KRAS MODULATORS

Abstract

The invention relates to a KRAS inhibitor, a pharmaceutical composition containing such an inhibitor, and a method for using such a KRAS inhibitor to treat diseases or disorders.

Description

Attorney Docket No.62619-726601 KRAS MODULATORS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Patent Application No.63 / 583,975, filed on September 20, 2023; U.S. Patent Application No.63 / 584,247, filed on September 21, 2023; U.S. Patent Application No.63 / 611,382, filed on December 18, 2023; U.S. Patent Application No. 63 / 636,328, filed on April 19, 2024; and U.S. Patent Application No.63 / 671,340, filed on July 15, 2024, 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 or solvate, thereof:wherein: X1is N or C-CN; X2is N, C-H, C-F, C-CH3, C-Cl, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C2-C6 alkenyl), or C-(optionally substituted C3-C6 carbocyclyl); X3is N, C-H, C-F, C-Cl, C-CN, or C-CF3; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Attorney Docket No.62619-726601 R1is L-G; wherein L is optionally substituted C1-C4 alkylene,and G is an optionally substituted 5- to 10-membered heterocyclyl; -N(R2)R3form an optionally substituted heterocyclyl substituent selected from the group consisting of : (a) optionally substituted azabicyclo[3.1.0]hexane; (b) optionally substituted azabicyclo[4.1.0]heptane; (c) optionally substituted oxazabicyclo[4.1.0]heptane; (d) optionally substituted azabicyclo[5.1.0]octane; (e) optionally substituted oxazabicyclo[5.1.0]octane; (f) optionally substituted azabicyclo[6.1.0]nonane; (g) optionally substituted oxazabicyclo[6.1.0]nonane; (h) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl; (i) optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl; (j) optionally substituted azabicyclo[6.1.0]non-6-en-2-yl; (k) optionally substituted azabicyclo[6.1.0]non-5-en-2-yl; (l) optionally substituted azabicyclo[6.1.0]non-4-en-2-yl; (m) optionally substituted 3-oxa-2,6-diazabicyclo[5.1.0]oct-1-en-6-yl; (n) optionally substituted 2-oxa-3,6-diazabicyclo[5.1.0]oct-3-en-6-yl; (o) optionally substituted 4-oxa-2,5-diazabicyclo[5.1.0]oct-5-en-2-yl; (p) optionally substituted 3-oxa-2,7-diazabicyclo[6.1.0]non-1-en-7-yl; (q) optionally substituted 2-oxa-3,7-diazabicyclo[6.1.0]non-3-en-7-yl; (r) optionally substituted 5-oxa-2,6-diazabicyclo[6.1.0]non-6-en-2-yl; (s) optionally substituted 6-oxa-2,5-diazabicyclo[6.1.0]non-4-en-2-yl; and (t) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; and R4is selected from H, -OH, -CN, halogen, optionally substituted C1-C4 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 cycloalkyl, or C1-C6 cycloalkylalkyl.

[0005] One embodiment provides a compound having the structure of Formula (Ia), or a pharmaceutically acceptable salt or solvate, thereof:Attorney Docket No.62619-726601wherein: X1is N or C-CN; X2is N, C-H, C-F, C-CH3, or C-Cl; X3is N, C-H, C-F, C-Cl, C-CN, or C-CF3; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; R1is L-G; wherein L is optionally substituted C1-C4 alkylene,and G is an optionally substituted 5- to 10-membered heterocyclyl; -N(R2)R3form an optionally substituted heterocyclyl substituent selected from the group consisting of : (a) optionally substituted azabicyclo[3.1.0]hexane; (b) optionally substituted azabicyclo[4.1.0]heptane; (c) optionally substituted oxazabicyclo[4.1.0]heptane; (d) optionally substituted azabicyclo[5.1.0]octane; (e) optionally substituted oxazabicyclo[5.1.0]octane; (f) optionally substituted azabicyclo[6.1.0]nonane; (g) optionally substituted oxazabicyclo[6.1.0]nonane; (h) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl; (i) optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl; (j) optionally substituted azabicyclo[6.1.0]non-6-en-2-yl; (k) optionally substituted azabicyclo[6.1.0]non-5-en-2-yl; (l) optionally substituted azabicyclo[6.1.0]non-4-en-2-yl; (m) optionally substituted 3-oxa-2,6-diazabicyclo[5.1.0]oct-1-en-6-yl; (n) optionally substituted 2-oxa-3,6-diazabicyclo[5.1.0]oct-3-en-6-yl; (o) optionally substituted 4-oxa-2,5-diazabicyclo[5.1.0]oct-5-en-2-yl; (p) optionally substituted 3-oxa-2,7-diazabicyclo[6.1.0]non-1-en-7-yl; (q) optionally substituted 2-oxa-3,7-diazabicyclo[6.1.0]non-3-en-7-yl; (r) optionally substituted 5-oxa-2,6-diazabicyclo[6.1.0]non-6-en-2-yl;Attorney Docket No.62619-726601 (s) optionally substituted 6-oxa-2,5-diazabicyclo[6.1.0]non-4-en-2-yl; and (t) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; and R4is selected from H, optionally substituted C1-C4 alkoxy, optionally substituted C1- C6 alkyl, optionally substituted C1-C6 cycloalkyl, C1-C6 cycloalkylalkyl, cyano, or halogen.

[0006] One embodiment provides a compound having the structure of Formula (Ib), or a pharmaceutically acceptable salt or solvate, thereof:wherein: X1is N or C-CN; X2is N, C-H, C-F, C-CH3, or C-Cl; X3is N, C-H, C-F, C-Cl or C-CF3; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; R1is L-G; wherein L is optionally substituted C1-C4 alkylene,and G is an optionally substituted 5- to 10-membered heterocyclyl; -N(R2)R3form an optionally substituted heterocyclyl substituent selected from the group consisting of : (a) optionally substituted azabicyclo[3.1.0]hexane; (b) optionally substituted azabicyclo[4.1.0]heptane; (c) optionally substituted oxazabicyclo[4.1.0]heptane; (d) optionally substituted azabicyclo[5.1.0]octane; (e) optionally substituted oxazabicyclo[5.1.0]octane; (f) optionally substituted azabicyclo[6.1.0]nonane; (g) optionally substituted oxazabicyclo[6.1.0]nonane; (h) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl; (i) optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl; (j) optionally substituted azabicyclo[6.1.0]non-6-en-2-yl; (k) optionally substituted azabicyclo[6.1.0]non-5-en-2-yl; (l) optionally substituted azabicyclo[6.1.0]non-4-en-2-yl;Attorney Docket No.62619-726601 (m) optionally substituted 3-oxa-2,6-diazabicyclo[5.1.0]oct-1-en-6-yl; (n) optionally substituted 2-oxa-3,6-diazabicyclo[5.1.0]oct-3-en-6-yl; (o) optionally substituted 4-oxa-2,5-diazabicyclo[5.1.0]oct-5-en-2-yl; (p) optionally substituted 3-oxa-2,7-diazabicyclo[6.1.0]non-1-en-7-yl; (q) optionally substituted 2-oxa-3,7-diazabicyclo[6.1.0]non-3-en-7-yl; (r) optionally substituted 5-oxa-2,6-diazabicyclo[6.1.0]non-6-en-2-yl; (s) optionally substituted 6-oxa-2,5-diazabicyclo[6.1.0]non-4-en-2-yl; and (t) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; and R4is selected from H, optionally substituted C1-C4 alkoxy, optionally substituted C1- C6 alkyl, optionally substituted C1-C6 cycloalkyl, C1-C6 cycloalkylalkyl, cyano, or halogen.

