AKT1 modulators

Abstract

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

Description

Attorney Docket No.62619-729601 AKT1 MODULATORS CROSS REFERENCE

[0001] This Application claims the benefit of US Provisional Application No. 63 / 562,188, filedMarch 6, 2024, which is incorporated by reference in its entirety herein. BACKGROUND

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

[0003] Provided herein are inhibitors of AKT1, pharmaceutical compositions comprising 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 or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is H, optionally substituted aryl, or optionally substituted heteroaryl;Attorney Docket No.62619-729601 R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , , , , , , , , , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle;T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;Attorney Docket No.62619-729601T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl;wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .

[0005] One embodiment provides a compound of Formula (I) having the structure of Formula (I-1), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3;Attorney Docket No.62619-729601 Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle;T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;Attorney Docket No.62619-729601T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl;wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .

[0006] One embodiment provides a compound having the structure of Formula (II), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is H, optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle;T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;Attorney Docket No.62619-729601T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl;wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N.

[0007] One embodiment provides a compound of Formula (II) having the structure of Formula(II-1), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , , , , , , , , , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle;T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;Attorney Docket No.62619-729601T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl;wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N.

[0008] One embodiment provides a compound having the structure of Formula (III), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is H, optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle;T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;Attorney Docket No.62619-729601T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl;wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N.

[0009] One embodiment provides a compound of Formula (III) having the structure of Formula(III-1), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , , , , , , , , , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle;T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;Attorney Docket No.62619-729601T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl;wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N.

[0010] One embodiment provides a compound having the structure of Formula (IV), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is H, optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle;T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;Attorney Docket No.62619-729601T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl;wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N.

[0011] One embodiment provides a compound of Formula (IV) having the structure of Formula(IV-1), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , , , , , , , , , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle;T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;Attorney Docket No.62619-729601T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl;wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N.

[0012] One embodiment provides a compound having the structure of Formula (V), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is H, optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle;T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;Attorney Docket No.62619-729601T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl;wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N.

[0013] One embodiment provides a compound of Formula (V) having the structure of Formula(V-1), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , , , , , , , , , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle;T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;Attorney Docket No.62619-729601T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl;wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .

[0014] One embodiment provides a pharmaceutical composition comprising a compound ofFormula (I)-(V), or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0015] 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)-(V), or pharmaceutically acceptable salt or solvate thereof. Another embodiment provides the method wherein the disease or disorder is cancer. INCORPORATION BY REFERENCE

[0016] All publications, patents, and patent applications mentioned in this specification areherein incorporated by reference for the specific purposes identified herein.Attorney Docket No.62619-729601 DETAILED DESCRIPTION OF THE INVENTION

[0017] As used herein and in the appended claims, the singular forms "a," "and," and "the"include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, "consist of" or "consist essentially of" the described features. Definitions

[0018] As used in the specification and appended claims, unless specified to the contrary, thefollowing terms have the meaning indicated below.

[0019] "Amino" refers to the –NH2 radical.

[0020] "Cyano" refers to the -CN radical.

[0021] "Nitro" refers to the -NO2 radical.

[0022] "Oxa" refers to the -O- radical.

[0023] "Oxo" refers to the =O radical.

[0024] "Thioxo" refers to the =S radical.

[0025] "Imino" refers to the =N-H radical.

[0026] "Oximo" refers to the =N-OH radical.

[0027] "Hydrazino" refers to the =N-NH2 radical.

[0028] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely ofcarbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13alkyl). 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-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). InAttorney Docket No.62619-729601 other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C1alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). 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-C5alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1- methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n- pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). In certain embodiments, an optionally substituted alkyl is a haloalkyl. In other embodiments, an optionally substituted alkyl is a fluoroalkyl. In other embodiments, an optionally substituted alkyl is a -CF3 group.

[0029] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula –O-alkyl,where alkyl is an alkyl chain as defined above.

[0030] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consistingsolely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl),Attorney Docket No.62619-729601 prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0031] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consistingsolely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl comprises two to six carbon atoms. In other embodiments, an alkynyl comprises two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, orAttorney Docket No.62619-729601 trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0032] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbonchain linking the rest of the molecule to a radical group, consisting solely of carbon andhydrogen, containing no unsaturation, and having from one to twelve carbon atoms, for example,methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., C1-C8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5alkylene). 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., C1alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C5-C8 alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-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).Attorney Docket No.62619-729601

[0033] "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 (e.g., C5-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).

[0034] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbonchain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C2-C8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C2-C5 alkynylene). In other embodiments,Attorney Docket No.62619-729601 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., C2alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C3-C5 alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (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).

[0035] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclichydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance 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 eachAttorney Docket No.62619-729601 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] "Aralkyl" refers to a radical of the formula -Rc-aryl where Rc is an alkylene chain asdefined 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.

[0037] "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.

[0038] "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.

[0039] "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.

[0040] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbonradical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond.Attorney Docket No.62619-729601 Carbocyclyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds). A fully saturated carbocyclyl radical is also referred to as "cycloalkyl." Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, oxo, thioxo, cyano, nitro, -Rb- ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb- C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb- N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0041] "Carbocyclylalkyl" refers to a radical of the formula –Rc-carbocyclyl where Rc is analkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0042] "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.Attorney Docket No.62619-729601

[0043] "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.

[0044] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.

[0045] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one ormore fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl,fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0046] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical thatcomprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are notlimited 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 (optionallyAttorney Docket No.62619-729601 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-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.

[0048] "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.

[0049] "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.

[0050] "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.

[0051] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radicalthat comprises two to seventeen carbon atoms and from one to six heteroatoms selected fromAttorney Docket No.62619-729601 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 molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, optionally substituted fluoroalkyl, optionally substituted haloalkenyl, optionallyAttorney Docket No.62619-729601 substituted haloalkynyl, oxo, thioxo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb- OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, - Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0052] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least onenitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0053] "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.

[0054] "Heteroarylalkyl" refers to a radical of the formula –Rc-heteroaryl, where Rc is analkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0055] "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 asAttorney Docket No.62619-729601 defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0056] The compounds disclosed herein, in some embodiments, contain one or more asymmetriccenters and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers(e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pureforms, and all tautomeric forms are also intended to be included. The term “geometric isomer”refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term“positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0057] 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:

[0058] 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 beAttorney Docket No.62619-729601 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.

[0059] Unless otherwise stated, structures depicted herein are intended to include compoundswhich differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0060] The compounds of the present disclosure optionally contain unnatural proportions ofatomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,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.

[0061] In certain embodiments, the compounds disclosed herein have some or all of the 1Hatoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0062] Deuterium substituted compounds are synthesized using various methods such asdescribed in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0063] Deuterated starting materials are readily available and are subjected to the syntheticmethods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0064] Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, suchas iodomethane-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.Attorney Docket No.62619-729601

[0065] Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAlD4), are employedto transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD4is illustrated, by way of example only, in the reaction schemes below.

[0066] 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.

[0067] In one embodiment, the compounds disclosed herein contain one deuterium atom. Inanother embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-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.

[0068] "Pharmaceutically acceptable salt" includes both acid and base addition salts. Apharmaceutically acceptable salt of any one of the AKT1 inhibitory compounds described hereinis intended to encompass any and all pharmaceutically suitable salt forms. PreferredAttorney Docket No.62619-729601 pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0069] "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.

[0070] "Pharmaceutically acceptable base addition salt" refers to those salts that retain thebiological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol,Attorney Docket No.62619-729601 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.

[0071] "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.

[0072] The term “subject” or “patient” encompasses mammals. Examples of mammals include,but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0073] 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” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made. AKT1 Protein and Function

[0074] AKT, also known as protein kinase B (PKB), is a serine / threonine protein kinase withthree isoforms, AKT1, AKT2, and AKT3. While the isoforms are encoded by different genes, they are highly homologous at the protein level and share a conserved domain structure comprising an N-terminal pleckstrin homology (PH) domain, a kinase domain, and a C-terminal regulatory domain comprising a hydrophobic moiety, which includes the regulatory serine residue (Nitulescu, G. M. et al., Int J Oncol., 2018; 53(6): 2319-2331).Attorney Docket No.62619-729601

[0075] AKT proteins play a crucial role in major cellular functions including cell cycleprogression, 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.

[0076] AKT1 is ubiquitously expressed, whereas AKT2 is primarily expressed in insulin-responsive tissues, and AKT3 is primarily expressed in brain and testes. A shared phosphorylation site of AKT in the catalytic domain corresponds to a threonine residue; specifically, Thr308 in AKT1, Thr309 in AKT2, and Thr305 in AKT3. A shared phosphorylation site in the C-terminus of the protein cis a serine residue; specifically, Ser473 in AKT1, Ser474 in AKT2, and Ser472 in AKT3.

[0077] 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.

[0078] 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

[0079] 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).

[0080] mTOR is a key component in the AKT signaling pathway, which is a downstreammember of AKT and important regulator for cell metabolism and growth. mTOR is also an activator which can directly phosphorylate AKT’s regulatory serine residue, Ser473. mTOR forms a complex with rapamycin-insensitive companion of mTOR (RICTOR) (and other proteins) to form mTOR complex 2 (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.Attorney Docket No.62619-729601

[0081] AKT is known as a survival kinase and mediates cell survival and proliferation byinhibiting pathways including, but not limited to Bcl2 and MDM2, which promotes apoptosis. Studies have shown that the AKT signaling cascade have frequent malfunctions in various cancers, and may be associated with tumor aggressiveness (Nitulescu, G. M. et al., Int J Oncol., 2018; 53(6): 2319-2331). Malfunctions of AKT typically lead to 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.

[0082] Additionally, AKT1 has been found to be involved in invasion and migration ofcancerous cells (Alwhaibi, A. et al., Pharmacol Res., 2019, 145: 104270). Researchers found that silencing the AKT1 isoform can abrogate specific types of cancer cell migration. However, there have been other studies which have demonstrated that activated AKT1 resulted in less metastatic propensity for lung metastatic lesion cells and breast cancer cells. AKT1 has also been identified as a key protein involved in angiogenesis, lung cancer, and tumorigenesis.

[0083] Furthermore, overexpression of AKT has been correlated to resistance tochemotherapeutic agents such as cisplatin, methotrexate, and paclitaxel. Thus, there remains a need to find AKT inhibitors given its role in cell survival and cancer proliferation.

[0084] 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.

[0085] The E17K mutation enhances migration of breast cancer cells, and also enhancesresistance to chemotherapeutic drugs. However, the E17K mutation can also selectively destroy chemo-resistant tumor-promoting AKT1 quiescent cancer cells, suggesting that the AKT1(E17K) mutation is crucial in the oncogenic / anti-tumor mechanism.

[0086] A major pathway that activates PI3K-AKT signaling pathway is somatic cell mutations,with the E17K mutation being the highest frequency of AKT1 mutations. It is nearly exclusivelyAttorney Docket No.62619-729601 present in AKT1. The AKT1(E17K) is a recurrent somatic cell mutation predominantly in breast cancer, ovarian cancer, meningioma, and Proteus syndrome.

[0087] AKT1(E17K) mutations mediate the PI3K-AKT signaling cascade by expanding PIPlipid specificity, which causes conformational changes. This also enhances subcellular localization to accelerate localization of the PH structural domain to the plasma membrane. The E17K mutation increases PIP3 binding specificity by 7-fold and phosphatidylinositol-(4,5)- bisphosphate (PIP2) by 100-fold.

[0088] 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.

[0089] Given the conformational and signaling effects of the AKT1(E17K) mutation, this targetmay be useful for targeted treatment of cancers. Prior Art AKT1 Inhibitors

[0090] 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.

