z are each independently N or C-R1; each R1is independently selected from H, D, halogen, or -CN; R2and R3are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R2and R3together form an oxo; or R2and R3join together to form a carbocycle or heterocycle; u is selected from O, S, C(R5)(R6), or NR7; m is 1, 2, or 3; R5and R6are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R5and R6together form an oxo; or R5and R6join together to form a carbocycle or heterocycle; R7is selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; w1, x1, y1, and z1 are each independently N or C-R8; each R8is selected from H, D, halogen, -CN, -OH, -SR4, -N(R4)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl-C(O)O-, -CON(R4)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; L is selected from -N(R4)-, -O-, or a divalent radical selected from:, ,; wherein the asterisk (*) indicates the bond to the LCG;each R4is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl; each R25are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R25together form an oxo; or two independently selected R25join together to form a carbocycle or heterocycle; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 1, or 2; n is 0 or 1; LCG is a group selected from the group consisting of: (a Q Qs O or S; Q3is a bond, O, S, N-R9a; R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R9is absent and Q3and L join together to form a heterocycle; and R9ais selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R9and R9ajoin together to form a heterocycle; (b)T1is N or C-R10; T2is N or C-R10; T3is N or C-R10; T4is N or C-R10; T5is O, S, or N-R11; each R10is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R11is hydrogen, or optionally substituted C1-C6 alkyl; nd; T6is N or C-R12; T7is N or C-R12; T8is N or C-R12; each R12is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionall substituted ar l(d)wherein each R13, R14, R15, and R16is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .

30. The compound of claim 29, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, having the structure of Formula (III’):’) wherein: a is N, or C; b is N, N-R30, or C-R24; R24is selected from H, D, halogen, -CN, -OH, -SR7, -N(R7)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl- C(O)O-, -CON(R7)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R30is selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, or optionally substituted (carbocyclyl)alkyl; c is N, or C; d is N, NH, O, S, or C-H; e is N, or C; provided that only one or two of a, b, c, d, or e are selected from N or NH; provided that a and e are not N; provided that a and c are not N; provided that e and c are not N; w, x, y, and z are each independently N or C-R1; each R1is independently selected from H, D, halogen, or -CN; R2and R3are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R2and R3together form an oxo; or R2and R3join together to form a carbocycle or heterocycle; u is selected from O, S, C(R5)(R6), or NR7; i 1 2R5and R6are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R5and R6together form an oxo; or R5and R6join together to form a carbocycle or heterocycle; R7is selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; w1, x1, y1, and z1 are each independently N or C-R8; each R8is selected from H, D, halogen, -CN, -OH, -SR4, -N(R4)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl-C(O)O-, -CON(R4)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; L is selected from -N(R4)-, -O-, or a divalent radical selected from:,* **wherein the asterisk (*) indicates the bond to the LCG; each R4is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl; each R25are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R25together form an oxo; or two independently selected R25join together to form a carbocycle or heterocycle; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 1, or 2; n is 0 or 1; LCG is a group selected from the group consisting of: (a Q 2Q is O or S; Q3is a bond, O, S, N-R9a; R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R9is absent and Q3and L join together to form a heterocycle; and R9ais selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or 99(b)T1is N or C-R10; T2is N or C-R10; T3is N or C-R10; T4is N or C-R10; T5is O, S, or N-R11; each R10is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R11is hydrogen, or optionally substituted C1-C6 alkyl; ndT6is N or C-R ; T7is N or C-R12; T8is N or C-R12; each R12is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl;(d weren eac , , , an s n epen en y se ec e rom , , , optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .

31. The compound of claim 29 or 30, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, having the structure of Formula (III’’):’) wherein: a is N, or C; b is N, N-R30, or C-R24; R24is selected from H, D, halogen, -CN, -OH, -SR7, -N(R7)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl- C(O)O-, -CON(R7)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R30is selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, or optionally substituted (carbocyclyl)alkyl; c is N, or C; d is N, NH, O, S, or C-H; e is N, or C; provided that only one or two of a, b, c, d, or e are selected from N or NH; provided that a and e are not N; provided that a and c are not N; provided that e and c are not N; w, x, y, and z are each independently N or C-R1; each R1is independently selected from H, D, halogen, or -CN;R2and R3are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R2and R3together form an oxo; or R2and R3join together to form a carbocycle or heterocycle; u is selected from O, S, C(R5)(R6), or NR7; m is 1 or 2; R5and R6are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R5and R6together form an oxo; or R5and R6join together to form a carbocycle or heterocycle; R7is selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; w1, x1, y1, and z1 are each independently N or C-R8; each R8is selected from H, D, halogen, -CN, -OH, -SR4, -N(R4)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl-C(O)O-, -CON(R4)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; L is selected from -N(R4)-, -O-, or a divalent radical selected from:* ,wherein the asterisk (*) indicates the bond to the LCG; each R4is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl; each R25are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R25together form an oxo; or two independently selected R25join together to form a carbocycle or heterocycle; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 1, or 2; n is 0 or 1; LCG is a roup selected from the group consisting of: (a Q2Q3is a bond, O, S, N-R9a; R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R9is absent and Q3and L join together to form a heterocycle; and R9ais selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R9and R9ajoin together to form a heterocycle; (b)T1is N or C-R10; T2is N or C-R10; T3is N or C-R10; T4is N or C-R10; T5is O, S, or N-R11; each R10is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R11is hydrogen, or optionally substituted C1-C6 alkyl; nd; T6is N or C-R12; T7is N or C-R12;each R12is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl; (dwherein each R13, R14, R15, and R16is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .

32. The compound of claim 29, 30, or 31, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, having the structure of Formula (III-i):).

33. The compound of claim 29, 30, or 31, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, having the structure of Formula (III-ii):(III-ii).

34. The compound of claim 29, 30, or 31, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, having the structure of Formula (III-iii):).

35. The compound of claim29, 30, or 31, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, having the structure of Formula (III-iv):I-iv).

36. The compound of claim 29, 30, or 31, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, having the structure of Formula (III-v):(III-v).

37. The compound of claim 29, 30, or 31, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, having the structure of Formula (III-vi):).

38. The compound of claim29, 30, or 31, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, having the structure of Formula (III-vii):I-vii).

39. The compound of claim 29, 30, or 31, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, having the structure of Formula (III-viii):(III-viii).

40. The compound of claim 29, 30, or 31, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, having the structure of Formula (III-ix):).

41. The compound of any oneof claims 29-33, 35-39, or 40, or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein R24is selected from optionally substituted aryl, or optionally substituted heteroaryl.

42. A compound having the structure of Formula (IV), or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof:) wherein: a is N, N-R30, or C-R24; b is N, N-R30, or C-R24; each R24is independently selected from H, D, halogen, -CN, -OH, -SR7, -N(R7)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl-C(O)O-, -CON(R7)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each R30is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, or optionally substituted (carbocyclyl)alkyl; c is N, or C; d is N, or C; e is N, or C; provided that only one or two of a, b, c, d, or e are selected from N and N-R30; w, x, y, and z are each independently N or C-R1;R2and R3are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R2and R3together form an oxo; or R2and R3join together to form a carbocycle or heterocycle; u is selected from O, S, C(R5)(R6), or NR7; m is 1 or 2; R5and R6are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R5and R6together form an oxo; or R5and R6join together to form a carbocycle or heterocycle; R7is selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; w1, x1, y1, and z1 are each independently N or C-R8; each R8is selected from H, D, halogen, -CN, -OH, -SR4, -N(R4)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl-C(O)O-, -CON(R4)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; L is selected from -N(R4)-, -O-, or a divalent radical selected from:* ,; wherein the asterisk (*) indicates the bond to the LCG; each R4is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl; each R25are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R25together form an oxo; or two independently selected R25join together to form a carbocycle or heterocycle; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0;h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 1, or 2; n is 0 or 1; LCG is a group selected from the group consisting of: (a Q QQ3is a bond, O, S, N-R9a; R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R9is absent and Q3and L join together to form a heterocycle; and R9ais selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R9and R9ajoin together to form a heterocycle; (b)T1is N or C-R10; T2is N or C-R10; T3is N or C-R10; T4is N or C-R10; T5is O, S, or N-R11;each R10is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R11is hydrogen, or optionally substituted C1-C6 alkyl; ndT6is N or C-R12; T7is N or C-R12; T8is N or C-R12; each R12is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl; (dwherein each R13, R14, R15, and R16is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .

43. The compound of claim 42, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, having the structure of Formula (IV’):(IV’)wherein: a is N, N-R30, or C-R24; b is N, N-R30, or C-R24; each R24is independently selected from H, D, halogen, -CN, -OH, -SR7, -N(R7)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl-C(O)O-, -CON(R7)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each R30is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, or optionally substituted (carbocyclyl)alkyl; c is N, or C; d is N, or C; e is N, or C; provided that only one or two of a, b, c, d, or e are selected from N and N-R30; w, x, y, and z are each independently N or C-R1; each R1is independently selected from H, D, halogen, or -CN; R2and R3are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R2and R3together form an oxo; or R2and R3join together to form a carbocycle or heterocycle; u is selected from O, S, C(R5)(R6), or NR7; m is 1 or 2; R5and R6are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R5and R6together form an oxo; or R5and R6join together to form a carbocycle or heterocycle; R7is selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; w1, x1, y1, and z1 are each independently N or C-R8; each R8is selected from H, D, halogen, -CN, -OH, -SR4, -N(R4)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl-C(O)O-, -CON(R4)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; L is selected from -N(R4)-, -O-, or a divalent radical selected from:wherein the asterisk (*) indicates the bond to the LCG; each R4is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl; each R25are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R25together form an oxo; or two independently selected R25join together to form a carbocycle or heterocycle; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4;d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 1, or 2; n is 0 or 1; LCG is a group selected from the group consisting of: (a Q QQ3is a bond, O, S, N-R9a; R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R9is absent and Q3and L join together to form a heterocycle; and R9ais selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R9and R9ajoin together to form a heterocycle;T1is N or C-R10; T2is N or C-R10; 310T4is N or C-R10; T5is O, S, or N-R11; each R10is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R11is hydrogen, or optionally substituted C1-C6 alkyl; ndT6is N or C-R12; T7is N or C-R12; T8is N or C-R12; each R12is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl; (d) wherein each R13, R14, R15, and R16is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .

44. The compound of claim 42 or 43, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, having the structure of Formula (IV-i):).

45. The compound of claim 42or 43, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, having the structure of Formula (IV-ii):V-ii).

46. The compound of claim 42 or 43, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, having the structure of Formula (IV-iii):(IV-iii).

47. The compound of claim 42 or 43, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, having the structure of Formula (IV-iv):V-iv).

48. The compound of claim42 or 43, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, having the structure of Formula (IV-v):).

49. The compound of claim 42 or 43, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, having the structure of Formula (IV-vi):(IV-vi).

50. The compound of claim 42 or 43, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, having the structure of Formula (IV-vii):V-vii).

51. The compound of claim42 or 43, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, having the structure of Formula (IV-viii):V-viii).

52. The compound of claim 42 or 43, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, having the structure of Formula (IV-ix):(IV-ix).

53. The compound of claim 42 or 43, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, having the structure of Formula (IV-x):).

54. The compound of claim 42or 43, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, having the structure of Formula (IV-xi):(IV-xi).

55. The compound of claim 42 or 43, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, having the structure of Formula (IV-xii):(IV-xii).

56. The compound of claim 42 or 43, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, having the structure of Formula (IV-xiii):V-xiii).

57. The compound of any one of claims 30-56, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein m is 1.

58. The compound of any one of claims 30-56, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein m is 2.

59. The compound of any one of claims 30-58, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein u is O.

60. A compound having the structure of Formula (V), or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof:(V) wherein: a is N, or C; b is N, N-R30, or C-R24; R24is selected from H, D, halogen, -CN, -OH, -SR7, -N(R7)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl- C(O)O-, -CON(R7)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R30is selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, or optionally substituted (carbocyclyl)alkyl; c is N, or C; d is N, NH, O, S, or C-H;e is N, or C; provided that only one or two of a, b, c, d, or e are selected from N or NH; provided that a and e are not N; provided that a and c are not N; provided that e and c are not N; w, x, y, and z are each independently N or C-R1; each R1is independently selected from H, D, halogen, or -CN; R2and R3are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R2and R3together form an oxo; or R2and R3join together to form a carbocycle or heterocycle; R5and R6are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R5and R6together form an oxo; or R5and R6join together to form a carbocycle or heterocycle; R7is selected from H, optionally substituted C1-C6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; w1, x1, y1, and z1 are each independently N or C-R8; each R8is selected from H, D, halogen, -CN, -OH, -SR4, -N(R4)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl-C(O)O-, -CON(R4)2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; L is selected from -N(R4)-, -O-, or a divalent radical selected from:, , ,; wherein the asterisk (*) indicates the bond to the LCG; each R4is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl; each R25are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R25together form an oxo; or two independently selected R25join together to form a carbocycle or heterocycle; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; 1 i 0 1 2 3 4f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 1, or 2; n is 0 or 1; LCG is a group selected from the group consisting of: (a Q QQ3is a bond, O, S, N-R9a; R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R9is absent and Q3and L join together to form a heterocycle; and R9ais selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R9and R9ajoin together to form a heterocycle; (b)T1is N or C-R10; T2is N or C-R10; T3is N or C-R10; T4is N or C-R10; 511each R10is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R11is hydrogen, or optionally substituted C1-C6 alkyl; ndT6is N or C-R12; T7is N or C-R12; T8is N or C-R12; each R12is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl; (dwherein each R13, R14, R15, and R16is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .

61. The compound of claim 60, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, having the structure of Formula (V-i):(V i)62. The compound of claim 60, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, having the structure of Formula (V-ii): ).

63. The compound of claim 60, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, having the structure of Formula (V-iii):).

64. The compound of claim 60, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, having the structure of Formula (V-iv):(V-iv).

65. The compound of claim 60, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, having the structure of Formula (V-v):).

66. The compound of claim 60, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, having the structure of Formula (V-vi):).

67. The compound of claim 60, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, having the structure of Formula (V-vii):(V-vii).

68. The compound of claim 60, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, having the structure of Formula (V-viii):).

69. The compound of claim60, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, having the structure of Formula (V-ix):).

70. The compound of any one of claims 29-33, 35-38, 40, 42, 43, 46, 52, 57-62, 64-67, or 69, or apharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R24is selected from optionally substituted aryl, or optionally substituted heteroaryl.

71. The compound of any one of claims 29, 30, 31, 34, 39, 42-45, 47-49, 54, 55, 57-60, 63, or 68,or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R30is selected from optionally substituted aryl, or optionally substituted heteroaryl.

72. The compound of any one of claims 29-71, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein w1 is N.

73. The compound of any one of claims 29-72, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein x1, y1, and z1 are C-H.

74. The compound of any one of claims 29-71, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein x1 is N.

75. The compound of any one of claims 29-71 or 74, or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, wherein w1, y1, and z1 are C-H.

76. The compound of any one of claims 29-71, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein y1 is N.

77. The compound of any one of claims 29-71 or 76, or a pharmaceutically acceptable salt,78. The compound of any one of claims 29-71, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein z1 is N.

79. The compound of any one of claims 29-71 or 78, or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, wherein w1, x1, and y1 are C-H.

80. The compound of any one of claims 29-71, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein w1 and y1 are N.

81. The compound of any one of claims 29-71, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein x1 and z1 are N.

82. The compound of any one of claims 29-71, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein x1 and y1 are N.

83. The compound of any one of claims 29-71, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein w1 and x1 are N.

84. The compound of any one of claims 29-71, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein z1 and y1 are N.

85. The compound of any one of claims 1-84, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein w, x, y, and z are C-H.

86. The compound of any one of claims 1-84, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R2and R3are H.

87. The compound of any one of claims 1-86, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein L is selected from:

88. The compound of claim 87, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein L is:.

89. The compound of any one of claims 1-86, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein L is selected from: .

90. The compound of any one of claims 1-86, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein L is selected from:.

91. The compound of any one of claims 1-90, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein n is 0.

92. The compound of any one of claims 1-90, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein n is 1.

93. The compound of any one of claims 1-92, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein LCG is:Q1is O or S;Q2is O or S; Q3is a bond, O, S, N-R9a; R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R9is absent and Q3and L join together to form a heterocycle; and R9ais selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R9and R9ajoin together to form a heterocycle.

94. The compound of any one of claims 1-92, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein LCG is:T1is N or C-R10; T2is N or C-R10; T3is N or C-R10; T4is N or C-R10; T5is O, S, or N-R11; each R10is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; and each R11is hydrogen, or optionally substituted C1-C6 alkyl.

95. The compound of claim 94, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein LCG is:.

96. The compound of claim 94, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein LCG is:.

97. The compound oc a m 9 , or a p armaceut ca y acceptab e sa t, so vate, or deuteroisotopethereof, wherein LCG is: .

98. The compound of any one of claims 1-92, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein LCG is:; T6is N or C-R12; T7is N or C-R12; T8is N or C-R12; each R12is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl.