[0007] One embodiment provides a compound having the structure of Formula (Ic), or a pharmaceutically acceptable salt or solvate, thereof:wherein: X1is N or C-CN; X2is N, C-H, C-F, or C-Cl; X3is N, C-H, C-F, C-Cl or C-CF3; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; R1is L-G; wherein L is optionally substituted C1-C4 alkylene,and G is an optionally substituted 5- to 10-membered heterocyclyl; -N(R2)R3form an optionally substituted heterocyclyl substituent selected from the group consisting of : (a) optionally substituted azabicyclo[3.1.0]hexane; (b) optionally substituted azabicyclo[4.1.0]heptane; (c) optionally substituted oxazabicyclo[4.1.0]heptane; (d) optionally substituted azabicyclo[5.1.0]octane; (e) optionally substituted oxazabicyclo[5.1.0]octane; (f) optionally substituted azabicyclo[6.1.0]nonane;Attorney Docket No.62619-726601 (g) optionally substituted oxazabicyclo[6.1.0]nonane; (h) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl; (i) optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl; (j) optionally substituted azabicyclo[6.1.0]non-6-en-2-yl; (k) optionally substituted azabicyclo[6.1.0]non-5-en-2-yl; (l) optionally substituted azabicyclo[6.1.0]non-4-en-2-yl; (m) optionally substituted 3-oxa-2,6-diazabicyclo[5.1.0]oct-1-en-6-yl; (n) optionally substituted 2-oxa-3,6-diazabicyclo[5.1.0]oct-3-en-6-yl; (o) optionally substituted 4-oxa-2,5-diazabicyclo[5.1.0]oct-5-en-2-yl; (p) optionally substituted 3-oxa-2,7-diazabicyclo[6.1.0]non-1-en-7-yl; (q) optionally substituted 2-oxa-3,7-diazabicyclo[6.1.0]non-3-en-7-yl; (r) optionally substituted 5-oxa-2,6-diazabicyclo[6.1.0]non-6-en-2-yl; (s) optionally substituted 6-oxa-2,5-diazabicyclo[6.1.0]non-4-en-2-yl; and (t) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; and R4is selected from H or optionally substituted C1-C4 alkoxy.

[0008] One embodiment provides a compound having the structure of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof:wherein: X1is N or C-CN; X2is N, C-H, C-F, or C-Cl; X3is N, C-H, C-F, or C-Cl; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; R1is L-G; wherein L is optionally substituted C1-C4 alkylene,and G is an optionally substituted 5- to 10-membered heterocyclyl; -N(R2)R3form an optionally substituted heterocyclyl selected from: (a) optionally substituted azabicyclo[4.1.0]heptane; (b) optionally substituted oxazabicyclo[4.1.0]heptane;Attorney Docket No.62619-726601 (c) optionally substituted azabicyclo[5.1.0]octane; (d) optionally substituted oxazabicyclo[5.1.0]octane; (e) optionally substituted azabicyclo[6.1.0]nonane; (f) optionally substituted oxazabicyclo[6.1.0]nonane; or (g) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl; and R4is selected from H or optionally substituted C1-C4 alkoxy.

[0009] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (Ia), or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (Ib), or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (Ic), or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (Id), or pharmaceutically acceptable salt or solvate 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), or pharmaceutically acceptable salt or solvate thereof. One embodiment provides a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (Ia), or pharmaceutically acceptable salt or solvate thereof. One embodiment provides a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (Ib), or pharmaceutically acceptable salt or solvate thereof. One embodiment provides a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (Ic), or pharmaceutically acceptable salt or solvate thereof. One embodiment provides a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (Id), or pharmaceutically acceptable salt or solvate thereof.

[0011] One embodiment provides a method of inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of Formula (I), wherein the KRAS protein is contacted in an in vitro setting. One embodiment provides a method of inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of Formula (Ia), wherein the KRAS protein is contacted in an in vitro setting. One embodiment provides a method ofAttorney Docket No.62619-726601 inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of Formula (Ib), wherein the KRAS protein is contacted in an in vitro setting. One embodiment provides a method of inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of Formula (Ic), wherein the KRAS protein is contacted in an in vitro setting. One embodiment provides a method of inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of Formula (Id), 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), wherein the KRAS protein is contacted in an in vivo setting. One embodiment provides a method of inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of Formula (Ia), wherein the KRAS protein is contacted in an in vivo setting. One embodiment provides a method of inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of Formula (Ib), wherein the KRAS protein is contacted in an in vivo setting. One embodiment provides a method of inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of Formula (Ic), wherein the KRAS protein is contacted in an in vivo setting. One embodiment provides a method of inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of Formula (Id), wherein the KRAS protein is contacted in an in vivo setting. INCORPORATION BY REFERENCE

[0013] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The features of the invention are set forth with particularity in the appended claims. A better understanding of the features of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0015] Figure 1 provides additional structures of compounds of Formula (I);

[0016] Figure 2 provides additional structures of compounds of Formula (I);

[0017] Figure 3 provides additional structures of compounds of Formula (I);

[0018] Figure 4 provides additional structures of compounds of Formula (I);

[0019] Figure 5 provides additional structures of compounds of Formula (I);

[0020] Figure 6 provides additional structures of compounds of Formula (I);

[0021] Figure 7 provides additional structures of compounds of Formula (I);Attorney Docket No.62619-726601

[0022] Figure 8 provides additional structures of compounds of Formula (I);

[0023] Figure 9 provides additional structures of compounds of Formula (I);

