KRAS modulators

Abstract

Provided herein are inhibitors of KRAS, pharmaceutical compositions comprising the inhibitory compounds, and methods for using the KRAS inhibitory compounds for the treatment of diseases or disorders.

Description

WSGR Docket No. 62619-756.601KRAS MODULATORS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of US Patent Application No. 63 / 737481, filed on December 20, 2024; US Patent Application No. 63 / 774512, filed on March 19, 2025; and US Patent Application No. 63 / 825319, filed on June 17, 2025; all of which are hereby incorporated by reference in their entirety.BACKGROUND

[0002] KRAS (Kirsten rat sarcoma viral oncogene homologue) is an oncoprotein that is a part of the RAS / MAPK pathway, and relays signals from outside of the cell to the cell’s nucleus. KRAS protein is a GTPase and involved in cellular signaling such as regulation of cell proliferation. KRAS can activate cellular signaling pathways including, but not limited to, the mitogen- activated protein kinase (MAPK) pathway. KRAS was previously considered un-targetable, but recent studies have shown that targeting codon 12 can lead to therapeutic effects. There remains an unmet need to identify and develop novel compounds for KRAS inhibition.BRIEF SUMMARY OF THE INVENTION

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

[0004] One embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereofwherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);WSGR Docket No. 62619-756.601X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), C-(optionally substituted C3-C6 carbocyclyl), or C-SF5;Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,; and G is an optionally substituted 5- to 10-membered heterocyclyl; andR2is optionally substituted C2-C6 alkynyl;R3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andR12is selected from H, D, fluoro, chloro, bromo, optionally substituted C1-C6 alkyl, - CF3, amino, -COOH, -CONH2, -CN, or -OH;optionally wherein R11and R12are taken together with the carbon atoms to which they are attached to form an optionally substituted methylidene or an oxo group;provided that if Y is O and R3, R4, R5, R6, R9, and R10is H, then R12is not H or D; and provided that if Z is O, and R3, R4, R5, R6, R7, and R8is H, then R12is not H or D.

[0005] One embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein:X1is N or C-CN;WSGR Docket No. 62619-756.601X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), C-(optionally substituted C3-C6 carbocyclyl), or C-SF5;Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,or; and G is an optionally substituted 5- to 10-membered heterocyclyl;each R2is independently selected from H, or optionally substituted C1-C6 alkyl;R3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andR12is selected from H, D, fluoro, chloro, bromo, optionally substituted C1-C6 alkyl, - CF3, amino, -COOH, -CONH2, -CN, or -OH;optionally wherein R11and R12are taken together with the carbon atoms to which they are attached to form an optionally substituted methylidene or an oxo group;Provided that if Y is O, Z is CR9R10, and R3, R4, R5, R6, R9, R10is H, then R12is not H or D;provided that if Y is CR7R8, Z is CR9R10, andR3, R4, R5, R6, R7, R8, R9, R10is H, then R12is not H or D; andprovided that if Y is CR7R8, and R3, R4, R5, R6, R7, R8is H, then Z cannot be O.

[0006] One embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:WSGR Docket No. 62619-756.601wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), C-(optionally substituted C3-C6 carbocyclyl), or C-SF5;Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,* * ’ *%; and G is an optionally substituted 5- to 10-membered heterocyclyl;R2is H or optionally substituted C1-C6 alkyl;R3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andR12is selected from H, D, fluoro, chloro, bromo, optionally substituted C1-C6 alkyl, -CF3, amino, -COOH, -CONH2, -CN, or -OH;optionally wherein R11and R12are taken together with the carbon atoms to which they are attached to form an optionally substituted methylidene or an oxo group;provided that if Z is O, then the compound is notWSGR Docket No. 62619-756.601

[0007] One embodiment provides a compound having the structure of Formula (IV), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:R2wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), C-(optionally substituted C3-C6 carbocyclyl), or C-SF5;Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,oor; and G is an optionally substituted 5- to 10-membered heterocyclyl;R2is optionally substituted C2-C6 alkenyl; andR3, R4, R5, R6, R7, R8, R9, R10, R13, R14, R15, R16each is independently selected from H or optionally substituted C1-C6 alkyl;WSGR Docket No. 62619-756.601optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;optionally wherein R14and R15together form an optionally substituted carbocyclyl ring;optionally wherein the carbocyclyl ring is further substituted with an optionally substituted methylidene.

[0008] One embodiment provides a compound having the structure of Formula (V), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), C-(optionally substituted C3-C6 carbocyclyl), or C-SF5;Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,*x; and G is an optionally substituted 5- to 10-membered heterocyclyl; andR3, R4, R5, R6, R7, R8, R9, R10, R13, R14, R15, R16each is independently selected from H or optionally substituted C1-C6 alkyl;WSGR Docket No. 62619-756.601optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;optionally wherein R14and R15together form an optionally substituted carbocyclyl ringoptionally wherein the carbocyclyl ring is further substituted with an optionally substituted methylidene.

[0009] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), (Yl), or Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and at least one pharmaceutically acceptable excipient.

[0010] One embodiment provides a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), (Yl), or Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof.

[0011] One embodiment provides a method of inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), (Yl), or Table 1, wherein the KRAS protein is contacted in an in vitro setting.

[0012] One embodiment provides a method of inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), (Yl), or Table 1, wherein the KRAS protein is contacted in an in vivo setting.BRIEF DESCRIPTION OF THE DRAWINGS

[0013] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompany drawings of which:

[0014] Figure 1 provides additional embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), (Yl), or Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof;

[0015] Figure 2 provides additional embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), (Yl), or Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof;WSGR Docket No. 62619-756.601

[0016] Figure 3 provides additional embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), (Yl), or Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof;

[0017] Figure 4 provides additional embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), (Yl), or Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof;

[0018] Figure 5 provides additional embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), (Yl), or Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof;

[0019] Figure 6 provides additional embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), (Yl), or Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof;

[0020] Figure 7 provides additional embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), (Yl), or Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof;

[0021] Figure 8 provides additional embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), (Yl), or Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof;

[0022] Figure 9 provides additional embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), (Yl), or Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof;

[0023] Figure 10 provides additional embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), (Yl), or Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof;

[0024] Figure 11 provides additional embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), (Yl), or Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof;

[0025] Figure 12 provides additional embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), (Yl), or Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof;

[0026] Figure 13 provides additional embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), (Yl), or Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof;WSGR Docket No. 62619-756.601

[0027] Figure 14 provides additional embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), (Yl), or Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof;

[0028] Figure 15 provides additional embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), (Yl), or Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof;

[0029] Figure 16 provides additional embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), (Yl), or Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof;

[0030] Figure 17 provides additional embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), (Yl), or Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof;

[0031] Figure 18 provides additional embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), (Yl), or Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof; and

[0032] Figure 19 provides additional embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), (Yl), or Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof.INCORPORATION BY REFERENCE

[0033] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein.DETAILED DESCRIPTION OF THE INVENTION

[0034] 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 sub-combinations 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 certainWSGR Docket No. 62619-756.601embodiments, 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

[0035] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0036] " Amino" refers to the -NH2 radical.

[0037] " Cyano" refers to the -CN radical.

[0038] " Nitro" refers to the -NO2 radical.

[0039] " Oxa" refers to the -O- radical.

[0040] " Oxo" refers to the =0 radical.

[0041] " Thioxo" refers to the =S radical.

[0042] " Imino" refers to the =N-H radical.

[0043] " Oximo" refers to the =N-0H radical.

[0044] " Hydrazino" refers to the =N-NH2 radical.

[0045] “Methylidene” refers to the =CH2 radical appended to a cyclic ring system.

[0046] " Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., Ci- Cx alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., Cs-Cs alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl (w-propyl), 1 -methylethyl ( / .w-propyl), 1 -butyl ( / / -butyl), 1 -methylpropyl ( ec-butyl), 2-methylpropyl (Ao-butyl), 1,1 -dimethylethyl (tert-butyl), 1 -pentyl (w-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, -WSGR Docket No. 62619-756.601N(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, oxo or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, oxo 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.

[0047] " Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0048] " Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -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, orWSGR Docket No. 62619-756.601trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0049] " Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl comprises two to six carbon atoms. In other embodiments, an alkynyl comprises two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0050] " Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, w-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., Ci-Cs alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In otherWSGR Docket No. 62619-756.601embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., Cs-Cs alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, - 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).

[0051] " Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkenylene comprises two to eight carbon atoms (e.g., C2-Cs alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (e.g., C2-Cs 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-Cs alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (e.g., C2alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., Cs-Cs alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C3-C5 alkenylene). Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -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 eachWSGR Docket No. 62619-756.601Rais 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).

[0052] " Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C2-C8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C2-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., 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, trimethyl silanyl, -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, orWSGR Docket No. 62619-756.601trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0053] " Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, z.e., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Hiickel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, - Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb- N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb- S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0054] " Aralkyl" refers to a radical of the formula -Rc-aryl where Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0055] " Aralkenyl" refers to a radical of the formula -Rd-aryl where Rdis an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described aboveWSGR Docket No. 62619-756.601for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0056] " Aralkynyl" refers to a radical of the formula -Re-aryl, where Reis an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0057] " Aralkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc-aryl where Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0058] " Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (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, norbomyl (i.e., bicyclo[2.2.1]heptanyl), norbomenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, oxo, thioxo, cyano, nitro, -Rb-0Ra, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-0C(0)-N(Ra)2, -Rb- N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)0Ra, -Rb-N(Ra)C(0)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, orWSGR Docket No. 62619-756.601trifluoromethyl), 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.

[0059] " Carbocyclylalkyl" refers to a radical of the formula -Rc-carbocyclyl where Rcis an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0060] " Carbocyclylalkynyl" refers to a radical of the formula -Rc-carbocyclyl where Rcis an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0061] " 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.

[0062] " Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.

[0063] " Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0064] " Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, andWSGR Docket No. 62619-756.6011,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, - Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb- C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb- N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0065] " A-heterocyclyl" or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An^'-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such A-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1- piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, and imidazolidinyl.

[0066] " C-heterocyclyl" or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. AC-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.

[0067] " Heterocyclylalkyl" refers to a radical of the formula -Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chainWSGR Docket No. 62619-756.601of 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.

[0068] " 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.

[0069] " Heteroaryl" refers to a radical derived from a 3 - to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, z.e., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Hiickel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[Z>][l,4]dioxepinyl, benzo[b][l,4]oxazinyl,1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotri azolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5.6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1.6-naphthyri dinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1 -phenyl- UT-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl,WSGR Docket No. 62619-756.601isoquinol inyl, 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 ( / .<?. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, optionally substituted fluoroalkyl, optionally substituted haloalkenyl, optionally substituted haloalkynyl, oxo, thioxo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, - Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc- C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb- S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0070] " A-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An A-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0071] " C-heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.WSGR Docket No. 62619-756.601

[0072] " Heteroarylalkyl" refers to a radical of the formula -Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroaryl alkyl 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.

[0073] " Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O- Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0074] The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (5 -. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term “geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0075] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:WSGR Docket No. 62619-756.601

[0076] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,nC,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in, for example, 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, in some instances, improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0077] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0078] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,nC,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35C1,37C1,79Br,81Br,125I are all contemplated. In some embodiments, isotopic substitution with18F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0079] In certain embodiments, the compounds disclosed herein have some or all of theatoms 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.WSGR Docket No. 62619-756.601

[0080] Deuterium substituted compounds are synthesized using various methods such as described in:Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0081] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0082] Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-ds (CD3I), are readily available and may be employed to transfer a deuteriumsubstituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD3I is illustrated, by way of example only, in the reaction schemes below.CD3IbaseCD3Ibaseo

[0083] Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAlD4), are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD4 is illustrated, by way of example only, in the reaction schemes below.R'cnLiAID4, R^NH2^CO2HLiAID4,CyDLiAID4D R'D DRR OH R R' *RXQH

[0084] Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.WSGR Docket No. 62619-756.601

[0085] In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable 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.

[0086] " Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the KRAS inhibitory compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0087] " Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S. M. etal., " Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1- 19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared byWSGR Docket No. 62619-756.601contacting 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.

[0088] " Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N, N- dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, A-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0089] " Pharmaceutically acceptable solvate" refers to a composition of matter that is the solvent addition form. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein exist in either unsolvated or solvated forms.

[0090] 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.

[0091] As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and / or a prophylactic benefit. By “therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement isWSGR Docket No. 62619-756.601observed 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.KRAS Protein and Function

[0092] RAS mutation is frequent in cancer, with approximately 19% of patients with cancer harboring RAS mutations (I. A. Prior et al., Cancer Res 2020; 80:2969-74). Ras proteins are important for activating signaling networks for controlling cell differentiation, proliferation, and survival, encoded by three genes HRAS, KRAS, and NRAS. The three genes share significant sequence homology and largely overlapping functions. Activation of RAS is facilitated by guanine nucleotide exchange factors (GEF), and activation causes conformational changes.

[0093] The KRAS gene encodes two highly related protein isoforms, KRAS-4A and KRAS-4B, which comprise of 189 and 188 amino acids. KRAS generally refers to KRAS-4B, because of the high level of mRNA encoding KRAS-4B in cells. KRAS has two major domains, the catalytic G domain and a hypervariable region (HVR).

[0094] KRAS G domain is the basis of biological function of GTPase proteins. The G domain comprises 6 beta-strands of the protein core, surrounded by five alpha-helices, and comprises residues 1-166. The G domain also consists of other regions: switch I, switch II, and the P loop. KRAS-GTP binding alters the conformation of the switches I and II in the G domain. When activated, KRAS binds to its downstream molecules as monomers or dimers to mediate series of signaling cascades. KRAS also has a flexible C-terminal, the hypervariable region (HVR), which is important for localizing KRAS to the membrane.

[0095] The RAS family comprises three isoforms, but about 85% of RAS-related cancers are caused by mutations in the KRAS isoform. The mutations in KRAS isoform occurs most frequently in solid tumors such as colorectal carcinoma, lung adenocarcinoma, and pancreatic ductal carcinoma. Further, nearly 80% of KRAS mutant tumors are located within codon 12, with the most common mutations being p. G12D, p. G12V, and p. G12C.

[0096] KRAS protein functions as a molecular switch in growth factor signaling pathways by regulating proliferation by alternating between a GDP -bound inactive form and a GTP -bound active form. The GTP -bound active form is capable of engaging downstream effector proteins to trigger a pro-proliferative response. This regulation cycle is impaired by mutations in codon 12 which disrupts association of GTPase activating proteins, which impairs the inactivation of KRAS, which leads to accumulation of the pro-proliferative form. Many growth factors such as but not limited to epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and fibroblast growth factors (FGF) can activate KRAS proteins through intermediary molecules afterWSGR Docket No. 62619-756.601activating receptor tyrosine kinases. Upstream regulation can promote binding of GTP and KRAS, converting KRAS from an inactive to an active state. Molecules upstream of KRAS mainly mediate the activation or inactivation of KRAS by regulating guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) (L. Huang et al., Signal Transduction and Targeted Therapy, 2021, 6, 386). Another molecule in KRAS activation is Src homology phosphatase 2 (SHP2) which plays a role in KRAS activation. SHP2 is a common signaling regulatory that mediates receptor tyrosine kinases signals to KRAS-ERK signaling, and dephosphorylation substrates of SHP2 have been shown to promote KRAS activation.

[0097] The RAF-MEK-ERK pathway is a downstream target of KRAS signaling. Another pathway KRAS is involved in is the PI3K-AKT-mTOR pathway (L. Huang et al., Signal Transduction and Targeted Therapy, 2021, 6, 386).

[0098] KRAS was previously considered to be an undruggable protein, but recently there have been advances in targeting codon 12, and specifically in G12C inhibitors. Many efforts have been focused on indirectly targeting KRAS, so there remains an unmet need of targeting KRAS, which the compounds provided herein fulfill. With the discovery of a new allosteric site of KRAS, G12C, several covalently binding inhibitors of KRAS have emerged and are under clinical investigation. However, KRAS inhibition is a complex issue with a lack of understanding of the underlying principles, and there still remains an unmet need for new inhibitors which target other KRAS mutations such as, but not limited to, G12D and G12V.

[0099] KRAS mutations are frequently found in colorectal cancer, pancreatic cancer, and non-small cell lung cancer (M. H. Hofmann et al., Cancer Discov 2022; 12:924-37). The KRAS allelic distribution varies between the tumor types, with G12C mutations in 13.6% of lung adenocarcinomas, whereas the G12D and G12V mutations are most common in colorectal and pancreatic cancer. The G12D, G12V, and G12C mutations are the three most frequent allele mutations. KRAS mutations, especially at codon 12, is strongly associated with cellular KRAS dependency, indicating that KRAS acts as an oncogenic driver.Prior Art Small Molecules Inhibitors

[0100] There have been advances for KRAS G12C inhibitors, such as sotorasib (AMG510) and adagrasib (MRTX849). Sotorasib is the first to be approved by the US Food and Drug Administration (FDA). Both inhibitors rely on the interaction with the nucleophilic cysteine 12 in the GDP state and occupy the switch II pocket.

[0101] NMR studies have shown that MRTX849 can engage mutant KRAS proteins lacking the nucleophilic mutant cysteine 12, but that the engagement is selected for inactive GDP -loaded state of KRAS protein. AMG510 exhibits weak binding and relies on irreversible reaction of theWSGR Docket No. 62619-756.601mutant cysteinel2 for KRAS (G12C) inhibitory activity (J. D. Vasta et al., Nature Chemical Biology, 2022, 18, 596-604).

[0102] AMG510 and additional KRAS inhibitors are described in Discovery of a Covalent Inhibitor of KRASG12C (AMG 510) for the Treatment of Solid Tumors (B. A Lanman et al., J. Med. Chem.2020, 63, 52-65).Novel Compounds Inhibiting KRAS

[0103] In one aspect, provided herein are KRAS inhibitory compounds.

[0104] One embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), C-(optionally substituted C3-C6 carbocyclyl), or C-SF5;Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,* * ’ *%; and G is an optionally substituted 5- to 10-membered heterocyclyl; andR2is optionally substituted C2-C6 alkynyl;WSGR Docket No. 62619-756.601R3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andR12is selected from H, D, fluoro, chloro, bromo, optionally substituted C1-C6 alkyl, - CF3, amino, -COOH, -CONH2, -CN, or -OH;optionally wherein R11and R12are taken together with the carbon atoms to which they are attached to form an optionally substituted methylidene or an oxo group;provided that if Y is O and R3, R4, R5, R6, R9, and R10is H, then R12is not H or D; and provided that if Z is O, and R3, R4, R5, R6, R7, and R8is H, then R12is not H or D.

[0105] One embodiment provides a compound having the structure of Formula (la), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), C-(optionally substituted C3-C6 carbocyclyl), or C-SF5;Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;WSGR Docket No. 62619-756.601R1is L-G; wherein L is optionally substituted C1-C4 alkylene,or; and G is an optionally substituted 5- to 10-membered heterocyclyl; andR2is optionally substituted C2-C6 alkynyl;R3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andR12is selected from H, D, fluoro, chloro, -CN, or -OHprovided that if Y is O and R3, R4, R5, R6, R9, and R10is H, then R12is not H or D; and provided that if Z is O, and R3, R4, R5, R6, R7, and R8is H, then R12is not H or D.

[0106] One embodiment provides a compound having the structure of Formula (lb), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;WSGR Docket No. 62619-756.601R1is L-G; wherein L is optionally substituted C1-C4 alkylene,or; and G is an optionally substituted 5- to 10-membered heterocyclyl; andR2is optionally substituted C2-C6 alkynyl;R3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andR12is selected from H, D, fluoro, chloro, -CN, or -OHprovided that if Y is O and R3, R4, R5, R6, R9, and R10is H, then R12is not H or D; and provided that if Z is O, and R3, R4, R5, R6, R7, and R8is H, then R12is not H or D.

[0107] One embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), C-(optionally substituted C3-C6 carbocyclyl), or C-SF5;Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;WSGR Docket No. 62619-756.601R1is L-G; wherein L is optionally substituted C1-C4 alkylene,or; and G is an optionally substituted 5- to 10-membered heterocyclyl;each R2is independently selected from H, or optionally substituted C1-C6 alkyl;R3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andR12is selected from H, D, fluoro, chloro, bromo, optionally substituted C1-C6 alkyl, - CF3, amino, -COOH, -CONH2, -CN, or -OH;optionally wherein R11and R12are taken together with the carbon atoms to which they are attached to form an optionally substituted methylidene or an oxo group;Provided that if Y is O, Z is CR9R10, and R3, R4, R5, R6, R9, R10is H, then R12is not H or D;provided that if Y is CR7R8, Z is CR9R10, andR3, R4, R5, R6, R7, R8, R9, R10is H, then R12is not H or D; andprovided that if Y is CR7R8, and R3, R4, R5, R6, R7, R8is H, then Z cannot be O.

[0108] One embodiment provides a compound having the structure of Formula (Ila), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);WSGR Docket No. 62619-756.601X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), C-(optionally substituted C3-C6 carbocyclyl), or C-SF5;Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,; and G is an optionally substituted 5- to 10-membered heterocyclyl;each R2is independently selected from H, or optionally substituted C1-C6 alkyl;R3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andR12is selected from H, D, fluoro, chloro, -CN, or -OHProvided that if Y is O, Z is CR9R10, and R3, R4, R5, R6, R9, R10is H, then R12is not H or D;provided that if Y is CR7R8, Z is CR9R10, andR3, R4, R5, R6, R7, R8, R9, R10is H, then R12is not H or D; andprovided that if Y is CR7R8, and R3, R4, R5, R6, R7, R8is H, then Z cannot be O.

[0109] One embodiment provides a compound having the structure of Formula (lib), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein:X1is N or C-CN;WSGR Docket No. 62619-756.601X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,or; and G is an optionally substituted 5- to 10-membered heterocyclyl;each R2is independently selected from H, or optionally substituted C1-C6 alkyl;R3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andR12is selected from H, D, fluoro, chloro, -CN, or -OHProvided that if Y is O, Z is CR9R10, and R3, R4, R5, R6, R9, R10is H, then R12is not H or D;provided that if Y is CR7R8, Z is CR9R10, andR3, R4, R5, R6, R7, R8, R9, R10is H, then R12is not H or D; andprovided that if Y is CR7R8, and R3, R4, R5, R6, R7, R8is H, then Z cannot be O.

[0110] One embodiment provides the compound of Formula (II), having the structure of Formula (lie), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:WSGR Docket No. 62619-756.601wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is CR7R8, and Z is CR9R10;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,O, and G is an optionally substituted 5- to 10-membered heterocyclyl;each R2is independently selected from H, or optionally substituted C1-C6 alkyl;R3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H;R12is selected from H, D, fluoro, chloro, -CN, or -OH; andprovided that if R3, R4, R5, R6, R7, R8, R9, R10is H, then R12is not H or D.

[0111] One embodiment provides the compound of Formula (II), having the structure of Formula (lid), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:WSGR Docket No. 62619-756.601wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,? x f; and G is an optionally substituted 5- to 10-membered heterocyclyl;each R2is independently selected from H, or optionally substituted C1-C6 alkyl;R3is optionally substituted C1-C6 alkylR4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;R11is H; andR12is selected from H, D, fluoro, chloro, -CN, or -OH.

[0112] One embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:WSGR Docket No. 62619-756.601wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), C-(optionally substituted C3-C6 carbocyclyl), or C-SF5;Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,* * ’ *%; and G is an optionally substituted 5- to 10-membered heterocyclyl;R2is H or optionally substituted C1-C6 alkyl;R3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andR12is selected from H, D, fluoro, chloro, bromo, optionally substituted C1-C6 alkyl, -CF3, amino, -COOH, -CONH2, -CN, or -OH;optionally wherein R11and R12are taken together with the carbon atoms to which they are attached to form an optionally substituted methylidene or an oxo group;provided that if Z is O, then the compound is notWSGR Docket No. 62619-756.601

[0113] One embodiment provides a compound having the structure of Formula (Illa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), C-(optionally substituted C3-C6 carbocyclyl), or C-SF5;Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,; and G is an optionally substituted 5- to 10-membered heterocyclyl;R2is H or optionally substituted C1-C6 alkyl;R3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;WSGR Docket No. 62619-756.601optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andR12is selected from H, D, fluoro, chloro, -CN, or -OHprovided that if Z is O, then the compound is not

[0114] One embodiment provides a compound having the structure of Formula (Illb), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;WSGR Docket No. 62619-756.601R1is L-G; wherein L is optionally substituted C1-C4 alkylene,or; and G is an optionally substituted 5- to 10-membered heterocyclyl;R2is H or optionally substituted C1-C6 alkyl;R3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andR12is selected from H, D, fluoro, chloro, -CN, or -OHprovided that if Z is O, then the compound is not

[0115] One embodiment provides a compound having the structure of Formula (IV), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:R2wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);WSGR Docket No. 62619-756.601X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), C-(optionally substituted C3-C6 carbocyclyl), or C-SF5;Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,; and G is an optionally substituted 5- to 10-membered heterocyclyl;R2is optionally substituted C2-C6 alkenyl; andR3, R4, R5, R6, R7, R8, R9, R10, R13, R14, R15, R16each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;optionally wherein R14and R15together form an optionally substituted carbocyclyl ring;optionally wherein the carbocyclyl ring is further substituted with an optionally substituted methylidene.