[0091] There are also ATP non-competitive AKT inhibitors which are allosteric modulatorswhich has greater specificity than the ATP targeting inhibitors. Many of these allosteric modulator inhibitors are classified as purine derivatives, thiourea derivatives, alkylphospholipids, sulfonamides, 2,3-diphenylquinoxaline analogs, and indole-3-carbinol derivatives. Novel AKT1 Inhibitory Compounds

[0092] In one aspect, provided herein is an AKT1 inhibitory compound.

[0093] One embodiment provides an AKT1 inhibitory compound, or a pharmaceuticallyacceptable salt or solvate thereof, having a structure presented in Table 1. Table 1Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Table 2Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601 N OH2NNO NAttorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601 N H2NNO N NAttorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Attorney Docket No.62619-729601Novel AKT1 Inhibitory Compounds: Numbered Embodiments[Embodiment 1] A compound having the structure of Formula (I), or a pharmaceutically acceptablesalt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is H, optionally substituted aryl, or optionally substituted heteroaryl;Attorney Docket No.62619-729601 R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , , , , , , , , , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle;T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;Attorney Docket No.62619-729601T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl;wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .[Embodiment 2] A compound having the structure of Formula (I-1), or a pharmaceuticallyacceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , , , , , , , , , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle;T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;Attorney Docket No.62619-729601T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl;wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .[Embodiment 3] The compound of embodiment 1 or embodiment 2 having the structure ofFormula (Ia), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the ;each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; Q1is O or S;Attorney Docket No.62619-729601 Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle.[Embodiment 4] The compound of any one of embodiments 1-3 having the structure of Formula(Ia-1), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the ;each R9is hydrogen, or optionally substituted C1-C6 alkyl;Attorney Docket No.62619-729601 R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; Q1is O or S; Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle.[Embodiment 5] The compound of embodiment 1 or embodiment 2 having the structure ofFormula (Ib), or a pharmaceutically acceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; wherein LCG is selected from the group consisting of:T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; and each R24is hydrogen, or optionally substituted C1-C6 alkyl.[Embodiment 6] The compound of embodiment 1-2, or embodiment 5, having the structure ofFormula (Ib-1), or a pharmaceutically acceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; wherein LCG is selected from the group consisting of:T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; and each R24is hydrogen, or optionally substituted C1-C6 alkyl.[Embodiment 7] The compound of embodiment 1 or embodiment 2 having the structure ofFormula (Ic), or a pharmaceutically acceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; and each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl.[Embodiment 8] The compound of embodiment 1, embodiment 2, or embodiment 7, having thestructure of Formula (Ic-1), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , , , , , , , , , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; and each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl.[Embodiment 9] The compound of embodiment 1 or embodiment 2 having the structure ofFormula (Id), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle;Attorney Docket No.62619-729601 R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601;Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy. [Embodiment 10]The compound of embodiment 1, embodiment 2, or embodiment 9, having the structure of Formula (Id-1), or a pharmaceutically acceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy. [Embodiment 11]The compound of embodiment 1 or embodiment 2 having the structure of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1-Attorney Docket No.62619-729601 C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , , , , , , , , , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-CN; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; and q is 0 or 1. [Embodiment 12]The compound of embodiment 1, embodiment 2, or embodiment 11, having the structure of Formula (Ie-1), or a pharmaceutically acceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-CN; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; and q is 0 or 1. [Embodiment 13]A compound having the structure of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is H, optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG;Attorney Docket No.62619-729601 each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle; (b)Attorney Docket No.62619-729601T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl; (d)Attorney Docket No.62619-729601 wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N. [Embodiment 14]A compound having the structure of Formula (II-1), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join together to form a carbocycle or heterocycle;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle; (b)Attorney Docket No.62619-729601T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl; (d)Attorney Docket No.62619-729601 wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N . [Embodiment 15]The compound of embodiment 13 or embodiment 14 having the structure of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the ;each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl;Attorney Docket No.62619-729601 each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; Q1is O or S; Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle. [Embodiment 16]The compound of any one of embodiments 13-15 having the structure of Formula (IIa-1), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1;Attorney Docket No.62619-729601 Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the ;each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; Q1is O or S;Attorney Docket No.62619-729601 Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle. [Embodiment 17]The compound of embodiment 13, or embodiment 14, having the structure of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG;Attorney Docket No.62619-729601 each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; wherein LCG is selected from the group consisting of:T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24;Attorney Docket No.62619-729601 each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; and each R24is hydrogen, or optionally substituted C1-C6 alkyl. [Embodiment 18]The compound of embodiment 13, embodiment 14, or embodiment 17 having the structure of Formula (IIb-1), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join together to form a carbocycle or heterocycle;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; wherein LCG is selected from the group consisting of:T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; and each R24is hydrogen, or optionally substituted C1-C6 alkyl. [Embodiment 19]The compound of embodiment 13 or embodiment 14 having the structure of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; and each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl. [Embodiment 20]The compound of embodiment 13, embodiment 14, or embodiment 19, having the structure of Formula (IIc-1), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , , , , , , , , , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; and each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl. [Embodiment 21]The compound of embodiment 13 or embodiment 14 having the structure of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl;Attorney Docket No.62619-729601 L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG;Attorney Docket No.62619-729601 each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy. [Embodiment 22]The compound of embodiment 13, embodiment 14, or embodiment 21, having the structure of Formula (IId-1), or a pharmaceutically acceptable salt or solvate thereof:wherein:Attorney Docket No.62619-729601 Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601 wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy. [Embodiment 23]The compound of embodiment 13 or embodiment 14 having the structure of Formula (IIe), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-CN; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join together to form a carbocycle or heterocycle;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1. [Embodiment 24]The compound of embodiment 13, embodiment 14, or embodiment 23, having the structure of Formula (IIe-1), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-CN;Attorney Docket No.62619-729601 each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1. [Embodiment 25]A compound having the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo;Attorney Docket No.62619-729601 R is H, optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , , , , , , , , , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle;T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;Attorney Docket No.62619-729601T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl;wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N. [Embodiment 26]A compound having the structure of Formula (III-1), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle;T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;Attorney Docket No.62619-729601T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl;wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N . [Embodiment 27]The compound of embodiment 25 or embodiment 26 having the structure of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3;Attorney Docket No.62619-729601 Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to theeach R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; Q1is O or S;Attorney Docket No.62619-729601 Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle. [Embodiment 28]The compound of any one of embodiments 25-27 having the structure of Formula (IIIa-1), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to theeach R9is hydrogen, or optionally substituted C1-C6 alkyl;Attorney Docket No.62619-729601 R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; Q1is O or S; Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle. [Embodiment 29]The compound of embodiment 25 or embodiment 26 having the structure of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; wherein LCG is selected from the group consisting of:T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; and each R24is hydrogen, or optionally substituted C1-C6 alkyl. [Embodiment 30]The compound of embodiment 25, embodiment 26, or embodiment 29, having the structure of Formula (IIIb-1), or a pharmaceutically acceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; wherein LCG is selected from the group consisting of:T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; and each R24is hydrogen, or optionally substituted C1-C6 alkyl. [Embodiment 31]The compound of embodiment 25 or embodiment 26 having the structure of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; and each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl. [Embodiment 32]The compound of embodiment 25, embodiment 26, or embodiment 31, having the structure of Formula (IIIc-1), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; and each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl. [Embodiment 33]The compound of embodiment 25 or embodiment 26 having the structure of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle;Attorney Docket No.62619-729601 L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG;Attorney Docket No.62619-729601 each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy. [Embodiment 34]The compound of embodiment 25, embodiment 26, or embodiment 33, having the structure of Formula (IIId-1), or a pharmaceutically acceptable salt or solvate thereof:wherein:Attorney Docket No.62619-729601 Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2;Attorney Docket No.62619-729601 n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy. [Embodiment 35]The compound of embodiment 25 or embodiment 26 having the structure of Formula (IIIe), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG;Attorney Docket No.62619-729601 each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; and LCG is -C≡N. [Embodiment 36]The compound of embodiment 25, embodiment 26, or embodiment 35, having the structure of Formula (IIIe-1), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; and LCG is -C≡N. [Embodiment 37]A compound having the structure of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is H, optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle; (b)T1is N or C-R23; T2is N or C-R23;Attorney Docket No.62619-729601 T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl;wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N. [Embodiment 38]A compound having the structure of Formula (IV-1), or a pharmaceutically acceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle; (b)T1is N or C-R23; T2is N or C-R23;Attorney Docket No.62619-729601 T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl;wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N . [Embodiment 39]The compound of embodiment 37 or embodiment 38 having the structure of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to theeach R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join together to form a carbocycle or heterocycle;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; Q1is O or S; Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle. [Embodiment 40]The compound of any one of embodiments 37-39, having the structure of Formula (IVa-1), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , , , , , , , , , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to theeach R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; Q1is O or S;Attorney Docket No.62619-729601 Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle. [Embodiment 41]The compound of embodiment 37 or embodiment 38 having the structure of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG;Attorney Docket No.62619-729601 each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; wherein LCG is selected from the group consisting of:T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24;Attorney Docket No.62619-729601 each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; and each R24is hydrogen, or optionally substituted C1-C6 alkyl. [Embodiment 42]The compound of embodiment 37, embodiment 38, or embodiment 41, having the structure of Formula (IVb-1), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join together to form a carbocycle or heterocycle;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; wherein LCG is selected from the group consisting of:T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; and each R24is hydrogen, or optionally substituted C1-C6 alkyl. [Embodiment 43]The compound of embodiment 37 or embodiment 38 having the structure of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; and each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl. [Embodiment 44]The compound of embodiment 37, embodiment 38, or embodiment 43, having the structure of Formula (IVc-1), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; and each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl. [Embodiment 45]The compound of embodiment 37 or embodiment 38 having the structure of Formula (IVd), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle;Attorney Docket No.62619-729601 R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601;Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy. [Embodiment 46]The compound of embodiment 37, embodiment 38, or embodiment 45, having the structure of Formula (IVd-1), or a pharmaceutically acceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy. [Embodiment 47]The compound of embodiment 37 or embodiment 38 having the structure of Formula (IVe), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1-Attorney Docket No.62619-729601 C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , , , , , , , , , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; and LCG is -C≡N. [Embodiment 48]The compound of embodiment 37, embodiment 38, or embodiment 47, having the structure of Formula (IVe-1), or a pharmaceutically acceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; and LCG is -C≡N. [Embodiment 49]A compound having the structure of Formula (V), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is H, optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG;Attorney Docket No.62619-729601 each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle; (b)Attorney Docket No.62619-729601T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl; (d)Attorney Docket No.62619-729601 wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N. [Embodiment 50]A compound having the structure of Formula (V-1), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join together to form a carbocycle or heterocycle;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle; (b)Attorney Docket No.62619-729601T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl; (d)Attorney Docket No.62619-729601 wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N . [Embodiment 51]The compound of embodiment 49 or embodiment 50 having the structure of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to theeach R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl;Attorney Docket No.62619-729601 each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; Q1is O or S; Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle. [Embodiment 52]The compound of any one of embodiments 49-51, having the structure of Formula (Va-1), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1;Attorney Docket No.62619-729601 Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to theeach R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; Q1is O or S;Attorney Docket No.62619-729601 Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle. [Embodiment 53]The compound of embodiment 49 or embodiment 50 having the structure of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG;Attorney Docket No.62619-729601 each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; wherein LCG is selected from the group consisting of:T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24;Attorney Docket No.62619-729601 each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; and each R24is hydrogen, or optionally substituted C1-C6 alkyl. [Embodiment 54]The compound of embodiment 49, embodiment 50, or embodiment 53, having the structure of Formula (Vb-1), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join together to form a carbocycle or heterocycle;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; wherein LCG is selected from the group consisting of:T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; and each R24is hydrogen, or optionally substituted C1-C6 alkyl. [Embodiment 55]The compound of embodiment 49 or embodiment 50 having the structure of Formula (Vc), or a pharmaceutically acceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; and each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl. [Embodiment 56]The compound of embodiment 49, embodiment 50, or embodiment 55, having the structure of Formula (Vc-1), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , , , , , , , , , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; and each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl. [Embodiment 57]The compound of embodiment 49 or embodiment 50 having the structure of Formula (Vd), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle;Attorney Docket No.62619-729601 