[0024] Figure 10 provides additional structures of compounds of Formula (I);

[0025] Figure 11 provides additional structures of compounds of Formula (I);

[0026] Figure 12 provides additional structures of compounds of Formula (I);

[0027] Figure 13 provides additional structures of compounds of Formula (I);

[0028] Figure 14 provides additional structures of compounds of Formula (I);

[0029] Figure 15 provides additional structures of compounds of Formula (I);

[0030] Figure 16 provides additional structures of compounds of Formula (I);

[0031] Figure 17 provides additional structures of compounds of Formula (I);

[0032] Figure 18 provides additional structures of compounds of Formula (I);

[0033] Figure 19 provides additional structures of compounds of Formula (I);

[0034] Figure 20 provides additional structures of compounds of Formula (I);

[0035] Figure 21 provides additional structures of compounds of Formula (I);

[0036] Figure 22 provides additional structures of compounds of Formula (I);

[0037] Figure 23 provides additional structures of compounds of Formula (I);

[0038] Figure 24 provides additional structures of compounds of Formula (I);

[0039] Figure 25 provides additional structures of compounds of Formula (I); and

[0040] Figure 26 provides additional structures of compounds of Formula (I). DETAILED DESCRIPTION OF THE INVENTION

[0041] 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 certain embodiments, for example, an embodiment of any composition ofAttorney Docket No.62619-726601 matter, composition, method, or process, or the like, described herein, "consist of" or "consist essentially of" the described features. Definitions

[0042] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0043] "Amino" refers to the –NH2radical.

[0044] "Cyano" refers to the -CN radical.

[0045] "Nitro" refers to the -NO2 radical.

[0046] "Oxa" refers to the -O- radical.

[0047] "Oxo" refers to the =O radical.

[0048] "Thioxo" refers to the =S radical.

[0049] "Imino" refers to the =N-H radical.

[0050] "Oximo" refers to the =N-OH radical.

[0051] "Hydrazino" refers to the =N-NH2 radical.

[0052] "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., C1-C8alkyl). 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-C2alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C1alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where eachAttorney Docket No.62619-726601 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 -CF3group.

[0053] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above.

[0054] "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-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).Attorney Docket No.62619-726601

[0055] "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).

[0056] "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, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., C1-C8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C1 alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C5-C8Attorney Docket No.62619-726601 alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0057] "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-C8alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (e.g., C2-C3alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (e.g., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., C5-C8alkenylene). 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 each Rais independently hydrogen, alkyl (optionally substituted with halogen,Attorney Docket No.62619-726601 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).

[0058] "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-C5alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C2alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C3-C5 alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, orAttorney Docket No.62619-726601 trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0059] "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, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb- OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, - Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally 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.

[0060] "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.

[0061] "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 describedAttorney Docket No.62619-726601 above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0062] "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.

[0063] "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.

[0064] "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, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, oxo, thioxo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb- N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb- S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, orAttorney Docket No.62619-726601 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] "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.

[0066] "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.

[0067] "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.

[0068] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.

[0069] "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, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0070] "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 quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl,Attorney Docket No.62619-726601 trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, - Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb- C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb- N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0071] "N-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 N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1- piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, and imidazolidinyl.

[0072] "C-heterocyclyl" or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. A C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0073] "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, theAttorney Docket No.62619-726601 heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0074] "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.

[0075] "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, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,Attorney Docket No.62619-726601 pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, optionally substituted fluoroalkyl, optionally substituted haloalkenyl, optionally substituted haloalkynyl, oxo, thioxo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, - Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc- C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb- S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0076] "N-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 N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0077] "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.Attorney Docket No.62619-726601

[0078] "Heteroarylalkyl" refers to a radical of the formula –Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0079] "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.

[0080] 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 (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically 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.

[0081] 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:Attorney Docket No.62619-726601

[0082] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,11C,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in, 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.

[0083] 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.

[0084] 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,11C,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35Cl,37Cl,79Br,81Br,125I are all contemplated. In some embodiments, isotopic substitution with18F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0085] In certain embodiments, the compounds disclosed herein have some or all of the1H atoms 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.Attorney Docket No.62619-726601

[0086] 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.

[0087] 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.

[0088] Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-d3(CD3I), are readily available and may be employed to transfer a deuterium- substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD3I is illustrated, by way of example only, in the reaction schemes below.

[0089] Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAlD4), are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD4is illustrated, by way of example only, in the reaction schemes below.

[0090] 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.Attorney Docket No.62619-726601

[0091] 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-exchangeable1H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.

[0092] "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.

[0093] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1- 19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared byAttorney Docket No.62619-726601 contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0094] "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, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0095] "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.

[0096] 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.

[0097] 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 isAttorney Docket No.62619-726601 observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made. KRAS Protein and Function

[0098] 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.

[0099] 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).

[0100] 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.

[0101] 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.

[0102] 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 moleculesAttorney Docket No.62619-726601 after activating 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.

[0103] 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).

[0104] 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.

[0105] 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

[0106] 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.

[0107] 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 theAttorney Docket No.62619-726601 mutant cysteine12 for KRAS (G12C) inhibitory activity (J.D. Vasta et al., Nature Chemical Biology, 2022, 18, 596-604).

[0108] 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

[0109] In one aspect, provided herein are KRAS inhibitory compounds.

[0110] One embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate, thereof:wherein: X1is N or C-CN; X2is N, C-H, C-F, C-CH3, C-Cl, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C2-C6 alkenyl), or C-(optionally substituted C3-C6 carbocyclyl); X3is N, C-H, C-F, C-Cl, C-CN, or C-CF3; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; R1is L-G; wherein L is optionally substituted C1-C4 alkylene,and G is an optionally substituted 5- to 10-membered heterocyclyl; -N(R2)R3form an optionally substituted heterocyclyl substituent selected from the group consisting of : (a) optionally substituted azabicyclo[3.1.0]hexane; (b) optionally substituted azabicyclo[4.1.0]heptane; (c) optionally substituted oxazabicyclo[4.1.0]heptane; (d) optionally substituted azabicyclo[5.1.0]octane; (e) optionally substituted oxazabicyclo[5.1.0]octane; (f) optionally substituted azabicyclo[6.1.0]nonane; (g) optionally substituted oxazabicyclo[6.1.0]nonane; (h) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl;Attorney Docket No.62619-726601 (i) optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl; (j) optionally substituted azabicyclo[6.1.0]non-6-en-2-yl; (k) optionally substituted azabicyclo[6.1.0]non-5-en-2-yl; (l) optionally substituted azabicyclo[6.1.0]non-4-en-2-yl; (m) optionally substituted 3-oxa-2,6-diazabicyclo[5.1.0]oct-1-en-6-yl; (n) optionally substituted 2-oxa-3,6-diazabicyclo[5.1.0]oct-3-en-6-yl; (o) optionally substituted 4-oxa-2,5-diazabicyclo[5.1.0]oct-5-en-2-yl; (p) optionally substituted 3-oxa-2,7-diazabicyclo[6.1.0]non-1-en-7-yl; (q) optionally substituted 2-oxa-3,7-diazabicyclo[6.1.0]non-3-en-7-yl; (r) optionally substituted 5-oxa-2,6-diazabicyclo[6.1.0]non-6-en-2-yl; (s) optionally substituted 6-oxa-2,5-diazabicyclo[6.1.0]non-4-en-2-yl; and (t) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; and R4is selected from H, -OH, -CN, halogen, optionally substituted C1-C4 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 cycloalkyl, or C1-C6 cycloalkylalkyl.