[0116] One embodiment provides a compound having the structure of Formula (IVa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:R2wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);WSGR Docket No. 62619-756.601X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), C-(optionally substituted C3-C6 carbocyclyl), or C-SF5;Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,; and G is an optionally substituted 5- to 10-membered heterocyclyl;R2is optionally substituted C2-C6 alkenyl; andR3, R4, R5, R6, R7, R8, R9, R10, R13, R14, R15, R16each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;optionally wherein R14and R15together form an optionally substituted carbocyclyl ring.

[0117] One embodiment provides a compound having the structure of Formula (IVb), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:R2wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);WSGR Docket No. 62619-756.601X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,; and G is an optionally substituted 5- to 10-membered heterocyclyl;R2is optionally substituted C2-C6 alkenyl; andR3, R4, R5, R6, R7, R8, R9, R10, R13, R14, R15, R16each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;optionally wherein R14and R15together form an optionally substituted carbocyclyl ring.

[0118] One embodiment provides the compound of Formula (IV), having the structure of Formula (IVc), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:R11is H; andR12is selected from H, D, fluoro, chloro, -CN, or -OH.

[0119] One embodiment provides the compound of Formula (IV), having the structure of Formula (IVd), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:WSGR Docket No. 62619-756.601wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,; and G is an optionally substituted 5- to 10-membered heterocyclyl;R2is optionally substituted C2-C6 alkenyl; andR3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andR12is selected from H, D, fluoro, chloro, -CN, or -OH.

[0120] One embodiment provides a compound having the structure of Formula (V), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:WSGR Docket No. 62619-756.601o6 Y xz Z R, 13...RV V-R14R5\R4^N PR15R3R16N, oX3R!x2Ar(V)wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), C-(optionally substituted C3-C6 carbocyclyl), or C-SF5;Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,ov; and G is an optionally substituted 5- to 10-membered heterocyclyl; andR3, R4, R5, R6, R7, R8, R9, R10, R13, R14, R15, R16each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;optionally wherein R14and R15together form an optionally substituted carbocyclyl ringoptionally wherein the carbocyclyl ring is further substituted with an optionally substituted methylidene.

[0121] One embodiment provides a compound having the structure of Formula (Va), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:WSGR Docket No. 62619-756.601-R14R15R1J-LV N X2Ar(Va)wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), C-(optionally substituted C3-C6 carbocyclyl), or C-SF5;Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,; and G is an optionally substituted 5- to 10-membered heterocyclyl; andR3, R4, R5, R6, R7, R8, R9, R10, R13, R14, R15, R16each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;optionally wherein R14and R15together form an optionally substituted carbocyclyl ring.

[0122] One embodiment provides the compound of Formula (V), having the structure of Formula (Vb), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:WSGR Docket No. 62619-756.601R11is H; andR12is selected from H, D, fluoro, chloro, -CN, or -OH.

[0123] In one aspect, provided herein is a compound of Formula (XI), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,oor; and G is an optionally substituted 5- to 10-membered heterocyclyl; and G is selected from:WSGR Docket No. 62619-756.601R2is optionally substituted C2-C6 alkynyl;R3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andR12is selected from H, D, fluoro, chloro, -CN, or -OH.

[0124] In one aspect, provided herein is a compound of Formula (X3), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;WSGR Docket No. 62619-756.601or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,Oor'; and G is an optionally substituted 5- to 10-membered heterocyclyl; and G is selected from:R2is H or optionally substituted C1-C6 alkyl;R3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andR12is selected from H, D, fluoro, chloro, -CN, or -OH.

[0125] One embodiment provides a compound of Formula (Yl), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);WSGR Docket No. 62619-756.601X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), C-(optionally substituted C3-C6 carbocyclyl), or C-SF5;Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Yi is O or CR7R8, Y2 is O or CR9R10, and Y3 is O or CR3aR3b, provided that no more than one of Yi, Y2, and Y3 is O;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,; and G is an optionally substituted 5- to 10-membered heterocyclyl; andR2is optionally substituted C2-C6 alkynyl;R3, R4, R5, R6, R7, R8, R9, R10, R3a, and R3beach is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andR12is selected from H, D, fluoro, chloro, bromo, optionally substituted C1-C6 alkyl, - CF3, amino, -COOH, -CONH2, -CN, or -OH;optionally wherein R11and R12are taken together with the carbon atoms to which they are attached to form an optionally substituted methylidene or an oxo group.

[0126] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, wherein, if Y is O, then R1is notand Ar is not FOH

[0127] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein, if Y is O, then R12is not H or D.WSGR Docket No. 62619-756.601

[0128] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt,Fsolvate, or deuteroisotope thereof, wherein, if Z is O, then Ar is not0H

[0129] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, wherein, if Z is O, then then R1is notF

[0130] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt,Fk|U solvate, or deuteroisotope thereof, wherein, if Z is O, then then Aris not2

[0131] One embodiment provides a compound of Formula (III), or a pharmaceutically acceptable salt,Fsolvate, or deuteroisotope thereof, wherein, if Z is O, then Ar is not0H

[0132] One embodiment provides a compound of Formula (III), or a pharmaceutically acceptable salt,solvate, or deuteroisotope thereof, wherein, if Z is O, R1is notF

[0133] One embodiment provides a compound of Formula (XI), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein,WSGR Docket No. 62619-756.601

[0134] Another embodiment provides a compound (e.g., as provided herein), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0135] Another embodiment provides a compound (e.g., as provided herein), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar isOH OH

[0137] Another embodiment provides a compound (e.g., as provided herein), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0138] Another embodiment provides a compound (e.g., as provided herein), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:WSGR Docket No. 62619-756.601

[0140] Another embodiment provides a compound (e.g., as provided herein), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar isNH2

[0141] Another embodiment provides a compound (e.g., as provided herein), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is

[0142] Another embodiment provides a compound (e.g., as provided herein), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is

[0143] Another embodiment provides a compound (e.g., as provided herein), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar isWSGR Docket No. 62619-756.601OH

[0144] Another embodiment provides a compound (e.g., as provided herein), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar isOH

[0145] Another embodiment provides a compound (e.g., as provided herein), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0146] Another embodiment provides a compound (e.g., as provided herein), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0147] Another embodiment provides a compound (e.g., as provided herein), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601

[0148] Another embodiment provides a compound (e.g., as provided herein), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0149] Another embodiment provides a compound (e.g., as provided herein), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0150] Another embodiment provides a compound (e.g., as provided herein), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0151] Another embodiment provides a compound (e.g., as provided herein), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0152] Another embodiment provides a compound (e.g., as provided herein), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0153] Another embodiment provides a compound (e.g., as provided herein), or a pharmaceutically acceptable salt or solvate thereof, wherein R1isWSGR Docket No. 62619-756.601

[0154] Another embodiment provides a compound (e.g., as provided herein), or a pharmaceutically acceptable salt or solvate thereof, wherein R1isy - zz- f / f /

[0155] Another embodiment provides a compound (e.g., as provided herein), or a pharmaceutically acceptable salt or solvate thereof, wherein R1isD DF

[0156] Another embodiment provides a compound (e.g., as provided herein), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0157] One embodiment provides a KRAS inhibitory compound, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having a structure presented in Table 1.Table 1Example No. Structure Name1 4-(2-(( 1 'H,3 'H,5 'H-dispiro [cyclopropane- 1,2'-pyrrolizine-6', 1 "-cyclopropan] -7a'(7'H)- yl)methoxy-d2)-5-ethynyl-8-fluoro-4- ((lS,7S,8S)-8-fluoro-5-oxa-2- _ D D azabicyclo[5.1,0]octan-2-yl)pyrido[4,3- d]pyrimidin-7 -yl) -5 -ethynyl-6- fluoronaphthalen-2 -amine2 5 -ethynyl-4-(5 -ethynyl-8-fluoro-2- o (((2R, 3 R, 7aS) -2-fluoro-3 -methyltetrahydro- 11lH-pyrrolizin-7a(5H)-yl)methoxy-d2)-4- ((lS,7S,8S)-8-fluoro-5-oxa-2- azabicyclo[5.1,0]octan-2-yl)pyrido[4,3- d]pyrimidin-7-yl)-6-fluoronaphthalen-2- amineft;WSGR Docket No. 62619-756.601Name _5-ethynyl-4-(5-ethynyl-8-fluoro-4- ((lS,7S,8S)-8-fluoro-5-oxa-2- azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2- fluorotetrahydro- 1 H-pyrrolizin-7 a(5H) - yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)- 6-fluoronaphthalen-2 -amine5 -ethynyl-4-(5 -ethynyl-8-fluoro-2- (((2R, 3 R, 7aS) -2-fluoro-3 -methyltetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy-d2)-4- ((lS,7S,8S)-8-fluoro-5-oxa-2- azabicyclo[5.1,0]octan-2-yl)pyrido[4,3- d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol5-ethynyl-4-(5-ethynyl-8-fluoro-4- ((lS,7S,8S)-8-fluoro-5-oxa-2- azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2- fluorotetrahydro- 1 H-pyrrolizin-7 a(5H) - yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)- 6-fluoronaphthalen-2-ol5-ethynyl-6-fluoro-4-(8-fluoro-2- (((2R, 3 R, 7aS) -2-fluoro-3 -methyltetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy-d2)-4- ((lS,7S,8S)-8-fluoro-5-oxa-2- azabicyclo [5.1,0]octan-2-yl)-5 -(prop- 1 -yn- 1 - yl)pyrido [4,3 -d]pyrimidin-7 -yl)naphthalen- 2-amine4-(2-(( 1 'H,3 'H,5 'H-dispiro [cyclopropane- 1,2'-pyrrolizine-6', 1 "-cyclopropan] -7a'(7'H)- yl)methoxy-d2)-5-ethynyl-8-fluoro-4- ((lS,7S,8S)-8-fluoro-5-oxa-2- azabicyclo[5.1,0]octan-2-yl)pyrido[4,3- d]pyrimidin-7 -yl) -5 -ethynyl-6- fluoronaphthalen-2-ol5-ethynyl-6-fluoro-4-(8-fluoro-4- ((lS,7S,8S)-8-fluoro-5-oxa-2- azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2- fluorotetrahydro- 1 H-pyrrolizin-7 a(5H) - yl)methoxy-d2) -5 -(prop- 1 -yn- 1 - yl)pyrido [4,3 -d]pyrimidin-7 -yl)naphthalen- 2-amineWSGR Docket No. 62619-756.601Name _5-ethynyl-6-fluoro-4-(8-fluoro-4- ((lS,7S,8S)-8-fluoro-5-oxa-2- azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2- fluorotetrahydro- 1 H-pyrrolizin-7 a(5H) - yl)methoxy-d2) -5 -(prop- 1 -yn- 1 - yl)pyrido [4,3 -d]pyrimidin-7 -yl)naphthalen- 2-ol4-(2-(( 1 'H,3 'H,5 'H-dispiro [cyclopropane- 1,2'-pyrrolizine-6', 1 "-cyclopropan] -7a'(7'H)- yl)methoxy-d2)-8-fluoro-4-((lS,7S,8S)-8- fluoro-5-oxa-2 -azabicyclo [5.1,0]octan-2-yl)- 5 -(prop- 1 -yn- 1 -yl)pyrido [4,3 -d]pyrimidin-7 - yl)-5-ethynyl-6-fluoronaphthalen-2 -amine5-ethynyl-6-fluoro-4-(8-fluoro-2- (((2R, 3 R, 7aS) -2-fluoro-3 -methyltetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy-d2)-4- ((lS,7S,8S)-8-fluoro-5-oxa-2- azabicyclo [5.1,0]octan-2-yl)-5 -(prop- 1 -yn- 1 - yl)pyrido [4,3 -d]pyrimidin-7 -yl)naphthalen- 2-ol4-(2-(( 1 'H, 3 'H, 5 'H-dispiro [cyclopropane- 1,2'-pyrrolizine-6', 1 "-cyclopropan] -7a'(7'H)- yl)methoxy-d2)-8-fluoro-4-((lS,7S,8S)-8- fluoro-5-oxa-2 -azabicyclo [5.1,0]octan-2-yl)- 5 -(prop- 1 -yn- 1 -yl)pyrido [4,3 -d]pyrimidin-7 - yl)-5-ethynyl-6-fluoronaphthalen-2-ol4-(2-(((R)-dihydro-5'H- dispi ro| cyclopropane- 1, 1 '-pyrrolizine-6', 1 "- cyclopropan]-7a'(7'H)-yl)methoxy-d2)-8- fluoro-4-(( 1 S,7S, 8 S)-8-fluoro-5 -oxa-2- azabicyclo [5.1,0]octan-2-yl)-5 -(prop- 1 -yn- 1 - yl)pyrido [4,3 -d]pyrimidin-7 -y 1) -5 -ethynyl-6- fluoronaphthalen-2 -amine4-(2-(((R)-dihydro-5'H- dispi ro| cyclopropane- 1, 1 '-pyrrolizine-6', 1"- cyclopropan]-7a'(7'H)-yl)methoxy-d2)-5- ethynyl-8-fluoro-4-((lS,7S,8S)-8-fluoro-5- oxa-2 -azabicyclo [5.1,0]octan-2- yl)pyrido [4,3 -d]pyrimidin-7 -y 1) -5 -ethynyl-6- fluoronaphthalen-2 -amineWSGR Docket No. 62619-756.601Name _4-(2-(((S)-dihydro-l'H,3'H- spiro [cyclopropane- 1,2'-pyrrolizin] -7a'(5 'H)- yl)methoxy-d2)-8-fluoro-4-((lS,7S,8S)-8- fluoro-5-oxa-2 -azabicyclo [5.1,0]octan-2-yl)- 5 -(prop- 1 -yn- 1 -yl)pyrido [4,3 -d]pyrimidin-7 - yl)-5-ethynyl-6-fluoronaphthalen-2 -amine 4-(2-(((R)-dihydro-5'H- dispi ro| cyclopropane- 1, 1 '-pyrrolizine-6', 1 "- cyclopropan]-7a'(7'H)-yl)methoxy-d2)-8- fluoro-4-(( 1 S,7S, 8 S)-8-fluoro-5 -oxa-2- azabicyclo [5.1,0]octan-2-yl)-5 -(prop- 1 -yn- 1 - yl)pyrido [4,3 -d]pyrimidin-7 -yl)-6-fluoro-5 - (fluoromethoxy-d2)naphthalen-2 -amine 4-(4-((lR,7S)-2-oxa-6- azabicyclo[5.1,0]octan-6-yl)-8-fluoro-2- (((2R, 3 R, 7aS) -2-fluoro-3 -methyltetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy-d2)-5- (prop- 1 -yn- 1 -yl)pyrido [4,3 -d]pyrimidin-7 - yl)-5-ethynyl-6-fluoronaphthalen-2 -amine 4-(2-(((S)-dihydro-l'H,3'H- spiro [cyclopropane- 1,2'-pyrrolizin] -7a'(5 'H)- yl)methoxy-d2)-5-ethynyl-8-fluoro-4- ((lS,7S,8S)-8-fluoro-5-oxa-2- azabicyclo[5.1,0]octan-2-yl)pyrido[4,3- d]pyrimidin-7 -yl) -5 -ethynyl-6- fluoronaphthalen-2 -amine4-(4-((lS,7R)-2-oxa-6- azabicyclo[5.1,0]octan-6-yl)-8-fluoro-2- (((2R, 3 R, 7aS) -2-fluoro-3 -methyltetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy-d2)-5- (prop- 1 -yn- 1 -yl)pyrido [4,3 -d]pyrimidin-7 - yl)-5-ethynyl-6-fluoronaphthalen-2 -amine 4-(4-((lR,7S)-5-oxa-2- azabicyclo[5.1,0]octan-2-yl)-8-fluoro-2- (((2R, 3 R, 7aS) -2-fluoro-3 -methyltetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy-d2)-5- (prop- 1 -yn- 1 -yl)pyrido [4,3 -d]pyrimidin-7 - yl)-5-ethynyl-6-fluoronaphthalen-2 -amineWSGR Docket No. 62619-756.601Name _4-(2-(((2R,3R,7aS)-3-ethyl-2- fluorotetrahydro- 1 H-pyrrolizin-7 a(5H)- yl)methoxy-d2)-8-fluoro-4-((lS,7S,8S)-8- fluoro-5-oxa-2 -azabicyclo [5.1,0]octan-2-yl)- 5 -(prop- 1 -yn- 1 -yl)pyrido [4,3 -d]pyrimidin-7 - yl)-5-ethynyl-6-fluoronaphthalen-2 -amine5-ethynyl-6-fluoro-4-(8-fluoro-4- ((lS,7S,8S)-8-fluoro-5-oxa-2- azabicyclo[5.1,0]octan-2-yl)-2- (((2" R,6'S,7a'R)-2"-fluorodihydro-5'H- dispiro[cyclopropane- 1, 1 '-pyrrolizine-6', 1 "- cyclopropan]-7a'(7'H)-yl-3',3'-d2)methoxy- d2)-5 -(prop- 1 -yn- 1 -yl)pyrido [4,3 - d]pyrimidin-7-yl)naphthalen-2 -amine 5-ethynyl-6-fluoro-4-(8-fluoro-4- ((lS,7S,8S)-8-fluoro-5-oxa-2- azabicyclo[5.1,0]octan-2-yl)-2- (((2" S,6'R,7a'R)-2"-fluorodihydro-5'H- dispi ro| cyclopropane- 1, 1 '-pyrrolizine-61, 1 "- cyclopropan]-7a'(7'H)-yl)methoxy-d2)-5- (prop- 1 -yn- 1 -yl)pyrido [4,3 -d]pyrimidin-7 - yl)naphthalen-2 -amine5-ethynyl-6-fluoro-4-(8-fluoro-4- ((lS,7S,8S)-8-fluoro-5-oxa-2- azabicyclo[5.1,0]octan-2-yl)-2- (((2" R,6'R,7a'R)-2"-fluorodihydro-5'H- dispi ro| cyclopropane- 1, 1 '-pyrrolizine-6', 1 "- cyclopropan]-7a'(7'H)-yl-3',3'-d2)methoxy- d2)-5 -(prop- 1 -yn- 1 -yl)pyrido [4,3 - d]pyrimidin-7-yl)naphthalen-2 -amine 4-(2-(((R)-dihydro-5'H- dispi ro| cyclopropane- 1, 1 '-pyrrolizine-6', 1"- cyclopropan]-7a'(7'H)-yl-3',3'-d2)methoxy)- 8-fluoro-4-((lS,7R,8S)-8-fluoro-2- azabicyclo [5.1,0]octan-2-yl)-5 -(prop- 1 -yn- 1 - yl)pyrido [4,3 -d]pyrimidin-7 -y 1) -5 -ethynyl-6- fluoronaphthalen-2 -amine4-(4-((lS,7S,8S)-8-chloro-5-oxa-2- azabicyclo[5.1,0]octan-2-yl)-2-(((R)- dihydro-5 'H-dispiro [cyclopropane- 1, 1'- pyrrolizine-6',l"-cyclopropan]-7a'(7'H)-yl- 3',3'-d2)methoxy-d2)-8-fluoro-5-(prop-l-yn- 1 -yl)pyndo [4,3 -d]pyrimidin-7 -y 1) -5 -ethynyl- 6-fluoronaphthalen-2 -amineWSGR Docket No. 62619-756.601Name _4-(2-(((R)-dihydro-5'H- dispiro[cyclopropane- 1, 1 '-pyrrolizine-61, 1"- cyclopropan]-7a'(7'H)-yl-3',3'-d2)methoxy)- 8-fluoro-4-((lS,7R,8S)-8-fluoro-2- azabicyclo [5.1,0]octan-2-yl)-5 -(prop- 1 -yn- 1 - yl)pyrido [4,3 -d]pyrimidin-7 -yl)-6-fluoro-5 - (fluoromethoxy-d2)naphthalen-2 -amine 4-(4-((lS,7S,8S)-8-chloro-5-oxa-2- azabicyclo[5.1,0]octan-2-yl)-2-(((R)- dihydro-5 'H-dispiro [cyclopropane- 1, 1'- pyrrolizine-6',l"-cyclopropan]-7a'(7'H)-yl- 3',3'-d2)methoxy-d2)-8-fluoro-5-(prop-l-yn- 1 -yl)pyndo [4,3 -d]pyrimidin-7 -yl)-6-fluoro- 5-(fluoromethoxy-d2)naphthalen-2 -amine 4-(4-((lS,7S,8S)-8-chloro-5-oxa-2- azabicyclo[5.1,0]octan-2-yl)-8-fluoro-2- (((2" S,6'S,7a'R)-2"-fluorodihydro-5'H- dispi ro| cyclopropane- 1, 1 '-pyrrolizine-61, 1 "- cyclopropan]-7a'(7'H)-yl-3',3'-d2)methoxy- d2)-5 -(prop- 1 -yn- 1 -yl)pyrido [4,3 - d]pyrimidin-7 -yl)-6-fluoro-5 - (fluoromethoxy-d2)naphthalen-2 -amine 5-ethynyl-6-fluoro-4-(8-fluoro-4- ((lS,7S,8S)-8-fluoro-5-oxa-2- azabicyclo[5.1,0]octan-2-yl)-2- (((2" S,6'S,7a'R)-2"-fluorodihydro-5'H- dispi ro| cyclopropane- 1, 1 '-pyrrolizine-61, 1 "- cyclopropan]-7a'(7'H)-yl-3',3'-d2)methoxy- d2)-5 -(prop- 1 -yn- 1 -yl)pyrido [4,3- d]pyrimidin-7-yl)naphthalen-2 -amine _ 5-ethynyl-6-fluoro-4-(8-fluoro-4- ((lS,7R,8S)-8-fluoro-2- azabicyclo[5.1,0]octan-2-yl)-2- (((2" S,6'S,7a'R)-2"-fluorodihydro-5'H- dispi ro| cyclopropane- 1, 1 '-pyrrolizine-6', 1 "- cyclopropan]-7a'(7'H)-yl-3',3'-d2)methoxy- d2)-5 -(prop- 1 -yn- 1 -yl)pyrido [4,3- d]pyrimidin-7-yl)naphthalen-2 -amine _ 4-(4-((lS,7S,8S)-8-chloro-5-oxa-2- azabicyclo[5.1,0]octan-2-yl)-8-fluoro-2- (((2" S,6'S,7a'R)-2"-fluorodihydro-5'H- dispi ro| cyclopropane- 1, 1 '-pyrrolizine-6', 1 "- cyclopropan]-7a'(7'H)-yl-3',3'-d2)methoxy- d2)-5 -(prop- 1 -yn- 1 -yl)pyrido [4,3 - d]pyrimidin-7 -yl) -5 -ethynyl-6-fluoronaphthalen-2 -amine _WSGR Docket No. 62619-756.601Example No. Structure Name33 6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro- > X 5 -oxa-2 -azabicyclo [5.1,0]octan-2-yl)-2- (((2" S,6'S,7a'R)-2"-fluorodihydro-5'H- dispiro[cyclopropane- 1, 1 '-pyrrolizine-6', 1 "- J1X- t cyclopropan]-7a'(7'H)-yl-3',3'-d2)methoxy- d2)-5 -(prop- 1 -yn- 1 -yl)pyrido [4,3 - d]pyrimidin-7 -yl) -5 -(fluoromethoxy-z / * r ■ x NxH2d2)naphthalen-2 -amine 34 o c> 6-fluoro-4-(8-fluoro-4-((lS,7R,8S)-8-fluoro- N*^ 2-azabicyclo[5.1,0]octan-2-yl)-2- (((2" S,6'S,7a'R)-2"-fluorodihydro-5'H- dispiro[cyclopropane- 1, 1 '-pyrrolizine-6', 1 "- _57D„N<1D N^X A H 7 cyclopropan]-7a'(7'H)-yl-3',3'-d2)methoxy- / < / = / / _ d2)-5 -(prop- 1 -yn- 1 -yl)pyrido [4,3 - X FVQ / =yD„z-- d]pyrimidin-7 -yl) -5 -(fluoromethoxy- P>F^uw t T1 y N— d2)naphthalen-2 -amine 35 5-ethynyl-6-fluoro-4-(4-((lS,7S,8S)-8- fluoro-5 -oxa-2 -azabicyclo [5.1,0]octan-2-yl)- 2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy- d2)pyrido [3,2-d]pyrimidin-7 -yl)naphthalen- 2-amine36 / J. 5-ethynyl-6-fluoro-4-(4-((lS,7S,8S)-8- fluoro-5 -oxa-2 -azabicyclo [5.1,0]octan-2-yl)- 2-(((2R,7aS)-2-fluorotetrahydro-lH- O Q pyrrolizin-7a(5H)-yl)methoxy-d2)-8- methylpyrido [3,2-d]pyrimidin-7 - yl)naphthalen-2 -amineLz*J37 5-ethynyl-6-fluoro-4-(6-fluoro-4- ((lS,7S,8S)-8-fluoro-5-oxa-2- azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2- fluorotetrahydro- 1 H-pyrrolizin-7 a(5H) - yl)methoxy-d2)-8-methylpyrido[3,2- d]pyrimidin-7-yl)naphthalen-2 -amine 50 6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro- c < 5 -oxa-2 -azabicyclo [5.1,0]octan-2-yl)-2- (((2" S,6'S,7a'R)-2"-fluorodihydro-5'H- 1 F dispi ro| cyclopropane- 1, 1 '-pyrrolizine-6', 1 "- > N cyclopropan]-7a'(7'H)-yl)methoxy)-5-(prop- HX X" 1 -yn- 1 -yl)pyrido [4,3 -d]pyrimidin-7 -yl) -5 - SA °NAJOF (fluoromethoxy )naphthalen-2 -amine IQJl^sFNHj51 (lS,7S,8S)-8-fluoro-2-(8-fluoro-7-(7-fluoro- 8 -(fluoromethoxy )naphthalen- 1 -yl)-2- c > < (((2" S,6'S,7a'R)-2"-fluorodihydro-5'H- 1 1 X F dispi ro| cyclopropane- 1, 1 '-pyrrolizine-6', 1 "- cyclopropan]-7a'(7'H)-yl)methoxy)-5-(prop- / — 4^ 1 -yn- 1 -yl)pyrido [4,3 -d]pyrimidin-4-yl)-5 - V\'x°ArX oxa-2 -azabicyclo [5.1.0]octaneIx'Sp ^XXWSGR Docket No. 62619-756.601Name _6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro- 5 -oxa-2 -azabicyclo [5.1,0]octan-2-yl)-2- (((S, E)-2-(fluoromethylene)tetrahydro-lH- pyrrolizin-7a(5H)-yl-5,5 -d2)methoxy-d2)-5 - (prop- 1 -yn- 1 -yl)pyrido [4,3 -d]pyrimidin-7 - yl)-5-(fluoromethoxy-d2)naphthalen-2 -amine6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro- 5 -oxa-2 -azabicyclo [5.1,0]octan-2-yl)-2- (((S, Z)-2-(fluoromethylene)tetrahydro-lH- pyrrolizin-7a(5H)-yl-5,5 -d2)methoxy-d2)-5 - (prop- 1 -yn- 1 -yl)pyrido [4,3 -d]pyrimidin-7 - yl)-5-(fluoromethoxy-d2)naphthalen-2 -amine(lS,3S,7S,8S)-8-fluoro-2-(8-fluoro-7-(7- fluoro-8-(fluoromethoxy)naphthalen- 1 -yl)-2- (((2" S,6'S,7a'R)-2"-fluorodihydro-5'H- dispi ro| cyclopropane- 1, 1 '-pyrrolizine-6', 1 "- cyclopropan]-7a'(7'H)-yl)methoxy)-5-(prop- 1 -yn- 1 -yl)pyrido [4,3 -d]pyrimidin-4-yl)-3 - methyl-5-oxa-2-azabicyclo[5.1.0]octane 6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro- 5 -oxa-2 -azabicyclo [5.1,0]octan-2-yl)-2- ((( 1 S,7aR)- 1 -methyl-6-methylenetetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)-5-(prop- 1 -yn- 1 -yl)pyrido [4,3 -d]pyrimidin-7 -yl) -5 - (fluoromethoxy )naphthalen-2 -amine5-ethynyl-6-fluoro-4-(8-fluoro-4- ((lS,7S,8S)-8-fluoro-5-oxa-2- azabicyclo[5.1.0]octan-2-yl)-2-(((lS,7aR)-l- methyl-6-methylenetetrahydro- 1H- pyrrolizin-7a(5H)-yl)methoxy)-5-(prop-l-yn- 1 -yl)pyndo [4,3 -d]pyrimidin-7 - yl)naphthalen-2 -amine(15.75.85)-8-fluoro-2-(8-fluoro-7-(7-fluoro- 8 -(fluoromethoxy )naphthalen- 1 -yl)-2-(((S)- 2-methylenetetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-(prop- 1 -yn- 1 - yl)pyrido [4,3 -d]pyrimidin-4-yl)-5 -oxa-2 - azabicyclo[5.1.0] octane(15.75.85)-2-(7-(8-ethynyl-7- fluoronaphthalen-l-yl)-8-fluoro-2-(((S)-2- methylenetetrahydro- 1 H-pyrrolizin-7 a(5H) - yl)methoxy) -5 -(prop- 1 -yn- 1 -yl)pyrido [4,3- d]pyrimidin-4-yl)-8-fluoro-5-oxa-2- azabicyclo[5.1.0] octaneWSGR Docket No. 62619-756.601Name _5-ethynyl-6-fluoro-4-(8-fluoro-4- ((lS,7S,8S)-8-fluoro-5-oxa-2- azabicyclo[5.1,0]octan-2-yl)-2-(((S)-2- methylenetetrahydro- 1 H-pyrrolizin-7 a(5H) - yl)methoxy) -5 -(prop- 1 -yn- 1 -yl)pyrido [4,3- d]pyrimidin-7-yl)naphthalen-2 -amine 6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro- 5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S)- 2-methylenetetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-(prop- 1 -yn- 1 - yl)pyrido [4,3 -d] pyrimidin-7 -yl) -5 - (fluoromethoxy )naphthalen-2 -amine (lS,7S,8S)-2-(7-(8-ethynyl-7- fluoronaphthalen- 1 -yl)-8-fluoro-2- (((2" S,6'S,7a'R)-2"-fluorodihydro-5'H- dispi ro| cyclopropane- 1, 1 '-pyrrolizine-6', 1 "- cyclopropan]-7a'(7'H)-yl)methoxy)-5-(prop- 1 -yn- 1 -yl)pyrido[4,3-d]pyrimidin-4-yl)-8- fluoro-5-oxa-2 -azabicyclo [5.1.0]octane (lS,7S,8S)-2-(7-(8-ethynyl-7- fluoronaphthalen- 1 -yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy-d2)-5 -(prop- 1 -yn- 1 - yl)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5- oxa-2 -azabicyclo [5.1.0]octane (lS,7S,8S)-8-fluoro-2-(8-fluoro-7-(7-fluoro- 8 -(fluoromethoxy )naphthalen- 1 -yl)-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy-d2)-5 -(prop- 1 -yn- 1 - yl)pyrido [4,3 -d]pyrimidin-4-yl)-5 -oxa-2- azabicyclo[5.1.0] octane(15.75.85)-2-(5 -ethynyl-7 -(8 -ethynyl-7 - fluoronaphthalen- 1 -yl)-8-fluoro-2- (((2" S,6'S,7a'R)-2"-fluorodihydro-5'H- dispi ro| cyclopropane- 1, 1 '-pyrrolizine-61, 1 "- cyclopropan]-7a'(7'H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8- fluoro-5-oxa-2 -azabicyclo [5, 1,0]octane _ (15.75.85)-2-(2-(((R)-dihydro-5'H- dispi ro| cyclopropane- 1, 1 '-pyrrolizine-6', 1 "- cyclopropan] -7a'(7'H) -yl)methoxy)-7 -( 8 - ethynyl-7 -fluoronaphthalen- 1 -yl)-8-fluoro-5 - (prop- 1 -yn- 1 -yl)pyrido [4,3 -d]pyrimidin-4- yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octaneWSGR Docket No. 62619-756.601Example No. Structure Name68 (lS,7S,8S)-2-(2-(((R)-dihydro-5'H- dispiro[cyclopropane- 1, 1 '-pyrrolizine-61, 1 "- cyclopropan]-7a'(7'H)-yl)methoxy)-8-fluoro- 7 -(7 -fluoro-8-(fluoromethoxy)naphthalen- 1 - yl)-5 -(prop- 1 -yn- 1 -yl)pyrido [4,3 - d]pyrimidin-4-yl)-8-fluoro-5-oxa-2- azabicyclo[5.1.0] octane69 (lS,7S,8S)-2-(5-ethynyl-8-fluoro-7-(7- a fluoro-8-(fluoromethoxy)naphthalen- 1 -yl)-2- (((2" S,6'S,7a'R)-2"-fluorodihydro-5'H- dispiro[cyclopropane- 1, 1 '-pyrrolizine-6', 1 "- cyclopropan]-7a'(7'H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8- fluoro-5 -oxa-2 -azabicyclo [5.1.0] octane 70 (lS,7S,8S)-2-(7-(8-ethynyl-7- fluoronaphthalen- 1 -yl)-8-fluoro-2- ((( 1 S,7aR)- 1 -methyl-6-methylenetetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)-5-(prop- 1 -yn- 1 -yl)pyrido[4,3-d]pyrimidin-4-yl)-8- fluoro-5 -oxa-2 -azabicyclo [5.1.0]octane 71 c. (lS,7S,8S)-8-fluoro-2-(8-fluoro-7-(7-fluoro- > 8 -(fluoromethoxy )naphthalen- 1 -yl)-2- ((( 1 S,7aR)- 1 -methyl-6-methylenetetrahydro- V.. v n — M - lH-pyrrolizin-7a(5H)-yl)methoxy)-5-(prop- 1 -yn- 1 -yl)pyrido [4,3 -d]pyrimidin-4-yl)-5 - A1,A AjOXX oxa-2 -azabicyclo [5.1.0]octane72 6-fluoro-4-(8-fluoro-4-((lS,3S,7S,8S)-8- N fluoro-3 -methyl-5 -oxa-2- azabicyclo[5.1,0]octan-2-yl)-2- (((2" S,6'S,7a'R)-2"-fluorodihydro-5'H- GV X dispiro[cyclopropane- 1, 1 '-pyrrolizine-6', 1 "- r iQr cyclopropan]-7a'(7'H)-yl)methoxy)-5-(prop- NH21 -yn- 1 -yl)pyrido [4,3 -d]pyrimidin-7 -yl) -5 -(fluoromethoxy )naphthalen-2 -amine