99. The compound of any one of claims 1-92, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein LCG is:; wherein each R13, R14, R15, and R16is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy.

100. The compound of any one of claims 1-92, or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein LCG is -C≡N.

101. The compound of claim 37, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein LCG is:.

102. The compound of claim 101, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein L is: .

103. The compound of claims 101 or 102 or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, wherein y1 is N.

104. The compound of claims 101, 102 or 103, or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein w1, x1, and z1 are C-H.

105. The compound of any one of claims 101-104, or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein R24is selected from optionally substituted aryl, or optionally substituted heteroaryl.

106. The compound of any one of claims 101-105, or a pharmaceutically acceptablesalt, solvate, or deuteroisotope thereof, wherein n is 0, u is O, and m is 1.

107. A compound, or pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, as described in Table 1.

108. A compound, or pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, as described in Table 2.

109. A pharmaceutical composition comprising a compound, or pharmaceuticallyacceptable salt, solvate, or deuteroisotope thereof, as described in any one of claims 1-108 and a pharmaceutically acceptable excipient.

110. A method of preparing a pharmaceutical composition comprising mixing acompound, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, of any one of claims 1-108, and a pharmaceutically acceptable carrier.

111. A compound of any one of claims 1-108, or pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, for use in a method of treatment of the human or animal body.

112. A compound of any one of claims 1-108, or pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, for use in a method of treatment of cancer or neoplastic disease.

113. Use of a compound of any one of claims 1-108, or pharmaceuticallyacceptable salt, solvate, or deuteroisotope thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

114. A method of treating cancer in a patient in need thereof, comprisingadministering to the patient a compound as described in any one of claims 1-108, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof.

115. A method of treating cancer in a patient in need thereof, comprisingadministering to the patient a pharmaceutical composition comprising a compound as described in any one of claims 1-108, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient.

116. The method of claim 114 or 115, wherein the cancer is breast cancer.

117. The method of claim 116, wherein the cancer is a hormone receptor positive(HR+) breast cancer.

118. The method of claim 116, wherein the cancer is a human epidermal growthfactor receptor 2 negative (HER2-) breast cancer.

119. The method of claim 116, wherein the cancer is a HR+ / HER2- breast cancer.

120. The method of claim 116, wherein the cancer is a HR+ / HER2-low breastcancer.

121. The method of claim 116, wherein the cancer is a HR+ / HER2+ breast cancer.

122. The method of claim 116, wherein the cancer is a triple negative breast cancer(TNBC).

123. The method of claim 116, wherein the cancer is an invasive breast cancer.

124. The method of claim 114 or 115, wherein the cancer is uterine cancer.

125. The method of claim 124, wherein the cancer is uterine sarcoma.

126. The method of claim 124, wherein the cancer is endometrial cancer.

127. The method of claim 124, wherein the cancer is Type I endometrial cancer.

128. The method of claim 124, wherein the cancer is Type II endometrial cancer.

129. The method of claim 128, wherein the cancer is Type II endometrial papillaryserous carcinoma.

130. The method of claim 128, wherein the cancer is Type II endometrial clear cellcarcinoma.

131. The method of claim 128, wherein the cancer is Type II endometrialundifferentiated carcinoma.

132. The method of claim 128, wherein the cancer is Type II endometrioidcarcinoma.

133. The method of claim 124, wherein the cancer is microsatellite instability(MSI) high and / or DNA mismatch repair (MMR) deficient134. The method of claim 124, wherein the cancer is tumor mutational burden(TMB) high.