[0111] One embodiment provides a compound having the structure of Formula (Ia), or a pharmaceutically acceptable salt or solvate, thereof:wherein: X1is N or C-CN; X2is N, C-H, C-F, C-CH3, or C-Cl; X3is N, C-H, C-F, C-Cl, C-CN, or C-CF3; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; R1is L-G; wherein L is optionally substituted C1-C4 alkylene,and G is an optionally substituted 5- to 10-membered heterocyclyl; -N(R2)R3form an optionally substituted heterocyclyl substituent selected from the group consisting of : (a) optionally substituted azabicyclo[3.1.0]hexane;Attorney Docket No.62619-726601 (b) optionally substituted azabicyclo[4.1.0]heptane; (c) optionally substituted oxazabicyclo[4.1.0]heptane; (d) optionally substituted azabicyclo[5.1.0]octane; (e) optionally substituted oxazabicyclo[5.1.0]octane; (f) optionally substituted azabicyclo[6.1.0]nonane; (g) optionally substituted oxazabicyclo[6.1.0]nonane; (h) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl; (i) optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl; (j) optionally substituted azabicyclo[6.1.0]non-6-en-2-yl; (k) optionally substituted azabicyclo[6.1.0]non-5-en-2-yl; (l) optionally substituted azabicyclo[6.1.0]non-4-en-2-yl; (m) optionally substituted 3-oxa-2,6-diazabicyclo[5.1.0]oct-1-en-6-yl; (n) optionally substituted 2-oxa-3,6-diazabicyclo[5.1.0]oct-3-en-6-yl; (o) optionally substituted 4-oxa-2,5-diazabicyclo[5.1.0]oct-5-en-2-yl; (p) optionally substituted 3-oxa-2,7-diazabicyclo[6.1.0]non-1-en-7-yl; (q) optionally substituted 2-oxa-3,7-diazabicyclo[6.1.0]non-3-en-7-yl; (r) optionally substituted 5-oxa-2,6-diazabicyclo[6.1.0]non-6-en-2-yl; (s) optionally substituted 6-oxa-2,5-diazabicyclo[6.1.0]non-4-en-2-yl; and (t) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; and R4is selected from H, optionally substituted C1-C4 alkoxy, optionally substituted C1- C6 alkyl, optionally substituted C1-C6 cycloalkyl, C1-C6 cycloalkylalkyl, cyano, or halogen.

[0112] One embodiment provides a compound having the structure of Formula (Ib), or a pharmaceutically acceptable salt or solvate, thereof:wherein: X1is N or C-CN; X2is N, C-H, C-F, C-CH3, or C-Cl; X3is N, C-H, C-F, C-Cl or C-CF3; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Attorney Docket No.62619-726601 R1is L-G; wherein L is optionally substituted C1-C4 alkylene,and G is an optionally substituted 5- to 10-membered heterocyclyl; -N(R2)R3form an optionally substituted heterocyclyl substituent selected from the group consisting of : (a) optionally substituted azabicyclo[3.1.0]hexane; (b) optionally substituted azabicyclo[4.1.0]heptane; (c) optionally substituted oxazabicyclo[4.1.0]heptane; (d) optionally substituted azabicyclo[5.1.0]octane; (e) optionally substituted oxazabicyclo[5.1.0]octane; (f) optionally substituted azabicyclo[6.1.0]nonane; (g) optionally substituted oxazabicyclo[6.1.0]nonane; (h) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl; (i) optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl; (j) optionally substituted azabicyclo[6.1.0]non-6-en-2-yl; (k) optionally substituted azabicyclo[6.1.0]non-5-en-2-yl; (l) optionally substituted azabicyclo[6.1.0]non-4-en-2-yl; (m) optionally substituted 3-oxa-2,6-diazabicyclo[5.1.0]oct-1-en-6-yl; (n) optionally substituted 2-oxa-3,6-diazabicyclo[5.1.0]oct-3-en-6-yl; (o) optionally substituted 4-oxa-2,5-diazabicyclo[5.1.0]oct-5-en-2-yl; (p) optionally substituted 3-oxa-2,7-diazabicyclo[6.1.0]non-1-en-7-yl; (q) optionally substituted 2-oxa-3,7-diazabicyclo[6.1.0]non-3-en-7-yl; (r) optionally substituted 5-oxa-2,6-diazabicyclo[6.1.0]non-6-en-2-yl; (s) optionally substituted 6-oxa-2,5-diazabicyclo[6.1.0]non-4-en-2-yl; and (t) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; and R4is selected from H, optionally substituted C1-C4 alkoxy, optionally substituted C1- C6 alkyl, optionally substituted C1-C6 cycloalkyl, C1-C6 cycloalkylalkyl, cyano, or halogen.