[0158] Another embodiment provides a KRAS inhibitory compound, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having a structure presented in Table 2.WSGR Docket No. 62619-756.601WSGR Docket No. 62619-756.601WSGR Docket No. 62619-756.601WSGR Docket No. 62619-756.601WSGR Docket No. 62619-756.601c c K;KD D / ND DOp > 9^NH2NH2o c ^'„Fv AOH OH^F C o HDOpvOH OHc c K; / ND D f|1^W0V 9^ ^ ■- OH OH^'F \e'F'H ”^HW O NH2NH2WSGR Docket No. 62619-756.601WSGR Docket No. 62619-756.601WSGR Docket No. 62619-756.601WSGR Docket No. 62619-756.601WSGR Docket No. 62619-756.601WSGR Docket No. 62619-756.601WSGR Docket No. 62619-756.601

[0159] Another embodiment provides a KRAS inhibitory compound, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having a structure presented in Figures 1-19.Preparation of Compounds

[0160] The compounds used in the synthetic chemistry reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and / or from compounds described in the chemical literature. " Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U. K.), BDH Inc. (Toronto,WSGR Docket No. 62619-756.601Canada), 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).

[0161] Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, " Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., " Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, " Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, " Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, " Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. " Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 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.WSGR Docket No. 62619-756.601

[0162] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (contact the American Chemical Society, Washington, D. C. for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference useful for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth " Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.Pharmaceutical Compositions

[0163] In certain embodiments, the KRAS inhibitory compound described herein is administered as a pure chemical. In other embodiments, the KRAS 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)).

[0164] Provided herein is a pharmaceutical composition comprising at least one KRAS inhibitory compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or the patient) of the composition.

[0165] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), or (Yl), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof.

[0166] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), or (Yl), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable carrier.

[0167] In certain embodiments, the KRAS inhibitory compound as described by Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), or (Yl), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, isWSGR Docket No. 62619-756.601substantially 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.

[0168] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof.

[0169] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable carrier.

[0170] In certain embodiments, the KRAS inhibitory compound as described by Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0171] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. See, e.g, Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0172] In some embodiments, the KRAS inhibitory compound as described by Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), (Yl), or Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, is formulated for administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a nonaqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like.

[0173] The dose of the composition comprising at least one KRAS inhibitory compound as described herein differs depending upon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors.

[0174] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency ofWSGR Docket No. 62619-756.601administration 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.

[0175] Oral doses typically range from about 0.01 mg to about 1000 mg, one to four times, or more, per day.Methods of Treatment

[0176] One embodiment provides a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), or (Yl), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treatment of the human or animal body.

[0177] One embodiment provides a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), or (Yl), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treating cancer.

[0178] One embodiment provides a use of a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), or (Yl), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, in the manufacture of a medicament for the treatment of cancer.

[0179] In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), or (Yl), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), or (Yl), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient.

[0180] One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treatment of the human or animal body.WSGR Docket No. 62619-756.601

[0181] One embodiment provides a compound of Table 1, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treating cancer.

[0182] One embodiment provides a use of a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, in the manufacture of a medicament for the treatment of cancer.

[0183] In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a compound Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient.

[0184] Provided herein is the method wherein the pharmaceutical composition is administered orally.Provided herein is the method wherein the pharmaceutical composition is administered by injection.

[0185] One embodiment provides a method of inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), or (Yl), or Table 1. Another embodiment provides the method of inhibiting KRAS protein activity, wherein the KRAS protein is contacted in an in vivo setting. Another embodiment provides the method of inhibiting KRAS protein activity, wherein the KRAS protein is contacted in an in vitro setting.

[0186] One embodiment provides a method of treating cancer in a patient in need thereof, the method comprising administering to the patient a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), (Yl), or Table 1, or pharmaceutically acceptable salt or solvate thereof.

[0187] One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (III), (Illa), (Illb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (XI), (X3), (Yl), or Table 1, or pharmaceutically acceptable salt or solvate thereof.

[0188] One embodiment provides the method wherein the cancer is breast cancer. Another embodiment provides the method wherein the breast cancer is a hormone receptor positive (HR+) breast cancer. Another embodiment provides the method wherein the breast cancer is a HER2+ breast cancer. Another embodiment provides the method wherein the breast cancer is a triple negative breast cancer (TNBC). Another embodiment provides the method wherein the breast cancer is ductal carcinoma, lobular carcinoma, or inflammatory breast cancer.WSGR Docket No. 62619-756.601

[0189] One embodiment provides the method wherein the cancer is uterine cancer. Another embodiment provides the method wherein the cancer is uterine sarcoma.

[0190] One embodiment provides the method wherein the cancer is endometrial cancer. Another embodiment provides the method wherein the endometrial cancer is selected from endometrioid adenocarcinoma, serous adenocarcinoma (uterine papillary serous carcinoma), uterine carcinosarcoma, uterus sarcoma, endometrial undifferentiated carcinoma, endometrial squamous cell carcinoma, endometrial small cell carcinoma, endometrial transitional carcinoma, endometrial mucinous adenocarcinoma, or endometrial clear cell adenocarcinoma.

[0191] One embodiment provides the method wherein the cancer is cervical cancer. Another embodiment provides the method wherein the cervical cancer is a cervical squamous cell carcinoma, cervical adenocarcinoma, cervical adenosquamous carcinoma, cervical clear cell carcinoma, or cervical small cell carcinoma.

[0192] One embodiment provides the method wherein the cancer is fallopian tube cancer (FTC).Another embodiment provides the method wherein the fallopian tube cancer (FTC) cancer is FTC papillary serous adenocarcinoma, FTC endometrioid carcinoma, FTC clear cell carcinoma, FTC mucinous carcinoma, FTC transitional cell carcinoma, FTC sarcoma, or primary fallopian tube cancer.

[0193] One embodiment provides the method wherein the cancer is prostate cancer. Another embodiment provides the method wherein the cancer is prostate adenocarcinoma. Another embodiment provides the method wherein the cancer is prostate transitional cell carcinoma. Another embodiment provides the method wherein the cancer is prostate squamous cell carcinoma. Another embodiment provides the method wherein the cancer is prostate small cell carcinoma. Another embodiment provides the method wherein the cancer is prostate lymphoma. Another embodiment provides the method wherein the cancer is prostate sarcoma.

[0194] One embodiment provides the method wherein the cancer is bladder cancer. Another embodiment provides the method wherein the bladder cancer is urothelial carcinoma (transitional cell carcinoma), bladder squamous cell carcinoma, urachal adenocarcinoma, non- urachal adenocarcinoma, bladder small cell carcinoma, or bladder sarcoma. Another embodiment provides the method wherein the cancer is urothelial cancer. Another embodiment provides the method wherein the cancer is squamous cell cancer of the bladder. Another embodiment provides the method wherein the cancer is small cell cancer of the bladder. Another embodiment provides the method wherein the cancer is adenocarcinoma of the bladder.

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

[0196] One embodiment provides the method wherein the cancer is non-small cell lung cancer. Another embodiment provides the method wherein the cancer is non-small cell lung cancer, squamousWSGR Docket No. 62619-756.601cell cancer. Another embodiment provides the method wherein the cancer is non-small cell lung cancer, adenocarcinoma. Another embodiment provides the method wherein the cancer is non- small cell lung cancer, large cell carcinoma. Another embodiment provides the method wherein the cancer is non-small cell lung cancer, adenosquamous carcinoma. Another embodiment provides the method wherein the cancer is non-small cell lung cancer, adenosquamous carcinoma. Another embodiment provides the method wherein the cancer is small cell lung cancer. Another embodiment provides the method wherein the cancer is combined small cell lung cancer.

[0197] One embodiment provides the method wherein the cancer is colon cancer (CRC). Another embodiment provides the method wherein the cancer is CRC, adenocarcinoma. Another embodiment provides the method wherein the cancer is CRC, squamous cell carcinoma. Another embodiment provides the method wherein the cancer is CRC, colon cancer. Another embodiment provides the method wherein the cancer is CRC, carcinoid. Another embodiment provides the method wherein the cancer is CRC, gastrointestinal stromal. Another embodiment provides the method wherein the cancer is CRC lymphoma.

[0198] One embodiment provides the method wherein the cancer is anal cancer. Another embodiment provides the method wherein the anal cancer is selected from squamous cell carcinoma anal cancer, or adenocarcinoma anal cancer.

[0199] One embodiment provides the method wherein the cancer is biliary cancer. Another embodiment provides the method wherein the biliary cancer is cholangiocarcinoma, extra-hepatic cholangiocarcinoma, perihilar bile duct cancer (Klatskin tumor), distal bile duct cancer, or intra- hepatic cholangiocarcinoma.

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

[0201] One embodiment provides the method wherein the cancer is a glioma.

[0202] One embodiment provides the method wherein the cancer is pancreatic cancer. Another embodiment provides the method wherein the cancer is pancreatic ductal adenocarcinoma (PDAC). Another embodiment provides the method wherein the cancer is PDAC, adenocarcinoma. Another embodiment provides the method wherein the cancer is PDAC, acinar cell carcinoma. Another embodiment provides the method wherein the cancer is exocrine pancreatic cancer. Another embodiment provides the method wherein the cancer is neuroendocrine pancreatic cancer. Another embodiment provides the method wherein the cancer is pancreatic cancer, squamous cell carcinoma. Another embodiment provides the method wherein the cancer is pancreatic cancer, adenosquamous carcinoma. Another embodiment provides the method wherein the cancer is pancreatoblastoma.WSGR Docket No. 62619-756.601

[0203] One embodiment provides the method wherein the cancer is thyroid cancer. Another embodiment provides the method wherein the thyroid cancer is selected from papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, or anaplastic thyroid cancer.

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

[0205] One embodiment provides the method wherein the cancer is esophageal cancer, esophageal adenocarcinoma, or esophageal squamous cell carcinoma.

[0206] One embodiment provides the method wherein the cancer is stomach cancer or gastric cancer.Another embodiment provides the method wherein the stomach cancer or gastric cancer is selected from gastric adenocarcinoma, intestinal type gastric adenocarcinoma, diffuse type gastric adenocarcinoma, adenocarcinoma of the stomach, gastroesophageal junction adenocarcinoma (GEJ), gastrointestinal neuroendocrine tumor (GNET), gastrointestinal stromal tumor (GIST), gastric adenosquamous carcinoma, gastric carcinoid tumor, or primary gastric lymphoma.

[0207] One embodiment provides the method wherein the cancer is small bowel adenocarcinoma, small bowel sarcoma, small bowel lymphoma, small bowel neuroendocrine tumor, or small bowel carcinoid tumor.

[0208] One embodiment provides the method wherein the cancer is skin cancer. Another embodiment provides the method wherein the skin cancer is basal cell carcinoma, or squamous cell carcinoma. Another embodiment provides the method wherein the cancer is non-melanoma skin cancer, squamous non-melanoma skin cancer, or non-squamous non-melanoma skin cancer.

[0209] One embodiment provides the method wherein the cancer is melanoma. Another embodiment provides the method wherein the melanoma is superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral lentiginous melanoma, or desmoplastic melanoma.

[0210] One embodiment provides the method wherein the cancer is ovarian cancer. Another embodiment provides the method wherein the ovarian cancer is epithelial ovarian cancer, ovarian fibrosarcoma, ovarian mucinous carcinoma, neuroendocrine cancer of ovary.

[0211] One embodiment provides the method wherein the cancer is renal cell cancer.

[0212] One embodiment provides the method wherein the cancer is an appendiceal cancer. Another embodiment provides the method wherein the cancer is appendiceal carcinoid tumor. Another embodiment provides the method wherein the cancer is appendiceal mucinous neoplasm.Another embodiment provides the method wherein the cancer is appendix adenocarcinoma. Another embodiment provides the method wherein the cancer is appendiceal adenocarcinoid or goblet cell appendiceal carcinoma. Another embodiment provides the method wherein the cancer is signet ring cell appendiceal carcinoma, colonic-type appendiceal adenocarcinoma,WSGR Docket No. 62619-756.601appendiceal paraganglioma, epithelial appendiceal cancer, or neuroendocrine appendiceal cancer.

[0213] One embodiment provides the method wherein the cancer is a peritoneal cancer or primary peritoneal carcinoma.

[0214] One embodiment provides the method wherein the cancer is a bone cancer, osteosarcoma, chondrosarcoma, or chordoma.

[0215] One embodiment provides the method wherein the cancer is a sarcoma.

[0216] One embodiment provides the method wherein the cancer is a primary brain tumor. Another embodiment provides the method wherein the brain cancer is glioblastoma, astrocytoma, anaplastic astrocytoma, oligodendroglioma, ependymoma, meningioma, pituitary adenoma.

[0217] One embodiment provides the method wherein the cancer is gallbladder cancer. Another embodiment provides the method wherein the gallbladder cancer is gallbladder adenocarcinoma, nonpapillary adenocarcinoma, papillary adenocarcinoma, mucinous adenocarcinoma, gallbladder squamous cell carcinoma, gallbladder adenosquamous carcinoma, or gallbladder carcinosarcoma.

[0218] One embodiment provides the method wherein the cancer is soft tissue sarcoma, or undifferentiated pleomorphic sarcoma.

[0219] One embodiment provides the method wherein the cancer is germ cell tumor. Another embodiment provides the method wherein the germ cell tumor is testicular germ cell cancer, ovarian germ cell tumor, brain germ cell tumor, or endodermal sinus tumor.

[0220] One embodiment provides the method wherein the cancer is plasma cell neoplasm. Another embodiment provides the method wherein the plasma cell neoplasm is selected from isolated plasmacytoma of bone, extramedullary plasmacytoma, multiple myeloma, or monoclonal gammopathy of undetermined significance (MGUS).

[0221] One embodiment provides the method wherein the cancer is myelodysplastic / myeloproliferative neoplasms (MDS / MPN).

[0222] One embodiment provides the method wherein the cancer is myelodysplastic neoplasm, myeloproliferative neoplasm, chronic myelomonocytic leukemia, atypical chronic myeloid leukemia, or juvenile myelomonocytic leukemia.

[0223] One embodiment provides the method wherein the cancer is acute leukemia, acute lymphocytic leukemia, or acute myelogenous leukemia.

[0224] One embodiment provides the method wherein the cancer is neuroendocrine carcinoma

[0225] One embodiment provides the method wherein the cancer is cancer of unknown primary (CUP).

[0226] One embodiment provides the method wherein the cancer is locally advanced.

[0227] One embodiment provides the method wherein the cancer is metastatic.WSGR Docket No. 62619-756.601

[0228] One embodiment provides the method wherein the method is adjuvant therapy following surgical resection.

[0229] One embodiment provides the method wherein the method is neo-adjuvant therapy.

[0230] One embodiment provides the method wherein the method is first-line systemic therapy for locally advanced or metastatic disease.

[0231] One embodiment provides the method wherein the patient has relapsed after prior therapy.

[0232] One embodiment provides the method wherein the patient has acquired resistance to prior therapy.

[0233] One embodiment provides the method wherein the patient is refractory to therapy.

[0234] Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way.NUMBERED EMBODIMENTS

[0235] Embodiment 1 provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), C-(optionally substituted C3-C6 carbocyclyl), or C-SF5;Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;WSGR Docket No. 62619-756.601R1is L-G; wherein L is optionally substituted C1-C4 alkylene,or; and G is an optionally substituted 5- to 10-membered heterocyclyl; andR2is optionally substituted C2-C6 alkynyl;R3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andR12is selected from H, D, fluoro, chloro, bromo, optionally substituted C1-C6 alkyl, - CF3, amino, -COOH, -CONH2, -CN, or -OH;optionally wherein R11and R12are taken together with the carbon atoms to which they are attached to form an optionally substituted methylidene or an oxo group;provided that if Y is O and R3, R4, R5, R6, R9, and R10is H, then R12is not H or D; and provided that if Z is O, and R3, R4, R5, R6, R7, and R8is H, then R12is not H or D.

[0236] Embodiment 2 provides a compound having the structure of Formula (lb), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);WSGR Docket No. 62619-756.601Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,or; and G is an optionally substituted 5- to 10-membered heterocyclyl; andR2is optionally substituted C2-C6 alkynyl;R3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andR12is selected from H, D, fluoro, chloro, -CN, or -OHprovided that if Y is O and R3, R4, R5, R6, R9, and R10is H, then R12is not H or D; and provided that if Z is O, and R3, R4, R5, R6, R7, and R8is H, then R12is not H or D.