L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG;Attorney Docket No.62619-729601 each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy. [Embodiment 58]The compound of embodiment 49, embodiment 50, or embodiment 57, having the structure of Formula (Vd-1), or a pharmaceutically acceptable salt or solvate thereof:wherein:Attorney Docket No.62619-729601 Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2;Attorney Docket No.62619-729601 n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy. [Embodiment 59]The compound of embodiment 49 or embodiment 50 having the structure of Formula (Ve), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG;Attorney Docket No.62619-729601 each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; and LCG is -C≡N. [Embodiment 60]The compound of embodiment 49, embodiment 50, or embodiment 59, having the structure of Formula (Ve-1), or a pharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , , , , , , , , , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; and LCG is -C≡N. [Embodiment 61]The compound of any one of embodiments 1-60, or a pharmaceutically acceptable salt or solvate thereof, wherein L is a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG;Attorney Docket No.62619-729601 each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; and n is 1, 2, or 3. [Embodiment 62]The compound of any one of embodiments 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; and n is 1, 2, or 3. [Embodiment 63]The compound of any one of embodiments 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; and R10is optionally substituted C1-C6 alkyl. [Embodiment 64]The compound of any one of embodiments 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein L is a divalent radical selected from:Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; and each R9is hydrogen, or optionally substituted C1-C6 alkyl; [Embodiment 65]The compound of any one of embodiments 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein L is a divalent radical selected from:; wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; and each R9is hydrogen, or optionally substituted C1-C6 alkyl. [Embodiment 66]The compound of any one of embodiments 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; and each R9is hydrogen, or optionally substituted C1-C6 alkyl. [Embodiment 67]The compound of any one of embodiments 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; and each R9is hydrogen, or optionally substituted C1-C6 alkyl. [Embodiment 68]The compound of any one of embodiments 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein L is a divalent radical selected from:Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG. [Embodiment 69]The compound of any one of embodiments 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein L is a divalent radical selected from:; wherein the asterisk (*) indicates the bond to the –(CO)q-LCG. [Embodiment 70]The compound of any one of embodiments 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; and m is 0, 1, or 2. [Embodiment 71]The compound of any one of embodiments 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the –(CO)q-LCG. [Embodiment 72]The compound of any one of embodiments 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein L is a divalent radical selected from:Attorney Docket No.62619-729601 wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; and each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join together to form a carbocycle or heterocycle. [Embodiment 73]The compound of any one of embodiments 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the –(CO)q-LCG. [Embodiment 74]The compound of any one of embodiments 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; 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; and 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.Attorney Docket No.62619-729601 [Embodiment 75]The compound of any one of embodiments 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; and each R9is hydrogen, or optionally substituted C1-C6 alkyl. [Embodiment 76]The compound of any one of embodiments 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the –(CO)q-LCG. [Embodiment 77]The compound of any one of embodiments 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the –(CO)q-LCG.Attorney Docket No.62619-729601 [Embodiment 78]The compound of any one of embodiments 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein L is; wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; and each R9is hydrogen, or optionally substituted C1-C6 alkyl. [Embodiment 79]The compound of any one of embodiments 1-78, or a pharmaceutically acceptable salt or solvate thereof, wherein Z2is C-R2. [Embodiment 80]The compound of embodiment 79, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted aryl. [Embodiment 81]The compound of embodiment 79, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted heteroaryl. [Embodiment 82]The compound of embodiment 79, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is H. [Embodiment 83]The compound of embodiment 79, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -CN. [Embodiment 84]The compound of embodiment 79, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted carbocyclyl. [Embodiment 85]The compound of embodiment 84, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted cyclopropyl. [Embodiment 86]The compound of embodiment 80, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted aryl is substituted with halogen. [Embodiment 87]The compound of embodiment 81, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heteroaryl is substituted with halogen. [Embodiment 88]The compound of embodiment 81, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heteroaryl is substituted with optionally substituted C1-C6 alkyl. [Embodiment 89]The compound of embodiment 88, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heteroaryl is substituted with optionally substituted C2-C3 alkyl. [Embodiment 90]The compound of embodiment 81, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heteroaryl is substituted with -O-(optionally substituted carbocyclyl).Attorney Docket No.62619-729601 [Embodiment 91]The compound of embodiment 81, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heteroaryl is substituted with optionally substituted C1-C6 alkoxy. [Embodiment 92]The compound of embodiment 79, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6 alkyl. [Embodiment 93]The compound of embodiment 79, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6 alkenyl. [Embodiment 94]The compound of embodiment 79, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is halo. [Embodiment 95]The compound of embodiment 92, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C3 alkyl. [Embodiment 96]The compound of embodiment 95, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1 alkyl or C2 alkyl. [Embodiment 97]The compound of embodiment 93, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C3 alkenyl. [Embodiment 98]The compound of any one of embodiments 1-97, or a pharmaceutically acceptable salt or solvate thereof, wherein Z3is N. [Embodiment 99]The compound of any one of embodiments 1-97, or a pharmaceutically acceptable salt or solvate thereof, wherein Z3is C-R3.[Embodiment 100] The compound of any one of embodiments 1-97, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R3is optionally substituted carbocyclyl.[Embodiment 101] The compound of embodiment 100, or a pharmaceutically acceptable saltor solvate thereof, wherein R3is optionally substituted aryl.[Embodiment 102] The compound of embodiment 100, or a pharmaceutically acceptable saltor solvate thereof, wherein R3is optionally substituted heteroaryl.[Embodiment 103] The compound of embodiment 100, or a pharmaceutically acceptable saltor solvate thereof, wherein R3is H.[Embodiment 104] The compound of embodiment 101, or a pharmaceutically acceptable saltor solvate thereof, wherein the optionally substituted aryl is substituted with halogen.[Embodiment 105] The compound of embodiment 102, or a pharmaceutically acceptable saltor solvate thereof, wherein the optionally substituted heteroaryl is substituted with halogen.[Embodiment 106] The compound of embodiment 102, or a pharmaceutically acceptable saltor solvate thereof, wherein the optionally substituted heteroaryl is substituted with optionally substituted C1-C6 alkoxy.Attorney Docket No.62619-729601[Embodiment 107] The compound of embodiment 100, or a pharmaceutically acceptable saltor solvate thereof, wherein R3is C1-C6 alkyl.[Embodiment 108] The compound of embodiment 100, or a pharmaceutically acceptable saltor solvate thereof, wherein R3is C1-C6 alkenyl.[Embodiment 109] The compound of embodiment 100, or a pharmaceutically acceptable saltor solvate thereof, wherein R3is halo.[Embodiment 110] The compound of embodiment 107, or a pharmaceutically acceptable saltor solvate thereof, wherein R3is C1-C3 alkyl.[Embodiment 111] The compound of embodiment 110, or a pharmaceutically acceptable saltor solvate thereof, wherein R3is C1 alkyl or C2 alkyl.[Embodiment 112] The compound of embodiment 108, or a pharmaceutically acceptable saltor solvate thereof, wherein R3is C1-C3 alkenyl.[Embodiment 113] The compound of any one of embodiments 1-112, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R is optionally substituted heteroaryl.[Embodiment 114] The compound of embodiment 113, or a pharmaceutically acceptable saltor solvate thereof, wherein the optionally substituted heteroaryl is substituted with amino.[Embodiment 115] The compound of embodiment 113, or a pharmaceutically acceptable saltor solvate thereof, wherein the optionally substituted heteroaryl is substituted with optionally substituted C1-C6 alkoxy.[Embodiment 116] The compound of any one of embodiments 1-112, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R is H.[Embodiment 117] The compound of any one of embodiments 1, 2, 13, 14, 25, 26, 37, 38, 49,50, 61-116, or a pharmaceutically acceptable salt or solvate thereof, wherein LCG is:T1is N or C-R23; T2is N or C-R23; T3is N or C-R23;Attorney Docket No.62619-729601 T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; and each R24is hydrogen, or optionally substituted C1-C6 alkyl.[Embodiment 118] The compound of embodiment 117, or a pharmaceutically acceptable saltor solvate thereof, wherein LCG is:.[Embodiment 119] The compound of embodiment 117, or a pharmaceutically acceptable saltor solvate thereof, wherein LCG is:.[Embodiment 120] The compound of embodiment 117, or a pharmaceutically acceptable saltor solvate thereof, wherein LCG is:.[Embodiment 121] The compound of any one of embodiments embodiment 5, 6, 17, 18, 29,30, 41, 42, 53, 54, 61-116, or a pharmaceutically acceptable salt or solvate thereof, wherein LCG is:.[Embodiment 122] The compound of embodiment 121, or a pharmaceutically acceptable saltor solvate thereof, wherein LCG is:.[Embodiment 123] The compound of embodiment 121, or a pharmaceutically acceptable saltor solvate thereof, wherein LCG is: .[Embodiment 124] The compound of any one of embodiments 1-123, or a pharmaceuticallyacceptable salt or solvate thereof, wherein W1, W2, W3, and W4are CH.Attorney Docket No.62619-729601[Embodiment 125] The compound of any one of embodiments 1-124, or a pharmaceuticallyacceptable salt or solvate thereof, wherein q is 0.[Embodiment 126] The compound of any one of embodiments 1-124, or a pharmaceuticallyacceptable salt or solvate thereof, wherein q is 1.[Embodiment 127] The compound of any one of embodiments 1-126, or a pharmaceuticallyacceptable salt or solvate thereof, wherein: Z1is C-R1; Z2is C-R2; Z3is C-R3; and Z4is C-R4.[Embodiment 128] The compound of any one of embodiments 1-126, or a pharmaceuticallyacceptable salt or solvate thereof, wherein: Z1is N; Z2is C-R2; Z3is C-R3; and Z4is C-R4.[Embodiment 129] The compound of any one of embodiments 1-126, or a pharmaceuticallyacceptable salt or solvate thereof, wherein: Z1is C-R1; Z2is N; Z3is C-R3; and Z4is C-R4.[Embodiment 130] The compound of any one of embodiments 1-126, or a pharmaceuticallyacceptable salt or solvate thereof, wherein: Z1is C-R1; Z2is C-R2; Z3is N; and Z4is C-R4.[Embodiment 131] The compound of any one of embodiments 1-126, or a pharmaceuticallyacceptable salt or solvate thereof, wherein: Z1is C-R1; Z2is C-R2; Z3is C-R3; and Z4is N.Attorney Docket No.62619-729601[Embodiment 132] The compound of any one of embodiments 1-126, or a pharmaceuticallyacceptable salt or solvate thereof, wherein: Z1is N; Z2is C-R2; Z3is N; and Z4is C-R4.[Embodiment 133] The compound of any one of embodiments 1-126, or a pharmaceuticallyacceptable salt or solvate thereof, wherein: Z1is N; Z2is C-R2; Z3is C-R3; and Z4is N.[Embodiment 134] The compound of any one of embodiments 1-133, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R7and R8are H.[Embodiment 135] The compound of any one of embodiments 1, 3, 5, 7, 9, 11, 13, 15, 17, 19,21, 23, 37, 39, 41, 43, 45, 47, or 61-113, or a pharmaceutically acceptable salt or solvate thereof, wherein R30is H.[Embodiment 136] The compound of any one of embodiments 1, 3, 5, 7, 9, 11, 13, 15, 17, 19,21, 23, 37, 39, 41, 43, 45, 47, or 61-113, or a pharmaceutically acceptable salt or solvate thereof, wherein R30is halo.[Embodiment 137] The compound of embodiment 120, or pharmaceutically acceptable salt orsolvate thereof, wherein L is; wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; R9is hydrogen or optionally substituted C1-C6 alkyl; and wherein q is 0.[Embodiment 138] The compound of embodiment 137, or pharmaceutically acceptable salt orsolvate thereof, wherein R9is hydrogen.[Embodiment 139] The compound of embodiment 137 or 138, or pharmaceutically acceptablesalt or solvate thereof, wherein R7and R8are H.[Embodiment 140] The compound of any one of embodiments 137-139, or pharmaceuticallyacceptable salt or solvate thereof, wherein R is optionally substituted heteroaryl.Attorney Docket No.62619-729601[Embodiment 141] The compound of embodiment 140, or pharmaceutically acceptable salt orsolvate thereof, wherein R is optionally substituted pyridin-3-yl.[Embodiment 142] The compound of embodiment 141, or pharmaceutically acceptable salt orsolvate thereof, wherein R is 2-fluoro-pyridin-3-yl.[Embodiment 143] The compound of any one of embodiments 137-142, or pharmaceuticallyacceptable salt or solvate thereof, wherein Z2is C-R2, and wherein R2is optionally substituted aryl.[Embodiment 144] The compound of embodiment 143, or pharmaceutically acceptable salt orsolvate thereof, wherein R2is optionally substituted phenyl.[Embodiment 145] The compound of 144, or pharmaceutically acceptable salt or solvatethereof, wherein R2is 4-fluoro-phenyl.[Embodiment 146] The compound of any one of embodiments 137-142, or pharmaceuticallyacceptable salt or solvate thereof, wherein Z2is C-R2, and wherein R2is optionally substituted heteroaryl.[Embodiment 147] The compound of embodiment 146, or pharmaceutically acceptable salt orsolvate thereof, wherein R2is optionally substituted pyridin-6-yl.[Embodiment 148] The compound of embodiment 147, or pharmaceutically acceptable salt orsolvate thereof, wherein R2is 3-fluoro-pyridin-6-yl.[Embodiment 149] The compound of any one of embodiments 137-142, or pharmaceuticallyacceptable salt or solvate thereof, wherein Z2is C-R2, and wherein R2is -CN.[Embodiment 150] The compound of any one of embodiments 137-142, or pharmaceuticallyacceptable salt or solvate thereof, wherein Z3is C-R3, and wherein R3is optionally substituted heteroaryl.[Embodiment 151] The compound of embodiment 150, or pharmaceutically acceptable salt orsolvate thereof, wherein R3is optionally substituted pyridin-6-yl.[Embodiment 152] The compound of embodiment 151, or pharmaceutically acceptable salt orsolvate thereof, wherein R3is 3-fluoro-pyridin-6-yl.[Embodiment 153] The compound of any one of embodiments 137-152, or a pharmaceuticallyacceptable salt or solvate thereof, wherein W1, W2, W3, and W4are CH.[Embodiment 154] The compound of any one of embodiments 137-153, or pharmaceuticallyacceptable salt or solvate thereof, comprising a compound of Formula (I), wherein R30is H; Z1is C-R1, and wherein R1is H; Z3is N; andAttorney Docket No.62619-729601 Z4is C-R4; and wherein R4is H.[Embodiment 155] The compound of any one of embodiments 137-153, or pharmaceuticallyacceptable salt or solvate thereof, comprising a compound of Formula (I), wherein R30is H; Z1is C-R1, and wherein R1is H; Z3is C-R3, and wherein R3is H; and Z4is N.[Embodiment 156] The compound of any one of embodiments 137-153, or pharmaceuticallyacceptable salt or solvate thereof, comprising a compound of Formula (I), wherein R30is H; Z1is N; Z3is N; and Z4is C-R4, and wherein R4is H.[Embodiment 157] The compound of any one of embodiments 137-153, or pharmaceuticallyacceptable salt or solvate thereof, comprising a compound of Formula (I), wherein R30is H; Z1is N; Z3is C-R3, and wherein R3is H; and Z4is N.[Embodiment 158] The compound of any one of embodiments 137-153, or pharmaceuticallyacceptable salt or solvate thereof, comprising a compound of Formula (II), wherein R30is H; Z1is C-R1, and wherein R1is H; and Z3is N; and Z4is C-R4, and wherein R4is H.[Embodiment 159] The compound of any one of embodiments 137-153, or pharmaceuticallyacceptable salt or solvate thereof, comprising a compound of Formula (III), wherein Z1is N; Z3is C-R3, and wherein R3is H; and Z4is C-R4, and wherein R4is H.[Embodiment 160] The compound of any one of embodiments 137-153, or pharmaceuticallyacceptable salt or solvate thereof, comprising a compound of Formula (III), wherein Z1is C-R1, and wherein R1is H; Z3is N; andAttorney Docket No.62619-729601 Z4is C-R4, and wherein R4is H.[Embodiment 161] The compound of any one of embodiments 137-153, or pharmaceuticallyacceptable salt or solvate thereof, comprising a compound of Formula (III), wherein Z1is C-R1, and wherein R1is H; Z3is C-R3, and wherein R3is H; and Z4is N.[Embodiment 162] The compound of any one of embodiments 137-153, or pharmaceuticallyacceptable salt or solvate thereof, comprising a compound of Formula (IV), wherein R30is H; Z1is C-R1, and wherein R1is H; Z2is H; and Z4is C-R4, and wherein R4is H.[Embodiment 163] The compound of any one of embodiments 137-153, or pharmaceuticallyacceptable salt or solvate thereof, comprising a compound of Formula (V), wherein Z1is N; Z3is C-R3, and wherein R3is H; and Z4is C-R4, and wherein R4is H.[Embodiment 164] A compound, or pharmaceutically acceptable salt or solvate thereof, asdescribed in Table 1.[Embodiment 165] A compound, or pharmaceutically acceptable salt or solvate thereof, asdescribed in Table 2.[Embodiment 166] A pharmaceutical composition comprising a compound, orpharmaceutically acceptable salt or solvate thereof, as described in any one of embodiments 1- 165, and a pharmaceutically acceptable excipient.[Embodiment 167] A method of preparing a pharmaceutical composition comprising mixing acompound, or pharmaceutically acceptable salt or solvate thereof, of any one of embodiments 1- 165, and a pharmaceutically acceptable carrier.[Embodiment 168] A compound of any one of embodiments 1-165, or pharmaceuticallyacceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.[Embodiment 169] A compound of any one of embodiments 1-165, or pharmaceuticallyacceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.Attorney Docket No.62619-729601[Embodiment 170] Use of a compound of any one of embodiments 1-165, orpharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.[Embodiment 171] A method of treating cancer in a patient in need thereof, comprisingadministering to the patient a compound as described in any one of embodiments 1-165, or pharmaceutically acceptable salt or solvate thereof.[Embodiment 172] 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 embodiments 1-165, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.[Embodiment 173] A method of inhibiting an AKT1 enzyme comprising contacting theenzyme with a compound of any one of embodiments 1-165, wherein the AKT1 enzyme is contacted in an in vitro setting.[Embodiment 174] A method of inhibiting an AKT1 enzyme comprising contacting theenzyme with a compound of any one of embodiments 1-165, wherein the AKT1 enzyme is contacted in an in vivo setting. Preparation of Compounds