[0113] One embodiment provides a compound having the structure of Formula (Ic), or a pharmaceutically acceptable salt or solvate, thereof:Attorney Docket No.62619-726601 wherein: X1is N or C-CN; X2is N, C-H, C-F, or C-Cl; X3is N, C-H, C-F, C-Cl or C-CF3; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; R1is L-G; wherein L is optionally substituted C1-C4 alkylene,and G is an optionally substituted 5- to 10-membered heterocyclyl; -N(R2)R3form an optionally substituted heterocyclyl substituent selected from the group consisting of : (a) optionally substituted azabicyclo[3.1.0]hexane; (b) optionally substituted azabicyclo[4.1.0]heptane; (c) optionally substituted oxazabicyclo[4.1.0]heptane; (d) optionally substituted azabicyclo[5.1.0]octane; (e) optionally substituted oxazabicyclo[5.1.0]octane; (f) optionally substituted azabicyclo[6.1.0]nonane; (g) optionally substituted oxazabicyclo[6.1.0]nonane; (h) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl; (i) optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl; (j) optionally substituted azabicyclo[6.1.0]non-6-en-2-yl; (k) optionally substituted azabicyclo[6.1.0]non-5-en-2-yl; (l) optionally substituted azabicyclo[6.1.0]non-4-en-2-yl; (m) optionally substituted 3-oxa-2,6-diazabicyclo[5.1.0]oct-1-en-6-yl; (n) optionally substituted 2-oxa-3,6-diazabicyclo[5.1.0]oct-3-en-6-yl; (o) optionally substituted 4-oxa-2,5-diazabicyclo[5.1.0]oct-5-en-2-yl; (p) optionally substituted 3-oxa-2,7-diazabicyclo[6.1.0]non-1-en-7-yl; (q) optionally substituted 2-oxa-3,7-diazabicyclo[6.1.0]non-3-en-7-yl; (r) optionally substituted 5-oxa-2,6-diazabicyclo[6.1.0]non-6-en-2-yl; (s) optionally substituted 6-oxa-2,5-diazabicyclo[6.1.0]non-4-en-2-yl; and (t) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; and R4is selected from H or optionally substituted C1-C4 alkoxy.

[0114] One embodiment provides a compound having the structure of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof:Attorney Docket No.62619-726601wherein: X1is N or C-CN; X2is N, C-H, C-F, or C-Cl; X3is N, C-H, C-F, or C-Cl; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; R1is L-G; wherein L is optionally substituted C1-C4 alkylene,and G is an optionally substituted 5- to 10-membered heterocyclyl; -N(R2)R3form an optionally substituted heterocyclyl selected from: (a) optionally substituted azabicyclo[4.1.0]heptane; (b) optionally substituted oxazabicyclo[4.1.0]heptane; (c) optionally substituted azabicyclo[5.1.0]octane; (d) optionally substituted oxazabicyclo[5.1.0]octane; (e) optionally substituted azabicyclo[6.1.0]nonane; (f) optionally substituted oxazabicyclo[6.1.0]nonane; or (g) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl; and R4is selected from H or optionally substituted C1-C4 alkoxy.

[0115] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is N.

[0116] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C-CN.

[0117] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein X2is N.

[0118] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein X2is C-CH3.

[0119] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein X2is C-(optionally substituted C1- C6 alkyl).Attorney Docket No.62619-726601

[0120] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein X2is C-(optionally substituted C2- C6 alkenyl).

[0121] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein X2is C-(optionally substituted C3- C6 carbocyclyl).

[0122] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, X2is C-H, C-F, or C-Cl.

[0123] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, X3is N.

[0124] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, X3is C-F.

[0125] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, X3is C-CF3.

[0126] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a monocyclic optionally substituted aryl.

[0127] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the monocyclic optionally substituted aryl is an optionally substituted phenyl.

[0128] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl is substituted with an -OH group at the meta-position.

[0129] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl is.

[0130] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl is selected from:Attorney Docket No.62619-726601.

[0131] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl is substituted with an -NH2 group at the meta-position.

[0132] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl is selected from:.

[0133] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl is selected from:.

[0134] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl is a 2,3,5-trisubstituted phenyl.Attorney Docket No.62619-726601

[0135] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the 2,3,5-trisubstituted phenyl is substituted with a 3-hydroxy group.

[0136] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a bicyclic optionally substituted aryl.

[0137] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted aryl is an optionally substituted naphthyl.

[0138] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted naphthyl is an optionally substituted 1-naphthyl.

[0139] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 1- naphthyl is further substituted at the 8-position.

[0140] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0141] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:Attorney Docket No.62619-726601.

[0142] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:.

[0143] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:.Attorney Docket No.62619-726601

[0144] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:.

[0145] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:.

[0146] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:Attorney Docket No.62619-726601.

[0147] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:.

[0148] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0149] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:Attorney Docket No.62619-726601.

[0150] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:.

[0151] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:.

[0152] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:.

[0153] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:Attorney Docket No.62619-726601.

[0154] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:.

[0155] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:Attorney Docket No.62619-726601.

[0156] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:.

[0157] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:Attorney Docket No.62619-726601.

[0158] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:.

[0159] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:.

[0160] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:Attorney Docket No.62619-726601.

[0161] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:.

[0162] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:.

[0163] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:.

[0164] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted aryl is described by Formula (a):wherein: R12is hydrogen, deuterium, or F;Attorney Docket No.62619-726601 R13is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me; R14is hydrogen, deuterium, F, Cl, or Br; R15is hydrogen, deuterium, F, Cl, or Br; R16is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3; R17is hydrogen, deuterium, F, Cl, or -CN; and R18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3,-CH=CH2, -C≡CH, -OCHF2, - OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

[0165] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a monocyclic optionally substituted heteroaryl.

[0166] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the monocyclic optionally substituted heteroaryl is an optionally substituted 2-pyridinyl.

[0167] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 2- pyridinyl is.

[0168] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 2- pyridinyl is.

[0169] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the monocyclic optionally substituted heteroaryl is an optionally substituted 4-pyridinyl. In some embodiments, the optionally substituted 4-pyridinyl is:.Attorney Docket No.62619-726601

[0170] In some embodiments, the optionally substituted 4-pyridinyl is:.

[0171] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a bicyclic optionally substituted heteroaryl.

[0172] In some embodiments, the bicyclic optionally substituted heteroaryl is selected from:.

[0173] In some embodiments, the bicyclic optionally substituted heteroaryl is selected from:,Attorney Docket No.62619-726601

[0174] In some embodiments, the bicyclic optionally substituted heteroaryl is selected from:

[0175] In some embodiments, the bicyclic optionally substituted heteroaryl is selected from:

[0177] In some embodiments, the bicyclic optionally substituted heteroaryl is described by Formula (b1):Attorney Docket No.62619-726601wherein: R13is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me; R14is hydrogen, deuterium, F, Cl, or Br; R15is hydrogen, deuterium, F, Cl, or Br; R16is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3; R17is hydrogen, deuterium, F, Cl, or -CN; and R18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C≡CH, -OCHF2, - OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

[0178] In some embodiments, the bicyclic optionally substituted heteroaryl is described by Formula (b2):wherein: R12is hydrogen, deuterium, or F; R14is hydrogen, deuterium, F, Cl, or Br; R15is hydrogen, deuterium, F, Cl, or Br; R16is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3; R17is hydrogen, deuterium, F, Cl, or -CN; and R18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3,-CH=CH2, -C≡CH, -OCHF2, - OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