[0237] Embodiment 3 provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), C-(optionally substituted C3-C6 carbocyclyl), or C-SF5;WSGR Docket No. 62619-756.601Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,or; and G is an optionally substituted 5- to 10-membered heterocyclyl;each R2is independently selected from H, or optionally substituted C1-C6 alkyl;R3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andR12is selected from H, D, fluoro, chloro, bromo, optionally substituted C1-C6 alkyl, - CF3, amino, -COOH, -CONH2, -CN, or -OH;optionally wherein R11and R12are taken together with the carbon atoms to which they are attached to form an optionally substituted methylidene or an oxo group;Provided that if Y is O, Z is CR9R10, and R3, R4, R5, R6, R9, R10is H, then R12is not H or D;provided that if Y is CR7R8, Z is CR9R10, andR3, R4, R5, R6, R7, R8, R9, R10is H, then R12is not H or D; andprovided that if Y is CR7R8, and R3, R4, R5, R6, R7, R8is H, then Z cannot be O.

[0238] Embodiment 4 provides a compound having the structure of Formula (lib), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein:X1is N or C-CN;WSGR Docket No. 62619-756.601X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,or; and G is an optionally substituted 5- to 10-membered heterocyclyl;each R2is independently selected from H, or optionally substituted C1-C6 alkyl;R3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andR12is selected from H, D, fluoro, chloro, -CN, or -OHProvided that if Y is O, Z is CR9R10, and R3, R4, R5, R6, R9, R10is H, then R12is not H or D;provided that if Y is CR7R8, Z is CR9R10, andR3, R4, R5, R6, R7, R8, R9, R10is H, then R12is not H or D; andprovided that if Y is CR7R8, and R3, R4, R5, R6, R7, R8is H, then Z cannot be O.

[0239] Embodiment 5 provides the compound of Formula (II), having the structure of Formula (lie), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:WSGR Docket No. 62619-756.601wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is CR7R8, and Z is CR9R10;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,? x f; and G is an optionally substituted 5- to 10-membered heterocyclyl;each R2is independently selected from H, or optionally substituted C1-C6 alkyl;R3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H;R12is selected from H, D, fluoro, chloro, -CN, or -OH; andprovided that if R3, R4, R5, R6, R7, R8, R9, R10is H, then R12is not H or D.

[0240] Embodiment 6 provides the compound of Formula (II), having the structure of Formula (lid), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:WSGR Docket No. 62619-756.601wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,? x f; and G is an optionally substituted 5- to 10-membered heterocyclyl;each R2is independently selected from H, or optionally substituted C1-C6 alkyl;R3is optionally substituted C1-C6 alkylR4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;R11is H; andR12is selected from H, D, fluoro, chloro, -CN, or -OH.

[0241] Embodiment 7 provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:WSGR Docket No. 62619-756.601wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), C-(optionally substituted C3-C6 carbocyclyl), or C-SF5;Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,* * ’ *%; and G is an optionally substituted 5- to 10-membered heterocyclyl;R2is H or optionally substituted C1-C6 alkyl;R3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andR12is selected from H, D, fluoro, chloro, bromo, optionally substituted C1-C6 alkyl, -CF3, amino, -COOH, -CONH2, -CN, or -OH;optionally wherein R11and R12are taken together with the carbon atoms to which they are attached to form an optionally substituted methylidene or an oxo group;provided that if Z is O, then the compound is notWSGR Docket No. 62619-756.601

[0242] Embodiment 8 provides a compound having the structure of Formula (Illb), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,; and G is an optionally substituted 5- to 10-membered heterocyclyl;R2is H or optionally substituted C1-C6 alkyl;R3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;WSGR Docket No. 62619-756.601optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andR12is selected from H, D, fluoro, chloro, -CN, or -OHprovided that if Z is O, then the compound is not

[0243] Embodiment 9 provides a compound having the structure of Formula (IV), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:R2wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), C-(optionally substituted C3-C6 carbocyclyl), or C-SF5;Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;WSGR Docket No. 62619-756.601R1is L-G; wherein L is optionally substituted C1-C4 alkylene,ov; and G is an optionally substituted 5- to 10-membered heterocyclyl;R2is optionally substituted C2-C6 alkenyl; andR3, R4, R5, R6, R7, R8, R9, R10, R13, R14, R15, R16each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;optionally wherein R14and R15together form an optionally substituted carbocyclyl ring;optionally wherein the carbocyclyl ring is further substituted with an optionally substituted methylidene.

[0244] Embodiment 10 provides a compound having the structure of Formula (IVb), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:PR15R16R2R1 JD JL'O N X2Ar(Ivb)wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;WSGR Docket No. 62619-756.601R1is L-G; wherein L is optionally substituted C1-C4 alkylene,or; and G is an optionally substituted 5- to 10-membered heterocyclyl;R2is optionally substituted C2-C6 alkenyl; andR3, R4, R5, R6, R7, R8, R9, R10, R13, R14, R15, R16each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;optionally wherein R14and R15together form an optionally substituted carbocyclyl ring.

[0245] Embodiment 11 provides the compound of Formula (IV), having the structure of Formula (IVc), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:R11is H; andR12is selected from H, D, fluoro, chloro, -CN, or -OH.

[0246] Embodiment 12 provides the compound of Formula (IV), having the structure of Formula (IVd), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6WSGR Docket No. 62619-756.601alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,? x f; and G is an optionally substituted 5- to 10-membered heterocyclyl;R2is optionally substituted C2-C6 alkenyl; andR3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andR12is selected from H, D, fluoro, chloro, -CN, or -OH.

[0247] Embodiment 13 provides a compound having the structure of Formula (V), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:pR6v Y Z,..\LR14R5\ / R4> R3± R16R15wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);WSGR Docket No. 62619-756.601X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), C-(optionally substituted C3-C6 carbocyclyl), or C-SF5;Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,; and G is an optionally substituted 5- to 10-membered heterocyclyl; andR3, R4, R5, R6, R7, R8, R9, R10, R13, R14, R15, R16each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;optionally wherein R14and R15together form an optionally substituted carbocyclyl ringoptionally wherein the carbocyclyl ring is further substituted with an optionally substituted methylidene.

[0248] Embodiment 14 provides the compound of Formula (V), having the structure of Formula (Vb), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:R11is H; andR12is selected from H, D, fluoro, chloro, -CN, or -OH.

[0249] Embodiment 15 provides the compound of any one of embodiments 1-14, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Y is O.

[0250] Embodiment 16 provides the compound of any one of embodiments 1-14, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Z is O.WSGR Docket No. 62619-756.601

[0251] Embodiment 17 provides the compound of any one of embodiments 1-14, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein -Y-Z- is -C(R8)=C(R9)-.

[0252] Embodiment 18 provides the compound of any one of embodiments 1-14, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond.

[0253] Embodiment 19 provides the compound of any one of embodiments 1-14, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Y is CR7R8, and Z is CR9R10.

[0254] Embodiment 20 provides the compound of any one of embodiments 1-19, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R3is optionally substituted C1-C6 alkyl.

[0255] Embodiment 21 provides the compound of any one of embodiments 1-20, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R3is optionally substituted C1-C2 alkyl.

[0256] Embodiment 22 provides the compound of any one of embodiments 1-21, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R3is -CH3.

[0257] Embodiment 23 provides the compound of any one of embodiments 1-21, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R3is -CH2CH3.

[0258] Embodiment 24 provides the compound of any one of embodiments 1-8, 11-12, or 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R12is H.

[0259] Embodiment 25 provides the compound of any one of embodiments 1-8, 11-12, or 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R12is chloro.

[0260] Embodiment 26 provides the compound of any one of embodiments 1-8, 11-12, or 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R12is fluoro.

[0261] Embodiment 27 provides the compound of any one of embodiments 1-8, 11-12, 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the

[0262] Embodiment 28 provides the compound of any one of embodiments 1-8, 11-12, 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein theWSGR Docket No. 62619-756.601

[0263] Embodiment 29 provides the compound of any one of embodiments 1-8, 11-12, 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the

[0264] Embodiment 30 provides the compound of any one of embodiments 1-8, 11-12, 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the

[0265] Embodiment 31 provides the compound of any one of embodiments 1-8, 11-12, 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the

[0266] Embodiment 32 provides the compound of any one of embodiments 1-8, 11-12, 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the

[0267] Embodiment 33 provides the compound of any one of embodiments 1-8, 11-12, 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the

[0268] Embodiment 34 provides the compound of any one of embodiments 1-8, 11-12, 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein theWSGR Docket No. 62619-756.601

[0269] Embodiment 35 provides the compound of any one of embodiments 1-8, 11-12, 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the

[0270] Embodiment 36 provides the compound of any one of embodiments 1-8, 11-12, 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the

[0271] Embodiment 37 provides the compound of any one of embodiments 1-8, 11-12, 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the

[0272] Embodiment 38 provides the compound of any one of embodiments 1-8, 11-12, 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein:

[0273] Embodiment 39 provides the compound of any one of embodiments 1-8, 11-12, 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein:WSGR Docket No. 62619-756.601

[0274] Embodiment 40 provides the compound of any one of embodiments 1, 3, 7, 9, 13, 15-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein:

[0275] Embodiment 41 provides the compound of any one of embodiments 9, 13, 15-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein:WSGR Docket No. 62619-756.601

[0276] Embodiment 42 provides the compound of any one of embodiments 1-41, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X1is N.

[0277] Embodiment 43 provides the compound of any one of embodiments 1-41, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X1is C-CN.

[0278] Embodiment 44 provides the compound of any one of embodiments 1-43, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is N.

[0279] Embodiment 45 provides the compound of any one of embodiments 1-43, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is C-H, C-D, C-F, or C-Cl.

[0280] Embodiment 46 provides the compound of any one of embodiments 1-43, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is C-CN.

[0281] Embodiment 47 provides the compound of any one of embodiments 1-43, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is C-CH3 or C-CD3.

[0282] Embodiment 48 provides the compound of any one of embodiments 1-43, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is C-CF3.

[0283] Embodiment 49 provides the compound of any one of embodiments 1-43, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is C-CH3.

[0284] Embodiment 50 provides the compound of any one of embodiments 1-43, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is C-F.WSGR Docket No. 62619-756.601

[0285] Embodiment 51 provides the compound of any one of embodiments 1-43, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is C-(optionally substituted C1-C6 alkyl).

[0286] Embodiment 52 provides the compound of any one of embodiments 1-43, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is C-(C2-C6 optionally substituted alkenyl).

[0287] Embodiment 53 provides the compound of any one of embodiments 1-43, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is C-(optionally substituted C1-C6 alkoxy).

[0288] Embodiment 54 provides the compound of any one of embodiments 1-43, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is C-(optionally substituted C2-C6 alkynyl).

[0289] Embodiment 55 provides the compound of any one of embodiments 1-43, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is C-(optionally substituted C3-C6 carbocyclyl).

[0290] Embodiment 56 provides the compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X3is N.

[0291] Embodiment 57 provides the compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X3is C-H, C-F, or C-Cl.

[0292] Embodiment 58 provides the compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X3is C-F.

[0293] Embodiment 59 provides the compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X3is C-CF3.

[0294] Embodiment 60 provides the compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X3is C-CN.

[0295] Embodiment 61 provides the compound of any one of embodiment 1, 2, or embodiments 15-60, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R2is optionally substituted C2-C4 alkynyl.

[0296] Embodiment 62 provides the compound of any one of embodiment 1, 2, or embodiments 15-61, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R2is optionally substituted C2-C3 alkynyl.

[0297] Embodiment 63 provides the compound of any one of embodiment 1, 2, or embodiments 15-62, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R2is optionally substituted ethynyl.WSGR Docket No. 62619-756.601

[0298] Embodiment 64 provides the compound of any one of embodiment 1, 2, or embodiments 15-62, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R2is optionally substituted propynyl.

[0299] Embodiment 65 provides the compound of any one of embodiments 3-6 or embodiments 15-60, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the N(R2)2 moiety is NHCH3.

[0300] Embodiment 66 provides the compound of any one of embodiments 3-6 or embodiments 15-60, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the N(R2)2 moiety is NHCD3.

[0301] Embodiment 67 provides the compound of any one of embodiment 7, 8, or embodiments 15-60, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the R2is -CH3.

[0302] Embodiment 68 provides the compound of any one of embodiment 7, 8, or embodiments 15-60, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the R2is -CD3.

[0303] Embodiment 69 provides the compound of any one of embodiment 7, 8, or embodiments 15-60, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the R2is H.

[0304] Embodiment 70 provides the compound of any one of embodiments 9-12, or 15-60, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the R2is optionally substituted C2-C4 alkenyl.

[0305] Embodiment 71 provides the compound of any one of embodiments 9-12, or 15-60, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the R2is optionally substituted C2-C3 alkenyl.

[0306] Embodiment 72 provides the compound of any one of embodiments 9-12, or 15-60, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the R2is optionally substituted vinyl.

[0307] Embodiment 73 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is a monocyclic optionally substituted aryl.

[0308] Embodiment 74 provides the compound of embodiment 73, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the monocyclic optionally substituted aryl is an optionally substituted phenyl.WSGR Docket No. 62619-756.601

[0309] Embodiment 75 provides the compound of embodiment 74, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted phenyl is substituted with an -OH group at the meta-position.

[0310] Embodiment 76 provides the compound of embodiment 74, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted phenyl isOH

[0311] Embodiment 77 provides the compound of embodiment 74, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted phenyl is selected from:

[0312] Embodiment 78 provides the compound of embodiment 74, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted phenyl is substituted with an -NH2 group at the meta-position.

[0313] Embodiment 79 provides the compound of embodiment 74, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted phenyl is

[0314] Embodiment 80 provides the compound of embodiment 74, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted phenyl is selected from:WSGR Docket No. 62619-756.601

[0315] Embodiment 81 provides the compound of embodiment 74, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted phenyl is o'CF’NH2

[0316] Embodiment 82 provides the compound of embodiment 74, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted phenyl is a 2, 3, 5 -tri substituted phenyl.

[0317] Embodiment 83 provides the compound of embodiment 82, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the 2,3,5-trisubstituted phenyl is substituted with a 3 -hydroxy group.

[0318] Embodiment 84 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is a bicyclic optionally substituted aryl.

[0319] Embodiment 85 provides the compound of embodiment 84, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted aryl is an optionally substituted naphthyl.

[0320] Embodiment 86 provides the compound of embodiment 85, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted naphthyl is an optionally substituted 1 -naphthyl.

[0321] Embodiment 87 provides the compound of embodiment 86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted 1 -naphthyl is further substituted at the 8-position.WSGR Docket No. 62619-756.601

[0322] Embodiment 88 provides the compound of any one of embodiments 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0323] Embodiment 89 provides the compound of any one of embodiments 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0324] Embodiment 90 provides the compound of any one of embodiments 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:FOH OH OH OH OH OHWSGR Docket No. 62619-756.601FOH OH OH OH

[0325] Embodiment 91 provides the compound of any one of embodiments 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0327] Embodiment 93 provides the compound of any one of embodiments 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:WSGR Docket No. 62619-756.601OH

[0328] Embodiment 94 provides the compound of any one of embodiments 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0329] Embodiment 95 provides the compound of any one of embodiments 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0330] Embodiment 96 provides the compound of any one of embodiments 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:WSGR Docket No. 62619-756.601

[0331] Embodiment 97 provides the compound of any one of embodiments 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0332] Embodiment 98 provides the compound of any one of embodiments 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:NH2, NH2, NH2and NH2WSGR Docket No. 62619-756.601

[0333] Embodiment 99 provides the compound of any one of embodiments 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0334] Embodiment 100 provides the compound of any one of embodiments 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0335] Embodiment 101 provides the compound of any one of embodiments 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0336] Embodiment 102 provides the compound of any one of embodiments 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:WSGR Docket No. 62619-756.601

[0338] Embodiment 104 provides the compound of any one of embodiments 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:WSGR Docket No. 62619-756.601

[0339] Embodiment 105 provides the compound of any one of embodiments 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0340] Embodiment 106 provides the compound of any one of embodiments 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0341] Embodiment 107 provides the compound of any one of embodiments 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:WSGR Docket No. 62619-756.601

[0342] Embodiment 108 provides the compound of any one of embodiments 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0343] Embodiment 109 provides the compound of any one of embodiments 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0345] Embodiment 111 provides the compound of embodiment 84, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted aryl is described by Formula (a):WSGR Docket No. 62619-756.601wherein:R17is hydrogen, deuterium, or F;R18is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me;R19is hydrogen, deuterium, F, Cl, or Br;R20is hydrogen, deuterium, F, Cl, or Br;R21is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3;R22is hydrogen, deuterium, F, Cl, or -CN; andR23is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C=CH, -OCHF2, - OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

[0346] Embodiment 112 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is a monocyclic optionally substituted heteroaryl.

[0347] Embodiment 113 provides the compound of embodiment 112, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the monocyclic optionally substituted heteroaryl is an optionally substituted 2-pyridinyl.

[0348] Embodiment 114 provides the compound of embodiment 113, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted 2-pyridinyl

[0349] Embodiment 115 provides the compound of embodiment 113, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted 2-pyridinyl isNH2

[0350] Embodiment 116 provides the compound of embodiment 112, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the monocyclic optionally substituted heteroaryl is an optionally substituted 4-pyridinyl.WSGR Docket No. 62619-756.601

[0351] Embodiment 117 provides the compound of embodiment 116, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted 4-pyridinyl isNH2

[0352] Embodiment 118 provides the compound of embodiment 116, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted 4-pyridinyl isOH

[0353] Embodiment 119 provides the compound of embodiment 112, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the monocyclic optionally substituted heteroaryl is

[0354] Embodiment 120 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is a bicyclic optionally substituted heteroaryl.

[0355] Embodiment 121 provides the compound of embodiment 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl is selected from:WSGR Docket No. 62619-756.601

[0356] Embodiment 122 provides the compound of embodiment 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl is selected from:

[0357] Embodiment 123 provides the compound of embodiment 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl is selected from:WSGR Docket No. 62619-756.601

[0358] Embodiment 124 provides the compound of embodiment 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl is selected from:

[0359] Embodiment 125 provides the compound of embodiment 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl isF

[0360] Embodiment 126 provides the compound of embodiment 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl is selected from:WSGR Docket No. 62619-756.601

[0361] Embodiment 127 provides the compound of embodiment 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl is selected from:

[0362] Embodiment 128 provides the compound of embodiment 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl is described by Formula (bl):R19R20(bl)wherein:R18is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me;R19is hydrogen, deuterium, F, Cl, or Br;R20is hydrogen, deuterium, F, Cl, or Br;R21is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3;R22is hydrogen, deuterium, F, Cl, or -CN; andR23is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C=CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

[0363] Embodiment 129 provides the compound of embodiment 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl is described by Formula (b2):R19R20 (b2)wherein:R17is hydrogen, deuterium, or F;R19is hydrogen, deuterium, F, Cl, or Br;R20is hydrogen, deuterium, F, Cl, or Br;WSGR Docket No. 62619-756.601R21is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3;R22is hydrogen, deuterium, F, Cl, or -CN; andR23is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C=CH, -OCHF2, - OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

[0364] Embodiment 130 provides the compound of embodiment 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl is described by Formula (b3):R20(b3)wherein:R17is hydrogen, deuterium, or F;R18is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me;R20is hydrogen, deuterium, F, Cl, or Br;R21is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3;R22is hydrogen, deuterium, F, Cl, or -CN; andR23is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C=CH, -OCHF2, - OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

[0365] Embodiment 131 provides the compound of embodiment 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl is described by Formula (b4):wherein:R17is hydrogen, deuterium, or F;R18is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me;R19is hydrogen, deuterium, F, Cl, or Br;R21is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3;R22is hydrogen, deuterium, F, Cl, or -CN; andR23is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C=CH, -OCHF2, - OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.WSGR Docket No. 62619-756.601

[0366] Embodiment 132 provides the compound of embodiment 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl is described by Formula (b5):wherein:R17is hydrogen, deuterium, or F;R18is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me;R19is hydrogen, deuterium, F, Cl, or Br;R20is hydrogen, deuterium, F, Cl, or Br;R22is hydrogen, deuterium, F, Cl, or -CN; andR23is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C=CH, -OCHF2, - OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

[0367] Embodiment 133 provides the compound of embodiment 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl is described by Formula (b6):wherein:R17is hydrogen, deuterium, or F;R18is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me;R19is hydrogen, deuterium, F, Cl, or Br;R20is hydrogen, deuterium, F, Cl, or Br;R21is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3; andR23is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C=CH, -OCHF2, - OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

[0368] Embodiment 134 provides the compound of embodiment 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl is described by Formula (b7):WSGR Docket No. 62619-756.601wherein:R17is hydrogen, deuterium, or F;R18is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me;R21is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3;R22is hydrogen, deuterium, F, Cl, or -CN; andR23is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C=CH, -OCHF2, - OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

[0369] Embodiment 135 provides the compound of embodiment 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl is described by Formula (b8):wherein:R18is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me;R20is hydrogen, deuterium, F, Cl, or Br;R21is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3;R22is hydrogen, deuterium, F, Cl, or -CN; andR23is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C=CH, -OCHF2, - OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

[0370] Embodiment 136 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is:H2N

[0371] Embodiment 137 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:WSGR Docket No. 62619-756.601

[0372] Embodiment 138 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0373] Embodiment 139 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0374] Embodiment 140 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0375] Embodiment 141 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0376] Embodiment 142 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0377] Embodiment 143 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:WSGR Docket No. 62619-756.601

[0379] Embodiment 145 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0380] Embodiment 146 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0381] Embodiment 147 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is:F

[0382] Embodiment 148 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:WSGR Docket No. 62619-756.601

[0383] Embodiment 149 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0384] Embodiment 150 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0385] Embodiment 151 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0386] Embodiment 152 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is:FNH2

[0387] Embodiment 153 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:WSGR Docket No. 62619-756.601

[0388] Embodiment 154 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0389] Embodiment 155 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0390] Embodiment 156 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0391] Embodiment 157 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0392] Embodiment 158 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:WSGR Docket No. 62619-756.601

[0393] Embodiment 159 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0394] Embodiment 160 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0395] Embodiment 161 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

[0396] Embodiment 162 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:WSGR Docket No. 62619-756.601

[0397] Embodiment 163 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is:F.

[0398] Embodiment 164 provides the compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is:

[0399] Embodiment 165 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is optionally substituted C1-C4 alkylene.

[0400] Embodiment 166 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is

[0401] Embodiment 167 provides the compound of embodiment 165, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is

[0402] Embodiment 168 provides the compound of embodiment 165, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is optionally substituted Cl alkylene.

[0403] Embodiment 169 provides the compound of embodiment 168, or a pharmaceutically D D

[0404] Embodiment 170 provides the compound of any one of embodiments 165-169, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is an optionally substituted 5- to 10-membered heterocyclyl.WSGR Docket No. 62619-756.601

[0405] Embodiment 171 provides the compound of any one of embodiments 165-169, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is described by formula (e):n is 0 or 1;V is absent, O, or CR34R35, and W is O or CR36R37,provided that -V-W- is not -O-O-; andR24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38and R39each is independently selected from H, D, optionally substituted C1-C6 alkyl, -OH, chloro, or fluoro;optionally wherein R24and R25, R26and R27, R28and R29, R30and R31, R32and R33, R34and R35, R36and R37, or R38and R39are taken together with the carbon atoms to which they are attached to form an optionally substituted alkene or optionally substituted carbocyclyl.

[0406] Embodiment 172 provides the compound of embodiment 171, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein V is O or CR34R35.

[0407] Embodiment 173 provides the compound of embodiment 171, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein V is absent.

[0408] Embodiment 174 provides the compound of embodiment 171, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein V is absent and n is 0.

[0409] Embodiment 175 provides the compound of embodiment 174, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R37and R38are taken together with the carbon atoms to which they are attached to form an optionally substituted carbocyclyl.

[0410] Embodiment 176 provides the compound of embodiment 175, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R37and R38are taken together with the carbon atoms to which they are attached to form an optionally substituted cyclopropyl.

[0411] Embodiment 177 provides the compound of embodiment 171, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein:n is 0;V is CR34R35and W is O; andWSGR Docket No. 62619-756.601R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R38and R39each is independently selected from H, D, optionally substituted C1-C6 alkyl, -OH, chloro, or fluoro; optionally wherein R24and R25, R26and R27, R28and R29, R30and R31, R32and R33, R34and R35, or R38and R39are taken together with the carbon atoms to which they are attached to form an optionally substituted alkene or optionally substituted carbocyclyl.

[0412] Embodiment 178 provides the compound of embodiment 171, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein:n is 1;V is CR34R35and W is O; andR24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R38and R39each is independently selected from H, D, optionally substituted C1-C6 alkyl, -OH, chloro, or fluoro; optionally wherein R24and R25, R26and R27, R28and R29, R30and R31, R32and R33, R34and R35, or R38and R39are taken together with the carbon atoms to which they are attached to form an optionally substituted alkene or optionally substituted carbocyclyl.