[0094] 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).

[0095] 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 theAttorney Docket No.62619-729601 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: 3-527- 29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471- 57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[0096] 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 ofpharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth"Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002. Pharmaceutical CompositionsAttorney Docket No.62619-729601

[0097] In certain embodiments, the AKT1 inhibitory compound described herein is administeredas a pure chemical. In other embodiments, the AKT1 inhibitory compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, 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)).

[0098] Provided herein is a pharmaceutical composition comprising at least one AKT1inhibitory compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or the patient) of the composition.

[0099] One embodiment provides a pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and a compound of Formula (I)-(V), or a pharmaceutically acceptable salt or solvate thereof.

[0100] One embodiment provides a method of preparing a pharmaceutical compositioncomprising mixing a compound of Formula (I)-(V), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0101] In certain embodiments, the AKT1 inhibitory compound as described by Formula(I)-(V), or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0102] One embodiment provides a pharmaceutical composition comprising apharmaceutically acceptable excipient and a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0103] One embodiment provides a method of preparing a pharmaceutical compositioncomprising mixing a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0104] In certain embodiments, the AKT1 inhibitory compound as described by Table 1,or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it containsAttorney Docket No.62619-729601 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.

[0105] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsulesof hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0106] In some embodiments, the AKT1 inhibitory compound as described by Formula(I)-(V) or Table 1, or a pharmaceutically acceptable salt or solvate thereof, is formulated for administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a non-aqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like.

[0107] The dose of the composition comprising at least one AKT1 inhibitory compoundas described herein differs depending upon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors.

[0108] Pharmaceutical compositions are administered in a manner appropriate to thedisease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0109] Oral doses typically range from about 1.0 mg to about 1000 mg, one to fourtimes, or more, per day. Methods of Treatment

[0110] One embodiment provides a compound of Formula (I)-(V), or a pharmaceuticallyacceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.Attorney Docket No.62619-729601

[0111] One embodiment provides a compound of Formula (I)-(V), or a pharmaceuticallyacceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.

[0112] One embodiment provides a pharmaceutical composition comprising a compoundof Formula (I)-(V), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or neoplastic disease.

[0113] One embodiment provides a use of a compound of Formula (I)-(V), or apharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

[0114] In some embodiments is provided a method of treating cancer, in a patient in needthereof, comprising administering to the patient a compound of Formula (I)-(V), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I)-(V), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0115] One embodiment provides a compound of Table 1, or a pharmaceuticallyacceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0116] One embodiment provides a compound of Table 1, or a pharmaceuticallyacceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.

[0117] One embodiment provides a pharmaceutical composition comprising a compoundof Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or neoplastic disease.

[0118] One embodiment provides a use of a compound of Table 1, or a pharmaceuticallyacceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

[0119] In some embodiments is provided a method of treating cancer, in a patient in needthereof, comprising administering to the patient a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.Attorney Docket No.62619-729601

[0120] One embodiment provides a compound of Table 2, or a pharmaceuticallyacceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0121] One embodiment provides a compound of Table 2, or a pharmaceuticallyacceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.

[0122] One embodiment provides a pharmaceutical composition comprising a compoundof Table 2, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or neoplastic disease.

[0123] One embodiment provides a use of a compound of Table 2, or a pharmaceuticallyacceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

[0124] In some embodiments is provided a method of treating cancer, in a patient in needthereof, comprising administering to the patient a compound of Table 2, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Table 2, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0125] Provided herein is the method wherein the pharmaceutical composition isadministered orally. Provided herein is the method wherein the pharmaceutical composition is administered by injection.

[0126] One embodiment provides a method of inhibiting a AKT1 enzyme comprisingcontacting the AKT1 enzyme with a compound of Formula (I)-(V), or Table 1. Another embodiment provides the method of inhibiting a AKT1 enzyme, wherein the AKT1 enzyme is contacted in an in vivo setting. Another embodiment provides the method of inhibiting a AKT1 enzyme, wherein the AKT1 enzyme is contacted in an in vitro setting.