135. The method of claim 124, wherein the cancer is HER2-.

136. The method of claim 114 or 115, wherein the cancer is cervical cancer.

137. The method of claim 136, wherein the cancer is a cervical squamous cellcarcinoma.

138. The method of claim 136, wherein the cancer is a cervical adenocarcinoma.

139. The method of claim 114 or 115, wherein the cancer is prostate cancer.

140. The method of claim 139, wherein the cancer is prostate adenocarcinoma.

141. The method of claim 139, wherein the cancer is prostate neuroendocrinecancer.

142. The method of claim 139, wherein the cancer is prostate small cellneuroendocrine cancer.

143. The method of claim 139, wherein the cancer is prostate large cell carcinoma.

144. The method of claim 139, wherein the cancer is prostate transitional cellcarcinoma.

145. The method of claim 139, wherein the cancer is prostate sarcoma.

146. The method of claim 114 or 115, wherein the cancer is bladder cancer.

147. The method of claim 146, wherein the cancer is urothelial cancer.

148. The method of claim 146, wherein the cancer is squamous cell cancer of thebladder.

149. The method of claim 146, wherein the cancer is small cell cancer of thebladder.

150. The method of claim 146, wherein the cancer is adenocarcinoma of thebladder.

151. The method of claim 114 or 115, wherein the cancer is lung cancer.

152. The method of claim 114 or 115, wherein the cancer is non-small cell lungcancer.

153. The method of claim 114 or 115, wherein the cancer is non-squamous non-small cell lung cancer.

154. The method of claim 114 or 115, wherein the cancer is squamous non-smallcell lung cancer.

155. The method of claim 114 or 115, wherein the cancer is colon cancer.

156. The method of claim 114 or 115, wherein the cancer is anal cancer.

157. The method of claim 114 or 115, wherein the cancer is a meningioma.

158. The method of claim 114 or 115, wherein the cancer is a glioma.

159. The method of claim 114 or 115, wherein the cancer is pancreatic cancer.

160. The method of claim 159, wherein the cancer is exocrine pancreatic cancer.

161. The method of claim 159, wherein the cancer is neuroendocrine pancreaticcancer.

162. The method of claim 114 or 115, wherein the cancer is thyroid cancer.

163. The method of claim 114 or 115, wherein the cancer is myxofibrosarcoma.

164. The method of claim 114 or 115, wherein the cancer is parotid gland cancer.

165. The method of claim 114 or 115, wherein the cancer is esophageal cancer.

166. The method of claim 114 or 115, wherein the cancer is stomach cancer.

167. The method of claim 114 or 115, wherein the cancer is skin cancer.

168. The method of claim 167, wherein the cancer is nonmelanoma skin cancer.

169. The method of claim 167, wherein the cancer is squamous nonmelanoma skincancer.

170. The method of claim 167, wherein the cancer is non-squamous nonmelanomaskin cancer.

171. The method of claim 114 or 115, wherein the cancer is ovarian cancer.

172. The method of claim 171, wherein the cancer is epithelial ovarian cancer.

173. The method of claim 171, wherein the cancer is serous epithelial ovariancancer.

174. The method of claim 171, wherein the cancer is endometrioid ovarian cancer.

175. The method of claim 171, wherein the cancer is clear cell ovarian cancer.

176. The method of claim 171, wherein the cancer is mucinous ovarian cancer.

177. The method of claim 114 or 115, wherein the cancer is adenoid cysticcarcinoma.

178. The method of claim 114 or 115, wherein the cancer is renal cell cancer.

179. The method of claim 114 or 115, wherein the cancer is appendix cancer.

180. The method of claim 114 or 115, wherein the cancer is multiple myeloma.

181. The method of claim 114 or 115, wherein the cancer is acute myeloidleukemia.

182. The method of claim 114 or 115, wherein the cancer is cancer of unknownprimary.

183. The method of claim 114 or 115, wherein the cancer is locally advanced.

184. The method of any one of claims 114-183, wherein the cancer is metastatic.

185. The method of any one of claims 114-183, wherein the method is adjuvanttherapy following surgical resection.

186. The method of any one of claims 114-183, wherein the method is neo-adjuvanttherapy.

187. The method of any one of claims 114-183, wherein the method is first-linesystemic therapy for locally advanced or metastatic disease.

188. The method of any one of claims 114-183, wherein the patient has relapsedafter prior therapy.

189. The method of any one of claims 114-183, wherein the patient has acquiredresistance to prior therapy.

190. The method of any one of claims 114-183, wherein the patient is refractory totherapy.

191. The method of any one of claims 114-190, wherein the cancer is characterizedby existence of AKT1-E17K mutation.

192. The method of any one of claims 114-191, wherein the cancer exhibits one ormore co-occurring alterations selected from a PIK3CA alteration, a PIK3R1 alteration, an AKT1 alteration, and PTEN alteration.

193. A method of inhibiting an AKT1 enzyme comprising contacting the enzymewith a compound of any one of claims 1-108, wherein the AKT1 enzyme is contacted in an in vitro setting.

194. A method of inhibiting an AKT1 enzyme comprising contacting the enzymewith a compound of any one of claims 1-108, wherein the AKT1 enzyme is contacted in an in vivo setting.

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