[0413] Embodiment 179 provides the compound of embodiment 171, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein:n is 1;V is O and W is CR36R37; andR24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R36, R37, R38and R39each is independently selected from H, D, optionally substituted C1-C6 alkyl, -OH, chloro, or fluoro; optionally wherein R24and R25, R26and R27, R28and R29, R30and R31, R32and R33, R36and R37, or R38and R39are taken together with the carbon atoms to which they are attached to form an optionally substituted alkene or optionally substituted carbocyclyl.

[0414] Embodiment 180 provides the compound of any one of embodiments 171-179, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R24and R25are H.

[0415] Embodiment 181 provides the compound of any one of embodiments 171-180, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R26and R27are fluoro.

[0416] Embodiment 182 provides the compound of any one of embodiments 171-180, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R26is H and R27is fluoro.WSGR Docket No. 62619-756.601

[0417] Embodiment 183 provides the compound of any one of embodiments 171-180, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R26and R27are taken together with the carbon atoms to which they are attached to form an optionally substituted alkene.

[0418] Embodiment 184 provides the compound of embodiment 183, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted alkene is substituted with fluoro.

[0419] Embodiment 185 provides the compound of embodiment 183, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted alkene is substituted with optionally substituted C1-C3 alkyl.

[0420] Embodiment 186 provides the compound of any one of embodiments 171-180, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R26and R27are taken together with the carbon atoms to which they are attached to form an optionally substituted carbocyclyl.

[0421] Embodiment 187 provides the compound of embodiment 186, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R26and R27are taken together with the carbon atoms to which they are attached to form an optionally substituted cyclopropyl.

[0422] Embodiment 188 provides the compound of embodiment 186, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R26and R27are taken together with the carbon atoms to which they are attached to form a cyclopropyl.

[0423] Embodiment 189 provides the compound of embodiment 187 or 188, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the cyclopropyl is substituted with fluoro or chloro.

[0424] Embodiment 190 provides the compound of any one of embodiments 171-173, or 177- 189, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R38and R39are taken together with the carbon atoms to which they are attached to form an optionally substituted carbocyclyl.

[0425] Embodiment 191 provides the compound of embodiment 190, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R38and R39are taken together with the carbon atoms to which they are attached to form an optionally substituted cyclopropyl.

[0426] Embodiment 192 provides the compound of any one of embodiments 171-191, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R28and R29are H.

[0427] Embodiment 193 provides the compound of any one of embodiments 171-191, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R28is H and R29is an optionally substituted C1-C2 alkyl.WSGR Docket No. 62619-756.601

[0428] Embodiment 194 provides the compound of embodiment 193, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R29is -CH3.

[0429] Embodiment 195 provides the compound of embodiment 193, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R29is -CH2CH3.

[0430] Embodiment 196 provides the compound of any one of embodiments 171-191, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R28and R29are H.

[0431] Embodiment 197 provides the compound of any one of embodiments 171-196, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R32and R33are H.

[0432] Embodiment 198 provides the compound of any one of embodiments 171-196, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R32and R33are D.

[0433] Embodiment 199 provides the compound of any one of embodiments 171-173, or 177- 189, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R38and R39are H.

[0434] Embodiment 200 provides the compound of embodiment 171, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein V is CR34R35and wherein R34and R35are H.

[0435] Embodiment 201 provides the compound of embodiment 171, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein W is CR36R37and wherein R36and R37are H.

[0436] Embodiment 202 provides the compound of any one of embodiments 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is selected from:

[0437] Embodiment 203 provides the compound of any one of embodiments 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is selected from:

[0438] Embodiment 204 provides the compound of any one of embodiments 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is selected from:WSGR Docket No. 62619-756.601

[0439] Embodiment 205 provides the compound of any one of embodiments 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is described by Formula (c):wherein,each R20-R30is independently selected from hydrogen or deuterium.

[0440] Embodiment 206 provides the compound of any one of embodiments 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is described by Formula (d):F(d)wherein,R31is selected from hydrogen, F, Cl, -CN, -OH, or optionally substituted C1-C4 alkyl;R32is hydrogen, deuterium or optionally substituted C1-C4 alkyl; andR33is hydrogen, deuterium, F, or optionally substituted C1-C4 alkyl.

[0441] Embodiment 207 provides the compound of any one of embodiments 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is selected from:

[0442] Embodiment 208 provides the compound of any one of embodiments 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is selected from:WSGR Docket No. 62619-756.601

[0443] Embodiment 209 provides the compound of any one of embodiments 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is selected from:O— ’ °—

[0444] Embodiment 210 provides the compound of any one of embodiments 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is selected from:

[0445] Embodiment 211 provides the compound of any one of embodiments 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:

[0446] Embodiment 212 provides the compound of any one of embodiments 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:WSGR Docket No. 62619-756.601

[0447] Embodiment 213 provides the compound of any one of embodiments 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:

[0448] Embodiment 214 provides the compound of any one of embodiments 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:

[0449] Embodiment 215 provides the compound of any one of embodiments 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:WSGR Docket No. 62619-756.601

[0450] Embodiment 216 provides the compound of any one of embodiments 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:

[0451] Embodiment 217 provides the compound of any one of embodiments 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:

[0452] Embodiment 218 provides the compound of any one of embodiments 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:WSGR Docket No. 62619-756.601

[0453] Embodiment 219 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1isF

[0454] Embodiment 220 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0455] Embodiment 221 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0456] Embodiment 222 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601

[0457] Embodiment 223 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0458] Embodiment 224 provides the compound of any one of embodiments 1-156, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0459] Embodiment 225 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1isFWSGR Docket No. 62619-756.601

[0460] Embodiment 226 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0461] Embodiment 227 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0462] Embodiment 228 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0463] Embodiment 229 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0464] Embodiment 230 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0465] Embodiment 231 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601

[0466] Embodiment 232 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0467] Embodiment 233 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0468] Embodiment 234 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0469] Embodiment 235 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601

[0470] Embodiment 236 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0471] Embodiment 237 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0472] Embodiment 238 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601

[0473] Embodiment 239 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0474] Embodiment 240 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0475] Embodiment 241 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601

[0476] Embodiment 242 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0477] Embodiment 243 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0478] Embodiment 244 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601D D, and

[0479] Embodiment 245 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0480] Embodiment 246 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0481] Embodiment 247 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601

[0482] Embodiment 248 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0483] Embodiment 249 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0484] Embodiment 250 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601

[0485] Embodiment 251 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0486] Embodiment 252 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:'ci

[0487] Embodiment 253 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601

[0488] Embodiment 254 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:r~~X. D O

[0489] Embodiment 255 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0490] Embodiment 256 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601

[0491] Embodiment 257 provides the compound any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0492] Embodiment 258 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0493] Embodiment 259 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0494] Embodiment 260 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601

[0495] Embodiment 261 provides the compound any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0496] Embodiment 262 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0497] Embodiment 263 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0498] Embodiment 264 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0499] Embodiment 265 provides the compound any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0500] Embodiment 266 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0501] Embodiment 267 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601

[0502] Embodiment 268 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0503] Embodiment 269 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0504] Embodiment 270 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0505] Embodiment 271 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0506] Embodiment 272 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0507] Embodiment 273 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0508] Embodiment 274 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601

[0509] Embodiment 275 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0510] Embodiment 276 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0511] Embodiment 277 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0512] Embodiment 278 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0513] Embodiment 279 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601

[0514] Embodiment 280 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0515] Embodiment 281 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0516] Embodiment 282 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0517] Embodiment 283 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0518] Embodiment 284 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0519] Embodiment 285 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601

[0520] Embodiment 286 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0521] Embodiment 287 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0522] Embodiment 288 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0523] Embodiment 289 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0524] Embodiment 290 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0525] Embodiment 291 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601

[0526] Embodiment 292 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0527] Embodiment 293 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0528] Embodiment 294 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is:

[0529] Embodiment 295 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is:

[0530] Embodiment 296 provides the compound of any one of embodiments 1-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:WSGR Docket No. 62619-756.601or

[0531] Embodiment 297 provides the compound of any one of embodiments 1-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:

[0532] Embodiment 298 provides the compound of any one of embodiments 1-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:

[0533] Embodiment 299 provides the compound of any one of embodiments 1-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:

[0534] Embodiment 300 provides the compound of any one of embodiments 1-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:WSGR Docket No. 62619-756.601

[0535] Embodiment 301 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is:

[0536] Embodiment 302 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is:_ D D5 P

[0537] Embodiment 303 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is:_ D D

[0538] Embodiment 304 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is:

[0539] Embodiment 305 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is:WSGR Docket No. 62619-756.601

[0540] Embodiment 306 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0541] Embodiment 307 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0542] Embodiment 308 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0543] Embodiment 309 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0544] Embodiment 310 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0545] Embodiment 311 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601

[0546] Embodiment 312 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0547] Embodiment 313 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0548] Embodiment 314 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0549] Embodiment 315 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0550] Embodiment 316 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0551] Embodiment 317 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601

[0552] Embodiment 318 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0553] Embodiment 319 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0554] Embodiment 320 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0555] Embodiment 321 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0556] Embodiment 322 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0557] Embodiment 323 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601

[0558] Embodiment 324 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0559] Embodiment 325 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0560] Embodiment 326 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0561] Embodiment 327 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0562] Embodiment 328 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601

[0563] Embodiment 329 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0564] Embodiment 330 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0565] Embodiment 331 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0566] Embodiment 332 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0567] Embodiment 333 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0568] Embodiment 334 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601

[0569] Embodiment 335 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0570] Embodiment 336 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0571] Embodiment 337 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0572] Embodiment 338 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0573] Embodiment 339 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601

[0574] Embodiment 340 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0575] Embodiment 341 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0576] Embodiment 342 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0577] Embodiment 343 provides the compound of any one of embodiments 1-164 selected from, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is:

[0578] Embodiment 344 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0579] Embodiment 345 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601and D

[0580] Embodiment 346 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0581] Embodiment 347 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0582] Embodiment 348 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0583] Embodiment 349 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0584] Embodiment 350 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601

[0585] Embodiment 351 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0586] Embodiment 352 provides the compound of any one of embodiments 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

[0587] Embodiment 353 provides the compound of embodiment 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein theRV R11RR54', N.. ^-R’2moiety is

[0588] Embodiment 354 provides the compound of embodiment 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein theRVZ\ R"R4', Nmoiety is

[0589] Embodiment 355 provides the compound of embodiment 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein theR6 Y-Z\ R11RR54? N ^R12f Hmoietyis —

[0590] Embodiment 356 provides the compound of any one of embodiments 353-355, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X1is N.

[0591] Embodiment 357 provides the compound of any one of embodiments 353-356, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is C-F, C-Cl, or C-H,

[0592] Embodiment 358 provides the compound of embodiment 357, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is C-F.WSGR Docket No. 62619-756.601

[0593] Embodiment 359 provides the compound of any one of embodiments 353-358, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X3is N.

[0594] Embodiment 360 provides the compound of any one of embodiments 353-358, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R2is optionally substituted C2-C4 alkynyl.

[0595] Embodiment 361 provides the compound of embodiment 360, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R2is optionally substituted C2-C3 alkynyl.

[0596] Embodiment 362 provides the compound of embodiment 360 or 361, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R2is optionally substituted ethynyl.

[0597] Embodiment 363 provides the compound of embodiment 360 or 361, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R2is optionally substituted propynyl.

[0598] Embodiment 364 provides the compound of any one of embodiments 353-363, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is optionally substituted C1-C2 alkylene.

[0599] Embodiment 365 provides the compound of any one of embodiments 353-364, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L isD D

[0600] Embodiment 366 provides the compound of any one of embodiments 353-365, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is described by formula (e):n is 0 or 1;V is absent, O, or CR34R35, and W is O or CR36R37,provided that -V-W- is not -O-O-; andWSGR Docket No. 62619-756.601R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38and R39each is independently selected from H, D, optionally substituted C1-C6 alkyl, -OH, chloro, or fluoro;optionally wherein R24and R25, R26and R27, R28and R29, R30and R31, R32and R33, R34and R35, R36and R37, or R38and R39are taken together with the carbon atoms to which they are attached to form an optionally substituted alkene or optionally substituted carbocyclyl.

[0601] Embodiment 367 provides the compound of embodiment 366, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein V is absent and n is 0.

[0602] Embodiment 368 provides the compound of embodiment 367, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R26is H and R27is fluoro.

[0603] Embodiment 369 provides the compound of embodiment 368, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R28is H and R29is an optionally substituted C1-C2 alkyl.

[0604] Embodiment 370 provides the compound of embodiment 369, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R29is -CH3.

[0605] Embodiment 371 provides the compound of embodiment 369, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R29is -CH2CH3.

[0606] Embodiment 372 provides the compound of embodiment 367, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R26and R27are taken together with the carbon atoms to which they are attached to form an optionally substituted alkene.

[0607] Embodiment 373 provides the compound of embodiment 372, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted alkene is substituted with fluoro.

[0608] Embodiment 374 provides the compound of embodiment 372 or 373, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R38is H and R39is an optionally substituted C1-C2 alkyl.

[0609] Embodiment 375 provides the compound of embodiment 372 or 373, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R38is H and R39is H.

[0610] Embodiment 376 provides the compound of embodiment 374, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R39is -CH3.

[0611] Embodiment 377 provides the compound of embodiment 367, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R26and R27are taken together with the carbon atoms to which they are attached to form an optionally substituted carbocyclyl.WSGR Docket No. 62619-756.601

[0612] Embodiment 378 provides the compound of embodiment 377, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R38and R39are taken together with the carbon atoms to which they are attached to form an optionally substituted carbocyclyl.

[0613] Embodiment 379 provides the compound of embodiment 377, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R26and R27are taken together with the carbon atoms to which they are attached to form an optionally substituted cyclopropyl.

[0614] Embodiment 380 provides the compound of embodiment 379, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the cyclopropyl is substituted with fluoro.

[0615] Embodiment 381 provides the compound of embodiment 378, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R38and R39are taken together with the carbon atoms to which they are attached to form an optionally substituted cyclopropyl.

[0616] Embodiment 382 provides the compound of any one of embodiments 353-365, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is

[0617] Embodiment 383 provides the compound of any one of embodiments 353-365, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is

[0618] Embodiment 384 provides the compound of any one of embodiments 353-365, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is

[0619] Embodiment 385 provides the compound of any one of embodiments 353-365, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G isWSGR Docket No. 62619-756.601

[0620] Embodiment 386 provides the compound of any one of embodiments 353-363, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is

[0621] Embodiment 387 provides the compound of any one of embodiments 353-363, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is

[0622] Embodiment 388 provides the compound of any one of embodiments 353-363, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is

[0623] Embodiment 389 provides the compound of any one of embodiments 353-363, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is

[0624] Embodiment 390 provides the compound of any one of embodiments 353-363, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1isF

[0625] Embodiment 391 provides the compound of any one of embodiments 353-363, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1isWSGR Docket No. 62619-756.601

[0626] Embodiment 392 provides the compound of any one of embodiments 353-363, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is

[0627] Embodiment 393 provides the compound of any one of embodiments 353-363, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is

[0628] Embodiment 394 provides the compound of any one of embodiments 353-363, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is

[0629] Embodiment 395 provides the compound of any one of embodiments 353-394, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar isFNH2

[0630] Embodiment 396 provides the compound of any one of embodiments 353-394, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar isFOHWSGR Docket No. 62619-756.601

[0631] Embodiment 397 provides the compound of any one of embodiments 353-394, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar isNH2

[0632] Embodiment 398 provides the compound of any one of embodiments 353-394, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar isNH2

[0633] Embodiment 399 provides the compound of any one of embodiments 353-394, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is

[0634] Embodiment 400 provides the compound of any one of embodiments 353-394, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar isF

[0635] Embodiment 401 provides a compound, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, as described in Table 1.

[0636] Embodiment 402 provides a compound, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, as described in Table 2.

[0637] Embodiment 403 provides a compound, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, as described in Figures 1-19.WSGR Docket No. 62619-756.601

[0638] Embodiment 404 provides the pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, as described in any one of embodiments 1-403, and a pharmaceutically acceptable excipient.

[0639] Embodiment 405 provides the method of preparing a pharmaceutical composition comprising mixing a compound, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, of any one of embodiments 1-403, and a pharmaceutically acceptable carrier.

[0640] Embodiment 406 provides the compound of any one of embodiments 1-403, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treatment of the human or animal body.

[0641] Embodiment 407 provides the compound of any one of embodiments 1-403, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treatment of cancer.

[0642] Embodiment 408 provides use of a compound of any one of embodiments 1-403, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, in the manufacture of a medicament for the treatment of cancer.

[0643] Embodiment 409 provides the method of treating cancer in a patient in need thereof, comprising administering to the patient a compound as described in any one of embodiments 1- 403, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof.

[0644] Embodiment 410 provides the method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound as described in any one of embodiments 1-403, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient.

[0645] Embodiment 411 provides the method of inhibiting KRAS comprising contacting the enzyme with a compound of any one of embodiments 1-403, wherein the KRAS is contacted in an in vitro setting.

[0646] Embodiment 412 provides the method of inhibiting KRAS comprising contacting the enzyme with a compound of any one of embodiments 1-403, wherein KRAS is contacted in an in vivo setting.EXAMPLESI. Chemical Synthesis

[0647] In some embodiments, the KRAS inhibitory compounds disclosed herein are synthesized according to the following examples. As used below, and throughout the description of theWSGR Docket No. 62619-756.601invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:ACN acetonitrile°C degrees Celsius6n chemical shift in parts per million downfield from tetramethylsilane DCM dichloromethane (CH2CI2)DIAD diisopropyl azodicarboxylateDIEA diisopropylethylamineDMF dimethylformamideDMSO dimethylsulfoxideEA ethyl acetateEtOAc ethyl acetateESI electrospray ionizationEt ethylg gram(s)h hour(s)HPLC high performance liquid chromatographyHz hertzJ coupling constant (in NMR spectrometry)LCMS liquid chromatography mass spectrometrymicrom multiplet (spectral); meter(s); milliM molarM+parent molecular ionMe methylMsCl methanesulfonyl chlorideMHz megahertzmin minute(s)mol mole(s); molecular (as in mol wt)mL milliliterMS mass spectrometrynm nanometer(s)NMR nuclear magnetic resonancepH potential of hydrogen; a measure of the acidity or basicity of an aqueous solutionWSGR Docket No. 62619-756.601PE petroleum etherRT room temperatures singlet (spectral)t triplet (spectral)SFC Supercritical fluid chromatographyT temperatureTFA trifluoroacetic acidTHF tetrahydrofuranTPP Triphenylphosphine

[0648] Intermediate 1 & 2: Benzyl 6,7-dihydro-5J / -l,4-oxazepine-4-carboxylate & benzyl 3,7-dihydro- 2H- 1,4-oxazepine-4-carboxylateIntermediate 1 Intermediate 2

[0649] Step 1: Benzyl l,4-oxazepane-4-carboxylate

[0650] To an ice-cooled mixture of 1,4-oxazepane (20 g, 197.73 mmol) and K2CO3 (54.65 g, 395.45 mmol) in THF (200 mL) under N2 was added Cbz-Cl (40.47 g, 237.27 mmol) dropwise at room temperature. The ice bath was removed, and the resulting mixture was stirred at room temperature for 16 h. The resulting mixture was quenched with sat. NaHCCh aq. (300 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with 35% EA in PE) to afford the title compound (44 g, 94% yield) as a colorless oil. MS: m / z = 236.05 [M + H]+. 1HNMR (400 MHz, Chloroform-d) 87.39 - 7.29 (m, 5H), 5.15 (s, 2H), 3.75 - 3.56 (m, 8H), 1.93 - 1.79 (m, 2H).

[0651] Step 2: Benzyl 3 -methoxy- l,4-oxazepane-4-carboxylate & benzyl 5 -methoxy- l,4-oxazepane-4- carboxylate

[0652] To a solution of benzyl l,4-oxazepane-4-carboxylate (40 g, 170.00 mmol) in MeOH (200 mL) was added tetraethyl ammonium tosylate (25.62 g, 85.00 mmol) at room temperature. The reaction mixture was electrolyzed with C (+) I C(-) electrodes at constant current 200 mA. The resulting mixture was stirred at 20 °C for 72 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted 35% EA in PE) to afford a mixture of the title compounds (37 g, 82.03%) as a light-yellow oil. 'H NMR (400 MHz, Chloroform-d) 37.39 - 7.31 (m, 5H), 5.53 - 5.09 (m, 3H), 4.12 - 3.20 (m, 9H), 2.72 - 2.22 (m, 1H), 2.12 - 1.24 (m, 1H).WSGR Docket No. 62619-756.601

[0653] Step 3: Benzyl 6,7-dihydro-5J / -l,4-oxazepine-4-carboxylate & benzyl 3,7-dihydro-2J / -l,4- oxazepine-4-carboxylate

[0654] To an ice-cooled solution of benzyl 3 -m ethoxy- l,4-oxazepane-4-carboxylate and benzyl 5- methoxy-l,4-oxazepane-4-carboxylate (8.3 g, 31.28 mmol) in DCM (830 mL) were added DIEA (4.85 g, 37.54 mmol) and TMSOTf (8.34 g, 37.54 mmol 1.2) under N2. The reaction mixture was stirred in an ice bath for 0.5 h. The solid was filtered, and the filter cake was washed with hexane (1660 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with 42% EA in PE) to afford two title compounds. The first eluting peak was collected and concentrated under reduced pressure to afford the title compound (Intermediate 1, 2.18 g, 29% yield).XH NMR (400 MHz, Chloroform- d) 37.40 - 7.29 (m, 5H), 5.96 - 5.74 (m, 2H), 5.18 (s, 2H), 4.11 - 4.07 (m, 2H), 3.84 - 3.87 (m, 2H), 2.04 - 1.94 (m, 2H). The second eluting peak was collected and concentrated under reduced pressure to afford the other title compound (Intermediate 2, 2.52 g, 34% yield). 'H NMR (400 MHz, Chloroform^ / ) 37.42 - 7.28 (m, 5H), 5.26 - 4.85 (m, 4H), 4.22 - 4.20 (m, 2H), 3.93 - 3.70 (m, 4H).

[0655] Intermediate 3 & 4: Benzyl 8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate (trans mixture) & Benzyl 8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate (cis mixture)CbzCBz cbzCbz Cbz Intermediate 2 Intermediate 3 Intermediate 4

[0656] Step 1: Benzyl 8-bromo-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate

[0657] To an ice-cooled solution of Intermediate 2 (2.0 g, 8.58 mmol) and TBAI (0.65 g, 1.76 mmol) in DCM (10 mL) under N2 were added 33 wt% NaOH aq. (20 mL) and dibromofluoromethane (4.94 g, 25.74 mmol). The ice bath was removed, and the reaction mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with ice water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with 0-30% EA in PE) to afford the title compound (2.4 g, 82% yield) as an off-white semi-solid. MS: m / z = 361.10, 363.10 [M + NH4]+.

[0658] Step 2 & 3: Benzyl 8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate (trans mixture) & Benzyl 8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate cis mixture)

[0659] To a stirred mixture of benzyl 8-bromo-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate (2.4 g, 7.00 mmol) in EtOH (25 mL) under N2 were added NH4CI (3.37 g, 63.00 mmol) and Zn (4.12 g, 63.00 mmol) at room temperature. The reaction mixture was heated at 70 °C for 16 h.WSGR Docket No. 62619-756.601The resulting mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with 0-20% EA in PE) to afford two title compounds. The first eluting mixture was collected and concentrated under reduced pressure to give the title compound (trans mixture) (Intermediate 3, 700 mg, 38% yield). MS: m / z = / 2 / [M + NH4]+. 'HNMR (300 MHz, Chloroforms / ) 67.39 - 7.32 (m, 5H), 5.30 - 5.21 (m, 2H), 4.72 - 4.52 (m, 1H), 4.41 - 4.35 (m, 1H), 4.06 - 4.01 (m, 1H), 3.85 - 3.80 (m, 1H), 3.49 - 3.30 (m, 1H), 3.25 - 3.14 (m, 3H), 2.05 - 1.92 (m, 1H).19F NMR (282 MHz, Chloroforms / ) 6 -207.85 (s, IF). The second eluting mixture was collected and concentrated under reduced pressure to give the other title compound (cis mixture) (Intermediate 4, 360 mg, 19% yield). MS: m / z = 283.20 [M + NH4]+. 'H NMR (300 MHz, Chloroform- ) 6 7.38 - 7.30 (m, 5H), 5.15 (s, 2H), 4.67 - 4.46 (m, 1H), 4.33 - 4.26 (m, 1H), 4.19 - 4.14 (m, 1H) 4.02 - 3.91 (m, 1H), 3.69 - 3.55 (m, 2H), 3.37 - 3.29 (m, 1H), 2.74 - 2.72 (m, 1H) 1.64 - 1.51 (m, 1H).19F NMR (282 MHz, Chloroform- ) 6 -232.23 (s, IF).

[0660] Intermediate 5: (15',75',85)-8-Fluoro-5-oxa-2-azabicyclo[5.1.0]octaneIntermediate 5

[0661] A mixture of benzyl (15',75',85)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate (2.0 g,102 mmol, refer to Intermediate 3 and 4 for detail procedures) and HBr (10 mL, 30% in AcOH) was stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound (Intermediate 5, 1.6 g, HBr salt), which was used in the next step without further purification.