[0127] One embodiment provides a method of inhibiting a AKT1 enzyme comprisingcontacting the AKT1 enzyme with a compound of Formula (I)-(V), Table 1, or Table 2. Another embodiment provides the method of inhibiting a AKT1 enzyme, wherein the AKT1 enzyme is contacted in an in vivo setting. Another embodiment provides the method of inhibiting a AKT1 enzyme, wherein the AKT1 enzyme is contacted in an in vitro setting. Methods of Treatment: Numbered Embodiments [Embodiment 1] A method of treating a cancer in a patient in need thereof, comprisingadministering to the patient a compound of Formula (I)-(V), or pharmaceutically acceptable salt or solvate thereof.Attorney Docket No.62619-729601[Embodiment 2] A method of treating a cancer in a patient in need thereof, comprisingadministering to the patient a compound of Table 1, or pharmaceutically acceptable salt or solvate thereof.[Embodiment 3] A method of treating a cancer in a patient in need thereof, comprisingadministering to the patient a compound, or pharmaceutically acceptable salt or solvate thereof, selected from: 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(5-fluoropyridin-2-yl)imidazo[1,2-b]pyridazin-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)imidazo[1,2-b]pyridazin-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)-1H-pyrrolo[3,2-c]pyridin-1- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-1- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(5-fluoropyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-1- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(6-(2-aminopyridin-3-yl)-2-(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(6-(2-aminopyridin-3-yl)-3-(4-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazin-5- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(7-(2-aminopyridin-3-yl)-3-(4-fluorophenyl)pyrrolo[1,2-a]pyrazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)imidazo[1,2-a]pyrimidin-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)imidazo[1,2-a]pyrazin-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)pyrazolo[1,5-a]pyrimidin-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(7-(2-aminopyridin-3-yl)-3-(5-fluoropyridin-2-yl)pyrrolo[1,2-a]pyrazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(7-(2-aminopyridin-3-yl)-3-(5-fluoropyridin-2-yl)pyrrolo[1,2-a]pyrazin-8- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(5-fluoropyridin-2-yl)-1H-pyrrolo[3,2-c]pyridin-1- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; andAttorney Docket No.62619-729601 2-(2-aminopyridin-3-yl)-1-(4-((4-((2-cyanopyrimidin-4-yl)amino)piperidin-1- yl)methyl)phenyl)-1H-pyrrolo[3,2-c]pyridine-6-carbonitrile.[Embodiment 4] A method of treating a cancer in a patient in need thereof, comprisingadministering to the patient a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a compound of Formula (I)-(V), or pharmaceutically acceptable salt or solvate thereof.[Embodiment 5] A method of treating a cancer in a patient in need thereof, comprisingadministering to the patient a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a compound of Table 1, or pharmaceutically acceptable salt or solvate thereof.[Embodiment 6] A method of treating a cancer in a patient in need thereof, comprisingadministering to the patient a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a compound, or pharmaceutically acceptable salt or solvate thereof, selected from: 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(5-fluoropyridin-2-yl)imidazo[1,2-b]pyridazin-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)imidazo[1,2-b]pyridazin-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)-1H-pyrrolo[3,2-c]pyridin-1- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-1- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(5-fluoropyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-1- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(6-(2-aminopyridin-3-yl)-2-(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(6-(2-aminopyridin-3-yl)-3-(4-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazin-5- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(7-(2-aminopyridin-3-yl)-3-(4-fluorophenyl)pyrrolo[1,2-a]pyrazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)imidazo[1,2-a]pyrimidin-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)imidazo[1,2-a]pyrazin-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;Attorney Docket No.62619-729601 4-((1-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)pyrazolo[1,5-a]pyrimidin-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(7-(2-aminopyridin-3-yl)-3-(5-fluoropyridin-2-yl)pyrrolo[1,2-a]pyrazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(7-(2-aminopyridin-3-yl)-3-(5-fluoropyridin-2-yl)pyrrolo[1,2-a]pyrazin-8- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(5-fluoropyridin-2-yl)-1H-pyrrolo[3,2-c]pyridin-1- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; and 2-(2-aminopyridin-3-yl)-1-(4-((4-((2-cyanopyrimidin-4-yl)amino)piperidin-1- yl)methyl)phenyl)-1H-pyrrolo[3,2-c]pyridine-6-carbonitrile. [Embodiment 7] A method of treating a cancer in a patient in need thereof, comprisingadministering to the patient: (a) a compound of Formula (I)-(V), or pharmaceutically acceptable salt or solvate thereof; and (b) at least one oncology therapeutic selected from an endocrine therapy, a hormonal therapy, an aromatase inhibitor, a selective estrogen receptor modulator (SERM) therapy, a selective estrogen receptor degrader (SERD) therapy, an anti-androgen, an androgen deprivation therapy, a taxane, a platinum agent, an anthracycline, an anti-metabolite, an alkylating agent, a microtubule affecting agent, an immune checkpoint inhibitor, a kinase inhibitor, a phosphatidylinositol 3-kinase (PI3K) inhibitor, a human epidermal growth factor receptor 2 (HER2) inhibitor, an antibody, a poly-ADP ribose polymerase (PARP) inhibitor, an antibody drug conjugate (ADC), a radiopharmaceutical, a neurotrophic tyrosine receptor kinase (NTRK) inhibitor, a rearranged during transfection (RET) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor, a rapidly accelerated fibrosarcoma (RAF) inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, or a cyclin dependent kinase (CDK) inhibitor. [Embodiment 8] A method of treating a cancer in a patient in need thereof, comprisingadministering to the patient: (a) a compound of Table 1, or pharmaceutically acceptable salt or solvate thereof; and (b) at least one oncology therapeutic selected from an endocrine therapy, a hormonal therapy, an aromatase inhibitor, a selective estrogen receptor modulator (SERM) therapy, a selective estrogen receptor degrader (SERD) therapy, an anti-androgen, an androgen deprivation therapy, a taxane, a platinum agent, an anthracycline, an anti-metabolite, an alkylating agent, a microtubule affecting agent, an immune checkpoint inhibitor, a kinase inhibitor, aAttorney Docket No.62619-729601 phosphatidylinositol 3-kinase (PI3K) inhibitor, a human epidermal growth factor receptor 2 (HER2) inhibitor, an antibody, a poly-ADP ribose polymerase (PARP) inhibitor, an antibody drug conjugate (ADC), a radiopharmaceutical, a neurotrophic tyrosine receptor kinase (NTRK) inhibitor, a rearranged during transfection (RET) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor, a rapidly accelerated fibrosarcoma (RAF) inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, or a cyclin dependent kinase (CDK) inhibitor. [Embodiment 9] A method of treating a cancer in a patient in need thereof, comprisingadministering to the patient: (a) a compound, or pharmaceutically acceptable salt or solvate thereof, selected from: 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(5-fluoropyridin-2-yl)imidazo[1,2-b]pyridazin-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)imidazo[1,2-b]pyridazin-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)-1H-pyrrolo[3,2-c]pyridin-1- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-1- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(5-fluoropyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-1- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(6-(2-aminopyridin-3-yl)-2-(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(6-(2-aminopyridin-3-yl)-3-(4-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazin-5- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(7-(2-aminopyridin-3-yl)-3-(4-fluorophenyl)pyrrolo[1,2-a]pyrazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)imidazo[1,2-a]pyrimidin-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)imidazo[1,2-a]pyrazin-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)pyrazolo[1,5-a]pyrimidin-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(7-(2-aminopyridin-3-yl)-3-(5-fluoropyridin-2-yl)pyrrolo[1,2-a]pyrazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;Attorney Docket No.62619-729601 4-((1-(4-(7-(2-aminopyridin-3-yl)-3-(5-fluoropyridin-2-yl)pyrrolo[1,2-a]pyrazin-8- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(5-fluoropyridin-2-yl)-1H-pyrrolo[3,2-c]pyridin-1- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; and 2-(2-aminopyridin-3-yl)-1-(4-((4-((2-cyanopyrimidin-4-yl)amino)piperidin-1- yl)methyl)phenyl)-1H-pyrrolo[3,2-c]pyridine-6-carbonitrile; and (b) at least one oncology therapeutic selected from an endocrine therapy, a hormonal therapy, an aromatase inhibitor, a selective estrogen receptor modulator (SERM) therapy, a selective estrogen receptor degrader (SERD) therapy, an anti-androgen, an androgen deprivation therapy, a taxane, a platinum agent, an anthracycline, an anti-metabolite, an alkylating agent, a microtubule affecting agent, an immune checkpoint inhibitor, a kinase inhibitor, a phosphatidylinositol 3-kinase (PI3K) inhibitor, a human epidermal growth factor receptor 2 (HER2) inhibitor, an antibody, a poly-ADP ribose polymerase (PARP) inhibitor, an antibody drug conjugate (ADC), a radiopharmaceutical, a neurotrophic tyrosine receptor kinase (NTRK) inhibitor, a rearranged during transfection (RET) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor, a rapidly accelerated fibrosarcoma (RAF) inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, or a cyclin dependent kinase (CDK) inhibitor. [Embodiment 10]The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is selected from an endocrine therapy, a hormonal therapy, a SERM therapy, a SERD therapy, an aromatase inhibitor, or an androgen deprivation therapy. [Embodiment 11]The method of embodiment 10, wherein the endocrine therapy, a hormonal therapy, a SERM therapy, a SERD therapy, an aromatase inhibitor, or an androgen deprivation therapy is selected from megestrol, exemestane, anastrozole, letrozole, tamoxifen, torimifene, raloxifene, fulvestrant, camizestrant, elacestrant, amcenestrant, giredestrant, imlunestrant, rintodestrant, SHR9549, ZN-c5, D0502, vepdegrestrant, palazestrant, AC682, DT2216, apalutamide, bicalutamide, darolutamide, enzalutamide, flutamide, nilutamide, abiraterone, buserelin, goserelin, leuprorelin, triptorelin, degarelix, or relugolix,. [Embodiment 12]The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a taxane. [Embodiment 13]The method of embodiment 12, wherein the taxane is selected from paclitaxel, docetaxel, cabazitaxel, or abraxane.Attorney Docket No.62619-729601 [Embodiment 14]The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a platinum agent. [Embodiment 15]The method of embodiment 14, wherein the platinum agent is selected from cisplatin, carboplatin, or oxaliplatin. [Embodiment 16]The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is an anthracycline. [Embodiment 17]The method of embodiment 16, wherein the anthracycline is selected from doxorubicin or epirubicin. [Embodiment 18]The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is an anti-metabolite. [Embodiment 19]The method of embodiment 18, wherein the anti-metabolite is selected from methotrexate, fluorouracil, pemetrexed, irinotecan, topotecan, capecitabine or gemcitabine. [Embodiment 20]The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is an alkylating agent. [Embodiment 21]The method of embodiment 20, wherein the alkylating agent is selected from ifosfamide, trabectedin, cyclophosphamide, melphalan, or dacarbazine. [Embodiment 22]The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a microtubule affecting agent. [Embodiment 23]The method of embodiment 22, wherein the microtubule affecting agent is selected from ixabepilone, viborelbine, or eribulin. [Embodiment 24]The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is an immune checkpoint inhibitor. [Embodiment 25]The method of embodiment 24, wherein the immune checkpoint inhibitor is selected from a CTLA-4 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a LAG-3 inhibitor, a TIGIT inhibitor, or a bi-specific PD-1 / CTLA4 inhibitor. [Embodiment 26]The method of embodiment 25, wherein the CTLA-4 inhibitor is selected from ipilimumab or tremelimumab. [Embodiment 27]The method of embodiment 25, wherein the PD-1 inhibitor is selected from spartalizumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, durvalumab, dostarlimab, retifanlimab, or toripalimab. [Embodiment 28]The method of embodiment 25, wherein the bi-specific PD-1 / CTLA4 inhibitor is selected from AK104, MGD019, XmAb20717, or MEDI5752.Attorney Docket No.62619-729601 [Embodiment 29]The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a kinase inhibitor. [Embodiment 30]The method of embodiment 29, wherein the kinase inhibitor is selected from lenvatinib, pazopanib, imatinib, sorafenib, or avutometinib. [Embodiment 31]The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a PI3K inhibitor. [Embodiment 32]The method of embodiment 31, wherein the PI3K inhibitor is selected from copanlisib, alpelisib, idelalisib, duvelisib, or umbralisib. [Embodiment 33]The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a HER2 inhibitor. [Embodiment 34]The method of embodiment 33, wherein the HER2 inhibitor is selected from lapatinib, neratinib, tucatinib, pyrotinib, or afatinib. [Embodiment 35]The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is an antibody. [Embodiment 36]The method of embodiment 35, wherein the antibody is selected from trastuzumab, pertuzumab, margetuxumab, bevacizumab, or rituximab. [Embodiment 37]The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a PARP inhibitor. [Embodiment 38]The method of embodiment 37, wherein the PARP inhibitor is selected from olaparib, rucaparib, talazoparib, or niraparib. [Embodiment 39]The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is an antibody drug conjugate (ADC). [Embodiment 40]The method of embodiment 39, wherein the antibody drug conjugate is selected from ado-trastuzumab emtansine, fam-trastuzumab deruxtecan-nxki, sacituzumab govitecan, disitamab vedotin, tisotumab vedotin, raludotatug deruxtecan, ARX-788, datopotamab deruxtecan, patritumab deruxtecan, ladiratuzumab vedotin, HS- 20089, pertuzumab, or margetuximab. [Embodiment 41]The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a radiopharmaceutical. [Embodiment 42]The method of embodiment 41, wherein the radiopharmaceutical is [111In] / [89Zr]-trastuzumab. [Embodiment 43]The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a NTRK inhibitor.Attorney Docket No.62619-729601 [Embodiment 44]The method of embodiment 43, wherein the NTRK inhibitor is selected from entrectinib or larotrectinib. [Embodiment 45]The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a RET inhibitor. [Embodiment 46]The method of embodiment 45, wherein the RET inhibitor is selpercatinib or pralsetinib. [Embodiment 47]The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is an EGFR inhibitor. [Embodiment 48]The method of embodiment 47, wherein the EGFR inhibitor is erlotinib, osimertinib, neratinib, cetuximab, gefitinib, panitumumab, dacomitinib, afatinib, lapatinib, necitumumab, mobocertinib, or vandetanib. [Embodiment 49]The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a mTOR inhibitor. [Embodiment 50]The method of embodiment 49, wherein the mTOR inhibitor is deforolimus, everolimus, sirolimus, or temsirolimus. [Embodiment 51]The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a RAF inhibitor. [Embodiment 52]The method of embodiment 51, wherein the RAF inhibitor is vemurafenib, dabrafenib, encorafenib, tovorafenib, naporafenib, belvarafenib, or exarafenib. [Embodiment 53]The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a MEK inhibitor. [Embodiment 54]The method of embodiment 53, wherein the MEK inhibitor is binimetinib, cobimetinib, trametinib, selumetinib, pimasertib, avutometinib, IMM-1-104, or NST-628. [Embodiment 55]The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a CDK inhibitor. [Embodiment 56]The method of embodiment 55, wherein the CDK inhibitor is selected from palbociclib, abemaciclib, ribociclib, tagtociclib, ebvaciclib, lerociclib, PF- 07220060, BLU-222, INX-315, or AVZO-021. [Embodiment 57]A method of treating a cancer in a patient in need thereof, comprising administering to the patient: (a) a compound of Formula (I)-(V), or pharmaceutically acceptable salt or solvate thereof; and (b) at least one oncology therapeutic selected from CAR-T therapy, tumor-infiltrating lymphocytes (TIL) or a neoantigen vaccine.Attorney Docket No.62619-729601 [Embodiment 58]A method of treating a cancer in a patient in need thereof, comprising administering to the patient: (a) a compound of Table 1, or pharmaceutically acceptable salt or solvate thereof; and (b) at least one oncology therapeutic selected from CAR-T therapy, tumor-infiltrating lymphocytes (TIL) or a neoantigen vaccine. [Embodiment 59]A method of treating a cancer in a patient in need thereof, comprising administering to the patient: (a) a compound, or pharmaceutically acceptable salt or solvate thereof, selected from: 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(5-fluoropyridin-2-yl)imidazo[1,2-b]pyridazin-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)imidazo[1,2-b]pyridazin-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)-1H-pyrrolo[3,2-c]pyridin-1- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-1- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(5-fluoropyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-1- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(6-(2-aminopyridin-3-yl)-2-(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(6-(2-aminopyridin-3-yl)-3-(4-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazin-5- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(7-(2-aminopyridin-3-yl)-3-(4-fluorophenyl)pyrrolo[1,2-a]pyrazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)imidazo[1,2-a]pyrimidin-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(4-fluorophenyl)imidazo[1,2-a]pyrazin-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)pyrazolo[1,5-a]pyrimidin-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(7-(2-aminopyridin-3-yl)-3-(5-fluoropyridin-2-yl)pyrrolo[1,2-a]pyrazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(7-(2-aminopyridin-3-yl)-3-(5-fluoropyridin-2-yl)pyrrolo[1,2-a]pyrazin-8- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile;Attorney Docket No.62619-729601 4-((1-(4-(2-(2-aminopyridin-3-yl)-6-(5-fluoropyridin-2-yl)-1H-pyrrolo[3,2-c]pyridin-1- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; and 2-(2-aminopyridin-3-yl)-1-(4-((4-((2-cyanopyrimidin-4-yl)amino)piperidin-1- yl)methyl)phenyl)-1H-pyrrolo[3,2-c]pyridine-6-carbonitrile; and (b) at least one oncology therapeutic selected from CAR-T therapy, tumor-infiltrating lymphocytes (TIL) or a neoantigen vaccine. [Embodiment 60]The method of any one of embodiments 1-59, wherein the cancer is breast cancer. [Embodiment 61]The method of embodiment 60, wherein the cancer is a hormone receptor positive (HR+) breast cancer. [Embodiment 62]The method of embodiment 60, wherein the cancer is a human epidermal growth factor receptor 2 negative (HER2-) breast cancer. [Embodiment 63]The method of embodiment 60, wherein the cancer is a HR+ / HER2- breast cancer. [Embodiment 64]The method of embodiment 60, wherein the cancer is a HR+ / HER2-low breast cancer. [Embodiment 65]The method of embodiment 60, wherein the cancer is a HR+ / HER2+ breast cancer. [Embodiment 66]The method of embodiment 60, wherein the cancer is a triple negative breast cancer (TNBC). [Embodiment 67]The method of embodiment 60, wherein the cancer is an invasive breast cancer. [Embodiment 68]The method of any one of embodiments 1-59, wherein the cancer is uterine cancer. [Embodiment 69]The method of embodiment 68, wherein the cancer is uterine sarcoma. [Embodiment 70]The method of embodiment 68, wherein the cancer is endometrial cancer. [Embodiment 71]The method of embodiment 68, wherein the cancer is Type I endometrial cancer. [Embodiment 72]The method of embodiment 68, wherein the cancer is Type II endometrial cancer. [Embodiment 73]The method of embodiment 72, wherein the cancer...