[0179] In some embodiments, the bicyclic optionally substituted heteroaryl is described by Formula (b3):wherein: R12is hydrogen, deuterium, or F; R13is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me;Attorney Docket No.62619-726601 R15is hydrogen, deuterium, F, Cl, or Br; R16is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3; R17is hydrogen, deuterium, F, Cl, or -CN; and R18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C≡CH, -OCHF2, - OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

[0180] In some embodiments, the bicyclic optionally substituted heteroaryl is described by Formula (b4):wherein: R12is hydrogen, deuterium, or F; R13is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me; R14is hydrogen, deuterium, F, Cl, or Br; R16is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3; R17is hydrogen, deuterium, F, Cl, or -CN; and R18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3,-CH=CH2, -C≡CH, -OCHF2, - OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

[0181] In some embodiments, the bicyclic optionally substituted heteroaryl is described by Formula (b5):wherein: R12is hydrogen, deuterium, or F; R13is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me; R14is hydrogen, deuterium, F, Cl, or Br; R15is hydrogen, deuterium, F, Cl, or Br; R17is hydrogen, deuterium, F, Cl, or -CN; and R18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3,-CH=CH2, -C≡CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

[0182] In some embodiments, the bicyclic optionally substituted heteroaryl is described by Formula (b6):Attorney Docket No.62619-726601wherein: R12is hydrogen, deuterium, or F; R13is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me; R14is hydrogen, deuterium, F, Cl, or Br; R15is hydrogen, deuterium, F, Cl, or Br; R16is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3; and R18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C≡CH, -OCHF2, - OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

[0183] In some embodiments, the bicyclic optionally substituted heteroaryl is is described by Formula (b8):wherein: R13is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me; R15is hydrogen, deuterium, F, Cl, or Br; R16is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3; R17is hydrogen, deuterium, F, Cl, or -CN; and R18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C≡CH, -OCHF2, - OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

[0184] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein L is optionally substituted C1-C4 alkylene.

[0185] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein L is.Attorney Docket No.62619-726601

[0186] . Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein L is.

[0187] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein L is optionally substituted C1 alkylene.

[0188] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein G is an optionally substituted 5- to 10-membered heterocyclyl.

[0189] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:.

[0190] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:.

[0191] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:.

[0192] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein G is described by Formula (c):wherein,Attorney Docket No.62619-726601 each R20-R30is independently selected from hydrogen or deuterium.

[0193] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate 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; and R33is hydrogen, deuterium, F, or optionally substituted C1-C4 alkyl.

[0194] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:.

[0195] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:.

[0196] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:Attorney Docket No.62619-726601

[0197] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:

[0198] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

[0199] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

[0200] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:Attorney Docket No.62619-726601.

[0201] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

[0202] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

[0203] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

[0204] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:Attorney Docket No.62619-726601.

[0205] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

[0206] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

[0207] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

[0208] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:Attorney Docket No.62619-726601.

[0209] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

[0210] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

[0211] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0212] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:Attorney Docket No.62619-726601.

[0213] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

[0214] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

[0215] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:Attorney Docket No.62619-726601.

[0216] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

[0217] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

[0218] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:Attorney Docket No.62619-726601.

[0219] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

[0220] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:Attorney Docket No.62619-726601.

[0221] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

[0222] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

[0223] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:Attorney Docket No.62619-726601.

[0224] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

[0225] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

[0226] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:Attorney Docket No.62619-726601.

[0227] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

[0228] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from: ,.

[0229] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:Attorney Docket No.62619-726601.

[0230] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

[0231] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted heterocyclyl selected from: (a) optionally substituted 2-azabicyclo[4.1.0]heptan-2-yl; (b) optionally substituted 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl; (c) optionally substituted 2-azabicyclo[5.1.0]octan-2-yl; (d) optionally substituted 2-oxa-6-azabicyclo[5.1.0]octan-6-yl (e) optionally substituted 5-oxa-2-azabicyclo[5.1.0]octan-2-yl; (f) optionally substituted 2-azabicyclo[6.1.0]nonan-2-yl; (g) optionally substituted 2-oxa-7-azabicyclo[6.1.0]nonan-7-yl; (h) optionally substituted 6-oxa-2-azabicyclo[6.1.0]nonan-2-yl; (i) optionally substituted 5-oxa-2-azabicyclo[6.1.0]nonan-2-yl (j) optionally substituted 2-azabicyclo[5.1.0]oct-5-en-2-yl; (k) optionally substituted 2-azabicyclo[5.1.0]oct-4-en-2-yl; (l) optionally substituted 2-azabicyclo[3.1.0]hexan-2-yl; (m) optionally substituted 2-azabicyclo[6.1.0]non-4-en-2-yl; (n) optionally substituted 2-azabicyclo[6.1.0]non-5-en-2-yl; orAttorney Docket No.62619-726601 (o) optionally substituted 2-azabicyclo[6.1.0]non-6-en-2-yl.

[0232] In some embodiments, -N(R2)R3form an optionally substituted 2- azabicyclo[4.1.0]heptan-2-yl. In some embodiments, -N(R2)R3form an optionally substituted 2- oxa-5-azabicyclo[4.1.0]heptan-5-yl. In some embodiments, -N(R2)R3form an optionally substituted 2-azabicyclo[5.1.0]octan-2-yl. In some embodiments, the optionally substituted 2- azabicyclo[5.1.0]octan-2-yl is substituted with an oxo group. In some embodiments, -N(R2)R3form an optionally substituted 2-oxa-6-azabicyclo[5.1.0]octan-6-yl. In some embodiments, - N(R2)R3form an optionally substituted 5-oxa-2-azabicyclo[5.1.0]octan-2-yl. In some embodiments, -N(R2)R3form an optionally substituted 2-azabicyclo[6.1.0]nonan-2-yl. In some embodiments, -N(R2)R3form an optionally substituted 2-oxa-7-azabicyclo[6.1.0]nonan-7-yl. In some embodiments, -N(R2)R3form an optionally substituted 6-oxa-2-azabicyclo[6.1.0]nonan-2- yl. In some embodiments, -N(R2)R3form an optionally substituted 5-oxa-2- azabicyclo[6.1.0]nonan-2-yl. In some embodiments, -N(R2)R3form an optionally substituted 2- azabicyclo[5.1.0]oct-5-en-2-yl. In some embodiments, -N(R2)R3form an optionally substituted 2-azabicyclo[5.1.0]oct-4-en-2-yl. In some embodiments, -N(R2)R3form an optionally substituted 2-azabicyclo[3.1.0]hexan-2-yl. In some embodiments, -N(R2)R3form an optionally substituted 2-azabicyclo[6.1.0]non-4-en-2-yl. In some embodiments, -N(R2)R3form an optionally substituted 2-azabicyclo[6.1.0]non-5-en-2-yl. In some embodiments, N(R2)R3form an optionally substituted 2-azabicyclo[6.1.0]non-6-en-2-yl. In some embodiments, the optionally substituted heterocyclyl is optionally substituted with a group selected from the group consisting of halogen, cyano, and hydroxyl. In some embodiments, the group is chloro. In some embodiments, the group is fluoro.