[0662] Intermediate 6: ((2A,7a5)-2-fluorotetrahydro-lZ / -pyrrolizin-7a(5J7)-yl)methan-t2-olIntermediate 6

[0663] Step 1: (2A,7a5)-2-Fluoro-hexahydropyrrolizine-7a-carboxylic acid

[0664] To a stirred solution of ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (500 mg, 3.141 mmol) and RUCI3. H2O (35.40 mg, 0.157 mmol) in CC14(4 mL), MeCN (4 mL) and H2O (6 mL) under N2 was added NaIO4(2686.99 mg, 12.564 mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 h. The resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with CH2Q2 (25% AcOH) / MeOH (5:1)) to afford the title compound (200 mg, 36% yield) as a brown-yellow semi-solid. MS: m / z = 174.10 [M + H]+.

[0665] Step 2: ((2 / ,7aA')-2-Fluorotetrahydro-17 / -pyrrolizin-7a(57 / )-yl)methans / 2-olWSGR Docket No. 62619-756.601

[0666] To an ice-cooled solution of (2A,7a5)-2-fluoro-hexahydropyrrolizine-7a-carboxylic acid (200 mg, 1.155 mmol) in Me-THF (2 mL) under N2 was added LiAlD4 (2.43 mL, 2.425 mmol, IM in THF) dropwise. The ice bath was removed, and the reaction mixture was heated at 90 °C for 2 h. The reaction mixture was cooled and quenched with MeOH (5 mL) in an ice bath. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with 1-20% methanol in di chloromethane) to afford the title compound (Intermediate 6, 100 mg, 53% yield). MS: m / z = 162.15 [M + H]+.

[0667] Intermediate 7 & 8: (6 / ,7aA')-7a-((( / c / 7-Butyldiphenylsilyl)oxy)rnethyl-t / 2)-6-fluorohexahydro- 3J / -pyrrolizin-3 -one & (2A,7a5 -7a-(((tert-bufyldiphenylsilyl)oxy)rnefhyl-t / 2)-2- fluorohexahydro-3J / -pyrrolizin-3-oneD >D^OTBDPS D^pOTBDPS D^OTBDPSStep 1 Step 2Intermediate 6Intermediate 7 Intermediate 8

[0668] Step 1: (2A,7a5)-7a-(((tertebutyldiphenylsilyl)oxy)methyl-t / 2)-2-fluorohexahydro-U / -pyrrolizine

[0669] To an ice-cooled solution of Intermediate 6 (30 g, 186.08 mmol) and imidazole (25.34 g, 372.17 mmol) in DMF (300 mL) under N2 was added tert-butyl (chi or o)di phenyl si lane (61.38 g, 223.30 mmol). The ice bath was removed, and the reaction mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with CH2CI2 (1000 mL), washed with water (3 x 300 mL), and brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with 0- 20% EA in PE) to afford the title compound (60 g, 80% yield) as a light-yellow oil. MS: m / z = 400.15 [M + H]+.XH NMR (400 MHz, Chloroform^ / ) 87.73 - 7.65 (m, 4H), 7.44 - 7.35 (m, 6H), 5.26 - 5.11 (m, 1H), 3.15 - 3.08 (m, 2H), 2.95 - 2.88 (m, 3H), 2.15 - 1.63 (m, 5H), 1.07 (s, 9H).

[0670] Step 2: (6A,7a5)-7a-(((terZ-Butyldiphenylsilyl)oxy)methyl-t / 2)-6-fluorohexahydro-3J / -pyrrolizin- 3-one & (2A,7a5 -7a-(((tert-butyldiphenylsilyl)oxy)methyl-t / 2)-2-fluorohexahydro-3J / - pyrrolizin-3-one

[0671] To an ice-cooled solution of (2A,7a5)-7a-(((tert-bufyldiphenylsilyl)oxy)rnefhyl-t / 2)-2- fluorohexahydro-UT-pyrrolizine (60 g, 150.14 mmol) and tri chlororuthenium hydrate (16.92 g, 75.07 mmol) in CCI4 (300 mL) and H2O (300 mL) was added NaICU (160.57 g, 750.71 mmol). The ice bath was removed, and the reaction mixture was stirred at room temperature for 30 min. The resulting mixture was filtered and extracted with DCM (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with 0-20% EA in PE) to afford a mixture of two isomers (60 g) as a light-yellow solid. The mixture was purifiedWSGR Docket No. 62619-756.601by re / ?-Achiral-SFC with the following conditions: Column: XA-GreenSep Naphthyl, 3 x 25 cm, 5 pm; Mobile Phase A: CO2; Mobile Phase B: IPA (0.1% 7 MNH3*MeOH); Flow rate: 200 mL / min; Gradient: isocratic 20% B; Detector: UV 220 nm; RT1 = 4.30 min; RT2: 6.07 min. The first eluting peak (RT1: 4.30 min) was concentrated and lyophilized to give the title compound (Intermediate 7, 40 g, 66% yield). MS: m / z = 414.30 [M + H]+.!H NMR (400 MHz, Chloroforms / ) 87.64 - 7.61 (m, 4H), 7.47 - 7.38 (m, 6H), 5.34 - 5.20 (m, 1H), 4.23 - 4.07 (m, 1H), 3.19 - 2.99 (m, 1H), 2.81 - 2.65 (m, 1H), 2.43 - 2.12 (m, 3H), 2.05 - 1.97 (m, 2H), 1.04 (s, 9H).19F NMR (376 MHz, Chloroforms / ) 3 -173.04 (s, IF). The second eluting peak (RT2: 6.07 min) was concentrated and lyophilized to give the other title compound (Intermediate 8, 12 g, 20% yield). MS: m / z = 414.30 [M + H]+. 'H NMR (400 MHz, Chloroforms / ) 67.65 - 7.58 (m, 4H), 7.47 - 7.37 (m, 6H), 5.74 - 5.51 (m, 1H), 3.84 - 3.72 (m, 1H), 2.94 - 2.86 (m, 2H), 2.10 - 1.71 (m, 4H), 1.66 - 1.55 (m, 1H), 1.05 (s, 9H).19F NMR (376 MHz, Chloroforms / ) 3 -184.21 (s, IF).

[0672] Intermediate 9 & 10: (2A,35,7a5)-7a-((( / erLButyldiphenylsilyl)oxy)methyl-t / 2)-2-fluoro-3- methylhexahydro- IT / -pyrrolizine. & (2A,3A,7a5)-7a-((( / erLbutyldiphenylsilyl)oxy)methyls / 2)- 2-fluoro-3 -methylhexahydro- 1 / 7-pyrrolizineD^pOTBDPS D^OTBDPS D^OTBDPSIntermediate s Intermediate s Intermediate 10

[0673] To a mixture of Intermediate 8 (3.6 g, 8.70 mmol) and chloroiridium;methanidylidyneoxidanium; bis(triphenylphosphane) (0.14 g, 0.17 mmol) in DCM (36 mL) under N2 was added 1,1,3,3-tetramethyldisiloxane (2.34 g, 17.40 mmol) at room temperature. The mixture was stirred at room temperature for 0.5 h. Methylmagnesium bromide (1.0 M in THF, 17.41 mL, 17.40 mmol) was added to the above mixture at -70 °C. The resulting mixture was stirred at room temperature for 4 h. The resulting mixture was quenched with sat. NH4CI aq. (100 mL) in an ice bath and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with PE / EA (7: 1)) to give two isomers. The first eluting isomer was concentrated to give the title compound (Intermediate 9, 0.6 g, 16% yield). MS: m / z = 414.20 [M + H]+.1H NMR (400 MHz, Chloroform- ) 67.71 - 7.57 (m, 4H), 7.43 - 7.35 (m, 6H), 4.78 - 4.63 (m, 1H), 3.16 - 2.70 (m, 3H), 2.39 - 2.31 (m, 1H), 2.03 - 1.78 (m, 3H), 1.75 - 1.62 (m, 2H), 1.08 - 1.06 (m, 12H).19F NMR (376 MHz, Chloroforms / ) 3 -182.46 (s, IF). The second eluting isomer was concentrated to give the other title compound (Intermediate 10, 1.8 g, 49% yield). MS: m / z = 414.25 [M + H]+. 'H NMR (400 MHz, Chloroforms / ) 67.68 - 7.64 (m, 4H), 7.43 - 7.34 (m, 6H), 5.00 - 4.85WSGR Docket No. 62619-756.601(m, 1H), 3.19 - 2.79 (m, 3H), 2.23 - 1.95 (m, 3H), 1.82 - 1.63 (m, 3H), 1.32 (d, J= 7.2 Hz, 3H), 1.06 (s, 9H).19F NMR (376 MHz, Chloroforms / ) 3 -187.10 (s, IF).

[0674] Intermediate 11: ((2 / ,3 / ,7ak)-2-fluoro-3-rnethyltetrahydro-l 7 / -pyrrolizin-7a(57 / )-yl)methans / 2- olDJP°HIntermediate 10 Intermediate 11

[0675] To a solution of Intermediate 10 (400 mg, 0.97 mmol) in methanol (4.0 mL) was added NH4F (1.43 g, 38.61 mmol) at room temperature. The reaction mixture was heated at 65 °C for 4 h. The resulting mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by / Vc -TLC (DCM: MeOH = 10: 1) to afford the title compound (Intermediate 11, 110 mg, 64% yield). MS: m / z = 176.05 [M + H]+. 'H NMR (400 MHz, DMSO-t / r,) 65.11 - 4.96 (m, 1H), 3.26 - 2.24 (m, 1H), 3.17 - 2.87 (m, 2H), 2.18 - 1.54 (m, 6H), 1.25 - 1.19 (m, 3H).19F NMR (376 MHz, DMSOs / r,) 6 -186.00 (s, IF).

[0676] Intermediate 12: 7-Chloro-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3- t / ]pyrimidin-4-ol

[0677] Step 1: Ethyl 4-(bis( / er / -butoxycarbonyl)amino)-6-chloro-5-fluoronicotinate

[0678] To a solution of ethyl 4-amino-6-chloro-5-fluoronicotinate (36 g, 164.7 mmol) and DMAP (2.0 g, 16.5 mmol) in CH2Q2 (300 mL) in a 1 L three-necked flask were added BOC2O (83 mL, 362.3 mmol) dropwise and TEA (69 mL, 494 mmol). The mixture was at 25 °C for 2 h. The reaction mixture was quenched with sat. NH4CI aq. (I L) and extracted with CH2CI2 (500 mL x 3). The combined organic layers were washed with brine (2 L), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to give the title compound (70 g, 93 % yield) as a yellow solid, which was used in the next step without further purification. MS: m / z = 419.2 [MWSGR Docket No. 62619-756.601+ H]+. 'H NMR (400 MHz, Chloroform^ / ) 68.79 (s, 1H), 4.37 (q, J= 12 Hz, 2H), 1.46 - 1.36 (m, 21H).19F NMR (376 MHz, Chloroforms / ) 6 -126.24.

[0679] Step 2: Ethyl 4-(bis(terLbutoxycarbonyl)amino)-2-bromo-6-chloro-5-fluoronicotinate & ethyl 2- bromo-4-((tert-butoxycarbonyl)amino)-6-chloro-5-fluoronicotinate

[0680] To a solution of ethyl 4-(bis(tert-butoxycarbonyl)amino)-6-chloro-5-fluoronicotinate (14 g, 33.4 mmol) in THF (100 mL) was added lithium:chloro-(2,2,6,6-tetramethyl-l- piperidyl)magnesium: chloride (60 mL, 1 M in THF) dropwise at -40 °C under N2 over 30 min. The mixture was stirred at this temperature for 4 h under N2. 1,2-Dibromo- 1, 1,2,2-tetrachloro- ethane (4.81 mL, 40.1 mmol) was added dropwise at -40 °C under N2. The resulting mixture was stirred at -40 °C for an additional 4 h under N2. The mixture was quenched with sat. NH4CI aq. (100 mL) slowly at -40 °C under N2 and extracted with EtOAc (100 mL x 4). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 25% of CH2CI2 in / / -hexane) to give the title compound (8.2 g, 47% yield, spot 1) as a white solid. MS: m / z = 519.0, 521.1 [M + Na]+.XH NMR (400 MHz, Chloroform- ) 84.40 (q, J= 12 Hz, 2H), 1.46 (s, 18H), 1.38 (t, J= 12 Hz, 3H).19F NMR (376 MHz, Chloroforms / ) 6 -127.79. Ethyl 2-bromo-4-(( / c / 7-butoxycarbonyl)amino)-6-chloro-5- fluoronicotinate (2.7 g, 20% yield, spot 2) was obtained as a white solid. MS: m / z = 397.0, 398.9 [M + H]+. 'H NMR (400 MHz, Chloroform- ) 67.13 (s, 1H), 4.42 (q, J= 12 Hz, 2H), 1.49 (s, 9H), 1.42 (t, J= 12 Hz, 3H).19F NMR (376 MHz, Chloroform- ) 6 -130.03.

[0681] Step 3: Ethyl 4-amino-2-bromo-6-chloro-5-fluoronicotinate

[0682] A solution of ethyl 4-(bis( / c77-butoxycarbonyl)amino)-2-bromo-6-chloro-5-fluoronicotinate (21 g, 42.2 mmol) in HC1 (200 mL, 2M in EtOAc) was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give the title compound (13.5 g, 93% yield, HC1 salt) as a yellow solid. MS: m / z = 296.9, 299.0 [M + H]+. 'H NMR (Dimethylsulfoxides / e) 67.21 (s, 2H), 4.36 - 4.32 (q, J = 12 Hz, 2H), 1.29 (t, J = 12 Hz, 3H).19F NMR (376 MHz, Dimethylsulfoxides / e) 6 -131.18.

[0683] Step 4: Ethyl 4-amino-6-chloro-5-fluoro-2-((triisopropylsilyl)ethynyl)nicotinate

[0684] A mixture of ethyl 4-amino-2-bromo-6-chloro-5-fluoronicotinate (13.5 g, 40.4 mmol, HC1 salt),Pd(PPh3)2C12 (2.3 g,) and Cui (1.15 g, 6.1 mmol) in THF (120 mL) were added TEA (161.7 mmol, 22.5 mL) and ethynyl(triisopropyl)silane (48.5 mmol, 10.9 mL). The mixture was degassed and purged with N2 three times. The mixture was stirred at 40 °C under N2 for 2 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 15% of EtOAc in petroleum ether) to give the title compound (12.6 g, 76% yield) as a yellow solid. MS: m / z = 399.3 [M + H]+. 'HWSGR Docket No. 62619-756.601NMR (400 MHz, Chloroform-^ 66.11 (s, 2H), 4.42 (q, J= 7.2 Hz, 2H), 1.39 (t, J= 7.2 Hz, 3H), 1.18 - 1.07 (m, 21H). 19F NMR (376 MHz, Chloroforms / ) 6 -143.40.

[0685] Step 5: 4-Amino-6-chloro-5-fluoro-2-((triisopropylsilyl)ethynyl)nicotinic acid

[0686] To a solution of ethyl 4-amino-6-chloro-5-fluoro-2-((triisopropylsilyl)ethynyl)nicotinate (7 g,17.5 mmol) in MeOH (20 mL) and THF (20 mL) was added NaOH (15 mL, 3 M in H2O). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The mixture was neutralized with 3M HC1 aq. and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (120 mL) and dried over anhydrous Na2SC>4, filtered, and concentrated to give the title compound (6.5 g, 98% yield) as a yellow solid. MS: m / z = 371.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxides / r,) 67.28 (s, 2H), 1.11 - 1.09 (m, 21H).19F NMR (376 MHz, Dimethylsulfoxide-t / 6) 6 -143.63.

[0687] Step 6: 7-Chloro-8-fluoro-2-mercapto-5-((triisopropylsilyl)ethynyl)pyrido[4,3-J]pyrimidin-4-ol

[0688] A mixture of 4-amino-6-chloro-5-fluoro-2-((triisopropylsilyl)ethynyl)nicotinic acid (20 g, 54 mmol) in SOCI2 (150 mL) was stirred at 50 °C under N2 for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in acetone (150 mL) under N2 and then NH4SCN (8.2 g, 108 mmol) was added at 25 °C. The mixture was stirred at this temperature for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 15% of EtOAc in petroleum ether) to give the title compound (17.5 g, 77% yield) as a yellow solid. MS: m / z = 412.2 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-t / 6) 6 13.19 (s, 1H), 12.75 (s, 1H), 1.11-1.08 (m, 21H).19F NMR (376 MHz, Dimethylsulfoxide-t / 6) 6 -132.06.

[0689] Step 7: 7-Chloro-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3s / ]pyrimidin-4- ol

[0690] To a mixture of 7-chloro-8-fluoro-2-mercapto-5-((triisopropylsilyl)ethynyl)pyrido[4,3- t / ]pyrimidin-4-ol (20 g, 42 mmol) and NaOH (62.6 mL, 1 M in H2O) in MeOH (150 mL) was added CH3I (2.4 mL, 39.1 mmol) dropwise at 25 °C under N2. The mixture was stirred at 25 °C under N2 for 1 h. The reaction mixture was quenched with water (150 mL) at 20 °C and neutralized with 3M HC1 aq. to give a precipitate. The precipitate was filtered. The filter cake was washed with water (120 mL) and dried under reduced pressure to give the title compound (Intermediate 12, 115.5 g, 85% yield). MS: m / z = 426.1 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxides / r,) 69.31 (s, 1H), 2.70 (s, 3H), 1.16 - 1.05 (m, 21H).19F NMR (376 MHz, Dimethylsulfoxide- e) 6 -131.17.WSGR Docket No. 62619-756.601

[0691] Intermediate 13: 6-Fluoro-4-(8-fluoro-4-((15',75',85)-8-fluoro-5-oxa-2-azabicyclo[5. L0]octan-2- yl)-2-(methylsulfmyl)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-J]pyrimidin-7-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-amine

[0692] Step 1: 4,7-Dichloro-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3- ]pyrimidine

[0693] To a solution of Intermediate 12 (5 g, 11.7 mmol) in CH2CI2 (50 mL) were added DIPEA (6.13 mL, 35.2 mmol) and POCI3 (5.47 mL, 58.7 mmol) dropwise at 0 °C under N2. The mixture was stirred at 25 °C under N2 for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound (5.2 g, crude) as a yellow solid, which was used in the next step without further purification. MS: m / z = 444.0 [M + H]+.

[0694] Step 2: (l£,7£,85)-2-(7-Chloro-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3- J]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

[0695] To a solution of 4,7-dichloro-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3- ]pyrimidine (5.1 g, 11.5 mmol) in CH2CI2 (70 mL) were added DIPEA (9.99 mL, 57.4 mmol) and Intermediate 5 (2.43 g, 11.5 mmol, HBr salt) at -40 °C under N2. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H2O (150 mL) and extracted with CH2Q2 (100 mL x 3). The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 10% of EtOAc in petroleum ether) to give the title compound (5.2 g, 84% yield for 2 steps) as a yellow solid. MS: m / z = 539.1 [M + H]+.!H NMR (400 MHz, Chloroforms / ) 84.63 - 4.38 (m, 3H), 4.03 - 3.82 (m, 2H), 3.67 - 3.47 (m, 2H), 2.73 - 2.60 (m, 1H), 2.58 (s, 3H), 2.27 - 2.10 (m, 1H), 1.20 - 1.10 (m, 21H).19F NMR (376 MHz, Chloroform- d) 6 -134.16, -205.31.WSGR Docket No. 62619-756.601

[0696] Step 3: 6-Fluoro-4-(8-fluoro-4-((15',75',85)-8-fluoro-5-oxa-2-azabicyclo[5.1,0]octan-2-yl)-2- (methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-J]pyrimidin-7-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-amine

[0697] A mixture of (l£,7£,85)-2-(7-chloro-8-fluoro-2-(methylthio)-5- ((triisopropylsilyl)ethynyl)pyrido[4,3-J]pyrimidin-4-yl)-8-fluoro-5-oxa-2- azabicyclo[5.1.0]octane (830 mg, 1.54 mmol), Intermediate 15 (776 mg, 1.54 mmol), K3PO4 (980 mg, 4.62 mmol), and Ad2nBuP-Pd-G3 (cataCXiumAPdG3) (112 mg, 154 pmol) in 1,4- di oxane (10 mL) and H2O (2 mL) was degassed and purged with N2 three times. The mixture was stirred at 100 °C under N2 for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 40% of EtOAc in petroleum ether) to give the title compound (1 g, 76% yield) as a yellow solid. MS: m / z = 844.3 [M + H]+. 'H NMR (400 MHz, Chloroform- ) 87.64 - 7.56 (m, 1H), 7.19 (t, J = 8.8 Hz, 1H), 7.08 (s, 1H), 6.92 (s, 1H), 4.70 - 4.54 (m, 2H), 4.47 - 4.35 (m, 1H), 4.04 - 3.92 (m, 2H), 3.72 - 3.54 (m, 2H), 2.75 - 2.65 (m, 1H), 2.59 (s, 3H), 2.21 - 2.12 (m, 1H), 1.18 - 1.10 (m, 21H), 0.91 - 0.84 (m, 18H), 0.68 - 0.58 (m, 3H).19F NMR (376 MHz, Chloroform^ / ) 6 -109.07, -136.72, -137.06, -205.63, -205.70.

[0698] Step 4: 6-Fluoro-4-(8-fluoro-4-((15',75',85)-8-fluoro-5-oxa-2-azabicyclo[5.1,0]octan-2-yl)-2- (methylsulfinyl)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-J]pyrimidin-7-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-amine

[0699] To a solution of 6-fluoro-4-(8-fluoro-4-((15',75',85)-8-fluoro-5-oxa-2-azabicyclo[5.1,0]octan-2- yl)-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-J]pyrimidin-7-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-amine (900 mg, 1.07 mmol) in CH2CI2 (15 mL) was added m-CPBA (216 mg, 1.07 mmol, 85% purity) at 25 °C. The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was quenched with sat. Na2S20s aq. (50 mL) at 0 °C and extracted with CH2Q2 (50 mL x 3). The combined organic layers were washed with sat.Na2S2C>3 aq (50 mL) and brine (50 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 20% of EtOAc in petroleum ether) to give the title compound (Intermediate 13, 680 mg, 70% yield). MS: m / z = 860.3 [M + H]+. 'H NMR (400 MHz, Chloroform- ) 67.69 - 7.59 (m, 1H), 7.26 - 7.24 (m, 1H), 7.24 - 7.19 (m, 1H), 7.16 - 6.97 (m, 1H), 4.93 - 4.66 (m, 2H), 4.48 - 4.34 (m, 1H), 4.31 - 3.78 (m, 3H), 3.73 - 3.65 (m, 1H), 3.09 - 2.96 (m, 3H), 2.88 - 2.68 (m, 1H), 2.26 - 2.17 (m, 1H), 1.18 - 1.08 (m, 21H), 0.89 - 0.78 (m, 18H), 0.66 - 0.54 (m, 3H).19F NMR (376 MHz, Chloroform- ) 6 -108.36, -133.82, -205.08.WSGR Docket No. 62619-756.601

[0700] Intermediate 14 & 15: A-(6-Fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-yl)-l,l-diphenylmethanimine & 6-fluoro-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine

[0701] Step 1: 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-l,3-diol

[0702] To a solution of 7-fluoronaphthalene-l,3-diol (50 g, 281 mmol) and 2- bromoethynyl(triisopropyl)silane (77 g, 295 mmol) in 1,4-dioxane (334 mL) were added KOAc (55.1 g, 561 mmol) and dichlororuthenium: l-isopropyl-4-methyl-benzene (17.2 g, 28.1 mmol). The mixture was stirred at 110 °C under N2 for 2 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent: 0 ~ 5% of EtOAc in petroleum ether) to give the title compound (70 g, 194 mmol, 69% yield) as a brown solid. MS: m / z = 359.1 [M+ H]+.!H NMR (400 MHz, Chloroforms / ) 89.15 (s, 1H), 7.59 (dd, J= 5.6, 9.2 Hz, 1H), 7.17 (t, J= 8.8 Hz, 1H), 6.77 - 6.62 (m, 2H), 1.21 - 1.15 (m, 21H).19F NMR (376 MHz, Chloroforms / ) 6 -112.51.

[0703] Step 2: 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-l,3- diylbis(trifluoromethanesulfonate)

[0704] To a solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-l,3-diol (140 g, 390 mmol) and DIPEA (408 mL, 2.34 mol) in CH2CI2 (3.5 L) was added TfzO (258 ml, 1.56 mol) dropwise under N2 at 0 °C. The mixture was stirred at 0 °C under N2 for 2 h. The reaction mixture was partitioned between CH2Q2 (500 mL) and H2O (2 L). The organic phase was separated, washed with brine (500 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent: 0 ~ 3% of EtOAc in petroleum ether) to give the title compound (218 g, 340 mmol, 87% yield) as a brown solid. 'H NMR (400 MHz, Chloroforms / ) 67.87 (dd, J= 5.2, 9.2 Hz, 1H), 7.80 (d, J= 2.4 Hz, 1H), 7.54 - 7.47 (m, 2H), 1.26 - 1.21 (m, 3H), 1.19 - 1.15 (m, 18H).