Claims

1. Attorney Docket No.62619-729601 CLAIMS We claim:

1. A compound having the structure of Formula (I), or a pharmaceutically acceptable salt orsolvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is H, optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join together to form a carbocycle or heterocycle;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle; (b)Attorney Docket No.62619-729601T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl; (d)Attorney Docket No.62619-729601 wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .

2. A compound having the structure of Formula (I-1), or a pharmaceutically acceptable salt orsolvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join together to form a carbocycle or heterocycle;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle; (b)Attorney Docket No.62619-729601T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl; (d)Attorney Docket No.62619-729601 wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .

3. The compound of claim 1 or claim 2 having the structure of Formula (Ia), or a pharmaceuticallyacceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the ;each R9is hydrogen, or optionally substituted C1-C6 alkyl;Attorney Docket No.62619-729601 R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; Q1is O or S; Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle.The compound of any one of claims 1-3 having the structure of Formula (Ia-1), or apharmaceutically acceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the ;each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join together to form a carbocycle or heterocycle;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; Q1is O or S; Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle.The compound of claim 1 or claim 2 having the structure of Formula (Ib), or a pharmaceuticallyacceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; wherein LCG is selected from the group consisting of:Attorney Docket No.62619-729601T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; and each R24is hydrogen, or optionally substituted C1-C6 alkyl.The compound of claim 1-2, or claim 5, having the structure of Formula (Ib-1), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl;Attorney Docket No.62619-729601 R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; wherein LCG is selected from the group consisting of:Attorney Docket No.62619-729601T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; and each R24is hydrogen, or optionally substituted C1-C6 alkyl.The compound of claim 1 or claim 2 having the structure of Formula (Ic), or a pharmaceuticallyacceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl;Attorney Docket No.62619-729601 R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; and each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl.The compound of claim 1, claim 2, or claim 7, having the structure of Formula (Ic-1), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG;Attorney Docket No.62619-729601 each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; and each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl.The compound of claim 1 or claim 2 having the structure of Formula (Id), or a pharmaceuticallyacceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy.The compound of claim 1, claim 2, or claim 9, having the structure of Formula (Id-1), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl;Attorney Docket No.62619-729601 R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601;Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy.The compound of claim 1 or claim 2 having the structure of Formula (Ie), or a pharmaceuticallyacceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-CN; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; and q is 0 or 1.The compound of claim 1, claim 2, or claim 11, having the structure of Formula (Ie-1), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-CN;Attorney Docket No.62619-729601 each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; and q is 0 or 1.A compound having the structure of Formula (II), or a pharmaceutically acceptable salt orsolvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is H, optionally substituted aryl, or optionally substituted heteroaryl;Attorney Docket No.62619-729601 R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , , , , , , , , , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle;T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;Attorney Docket No.62619-729601T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl;wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N.A compound having the structure of Formula (II-1), or a pharmaceutically acceptable salt orsolvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , , , , , , , , , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle;T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;Attorney Docket No.62619-729601T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl;wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .The compound of claim 13 or claim 14 having the structure of Formula (IIa), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the ;each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; Q1is O or S;Attorney Docket No.62619-729601 Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle.The compound of any one of claims 13-15 having the structure of Formula (IIa-1), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the ;each R9is hydrogen, or optionally substituted C1-C6 alkyl;Attorney Docket No.62619-729601 R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; Q1is O or S; Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle.The compound of claim 13, or claim 14, having the structure of Formula (IIb), or apharmaceutically acceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; wherein LCG is selected from the group consisting of:T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; and each R24is hydrogen, or optionally substituted C1-C6 alkyl.The compound of claim 13, claim 14, or claim 17 having the structure of Formula (IIb-1), or apharmaceutically acceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; wherein LCG is selected from the group consisting of:T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; and each R24is hydrogen, or optionally substituted C1-C6 alkyl.The compound of claim 13 or claim 14 having the structure of Formula (IIc), or apharmaceutically acceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; and each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl.The compound of claim 13, claim 14, or claim 19, having the structure of Formula (IIc-1), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , , , , , , , , , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; and each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl.The compound of claim 13 or claim 14 having the structure of Formula (IId), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl;Attorney Docket No.62619-729601 L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG;Attorney Docket No.62619-729601 each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy.The compound of claim 13, claim 14, or claim 21, having the structure of Formula (IId-1), or apharmaceutically acceptable salt or solvate thereof:wherein:Attorney Docket No.62619-729601 Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601 wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy.