[0233] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.

[0234] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has a structure selected from:Attorney Docket No.62619-726601.

[0235] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.

[0236] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has a structure selected from:wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl. In some embodiments, the halogen is fluor or chloro.

[0237] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has a structure selected from:wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl. In some embodiments, the halogen is fluoro or chloro.

[0238] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[4.1.0]heptane heterocyclyl has a structure selected from:Attorney Docket No.62619-726601 wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl. In some embodiments, the halogen is fluoro or chloro.

[0239] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[4.1.0]heptane heterocyclyl has a structure selected from:wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl. In some embodiments, the halogen is fluoro or chloro.

[0240] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[3.1.0]hexane heterocyclyl has a structure selected from:wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl. In some embodiments, the halogen is fluoro or chloro.

[0241] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.

[0242] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.

[0243] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl is:Attorney Docket No.62619-726601.

[0244] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.

[0245] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl. In some embodiments, the halogen is fluoro or chloro.

[0246] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.

[0247] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.

[0248] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:Attorney Docket No.62619-726601wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl. In some embodiments, the halogen is fluoro or chloro.

[0249] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.

[0250] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[6.1.0]nonane heterocyclyl has a structure selected from:wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl. In some embodiments, the halogen is fluoro or chloro.

[0251] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[6.1.0]nonane heterocyclyl has a structure selected from:wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl. In some embodiments, the halogen is fluoro or chloro.

[0252] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted azabicyclo[4.1.0]heptane heterocyclyl.

[0253] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted oxazabicyclo[4.1.0]heptane heterocyclyl.Attorney Docket No.62619-726601

[0254] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted azabicyclo[6.1.0]nonane heterocyclyl.

[0255] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted oxazabicyclo[6.1.0]nonane heterocyclyl.

[0256] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form a group selected from: optionally substituted 3-oxa-2,6-diazabicyclo[5.1.0]oct-1-en-6-yl; optionally substituted 2-oxa-3,6-diazabicyclo[5.1.0]oct-3-en-6-yl; optionally substituted 4-oxa-2,5-diazabicyclo[5.1.0]oct-5-en-2-yl; optionally substituted 3-oxa-2,7-diazabicyclo[6.1.0]non-1-en-7-yl; optionally substituted 2-oxa-3,7-diazabicyclo[6.1.0]non-3-en-7-yl; optionally substituted 5-oxa-2,6-diazabicyclo[6.1.0]non-6-en-2-yl; optionally substituted 6-oxa-2,5-diazabicyclo[6.1.0]non-4-en-2-yl; and optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl.

[0257] In some embodiments, the group is optionally substituted with a halogen.

[0258] In some embodiments, N(R2)R3form a group selected from:

[0259] In some embodiments, -N(R2)R3form a group selected from:wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl.Attorney Docket No.62619-726601

[0260] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is H. In some embodiments, R4is optionally substituted C1-C4 alkoxy. In some embodiments, R4is -OCH3. In some embodiments, R4is optionally substituted C1-C6 alkyl. In some embodiments, R4is selected from optionally substituted C1-C6 cycloalkyl or C1-C6 cycloalkylalkyl. In some embodiments, R4is cyano. In some embodiments, R4is halogen. In some embodiments, R4is selected from H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 cycloalkyl, C1-C6 cycloalkylalkyl, cyano, or halogen.

[0261] Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is H, and R1is:.

[0262] In some embodiments, X1and X3are N, and X2is C-F.

[0263] In some embodiments, Ar is selected from:.

[0264] In some embodiments, Ar is selected from:.

[0265] In some embodiments, Ar is selected from:.

[0266] In some embodiments, Ar is selected from:Attorney Docket No.62619-726601.

[0267] In some embodiments, Ar is selected from:.

[0268] In some embodiments, Ar is selected from:wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl. In some embodiments, the halogen is fluoro or chloro.

[0269] One embodiment provides a KRAS inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 1. Table 1Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601Attorney Docket No.62619-726601

[0270] One embodiment provides a KRAS inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in any one of Figures 1-26. Preparation of Compounds

[0271] The compounds used in the synthetic chemistry reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and / or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0272] 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 forAttorney Docket No.62619-726601 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.

[0273] 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

[0274] 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)).

[0275] Provided herein is a pharmaceutical composition comprising at least one KRAS inhibitory compound as described herein, or a stereoisomer, pharmaceutically acceptable salt,Attorney Docket No.62619-726601 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.

[0276] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.

[0277] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0278] In certain embodiments, the KRAS inhibitory compound as described by Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0279] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0280] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0281] In certain embodiments, the KRAS inhibitory compound as described by Table 1, or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0282] 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)).

[0283] In some embodiments, the KRAS inhibitory compound as described by Formula (I), Formula (Ia), or Table 1, or pharmaceutically acceptable salt or solvate thereof, is formulated forAttorney Docket No.62619-726601 administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a non-aqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like.

[0284] 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.

[0285] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0286] Oral doses typically range from about 0.01 mg to about 1000 mg, one to four times, or more, per day. Methods of Treatment

[0287] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body. One embodiment provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body. One embodiment provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body. One embodiment provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body. One embodiment provides a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0288] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer. One embodiment provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer. One embodiment provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer. One embodiment provides a compound of Formula (Ic), or a pharmaceutically acceptable salt orAttorney Docket No.62619-726601 solvate thereof, for use in a method of treating cancer. One embodiment provides a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer. One embodiment provides the method of treating cancer wherein the cancer is lung adenocarcinoma.

[0289] One embodiment provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer. One embodiment provides a use of a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer. One embodiment provides a use of a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer. One embodiment provides a use of a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer. One embodiment provides a use of a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer. One embodiment provides the use wherein the cancer is lung adenocarcinoma.

[0290] In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. One embodiment provides the method of treating cancer wherein the cancer is lung adenocarcinoma.

[0291] 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 (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. One embodiment provides the method of treating cancer wherein the cancer is lung adenocarcinoma.