[0705] Step 3: 3-((Diphenylmethylene)amino)-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl tri fluoromethanesulfonateWSGR Docket No. 62619-756.601

[0706] A mixture of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-l,3- diylbis(trifluoromethanesulfonate) (94 g, 151 mmol), diphenylmethanimine (54.7 g, 302 mmol, 50.7 mL), (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (17.5 g, 30.2 mmol), Pd2(dba)s (6.91 g, 7.55 mmol), and CS2CO3 (148 g, 453 mmol) in toluene (1800 mL) was degassed, purged with N2 three times, and stirred at 100 °C under N2 for 2 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent: 0 ~ 3% of EtOAc in petroleum ether) to give the crude product (80 g) as a brown solid. The crude was triturated with MeOH (150 mL) at 25°C for 20 min and filtered. The filter cake was dried under reduced pressure to give the title compound (70 g, 94.2 mmol, 62% yield) as a yellow solid. MS: m / z = 654.3 [M+ H]+.!H NMR (400 MHz, Chloroform^ / ) 87.78 (d, J= 8.0 Hz, 2H), 7.57 - 7.51 (m, 2H), 7.48 - 7.41 (m, 2H), 7.27 (s, 2H), 7.26 - 7.19 (m, 2H), 7.17 - 7.01 (m, 4H), 1.22 - 1.13 (m, 21H).19F NMR (376 MHz, Dimethylsulfoxide-d6) 6 -71.40, -104.22.

[0707] Step 4: A-(6-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-yl)- 1,1 -diphenylmethanimine & 6-fluoro-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine

[0708] A mixture of 3-((diphenylmethylene)amino)-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l- yl trifluoromethanesulfonate (50 g, 76.5 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (39 g, 153 mmol), KOAc (30 g, 306 mmol), and Pd(dppf)C12 (11.2 g, 15.3 mmol) in 1,4-dioxane (600 mL) was degassed, purged with N2 three times, and stirred at 100 °C under N2 for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent: 0-100% of EtOAc in petroleum ether) to give the title compound (Intermediate 14, 9 g, 14.3 mmol, 19% yield) and the other title compound (Intermediate 15, 10 g, 21.4 mmol, 28% yield). Spectra for Intermediate 14: MS: m / z = 632.4 [M+ H]+. 'H NMR (400 MHz, Dimethylsulfoxide-t / r,) 67.86 - 7.79 (m, 1H), 7.72 - 7.67 (m, 2H), 7.60 - 7.53 (m, 1H), 7.53 - 7.47 (m, 2H), 7.42 (t, J= 9.2 Hz, 1H), 7.34 - 7.27 (m, 4H), 7.22 - 7.16 (m, 2H), 7.14 - 7.10 (m, 1H), 1.27 (s, 12H), 1.14 - 1.08 (m, 21H).19F NMR (376 MHz, Dimethylsulfoxidede) 6 -106.71. Spectra for Intermediate 15: MS: m / z = 468.3 [M+ H]+. 'H NMR (400 MHz, Dimethylsulfoxide-t / r,) 67.67 - 7.57 (m, 1H), 7.27 (t, J= 9.0 Hz, 1H), 7.23 - 7.17 (m, 1H), 6.89 (d, = 2.4 Hz, 1H), 5.48 (s, 2H), 1.33 (s, 12H), 1.17 - 1.11 (m, 21H).19F NMR (376 MHz, Dimethylsulfoxide-d6) 6 -112.20.

[0709] Intermediate 16: 2,4,7-Trichloro-8-fhioro-5-(prop-l-yn-l-yl)pyrido[4,3-d]pyrimidineWSGR Docket No. 62619-756.601

[0710] Step 1: Ethyl 4-amino-6-chloro-5-fluoro-2-(prop-l-yn-l-yl)nicotinate

[0711] A mixture of ethyl 4-amino-2-bromo-6-chloro-5-fluoronicotinate (18.5 g, 57.8 mmol, refer to Intermediate 12 for detail procedures), Pd(PPh3)2C12 (4.0 g, 5.8 mmol), and Cui (2.2 g, 11.6 mmol) in THF (60 mL) was degassed and purged with N2 three times. To the mixture were added TEA (48.3 mL, 347 mmol), trimethyl(prop-l-ynyl)silane (10.3 mL, 69.4 mmol), and TABF (69.4 mL, 1 M in THF). The mixture was stirred at 50 °C under N2 for 6 h. The reaction mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 20% ~ 53% of CH2CI2 in / / -hexane) to give a crude product. The crude was triturated with a mixture solvent of CH2CI2 (30 mL) and / / -hexane (300 mL) at 20 °C for 30 min to give the title compound (12.4 g, 77% yield) as a yellow solid. MS: m / z = 257.1 [M + H]+. 'HNMR (400 MHz, Chloroform- ) 86.26 (s, 2H), 4.40 (q, J= 7.2 Hz, 2H), 2.08 (s, 3H), 1.43 (t, J= 7.2 Hz, 3H).19F NMR (376 MHz, Chloroforms / ) 6 -144.56.

[0712] Step 2: Ethyl 6-chloro-5-fluoro-2-(prop-l-yn-l-yl)-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate

[0713] To a solution of ethyl 4-amino-6-chloro-5-fluoro-2-(prop-l-yn-l-yl)nicotinate (12.4 g, 42.4 mmol) in THF (120 mL) was added 2,2,2-trichloroacetyl isocyanate (12 g, 63.5 mmol) slowly under N2. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound (20 g, crude) as a yellow solid, which was used in the next step without further purification. MS: m / z = 444.0, 446.0 [M + H]+.

[0714] Step 3: 7-Chloro-8-fhioro-5-(prop-l-yn-l-yl)pyrido[4,3s / ]pyrimidine-2,4-diol

[0715] To a solution of ethyl 6-chloro-5-fluoro-2-(prop-l-yn-l-yl)-4-(3-(2,2,2- trichloroacetyl)ureido)nicotinate (20 g, 41.2 mmol) in MeOH (50 mL) was added NH3 (60 mL, 7 M in MeOH). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was triturated with MTBE (200 mL) at 20 °C for 30 min and filtered. The filter cake was dried under reduced pressure to give the title compound (11 g, 90% yield for 2 steps) as a white solid. MS: m / z = 254.1 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide- e) 62.05 (s, 3H).19F NMR (376 MHz, Dimethylsulfoxide- e) 6 -138.64.WSGR Docket No. 62619-756.601

[0716] Step 4: 2,4,7-Trichloro-8-fluoro-5-(prop-l-yn-l-yl)pyrido[4,3-t / ]pyrimidine

[0717] A mixture of ethyl 7-chloro-8-fluoro-5-(prop-l-yn-l-yl)pyrido[4,3-J]pyrimidine-2,4-diol (10 g,39.43 mmol) and DIPEA (27.5 mL, 158 mmol) in toluene (100 mL) was degassed and purged with N2. POCI3 (18.38 mL, 197.15 mmol) was added to the mixture at 25 °C under N2. The mixture was stirred at 100 °C under N2 for 3 h. The mixture was concentrateed and azeotroped with toluene (50 mL) to remove excess POCI3. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 35% of CH2CI2 in / / -hexane) to give the title compound (Intermediate 16, 5.2 g, 45% yield). MS: m / z = 289.9, 291.9 [M + H]+. 'H NMR (400 MHz, Chloroforms / ) 62.25 (s, 3H).19F NMR (376 MHz, Chloroforms / ) 6 -133.48.

[0718] Intermediate 17: (lS,7S,8S)-2-(7-Chloro-2,8-difluoro-5-(prop-l-yn-l-yl)pyrido[4,3- d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octaneCl Step 1Intermediate 5 Step 2‘ClIntermediate 16 CI^JT Cl ClIntermediate 17

[0719] Step 1: (l£,7£,85)-2-(2,7-dichloro-8-fhioro-5-(prop-l-yn-l-yl)pyrido[4,3sZ]pyrimidin-4-yl)-8- fluoro-5-oxa-2-azabicyclo[5.1.0]octane

[0720] To a solution of Intermediate 16 (2.8 g, 9.64 mmol) and DIPEA (6.7 mL, 38.6 mmol) in CH2CI2(30 mL) was added a solution of Intermediate 5 (2.04 g, 9.64 mmol, HBr salt) in CH2CI2 (10 mL) at -78 °C under N2. The reaction mixture was stirred at -78 °C under N2 for 1 h. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (60 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 20% of EtOAc in petroleum ether) to give the title compound (3.4 g, 82% yield) as a yellow solid. MS: m / z = 385.1 [M + H]+.1H NMR (400 MHz, Chloroforms / ) 84.65 (d, J= 13.6 Hz, 1H), 4.51 - 4.38 (m, 1H), 4.34 - 4.20 (m, 1H), 4.06 - 3.97 (m, 1H), 3.88 (t, J= 11.6 Hz, 1H), 3.73 - 3.53 (m, 2H), 2.77 - 2.63 (m, 1H), 2.34 - 2.15 (m, 4H).

[0721] Step 2: (15',75',85)-2-(7-chloro-2,8-difluoro-5-(prop-l-yn-l-yl)pyrido[4,3- ]pyrimidin-4-yl)-8- fluoro-5-oxa-2-azabicyclo[5.1.0]octane

[0722] To a solution of (15',75',85)-2-(2,7-dichloro-8-fluoro-5-(prop-l-yn-l-yl)pyrido[4,3-t / ]pyrimidin- 4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (3.2 g, 8.31 mmol) in dry DMSO (30 mL) was added KF (965 mg, 16.6 mmol) at 25 °C under N2. The mixture was stirred at 100 °C under N2 for 2 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried overWSGR Docket No. 62619-756.601anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 40% of CH2Q2 in petroleum ether) to give the title compound (Intermediate 17, 1.9 g, 59% yield). MS: m / z = 369.0 [M + H]+.XH NMR (400 MHz, Chloroform^ / ) 64.61 (d, J= 14.0 Hz, 1H), 4.50 - 4.40 (m, 1H), 4.37 - 4.24 (m, 1H), 4.06 - 3.98 (m, 1H), 3.93 - 3.85 (m, 1H), 3.75 - 3.58 (m, 2H), 2.78 - 2.62 (m, 1H), 2.33 - 2.23 (m, 1H), 2.21 (s, 3H).19F NMR (376 MHz, Chloroform^ / ) 6 -41.49, -134.04, -205.36.

[0723] Intermediate 18: (1 / ,3 / ,5 / -dispiro[cyclopropane-l,2'-pyrrolizine-6',l"-cyclopropan]-7a'(777)- yl)methan-t / 2-olIntermediate 18

[0724] Step 1: 1'H, 3'H, 5 / -dispiro[cyclopropane-l, 2'-pyrrolizine-6', l"-cyclopropane]-7a'(7'Z / )- carboxylic acid

[0725] To a mixture of (17 / ,37 / ,5 / -dispiro[cyclopropane-l,2'-pyrrolizine-6',l"-cyclopropan]-7a'(777)- yl)methanol (1.4 g, 7.24 mmol) in acetone (15 mL) was added Jones reagent (14.5 mL, 2.5 M). The mixture was stirred at 25 °C under N2 for 1 h. The reaction mixture was quenched with isopropanol (100 mL) at 0 °C and neutralized with 6 N NaOH aq. The mixture was filtered and concentrated under reduced pressure. The residue was washed with a mixture of solvents (C LCh / MeOH (300 ml, 10:1)). The filtrate was concentrated under reduced pressure to give the title compound (1.5 g, 95% yield) as a yellow oil. MS: m / z = 208.2 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-t / e) 83.33 (d, J= 11.2 Hz, 2H), 3.08 (d, J= 11.2 Hz, 2H), 2.16 - 2.08 (m, 2H), 2.07 - 1.99 (m, 2H), 0.75 - 0.61 (m, 4H), 0.55 - 0.39 (m, 4H).

[0726] Step 2: Methyl 17 / ,37 / ,57 / -dispiro[cyclopropane-l,2'-pyrrolizine-6',l"-cyclopropane]-7a'(777)- carboxylate

[0727] A mixture of 17 / ,37 / ,5 / -dispiro[cyclopropane-l,2'-pyrrolizine-6',l"-cyclopropane]-7a'(777)- carboxylic acid (1.4 g, 6.75 mmol) in MeOH (15 mL) was degassed and purged with N2 three times. SOCI2 (1.23 mL, 16.9 mmol) was added to the mixture at 0 °C under N2. The mixture was stirred at 60 °C under N2 for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 5% of MeOH in CH2CI2) to give the title compound (640 mg, 41% yield) as a colorless oil. MS: m / z = 222.0 [M + H]+. 'HNMR (400 MHz, Chloroform- ) 63.76 (s, 3H), 3.06 (d, J= 9.2 Hz, 2H), 2.84 (d, J = 10.0 Hz, 2H), 2.19 (d, J= 12.4 Hz, 2H), 2.01 (d, J= 12.4 Hz, 2H), 0.64 - 0.43 (m, 8H).

[0728] Step 3: (17 / ,37 / ,57 / -dispiro[cyclopropane-l,2'-pyrrolizine-6',l"-cyclopropan]-7a'(7' )- yl)methan-t / 2-olWSGR Docket No. 62619-756.601

[0729] A mixture of methyl r / 7,3'7 / ,5' / 7-dispiro[cyclopropane-l,2'-pyrrolizine-6', l"-cyclopropane]- 7a'(7'Z / )-carboxylate (640 mg, 2.89 mmol) in THF (10 mL) was degassed and purged with N2 three times. IJAID4 (150 mg, 3.26 mmol) was added to the mixture at 0 °C under N2. The mixture was stirred at 0 °C under N2 for 1 h. The reaction mixture was quenched with Na2SC>4- 10 H2O (300 mg) at 0 °C till no air bubbles were formed. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 5% of MeOH in CH2CI2) to give the title compound (Intermediaet 18, 420 mg, 73% yield). MS: m / z = 196.2 [M + H]+. 'H NMR (400 MHz, Chloroform^ / ) 82.95 - 2.79 (m, 4H), 1.88 - 1.72 (m, 4H), 0.63 - 0.45 (m, 8H).

[0730] Intermediate 19 & 20: Ethyl (5)-6'-methylene-3'-oxotetrahydrospiro[cyclopropane-l, T- pyrrolizine]-7a'(577)-carboxylate & ethyl (A)-6'-methylene-3'-oxotetrahydrospiro[cyclopropane- l, T-pyrrolizine]-7a'(577)-carboxylateStep 3Step 1: Ethyl 2-(l-(2-ethoxy-2-oxoethyl)cyclopropyl)-2-nitroacetateA mixture of ethyl 2-cyclopropylideneacetate (150 g, 1.19 mol), ethyl 2-nitroacetate (152 mL, 1.37 mol) and K2CO3 (189 g, 1.37 mol) in THF (3000 mL) was degassed, purged with N2 three times, and stirred at 80 °C for 3 h under N2. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (1000 mL). The pH of the mixture was adjusted to around 3 with HC1 (1 L, 6 M in H2O). The mixture was extracted with CH2Q2 (1000 mL x 3). The combined organic layers were washed with brine (1000 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to give the title compound (308 g, crude), which was used in the next step without further purification.1H NMR (400 MHz, Chloroform- ) 65.02 (s, 1H), 4.30 - 4.20 (m, 2H), 4.15 - 4.06 (m, 2H), 2.64 - 2.53 (m, 1H), 1.32 - 1.27 (m, 3H), 1.27 - 1.20 (m, 3H), 1.07 - 0.99 (m, 1H), 0.94 - 0.77 (m, 3H).Step 2: Ethyl 6-oxo-5-azaspiro[2.4]heptane-4-carboxylateTo a solution of ethyl 2-(l-(2-ethoxy-2-oxoethyl)cyclopropyl)-2-nitroacetate (39.5 g, 152 mmol) in AcOH (400 mL) and EtOH (800 mL) was added Zn (99 g, 1.52 mol) in batches at 25 °C under N2. The mixture was stirred at 100 °C for 16 h under N2. The reaction mixture was filtered, and concentrated under reduced pressure. The residue was diluted with sat. NaHCCh aq. (500 mL)WSGR Docket No. 62619-756.601(pH was adjusted to around 8) and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 1% of MeOH in CH2CI2) to give the title compound (31.6 g, 56% yield). MS: m / z = 184.0 [M + H]+.1HNMR(400 MHz, Dimethylsulfoxide r,) 68.11 (s, 1H), 4.16 - 4.09 (m, 2H), 3.70 (s, 1H), 2.42 (d, J= 16.8 Hz, 1H) 2.01 - 1.95 (m, 1H), 1.20 (t, J= 7.2 Hz, 3H), 0.84 - 0.77 (m, 1H), 0.74 -0.66 (m, 1H), 0.66 - 0.58 (m, 2H).Step 3: Ethyl 6'-methylene-3'-oxotetrahydrospiro[cyclopropane-l,l'-pyrrolizine]-7a'(577)-carboxylateTo a solution of ethyl 6-oxo-5-azaspiro[2.4]heptane-4-carboxylate (20 g, 109 mmol) and 3-chloro-2-(chloromethyl)prop-l-ene (51 mL, 437 mmol) in THF (1000 mL) was added dropwise LiHMDS (229 mL, 1 M in THF) at -40 °C over 50 min under N2. The mixture was stirred at this temperature for 30 min, and continued to stirr at 25 °C for 15.5 h under N2. The reaction mixture was quenched with sat. NH4CI aq. (1000 mL) at 25 °C and extracted with EtOAc (lOOOmL x 3). The combined organic layers were washed with brine (2000 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 35% of EtOAc in petroleum ether) to give the title compound (6.5 g, 25% yield). MS: m / z = 236.1 [M + H]+.Step 4: Ethyl (5)-6'-methylene-3'-oxotetrahydrospiro[cyclopropane-l,l'-pyrrolizine]-7a'(577)-carboxylate & ethyl (A)-6'-methylene-3'-oxotetrahydrospiro[cyclopropane-l,l'-pyrrolizine]-7a'(577)-carboxylateEthyl 6'-methylene-3'-oxotetrahydrospiro[cyclopropane-l,l'-pyrrolizine]-7a'(5'H)-carboxylate (30 g) was separated by SFC (column: DAICEL CHIRALPAK AS (250 mm x 50 mm, 10 pm); mobile phase: [CO2-i-PrOH (0.1% NHi’^O)]; gradient: 45% ~ 50% B over 2.5 min) to give the title compound (Intermediate 19, 13.77 g, 46% yield, SFC peak 1, retention time: 1.216 min) and the other title compound (Intermediate 20, 14.4 g, 48% yield, SFC peak 2, retention time: 1.542 min). Spectra for Intermediate 19: MS: m / z = 236.0 [M + H]+.1H NMR (400 MHz, Chloroform-d) 85.10 - 4.98 (m...

Claims

WSGR Docket No. 62619-756.601CLAIMSWe claim:

1. A compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), C-(optionally substituted C3-C6 carbocyclyl), or C-SF5;Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,Oor'; and G is an optionally substituted 5- to 10-membered heterocyclyl; andR2is optionally substituted C2-C6 alkynyl;R3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andWSGR Docket No. 62619-756.601R12is selected from H, D, fluoro, chloro, bromo, optionally substituted C1-C6 alkyl, - CF3, amino, -COOH, -CONH2, -CN, or -OH;optionally wherein R11and R12are taken together with the carbon atoms to which they are attached to form an optionally substituted methylidene or an oxo group;provided that if Y is O and R3, R4, R5, R6, R9, and R10is H, then R12is not H or D; and provided that if Z is O, and R3, R4, R5, R6, R7, and R8is H, then R12is not H or D.

2. A compound having the structure of Formula (lb), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,; and G is an optionally substituted 5- to 10-membered heterocyclyl; andR2is optionally substituted C2-C6 alkynyl;R3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;WSGR Docket No. 62619-756.601optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andR12is selected from H, D, fluoro, chloro, -CN, or -OHprovided that if Y is O and R3, R4, R5, R6, R9, and R10is H, then R12is not H or D; and provided that if Z is O, and R3, R4, R5, R6, R7, and R8is H, then R12is not H or D.

3. A compound having the structure of Formula (II), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), C-(optionally substituted C3-C6 carbocyclyl), or C-SF5;Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,Oor'; and G is an optionally substituted 5- to 10-membered heterocyclyl;each R2is independently selected from H, or optionally substituted C1-C6 alkyl;R3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;WSGR Docket No. 62619-756.601optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andR12is selected from H, D, fluoro, chloro, bromo, optionally substituted C1-C6 alkyl, -CF3, amino, -COOH, -CONH2, -CN, or -OH;optionally wherein R11and R12are taken together with the carbon atoms to which they are attached to form an optionally substituted methylidene or an oxo group;Provided that if Y is O, Z is CR9R10, and R3, R4, R5, R6, R9, R10is H, then R12is not H or D;provided that if Y is CR7R8, Z is CR9R10, andR3, R4, R5, R6, R7, R8, R9, R10is H, then R12is not H or D; andprovided that if Y is CR7R8, and R3, R4, R5, R6, R7, R8is H, then Z cannot be O. A compound having the structure of Formula (lib), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;WSGR Docket No. 62619-756.601R1is L-G; wherein L is optionally substituted C1-C4 alkylene,or; and G is an optionally substituted 5- to 10-membered heterocyclyl;each R2is independently selected from H, or optionally substituted C1-C6 alkyl;R3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andR12is selected from H, D, fluoro, chloro, -CN, or -OHProvided that if Y is O, Z is CR9R10, and R3, R4, R5, R6, R9, R10is H, then R12is not H or D;provided that if Y is CR7R8, Z is CR9R10, andR3, R4, R5, R6, R7, R8, R9, R10is H, then R12is not H or D; andprovided that if Y is CR7R8, and R3, R4, R5, R6, R7, R8is H, then Z cannot be O.The compound of Formula (II), having the structure of Formula (lie), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);WSGR Docket No. 62619-756.601Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is CR7R8, and Z is CR9R10;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,or; and G is an optionally substituted 5- to 10-membered heterocyclyl;each R2is independently selected from H, or optionally substituted C1-C6 alkyl;R3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H;R12is selected from H, D, fluoro, chloro, -CN, or -OH; andprovided that if R3, R4, R5, R6, R7, R8, R9, R10is H, then R12is not H or D.The compound of Formula (II), having the structure of Formula (lid), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);WSGR Docket No. 62619-756.601Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,*x; and G is an optionally substituted 5- to 10-membered heterocyclyl;each R2is independently selected from H, or optionally substituted C1-C6 alkyl;R3is optionally substituted C1-C6 alkylR4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;R11is H; andR12is selected from H, D, fluoro, chloro, -CN, or -OH.A compound having the structure of Formula (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), C-(optionally substituted C3-C6 carbocyclyl), or C-SF5;Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;WSGR Docket No. 62619-756.601or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,O°r; and G is an optionally substituted 5- to 10-membered heterocyclyl;R2is H or optionally substituted C1-C6 alkyl;R3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andR12is selected from H, D, fluoro, chloro, bromo, optionally substituted C1-C6 alkyl, - CF3, amino, -COOH, -CONH2, -CN, or -OH;optionally wherein R11and R12are taken together with the carbon atoms to which they are attached to form an optionally substituted methylidene or an oxo group;provided that if Z is O, then the compound is notA compound having the structure of Formula (Illb), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6WSGR Docket No. 62619-756.601alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C- (optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,? x f; and G is an optionally substituted 5- to 10-membered heterocyclyl;R2is H or optionally substituted C1-C6 alkyl;R3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andR12is selected from H, D, fluoro, chloro, -CN, or -OHprovided that if Z is O, then the compound is notA compound having the structure of Formula (IV), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:WSGR Docket No. 62619-756.601p6 x Yz Z -r R, " D 4.RV \^R14R5\R4^N PR15R3R16R2X3R1J-L oL'O N X2Ar (IV)wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), C-(optionally substituted C3-C6 carbocyclyl), or C-SF5;Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,ov; and G is an optionally substituted 5- to 10-membered heterocyclyl;R2is optionally substituted C2-C6 alkenyl; andR3, R4, R5, R6, R7, R8, R9, R10, R13, R14, R15, R16each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;optionally wherein R14and R15together form an optionally substituted carbocyclyl ring;optionally wherein the carbocyclyl ring is further substituted with an optionally substituted methylidene.A compound having the structure of Formula (IVb), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:WSGR Docket No. 62619-756.601xz -t R 13D6 Y Z,A ARV ^R14R5\R4t? N FR15R3R16R2X3R1Jk ok <kV N X2Ar(Ivb)wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,ov; and G is an optionally substituted 5- to 10-membered heterocyclyl;R2is optionally substituted C2-C6 alkenyl; andR3, R4, R5, R6, R7, R8, R9, R10, R13, R14, R15, R16each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;optionally wherein R14and R15together form an optionally substituted carbocyclyl ring.The compound of Formula (IV), having the structure of Formula (IVc), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:WSGR Docket No. 62619-756.601R11is H; andR12is selected from H, D, fluoro, chloro, -CN, or -OH.The compound of Formula (IV), having the structure of Formula (IVd), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,or; and G is an optionally substituted 5- to 10-membered heterocyclyl;WSGR Docket No. 62619-756.601R2is optionally substituted C2-C6 alkenyl; andR3, R4, R5, R6, R7, R8, R9, and R10each is independently selected from H or optionally substituted C1-C6 alkyl;optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;R11is H; andR12is selected from H, D, fluoro, chloro, -CN, or -OH.A compound having the structure of Formula (V), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:wherein:X1is N or C-CN;X2is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CD3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), or C-(optionally substituted C3-C6 carbocyclyl);X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C1-C6 alkoxy), C-(optionally substituted C2-C6 alkenyl), C-(optionally substituted C2-C6 alkynyl), C-(optionally substituted C3-C6 carbocyclyl), or C-SF5;Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Y is O or CR7R8, and Z is O or CR9R10, provided that -Y-Z- is not -O-O-;or optionally -Y-Z- is -C(R8)=C(R9)-;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,; and G is an optionally substituted 5- to 10-membered heterocyclyl; andR3, R4, R5, R6, R7, R8, R9, R10, R13, R14, R15, R16each is independently selected from H or optionally substituted C1-C6 alkyl;WSGR Docket No. 62619-756.601optionally wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond;optionally wherein R14and R15together form an optionally substituted carbocyclyl ringoptionally wherein the carbocyclyl ring is further substituted with an optionally substituted methylidene.