23. The compound of claim 13 or claim 14 having the structure of Formula (IIe), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-CN; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join together to form a carbocycle or heterocycle;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1.The compound of claim 13, claim 14, or claim 23, having the structure of Formula (IIe-1), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-CN;Attorney Docket No.62619-729601 each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1.A compound having the structure of Formula (III), or a pharmaceutically acceptable salt orsolvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo;Attorney Docket No.62619-729601 R is H, optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , , , , , , , , , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle;T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;Attorney Docket No.62619-729601T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl;wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N.A compound having the structure of Formula (III-1), or a pharmaceutically acceptable salt orsolvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , , , , , , , , , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle;T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;Attorney Docket No.62619-729601T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl;wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .The compound of claim 25 or claim 26 having the structure of Formula (IIIa), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3;Attorney Docket No.62619-729601 Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to theeach R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; Q1is O or S;Attorney Docket No.62619-729601 Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle.The compound of any one of claims 25-27 having the structure of Formula (IIIa-1), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to theeach R9is hydrogen, or optionally substituted C1-C6 alkyl;Attorney Docket No.62619-729601 R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; Q1is O or S; Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle.The compound of claim 25 or claim 26 having the structure of Formula (IIIb), or apharmaceutically acceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; wherein LCG is selected from the group consisting of:T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; and each R24is hydrogen, or optionally substituted C1-C6 alkyl.The compound of claim 25, claim 26, or claim 29, having the structure of Formula (IIIb-1), or apharmaceutically acceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; wherein LCG is selected from the group consisting of:T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; and each R24is hydrogen, or optionally substituted C1-C6 alkyl.The compound of claim 25 or claim 26 having the structure of Formula (IIIc), or apharmaceutically acceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; and each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl.The compound of claim 25, claim 26, or claim 31, having the structure of Formula (IIIc-1), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , , , , , , , , , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; and each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl.The compound of claim 25 or claim 26 having the structure of Formula (IIId), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle;Attorney Docket No.62619-729601 L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG;Attorney Docket No.62619-729601 each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy.The compound of claim 25, claim 26, or claim 33, having the structure of Formula (IIId-1), or apharmaceutically acceptable salt or solvate thereof:wherein:Attorney Docket No.62619-729601 Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2;Attorney Docket No.62619-729601 n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy.The compound of claim 25 or claim 26 having the structure of Formula (IIIe), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG;Attorney Docket No.62619-729601 each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; and LCG is -C≡N.The compound of claim 25, claim 26, or claim 35, having the structure of Formula (IIIe-1), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; and LCG is -C≡N.A compound having the structure of Formula (IV), or a pharmaceutically acceptable salt orsolvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is H, optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle; (b)T1is N or C-R23; T2is N or C-R23;Attorney Docket No.62619-729601 T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl;wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N.A compound having the structure of Formula (IV-1), or a pharmaceutically acceptable salt orsolvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle; (b)T1is N or C-R23; T2is N or C-R23;Attorney Docket No.62619-729601 T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl;wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .The compound of claim 37 or claim 38 having the structure of Formula (IVa), or apharmaceutically acceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to theeach R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join together to form a carbocycle or heterocycle;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; Q1is O or S; Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle.The compound of any one of claims 37-39, having the structure of Formula (IVa-1), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , , , , , , , , , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to theeach R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; Q1is O or S;Attorney Docket No.62619-729601 Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle.The compound of claim 37 or claim 38 having the structure of Formula (IVb), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG;Attorney Docket No.62619-729601 each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; wherein LCG is selected from the group consisting of:T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24;Attorney Docket No.62619-729601 each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; and each R24is hydrogen, or optionally substituted C1-C6 alkyl.

42. The compound of claim 37, claim 38, or claim 41, having the structure of Formula (IVb-1), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join together to form a carbocycle or heterocycle;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; wherein LCG is selected from the group consisting of:T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; and each R24is hydrogen, or optionally substituted C1-C6 alkyl.The compound of claim 37 or claim 38 having the structure of Formula (IVc), or apharmaceutically acceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; and each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl.The compound of claim 37, claim 38, or claim 43, having the structure of Formula (IVc-1), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; and each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl.The compound of claim 37 or claim 38 having the structure of Formula (IVd), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle;Attorney Docket No.62619-729601 R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601;Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy.The compound of claim 37, claim 38, or claim 45, having the structure of Formula (IVd-1), or apharmaceutically acceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy.The compound of claim 37 or claim 38 having the structure of Formula (IVe), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1-Attorney Docket No.62619-729601 C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; R30is selected from H, halo, or optionally substituted C1-C6 alkyl; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , , , , , , , , , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; and LCG is -C≡N.The compound of claim 37, claim 38, or claim 47, having the structure of Formula (IVe-1), or apharmaceutically acceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601, , ,Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; and LCG is -C≡N.A compound having the structure of Formula (V), or a pharmaceutically acceptable salt orsolvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is H, optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG;Attorney Docket No.62619-729601 each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle; (b)Attorney Docket No.62619-729601T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl; (d)Attorney Docket No.62619-729601 wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N.

50. A compound having the structure of Formula (V-1), or a pharmaceutically acceptable salt orsolvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join together to form a carbocycle or heterocycle;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle; (b)Attorney Docket No.62619-729601T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; each R24is hydrogen, or optionally substituted C1-C6 alkyl;T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl; (d)Attorney Docket No.62619-729601 wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy; and (e) -C≡N .

51. The compound of claim 49 or claim 50 having the structure of Formula (Va), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to theeach R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl;Attorney Docket No.62619-729601 each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; Q1is O or S; Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle.The compound of any one of claims 49-51, having the structure of Formula (Va-1), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1;Attorney Docket No.62619-729601 Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to theeach R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; Q1is O or S;Attorney Docket No.62619-729601 Q2is O or S; Q3is a bond, O, S, N-R22; R21is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R21is absent and Q3and L join together to form a heterocycle; and R22is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R21and R22join together to form a heterocycle.The compound of claim 49 or claim 50 having the structure of Formula (Vb), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG;Attorney Docket No.62619-729601 each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; wherein LCG is selected from the group consisting of:T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24;Attorney Docket No.62619-729601 each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; and each R24is hydrogen, or optionally substituted C1-C6 alkyl.

54. The compound of claim 49, claim 50, or claim 53, having the structure of Formula (Vb-1), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join together to form a carbocycle or heterocycle;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; wherein LCG is selected from the group consisting of:T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; and each R24is hydrogen, or optionally substituted C1-C6 alkyl.The compound of claim 49 or claim 50 having the structure of Formula (Vc), or apharmaceutically acceptable salt or solvate thereof:Attorney Docket No.62619-729601wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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;Attorney Docket No.62619-729601 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; and each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl.The compound of claim 49, claim 50, or claim 55, having the structure of Formula (Vc-1), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:Attorney Docket No.62619-729601T6is N or C-R25; T7is N or C-R25; T8is N or C-R25; and each R25is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl.The compound of claim 49 or claim 50 having the structure of Formula (Vd), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle;Attorney Docket No.62619-729601 L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG;Attorney Docket No.62619-729601 each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy.The compound of claim 49, claim 50, or claim 57, having the structure of Formula (Vd-1), or apharmaceutically acceptable salt or solvate thereof:wherein:Attorney Docket No.62619-729601 Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2;Attorney Docket No.62619-729601 n is 1, 2, or 3; q is 0 or 1; LCG is a group selected from the group consisting of:wherein each R26, R27, R28, and R29is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy.The compound of claim 49 or claim 50 having the structure of Formula (Ve), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4; W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG;Attorney Docket No.62619-729601 each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; and LCG is -C≡N.The compound of claim 49, claim 50, or claim 59, having the structure of Formula (Ve-1), or apharmaceutically acceptable salt or solvate thereof:wherein: Z1is N, or C-R1; Z2is N, or C-R2; Z3is N, or C-R3; Z4is N, or C-R4;Attorney Docket No.62619-729601 W1, W2, W3, and W4are each independently selected from CH, CD, N, C-CN, or C-halo; R is optionally substituted aryl, or optionally substituted heteroaryl; R1, R2, R3, and R4are each independently selected from H, D, -OR12, -SR12, -N(R12)2, - CN, halo, -CO2R11, -CON(R12)2, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl; R7and R8are each independently H, D, halogen, -CN, -OH, or optionally substituted C1- C6 alkyl; or R7and R8together form an oxo; or R7and R8join together to form a carbocycle or heterocycle; L is selected from -N(R9)-, -O-, or a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; R11is optionally substituted C1-C6 alkyl; R12is H or optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; n is 1, 2, or 3; q is 0 or 1; and LCG is -C≡N.The compound of any one of claims 1-60, or a pharmaceutically acceptable salt or solvatethereof, wherein L is a divalent radical selected from:Attorney Docket No.62619-729601Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG;Attorney Docket No.62619-729601 each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join 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; m is 0, 1, or 2; and n is 1, 2, or 3.

62. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvatethereof, wherein L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; and n is 1, 2, or 3.

63. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvatethereof, wherein L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; and R10is optionally substituted C1-C6 alkyl.

64. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvatethereof, wherein L is a divalent radical selected from:Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; and each R9is hydrogen, or optionally substituted C1-C6 alkyl;65. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvatethereof, wherein L is a divalent radical selected from:; wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; and each R9is hydrogen, or optionally substituted C1-C6 alkyl.

66. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvatethereof, wherein L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; and each R9is hydrogen, or optionally substituted C1-C6 alkyl.

67. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvatethereof, wherein L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; and each R9is hydrogen, or optionally substituted C1-C6 alkyl.

68. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvatethereof, wherein L is a divalent radical selected from:Attorney Docket No.62619-729601wherein the asterisk (*) indicates the bond to the –(CO)q-LCG.

69. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvatethereof, wherein L is a divalent radical selected from:; wherein the asterisk (*) indicates the bond to the –(CO)q-LCG.

70. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvatethereof, wherein L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; and m is 0, 1, or 2.

71. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvatethereof, wherein L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the –(CO)q-LCG.

72. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvatethereof, wherein L is a divalent radical selected from:Attorney Docket No.62619-729601 wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; R10is optionally substituted C1-C6 alkyl; and each R13are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R13together form an oxo; or two independently selected R13join together to form a carbocycle or heterocycle.The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvatethereof, wherein L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the –(CO)q-LCG.The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvatethereof, wherein L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; each R9is hydrogen, or optionally substituted C1-C6 alkyl; 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; and 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.Attorney Docket No.62619-72960175. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvatethereof, wherein L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the –(CO)q-LCG; and each R9is hydrogen, or optionally substituted C1-C6 alkyl.

76. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvatethereof, wherein L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the –(CO)q-LCG.

77. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvatethereof, wherein L is a divalent radical selected from:wherein the asterisk (*) indicates the bond to the –(CO)q-LCG.Attorney Docket No.62619-72960178. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvatethereof, whereinwherein the asterisk (*) indicates the bond to the –(CO)q-LCG; and each R9is hydrogen, or optionally substituted C1-C6 alkyl.

79. The compound of any one of claims 1-78, or a pharmaceutically acceptable salt or solvatethereof, wherein Z2is C-R2.

80. The compound of claim 79, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted aryl.

81. The compound of claim 79, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted heteroaryl.

82. The compound of claim 79, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is H.

83. The compound of claim 79, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -CN.

84. The compound of claim 79, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted carbocyclyl.

85. The compound of claim 84, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted cyclopropyl.

86. The compound of claim 80, or a pharmaceutically acceptable salt or solvate thereof, wherein theoptionally substituted aryl is substituted with halogen.

87. The compound of claim 81, or a pharmaceutically acceptable salt or solvate thereof, wherein theoptionally substituted heteroaryl is substituted with halogen.

88. The compound of claim 81, or a pharmaceutically acceptable salt or solvate thereof, wherein theoptionally substituted heteroaryl is substituted with optionally substituted C1-C6 alkyl.

89. The compound of claim 88, or a pharmaceutically acceptable salt or solvate thereof, wherein theoptionally substituted heteroaryl is substituted with optionally substituted C2-C3 alkyl.

90. The compound of claim 81, or a pharmaceutically acceptable salt or solvate thereof, wherein theoptionally substituted heteroaryl is substituted with -O-(optionally substituted carbocyclyl).