14. The compound of Formula (V), having the structure of Formula (Vb), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof:R11is H; andR12is selected from H, D, fluoro, chloro, -CN, or -OH.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Y is O.

16. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Z is O.

17. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein -Y-Z- is -C(R8)=C(R9)-.

18. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R6and R7are taken together with the carbon atoms to which they are attached to form a double bond.

19. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Y is CR7R8, and Z is CR9R10.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R3is optionally substituted C1-C6 alkyl.

21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R3is optionally substituted C1-C2 alkyl.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R3is -CH3.

23. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R3is -CH2CH3.WSGR Docket No. 62619-756.60124. The compound of any one of claims 1-8, 11-12, or 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R12is H.

25. The compound of any one of claims 1-8, 11-12, or 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R12is chloro.

26. The compound of any one of claims 1-8, 11-12, or 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R12is fluoro.

27. The compound of any one of claims 1-8, 11-12, 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the28. The compound of any one of claims 1-8, 11-12, 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the29. The compound of any one of claims 1-8, 11-12, 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the30. The compound of any one of claims 1-8, 11-12, 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the31. The compound of any one of claims 1-8, 11-12, 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the32. The compound of any one of claims 1-8, 11-12, 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein theWSGR Docket No. 62619-756.60133. The compound of any one of claims 1-8, 11-12, 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the34. The compound of any one of claims 1-8, 11-12, 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the35. The compound of any one of claims 1-8, 11-12, 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the36. The compound of any one of claims 1-8, 11-12, 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the37. The compound of any one of claims 1-8, 11-12, 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the38. The compound of any one of claims 1-8, 11-12, 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein:WSGR Docket No. 62619-756.60139. The compound of any one of claims 1-8, 11-12, 14-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein:

0. The compound of any one of claims 1, 3, 7, 9, 13, 15-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein:WSGR Docket No. 62619-756.60141. The compound of any one of claims 9, 13, 15-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein:

42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X1is N.

43. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X1is C-CN.

44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is N.

45. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is C-H, C-D, C-F, or C-Cl.WSGR Docket No. 62619-756.60146. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is C-CN.

47. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is C-CH3 or C-CD3.

48. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is C-CF3.

49. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is C-CH3.

50. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is C-F.

51. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is C-(optionally substituted C1-C6 alkyl).

52. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is C-(C2-C6 optionally substituted alkenyl).

53. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is C-(optionally substituted C1-C6 alkoxy).

54. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is C-(optionally substituted C2-C6 alkynyl).

55. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is C-(optionally substituted C3-C6 carbocyclyl).

56. The compound of any one of claims 1-55, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X3is N.

57. The compound of any one of claims 1-55, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X3is C-H, C-F, or C-Cl.

58. The compound of any one of claims 1-55, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X3is C-F.

59. The compound of any one of claims 1-55, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X3is C-CF3.

60. The compound of any one of claims 1-55, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X3is C-CN.

61. The compound of any one of claim 1, 2, or claims 15-60, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R2is optionally substituted C2-C4 alkynyl.

62. The compound of any one of claim 1, 2, or claims 15-61, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R2is optionally substituted C2-C3 alkynyl.WSGR Docket No. 62619-756.60163. The compound of any one of claim 1, 2, or claims 15-62, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R2is optionally substituted ethynyl.

64. The compound of any one of claim 1, 2, or claims 15-62, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R2is optionally substituted propynyl.

65. The compound of any one of claims 3-6 or claims 15-60, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the N(R2)2 moiety is NHCH3.

66. The compound of any one of claims 3-6 or claims 15-60, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the N(R2)2 moiety is NHCD3.

67. The compound of any one of claim 7, 8, or claims 15-60, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the R2is -CH3.

68. The compound of any one of claim 7, 8, or claims 15-60, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the R2is -CD3.

69. The compound of any one of claim 7, 8, or claims 15-60, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the R2is H.

70. The compound of any one of claims 9-12, or 15-60, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the R2is optionally substituted C2-C4 alkenyl.

71. The compound of any one of claims 9-12, or 15-60, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the R2is optionally substituted C2-C3 alkenyl.

72. The compound of any one of claims 9-12, or 15-60, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the R2is optionally substituted vinyl.

73. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is a monocyclic optionally substituted aryl.

74. The compound of claim 73, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the monocyclic optionally substituted aryl is an optionally substituted phenyl.

75. The compound of claim 74, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted phenyl is substituted with an -OH group at the metaposition.

76. The compound of claim 74, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, wherein the optionally substituted phenylis0H77. The compound of claim 74, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted phenyl is selected from:WSGR Docket No. 62619-756.60178. The compound of claim 74, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted phenyl is substituted with an -NH2 group at the metaposition.

79. The compound of claim 74, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted phenyl is selected from:

80. The compound of claim 74, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted phenyl is selected from:

81. The compound of claim 74, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted phenyl isWSGR Docket No. 62619-756.601o'CF’NH282. The compound of claim 74, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted phenyl is a 2,3,5-trisubstituted phenyl.

83. The compound of claim 82, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the 2,3,5-trisubstituted phenyl is substituted with a 3 -hydroxy group.

84. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is a bicyclic optionally substituted aryl.

85. The compound of claim 84, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted aryl is an optionally substituted naphthyl.

86. The compound of claim 85, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted naphthyl is an optionally substituted 1-naphthyl.

87. The compound of claim 86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted 1-naphthyl is further substituted at the 8-position.

88. The compound of any one of claims 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

89. The compound of any one of claims 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:WSGR Docket No. 62619-756.60190. The compound of any one of claims 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:FOH OH OH OH OHOH OH OH OH91. The compound of any one of claims 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

92. The compound of any one of claims 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:WSGR Docket No. 62619-756.601The compound of any one of claims 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:The compound of any one of claims 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:WSGR Docket No. 62619-756.60195. The compound of any one of claims 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

96. The compound of any one of claims 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

97. The compound of any one of claims 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:WSGR Docket No. 62619-756.60198. The compound of any one of claims 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

99. The compound of any one of claims 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

00. The compound of any one of claims 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

01. The compound of any one of claims 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:WSGR Docket No. 62619-756.60102. The compound of any one of claims 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

03. The compound of any one of claims 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:WSGR Docket No. 62619-756.60104. The compound of any one of claims 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

05. The compound of any one of claims 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:WSGR Docket No. 62619-756.601106. The compound of any one of claims 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

107. The compound of any one of claims 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

108. The compound of any one of claims 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:WSGR Docket No. 62619-756.601109. The compound of any one of claims 84-86, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

11. The compound of claim 84, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted aryl is described by Formula (a):R23R17R22R18R21R19R20(a)wherein:R17is hydrogen, deuterium, or F;R18is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me;R19is hydrogen, deuterium, F, Cl, or Br;R20is hydrogen, deuterium, F, Cl, or Br;R21is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3;R22is hydrogen, deuterium, F, Cl, or -CN; andR23is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C=CH, -OCHF2, - OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.WSGR Docket No. 62619-756.601112. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is a monocyclic optionally substituted heteroaryl.

113. The compound of claim 112, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the monocyclic optionally substituted heteroaryl is an optionally substituted 2- pyridinyl.

114. The compound of claim 113, or a pharmaceutically acceptable salt, solvate, or deuteroisotopeKIMthereof, wherein the optionally substituted 2-pyridinylis2115. The compound of claim 113, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted 2-pyridinyl isNH2116. The compound of claim 112, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the monocyclic optionally substituted heteroaryl is an optionally substituted 4- pyridinyl.

117. The compound of claim 116, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted 4-pyridinyl isNH2118. The compound of claim 116, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted 4-pyridinyl isOH119. The compound of claim 112, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the monocyclic optionally substituted heteroaryl isWSGR Docket No. 62619-756.601120. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is a bicyclic optionally substituted heteroaryl.

121. The compound of claim 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl is selected from:

122. The compound of claim 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl is selected from:WSGR Docket No. 62619-756.601123. The compound of claim 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl is selected from:

124. The compound of claim 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl is selected from:

125. The compound of claim 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl isWSGR Docket No. 62619-756.601126. The compound of claim 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl is selected from:

127. The compound of claim 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl is selected from:

128. The compound of claim 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl is described by Formula (bl):R19R20(bl)wherein:R18is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me;R19is hydrogen, deuterium, F, Cl, or Br;R20is hydrogen, deuterium, F, Cl, or Br;R21is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3;R22is hydrogen, deuterium, F, Cl, or -CN; andR23is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C=CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

129. The compound of claim 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl is described by Formula (b2):WSGR Docket No. 62619-756.601R19R20(b2)wherein:R17is hydrogen, deuterium, or F;R19is hydrogen, deuterium, F, Cl, or Br;R20is hydrogen, deuterium, F, Cl, or Br;R21is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3;R22is hydrogen, deuterium, F, Cl, or -CN; andR23is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C=CH, -OCHF2, - OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

30. The compound of claim 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl is described by Formula (b3):R20(b3)wherein:R17is hydrogen, deuterium, or F;R18is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me; R20is hydrogen, deuterium, F, Cl, or Br;R21is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3;R22is hydrogen, deuterium, F, Cl, or -CN; andR23is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C=CH, -OCHF2, - OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

31. The compound of claim 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl is described by Formula (b4):R19(b4)wherein:R17is hydrogen, deuterium, or F;WSGR Docket No. 62619-756.601R18is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me;R19is hydrogen, deuterium, F, Cl, or Br;R21is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3;R22is hydrogen, deuterium, F, Cl, or -CN; andR23is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C=CH, -OCHF2, - OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

132. The compound of claim 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl is described by Formula (b5):R19R20(b5)wherein:R17is hydrogen, deuterium, or F;R18is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me;R19is hydrogen, deuterium, F, Cl, or Br;R20is hydrogen, deuterium, F, Cl, or Br;R22is hydrogen, deuterium, F, Cl, or -CN; andR23is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C=CH, -OCHF2, - OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

33. The compound of claim 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl is described by Formula (b6):wherein:R17is hydrogen, deuterium, or F;R18is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me;R19is hydrogen, deuterium, F, Cl, or Br;R20is hydrogen, deuterium, F, Cl, or Br;R21is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3; andR23is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C=CH, -OCHF2, - OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.WSGR Docket No. 62619-756.601134. The compound of claim 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl is described by Formula (b7):R23RV^ X A R22R21(b7)wherein:R17is hydrogen, deuterium, or F;R18is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me;R21is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3;R22is hydrogen, deuterium, F, Cl, or -CN; andR23is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C=CH, -OCHF2, - OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

135. The compound of claim 120, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the bicyclic optionally substituted heteroaryl is described by Formula (b8):wherein:R18is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me;R20is hydrogen, deuterium, F, Cl, or Br;R21is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3;R22is hydrogen, deuterium, F, Cl, or -CN; andR23is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C=CH, -OCHF2, - OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

136. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is:H2N137. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:WSGR Docket No. 62619-756.601138. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:H2N H2N139. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

140. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

141. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

142. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:WSGR Docket No. 62619-756.601143. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

144. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

145. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

146. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

147. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is:F148. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:WSGR Docket No. 62619-756.601149. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

150. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

151. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

152. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is:FNH2153. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:WSGR Docket No. 62619-756.601154. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

155. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

156. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

157. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

158. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:WSGR Docket No. 62619-756.601159. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

160. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

161. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

162. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is selected from:

163. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is:WSGR Docket No. 62619-756.601164. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is:F165. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is optionally substituted C1-C4 alkylene.

166. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein L is167. The compound of claim 165, or a pharmaceutically acceptable salt, solvate, or deuteroisotopethereof, whereinL is168. The compound of claim 165, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is optionally substituted Cl alkylene.

169. The compound of claim 168, or a pharmaceutically acceptable salt, solvate, or deuteroisotope D Dthereof, wherein Lis170. The compound of any one of claims 165-169, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is an optionally substituted 5- to 10-membered heterocyclyl.

171. The compound of any one of claims 165-169, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is described by formula (e):WSGR Docket No. 62619-756.601n is 0 or 1;V is absent, O, or CR34R35, and W is O or CR36R37,provided that -V-W- is not -O-O-; andR24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38and R39each is independently selected from H, D, optionally substituted C1-C6 alkyl, -OH, chloro, or fluoro;optionally wherein R24and R25, R26and R27, R28and R29, R30and R31, R32and R33, R34and R35, R36and R37, or R38and R39are taken together with the carbon atoms to which they are attached to form an optionally substituted alkene or optionally substituted carbocyclyl.

172. The compound of claim 171, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein V is O or CR34R35.

173. The compound of claim 171, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein V is absent.

174. The compound of claim 171, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein V is absent and n is 0.

175. The compound of claim 174, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R37and R38are taken together with the carbon atoms to which they are attached to form an optionally substituted carbocyclyl.

176. The compound of claim 175, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R37and R38are taken together with the carbon atoms to which they are attached to form an optionally substituted cyclopropyl.

177. The compound of claim 171, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein:n is 0;V is CR34R35and W is O; andR24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R38and R39each is independently selected from H, D, optionally substituted C1-C6 alkyl, -OH, chloro, or fluoro; optionally wherein R24and R25, R26and R27, R28and R29, R30and R31, R32and R33, R34and R35, or R38and R39are taken together with the carbon atoms to which they are attached to form an optionally substituted alkene or optionally substituted carbocyclyl.

178. The compound of claim 171, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein:n is 1;WSGR Docket No. 62619-756.601V is CR34R35and W is O; andR24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R38and R39each is independently selected from H, D, optionally substituted C1-C6 alkyl, -OH, chloro, or fluoro; optionally wherein R24and R25, R26and R27, R28and R29, R30and R31, R32and R33, R34and R35, or R38and R39are taken together with the carbon atoms to which they are attached to form an optionally substituted alkene or optionally substituted carbocyclyl.

179. The compound of claim 171, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein:n is 1;V is O and W is CR36R37; andR24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R36, R37, R38and R39each is independently selected from H, D, optionally substituted C1-C6 alkyl, -OH, chloro, or fluoro; optionally wherein R24and R25, R26and R27, R28and R29, R30and R31, R32and R33, R36and R37, or R38and R39are taken together with the carbon atoms to which they are attached to form an optionally substituted alkene or optionally substituted carbocyclyl.

180. The compound of any one of claims 171-179, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R24and R25are H.

181. The compound of any one of claims 171-180, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R26and R27are fluoro.

182. The compound of any one of claims 171-180, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R26is H and R27is fluoro.

183. The compound of any one of claims 171-180, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R26and R27are taken together with the carbon atoms to which they are attached to form an optionally substituted alkene.

184. The compound of claim 183, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted alkene is substituted with fluoro.

185. The compound of claim 183, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted alkene is substituted with optionally substituted Cl- C3 alkyl.

186. The compound of any one of claims 171-180, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R26and R27are taken together with the carbon atoms to which they are attached to form an optionally substituted carbocyclyl.WSGR Docket No. 62619-756.601187. The compound of claim 186, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R26and R27are taken together with the carbon atoms to which they are attached to form an optionally substituted cyclopropyl.

188. The compound of claim 186, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R26and R27are taken together with the carbon atoms to which they are attached to form a cyclopropyl.

189. The compound of claim 187 or 188, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the cyclopropyl is substituted with fluoro or chloro.

190. The compound of any one of claims 171-173, or 177-189, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R38and R39are taken together with the carbon atoms to which they are attached to form an optionally substituted carbocyclyl.

191. The compound of claim 190, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R38and R39are taken together with the carbon atoms to which they are attached to form an optionally substituted cyclopropyl.

192. The compound of any one of claims 171-191, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R28and R29are H.

193. The compound of any one of claims 171-191, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R28is H and R29is an optionally substituted C1-C2 alkyl.

194. The compound of claim 193, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R29is -CH3.

195. The compound of claim 193, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R29is -CH2CH3.

196. The compound of any one of claims 171-191, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R28and R29are H.

197. The compound of any one of claims 171-196, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R32and R33are H.

198. The compound of any one of claims 171-196, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R32and R33are D.

199. The compound of any one of claims 171-173, or 177-189, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R38and R39are H.

200. The compound of claim 171, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein V is CR34R35and wherein R34and R35are H.

201. The compound of claim 171, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein W is CR36R37and wherein R36and R37are H.WSGR Docket No. 62619-756.601202. The compound of any one of claims 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is selected from:NY N Y NN203. The compound of any one of claims 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is selected from:NO’ 204. The compound of any one of claims 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is selected from:N N205. The compound of any one of claims 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is described by Formula (c):N 'R'"RR2:(wherein,each R20-R30is independently selected from hydrogen or deuterium.

206. The compound of any one of claims 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is described by Formula (d):wherein,R31is selected from hydrogen, F, Cl, -CN, -OH, or optionally substituted C1-C4 alkyl; R32is hydrogen, deuterium or optionally substituted C1-C4 alkyl; andWSGR Docket No. 62619-756.601R33is hydrogen, deuterium, F, or optionally substituted C1-C4 alkyl.

207. The compound of any one of claims 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is selected from:

208. The compound of any one of claims 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is selected from:

209. The compound of any one of claims 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is selected from:

210. The compound of any one of claims 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is selected from:WSGR Docket No. 62619-756.601211. The compound of any one of claims 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:

212. The compound of any one of claims 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:

213. The compound of any one of claims 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:

214. The compound of any one of claims 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:WSGR Docket No. 62619-756.601215. The compound of any one of claims 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:

216. The compound of any one of claims 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:

217. The compound of any one of claims 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:WSGR Docket No. 62619-756.601218. The compound of any one of claims 165-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:

219. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, whereinR1isF220. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

221. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601222. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

223. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

224. The compound of any one of claims 1-156, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601225. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, ordeuteroisotope thereof, wherein R1isF.

226. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

227. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

228. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

229. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601230. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

231. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

232. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:er**F 233. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601234. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

235. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

236. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

237. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601238. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

239. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:cis cis240. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601241. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

242. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

243. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601244. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

245. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

246. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601247. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

248. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

249. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601250. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

251. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

252. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601'ci253. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

254. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:_ D D255. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601256. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

257. The compound any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

258. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

259. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601260. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

261. The compound any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

262. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

263. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

264. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

265. The compound any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

266. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601267. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

268. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

269. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

270. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

271. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

272. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601273. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

274. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

275. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

276. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

277. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

278. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601279. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

280. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

281. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

282. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

283. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

284. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601285. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

286. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

287. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

288. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

289. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

290. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601291. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

292. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

293. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

294. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is:

295. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is:

296. The compound of any one of claims 1-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:WSGR Docket No. 62619-756.601or297. The compound of any one of claims 1-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:

298. The compound of any one of claims 1-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:

299. The compound of any one of claims 1-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:

300. The compound of any one of claims 1-170, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:WSGR Docket No. 62619-756.601301. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is:1 D302. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is:

303. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is:

304. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is:

305. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is:WSGR Docket No. 62619-756.601306. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

307. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

308. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

309. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

310. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

311. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601312. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

314. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

315. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

316. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

317. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601318. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

319. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

320. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

321. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

322. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

323. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601324. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

325. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

326. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

327. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

328. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601329. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

330. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

331. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

332. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

333. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

334. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601335. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

336. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

337. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

338. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

339. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601340. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

341. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

342. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

343. The compound of any one of claims 1-164 selected from, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is:

344. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

345. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601346. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

347. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

348. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:D D / K D DN Xand f 4349. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

350. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:WSGR Docket No. 62619-756.601351. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

352. The compound of any one of claims 1-164, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is selected from:

353. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein theR6VY’Z\ R11R5X >^RR4T^N12~~ moiety is354. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein theR6 Y-Z\ R11R5^RR4? N12—J— moiety is355. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein theRRV5\ R”X N.. J^-R12moiety is356. The compound of any one of claims 353-355, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X1is N.

357. The compound of any one of claims 353-356, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is C-F, C-Cl, or C-H,358. The compound of claim 357, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X2is C-F.

359. The compound of any one of claims 353-358, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X3is N.WSGR Docket No. 62619-756.601360. The compound of any one of claims 353-358, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R2is optionally substituted C2-C4 alkynyl.

361. The compound of claim 360, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R2is optionally substituted C2-C3 alkynyl.

362. The compound of claim 360 or 361, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R2is optionally substituted ethynyl.

363. The compound of claim 360 or 361, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R2is optionally substituted propynyl.

364. The compound of any one of claims 353-363, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is optionally substituted C1-C2 alkylene.

365. The compound of any one of claims 353-364, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L isD Dor366. The compound of any one of claims 353-365, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is described by formula (e):R38A\nR31^T NR3O0> )R29(e)wherein:n is 0 or 1;V is absent, O, or CR34R35, and W is O or CR36R37,provided that -V-W- is not -O-O-; andR24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38and R39each is independently selected from H, D, optionally substituted C1-C6 alkyl, -OH, chloro, or fluoro;optionally wherein R24and R25, R26and R27, R28and R29, R30and R31, R32and R33, R34and R35, R36and R37, or R38and R39are taken together with the carbon atoms to which they are attached to form an optionally substituted alkene or optionally substituted carbocyclyl.

367. The compound of claim 366, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein V is absent and n is 0.WSGR Docket No. 62619-756.601368. The compound of claim 367, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R26is H and R27is fluoro.

369. The compound of claim 368, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R28is H and R29is an optionally substituted C1-C2 alkyl.

370. The compound of claim 369, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R29is -CH3.

371. The compound of claim 369, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R29is -CH2CH3.

372. The compound of claim 367, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R26and R27are taken together with the carbon atoms to which they are attached to form an optionally substituted alkene.

373. The compound of claim 372, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the optionally substituted alkene is substituted with fluoro.

374. The compound of claim 372 or 373, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R38is H and R39is an optionally substituted C1-C2 alkyl.

375. The compound of claim 372 or 373, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R38is H and R39is H.

376. The compound of claim 374, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R39is -CH3.

377. The compound of claim 367, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R26and R27are taken together with the carbon atoms to which they are attached to form an optionally substituted carbocyclyl.

378. The compound of claim 377, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R38and R39are taken together with the carbon atoms to which they are attached to form an optionally substituted carbocyclyl.

379. The compound of claim 377, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R26and R27are taken together with the carbon atoms to which they are attached to form an optionally substituted cyclopropyl.

380. The compound of claim 379, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the cyclopropyl is substituted with fluoro.

381. The compound of claim 378, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R38and R39are taken together with the carbon atoms to which they are attached to form an optionally substituted cyclopropyl.

382. The compound of any one of claims 353-365, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G isWSGR Docket No. 62619-756.601383. The compound of any one of claims 353-365, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is384. The compound of any one of claims 353-365, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is385. The compound of any one of claims 353-365, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is386. The compound of any one of claims 353-363, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is387. The compound of any one of claims 353-363, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is_ D D‘S '388. The compound of any one of claims 353-363, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1isWSGR Docket No. 62619-756.601389. The compound of any one of claims 353-363, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is390. The compound of any one of claims 353-363, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is391. The compound of any one of claims 353-363, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is392. The compound of any one of claims 353-363, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is393. The compound of any one of claims 353-363, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1isWSGR Docket No. 62619-756.601394. The compound of any one of claims 353-363, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R1is395. The compound of any one of claims 353-394, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar isFNH2396. The compound of any one of claims 353-394, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar isFOH397. The compound of any one of claims 353-394, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar isNH2398. The compound of any one of claims 353-394, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar isNH2WSGR Docket No. 62619-756.601399. The compound of any one of claims 353-394, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar is'i FCk400. The compound of any one of claims 353-394, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ar isF401. A compound, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, as described in Table 1.

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

403. A compound, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, as described in Figures 1-19.

404. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, as described in any one of claims 1-403, and a pharmaceutically acceptable excipient.

405. A method of preparing a pharmaceutical composition comprising mixing a compound, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, of any one of claims 1-403, and a pharmaceutically acceptable carrier.

406. A compound of any one of claims 1-403, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treatment of the human or animal body.

407. A compound of any one of claims 1-403, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treatment of cancer.

408. Use of a compound of any one of claims 1-403, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, in the manufacture of a medicament for the treatment of cancer.

409. A method of treating cancer in a patient in need thereof, comprising administering to the patient a compound as described in any one of claims 1-403, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof.

410. A method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound as described in any one of claims 1-403,WSGR Docket No. 62619-756.601or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient.

411. A method of inhibiting KRAS comprising contacting the enzyme with a compound of any one of claims 1-403, wherein the KRAS is contacted in an in vitro setting.

412. A method of inhibiting KRAS comprising contacting the enzyme with a compound of any one of claims 1-403, wherein KRAS is contacted in an in vivo setting.

Images