91. The compound of claim 81, or a pharmaceutically acceptable salt or solvate thereof, wherein theoptionally substituted heteroaryl is substituted with optionally substituted C1-C6 alkoxy.Attorney Docket No.62619-729601 92. The compound of claim 79, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6 alkyl.

93. The compound of claim 79, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6 alkenyl.

94. The compound of claim 79, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is halo.

95. The compound of claim 92, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C3 alkyl.

96. The compound of claim 95, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1 alkyl or C2 alkyl.

97. The compound of claim 93, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C3 alkenyl.

98. The compound of any one of claims 1-97, or a pharmaceutically acceptable salt or solvatethereof, wherein Z3is N.

99. The compound of any one of claims 1-97, or a pharmaceutically acceptable salt or solvatethereof, wherein Z3is C-R3.

100. The compound of any one of claims 1-97, or a pharmaceutically acceptable salt or solvatethereof, wherein R3is optionally substituted carbocyclyl.

101. The compound of claim 100, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted aryl.

102. The compound of claim 100, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted heteroaryl.

103. The compound of claim 100, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is H.

104. The compound of claim 101, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted aryl is substituted with halogen.

105. The compound of claim 102, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted heteroaryl is substituted with halogen.

106. The compound of claim 102, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted heteroaryl is substituted with optionally substituted C1-C6 alkoxy.

107. The compound of claim 100, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is C1-C6 alkyl.

108. The compound of claim 100, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is C1-C6 alkenyl.Attorney Docket No.62619-729601109. The compound of claim 100, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is halo.

110. The compound of claim 107, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is C1-C3 alkyl.

111. The compound of claim 110, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is C1 alkyl or C2 alkyl.

112. The compound of claim 108, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is C1-C3 alkenyl.

113. The compound of any one of claims 1-112, or a pharmaceutically acceptable salt or solvatethereof, wherein R is optionally substituted heteroaryl.

114. The compound of claim 113, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted heteroaryl is substituted with amino.

115. The compound of claim 113, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted heteroaryl is substituted with optionally substituted C1-C6 alkoxy.

116. The compound of any one of claims 1-112, or a pharmaceutically acceptable salt or solvatethereof, wherein R is H.

117. The compound of any one of claims 1, 2, 13, 14, 25, 26, 37, 38, 49, 50, 61-116, or apharmaceutically acceptable salt or solvate thereof, wherein LCG is:T1is N or C-R23; T2is N or C-R23; T3is N or C-R23; T4is N or C-R23; T5is O, S, or N-R24; each R23is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; andAttorney Docket No.62619-729601 each R24is hydrogen, or optionally substituted C1-C6 alkyl.

118. The compound of claim 117, or a pharmaceutically acceptable salt or solvate thereof, whereinLCG is:.

119. The compound of claim 117, or a pharmaceutically acceptable salt or solvate thereof, whereinLCG is:.

120. The compound of claim 117, or a pharmaceutically acceptable salt or solvate thereof, whereinLCG is:.

121. The compound of any one of claims claim 5, 6, 17, 18, 29, 30, 41, 42, 53, 54, 61-116, or apharmaceutically acceptable salt or solvate thereof, wherein LCG is:.

122. The compound of claim 121, or a pharmaceutically acceptable salt or solvate thereof, whereinLCG is:.

123. The compound of claim 121, or a pharmaceutically acceptable salt or solvate thereof, whereinLCG is:.

124. The compound of any one of claims 1-123, or a pharmaceutically acceptable salt or solvatethereof, wherein W1, W2, W3, and W4are CH.

125. The compound of any one of claims 1-124, or a pharmaceutically acceptable salt or solvatethereof, wherein q is 0.

126. The compound of any one of claims 1-124, or a pharmaceutically acceptable salt or solvatethereof, wherein q is 1.

127. The compound of any one of claims 1-126, or a pharmaceutically acceptable salt or solvatethereof, wherein:Attorney Docket No.62619-729601 Z1is C-R1; Z2is C-R2; Z3is C-R3; and Z4is C-R4.

128. The compound of any one of claims 1-126, or a pharmaceutically acceptable salt or solvatethereof, wherein: Z1is N; Z2is C-R2; Z3is C-R3; and Z4is C-R4.

129. The compound of any one of claims 1-126, or a pharmaceutically acceptable salt or solvatethereof, wherein: Z1is C-R1; Z2is N; Z3is C-R3; and Z4is C-R4.

130. The compound of any one of claims 1-126, or a pharmaceutically acceptable salt or solvatethereof, wherein: Z1is C-R1; Z2is C-R2; Z3is N; and Z4is C-R4.

131. The compound of any one of claims 1-126, or a pharmaceutically acceptable salt or solvatethereof, wherein: Z1is C-R1; Z2is C-R2; Z3is C-R3; and Z4is N.

132. The compound of any one of claims 1-126, or a pharmaceutically acceptable salt or solvatethereof, wherein: Z1is N; Z2is C-R2; Z3is N; and Z4is C-R4.Attorney Docket No.62619-729601133. The compound of any one of claims 1-126, or a pharmaceutically acceptable salt or solvatethereof, wherein: Z1is N; Z2is C-R2; Z3is C-R3; and Z4is N.

134. The compound of any one of claims 1-133, or a pharmaceutically acceptable salt or solvatethereof, wherein R7and R8are H.

135. The compound of any one of claims 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 37, 39, 41, 43, 45, 47,or 61-113, or a pharmaceutically acceptable salt or solvate thereof, wherein R30is H.

136. The compound of any one of claims 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 37, 39, 41, 43, 45, 47,or 61-113, or a pharmaceutically acceptable salt or solvate thereof, wherein R30is halo.

137. The compound of claim 120, or pharmaceutically acceptable salt or solvate thereof, wherein L iswherein the asterisk (*) indicates the bond to the –(CO)q-LCG; R9is hydrogen or optionally substituted C1-C6 alkyl; and wherein q is 0.

138. The compound of claim 137, or pharmaceutically acceptable salt or solvate thereof, wherein R9is hydrogen.

139. The compound of claim 137 or 138, or pharmaceutically acceptable salt or solvate thereof,wherein R7and R8are H.

140. The compound of any one of claims 137-139, or pharmaceutically acceptable salt or solvatethereof, wherein R is optionally substituted heteroaryl.

141. The compound of claim 140, or pharmaceutically acceptable salt or solvate thereof, wherein R isoptionally substituted pyridin-3-yl.

142. The compound of claim 141, or pharmaceutically acceptable salt or solvate thereof, wherein R is2-fluoro-pyridin-3-yl.

143. The compound of any one of claims 137-142, or pharmaceutically acceptable salt or solvatethereof, wherein Z2is C-R2, and wherein R2is optionally substituted aryl.

144. The compound of claim 143, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted phenyl.Attorney Docket No.62619-729601145. The compound of 144, or pharmaceutically acceptable salt or solvate thereof, wherein R2 is 4-fluoro-phenyl.

146. The compound of any one of claims 137-142, or pharmaceutically acceptable salt or solvatethereof, wherein Z2is C-R2, and wherein R2is optionally substituted heteroaryl.

147. The compound of claim 146, or pharmaceutically acceptable salt or solvate thereof, wherein R2is optionally substituted pyridin-6-yl.

148. The compound of claim 147, or pharmaceutically acceptable salt or solvate thereof, wherein R2is 3-fluoro-pyridin-6-yl.

149. The compound of any one of claims 137-142, or pharmaceutically acceptable salt or solvatethereof, wherein Z2is C-R2, and wherein R2is -CN.

150. The compound of any one of claims 137-142, or pharmaceutically acceptable salt or solvatethereof, wherein Z3is C-R3, and wherein R3is optionally substituted heteroaryl.

151. The compound of claim 150, or pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted pyridin-6-yl.

152. The compound of claim 151, or pharmaceutically acceptable salt or solvate thereof, wherein R3is 3-fluoro-pyridin-6-yl.

153. The compound of any one of claims 137-152, or a pharmaceutically acceptable salt or solvatethereof, wherein W1, W2, W3, and W4are CH.

154. The compound of any one of claims 137-153, or pharmaceutically acceptable salt or solvatethereof, comprising a compound of Formula (I), wherein R30is H; Z1is C-R1, and wherein R1is H; Z3is N; and Z4is C-R4; and wherein R4is H.

155. The compound of any one of claims 137-153, or pharmaceutically acceptable salt or solvatethereof, comprising a compound of Formula (I), wherein R30is H; Z1is C-R1, and wherein R1is H; Z3is C-R3, and wherein R3is H; and Z4is N.

156. The compound of any one of claims 137-153, or pharmaceutically acceptable salt or solvatethereof, comprising a compound of Formula (I), wherein R30is H; Z1is N;Attorney Docket No.62619-729601 Z3is N; and Z4is C-R4, and wherein R4is H.

157. The compound of any one of claims 137-153, or pharmaceutically acceptable salt or solvatethereof, comprising a compound of Formula (I), wherein R30is H; Z1is N; Z3is C-R3, and wherein R3is H; and Z4is N.

158. The compound of any one of claims 137-153, or pharmaceutically acceptable salt or solvatethereof, comprising a compound of Formula (II), wherein R30is H; Z1is C-R1, and wherein R1is H; and Z3is N; and Z4is C-R4, and wherein R4is H.

159. The compound of any one of claims 137-153, or pharmaceutically acceptable salt or solvatethereof, comprising a compound of Formula (III), wherein Z1is N; Z3is C-R3, and wherein R3is H; and Z4is C-R4, and wherein R4is H.

160. The compound of any one of claims 137-153, or pharmaceutically acceptable salt or solvatethereof, comprising a compound of Formula (III), wherein Z1is C-R1, and wherein R1is H; Z3is N; and Z4is C-R4, and wherein R4is H.

161. The compound of any one of claims 137-153, or pharmaceutically acceptable salt or solvatethereof, comprising a compound of Formula (III), wherein Z1is C-R1, and wherein R1is H; Z3is C-R3, and wherein R3is H; and Z4is N.

162. The compound of any one of claims 137-153, or pharmaceutically acceptable salt or solvatethereof, comprising a compound of Formula (IV), wherein R30is H; Z1is C-R1, and wherein R1is H; Z2is H; andAttorney Docket No.62619-729601 Z4is C-R4, and wherein R4is H.

163. The compound of any one of claims 137-153, or pharmaceutically acceptable salt or solvatethereof, comprising a compound of Formula (V), wherein Z1is N; Z3is C-R3, and wherein R3is H; and Z4is C-R4, and wherein R4is H.

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

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

166. A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt orsolvate thereof, as described in any one of claims 1-165, and a pharmaceutically acceptable excipient.

167. A method of preparing a pharmaceutical composition comprising mixing a compound, orpharmaceutically acceptable salt or solvate thereof, of any one of claims 1-165, and a pharmaceutically acceptable carrier.

168. A compound of any one of claims 1-165, or pharmaceutically acceptable salt or solvate thereof,for use in a method of treatment of the human or animal body.

169. A compound of any one of claims 1-165, or pharmaceutically acceptable salt or solvate thereof,for use in a method of treatment of cancer or neoplastic disease.

170. Use of a compound of any one of claims 1-165, or pharmaceutically acceptable salt or solvatethereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

171. A method of treating cancer in a patient in need thereof, comprising administering to the patienta compound as described in any one of claims 1-165, or pharmaceutically acceptable salt or solvate thereof.

172. A method of treating cancer in a patient in need thereof, comprising administering to the patienta pharmaceutical composition comprising a compound as described in any one of claims 1-165, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

173. A method of inhibiting an AKT1 enzyme comprising contacting the enzyme with a compound ofany one of claims 1-165, wherein the AKT1 enzyme is contacted in an in vitro setting.

174. A method of inhibiting an AKT1 enzyme comprising contacting the enzyme with a compound ofany one of claims 1-165, wherein the AKT1 enzyme is contacted in an in vivo setting.