[0292] 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 (Ib), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (Ib), or a pharmaceuticallyAttorney Docket No.62619-726601 acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. One embodiment provides the method of treating cancer wherein the cancer is lung adenocarcinoma.

[0293] 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 (Ic), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. One embodiment provides the method of treating cancer wherein the cancer is lung adenocarcinoma.

[0294] 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 (Id), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. One embodiment provides the method of treating cancer wherein the cancer is lung adenocarcinoma.

[0295] One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0296] One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer. One embodiment provides the method of treating cancer wherein the cancer is lung adenocarcinoma.

[0297] In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. One embodiment provides the method of treating cancer wherein the cancer is lung adenocarcinoma.

[0298] One embodiment provides a use of a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer. One embodiment provides the use wherein the cancer is lung adenocarcinoma.

[0299] 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.Attorney Docket No.62619-726601

[0300] One embodiment provides a method of inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), 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.

[0301] 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. EXAMPLES I. Chemical Synthesis

[0302] In some embodiments, the KRAS inhibitory compounds disclosed herein are synthesized according to the following examples. As used below, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: ACN acetonitrileoC degrees Celsius δH chemical shift in parts per million downfield from tetramethylsilane DCM dichloromethane (CH2Cl2) DIAD diisopropyl azodicarboxylate DIEA diisopropylethylamine DMF dimethylformamide DMSO dimethylsulfoxide EA ethyl acetate EtOAc ethyl acetate ESI electrospray ionization Et ethyl g gram(s) h hour(s) HPLC high performance liquid chromatography Hz hertz J coupling constant (in NMR spectrometry) LCMS liquid chromatography mass spectrometry μ microAttorney Docket No.62619-726601 m multiplet (spectral); meter(s); milli M molar M+parent molecular ion Me methyl MsCl methanesulfonyl chloride MHz megahertz min minute(s) mol mole(s); molecular (as in mol wt) mL milliliter MS mass spectrometry nm nanometer(s) NMR nuclear magnetic resonance pH potential of hydrogen; a measure of the acidity or basicity of an aqueous solution PE petroleum ether RT room temperature s singlet (spectral) t triplet (spectral) SFC Supercritical fluid chromatography T temperature TFA trifluoroacetic acid THF tetrahydrofuran TPP Triphenylphosphine

[0303] Intermediate 1 & 2: Benzyl 6,7-dihydro-5H-1,4-oxazepine-4-carboxylate & benzyl 3,7- dihydro-2H-1,4-oxazepine-4-carboxylateStep 1: Benzyl 1,4-oxazepane-4-carboxylate 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 nitrogen atmosphere 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 hours. The resulting mixture was quenched with saturated aq. NaHCO3 (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, andAttorney Docket No.62619-726601 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]+. 1H NMR (400 MHz, Chloroform-d) δ 7.39 - 7.29 (m, 5H), 5.15 (s, 2H), 3.75 - 3.56 (m, 8H), 1.93 - 1.79 (m, 2H). Step 2: Benzyl 3-methoxy-1,4-oxazepane-4-carboxylate & benzyl 5-methoxy-1,4-oxazepane-4- carboxylate To a solution of benzyl 1,4-oxazepane-4-carboxylate (40 g, 170.00 mmol) in MeOH (200 mL) was added tetraethylammonium tosylate (25.62 g, 85.00 mmol) at room temperature. The reaction mixture was electrolysis with C (+) I C(-) electrodes at constant current 200 mA. The resulting mixture was stirred at 20 °C for 72 hours. 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.1H NMR (400 MHz, Chloroform-d) δ 7.39 - 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). Step 3: Benzyl 6,7-dihydro-5H-1,4-oxazepine-4-carboxylate & benzyl 3,7-dihydro-2H-1,4- oxazepine-4-carboxylate To an ice-cooled solution of benzyl 3-methoxy-1,4-oxazepane-4-carboxylate and benzyl 5- methoxy-1,4-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 nitrogen atmosphere. The reaction mixture was stirred in an ice bath for 0.5 hour. The solid was filtered out, 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 peaks. The first eluting peak was collected and concentrated under reduced pressure to afford the title compound (Intermediate 1, 2.18 g, 29% yield) as a yellow solid.1H NMR (400 MHz, Chloroform-d) δ 7.40 - 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 title compound (Intermediate 2, 2.52 g, 34% yield) as a yellow solid.1H NMR (400 MHz, Chloroform-d) δ 7.42 - 7.28 (m, 5H), 5.26 - 4.85 (m, 4H), 4.22 - 4.20 (m, 2H), 3.93 - 3.70 (m, 4H).

[0304] Intermediate 3: 6-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6- azabicyclo[5.1.0]octaneAttorney Docket No.62619-726601 Step 1: Benzyl 2-oxa-6-azabicyclo[5.1.0]octane-6-carboxylate To a solution of Intermediate 1 (2.18 g, 9.35 mmol) in DCM (25 mL) was added ZnEt2(24.93 mL, 24.93 mmol, 1 M in n-hexane) at room temperature. The mixture was stirred at room temperature for 0.5 hours. A solution of diiodomethane (10.02 g, 37.40 mmol) in DCM (12 mL) was added to the mixture dropwise in an ice bath, and the mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into cold saturated aq. NH4Cl (100 mL), extracted with DCM (3 x 100 mL), washed with brine (100 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 40% EA in PE to afford the title compound (1.8 g, 77% yield) as a yellow oil. MS: m / z = 248.10 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 7.38 - 7.28 (m, 5H), 5.29 - 5.07 (m, 2H), 4.18 - 3.92 (m, 2H), 3.69 - 3.63 (m, 1H), 3.42 - 3.39 (m, 1H), 3.16 - 3.10 (m, 1H), 2.45 - 2.40 (m, 1H), 1.91 - 1.74 (m, 2H), 1.46 - 1.10 (m, 2H). Step 2: 2-Oxa-6-azabicyclo[5.1.0]octane To an ice-cooled solution of benzyl 2-oxa-6-azabicyclo[5.1.0]octane-6-carboxylate (4 g, 16.17 mmol) in MeOH (200 mL) was added Pd / C (1.3 g, 10wt%) under nitrogen atmosphere. The resulting mixture was stirred in an ice bath for 40 min under hydrogen atmosphere. The resulting mixture was filtered and concentrated under reduced pressure to afford the title compound (1.55 g, crude used through) as a light yellow oil. Step 3: 6-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane To a stirred solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (3.46 g, 13.70 mmol) and 2-oxa-6-azabicyclo[5.1.0]octane (1.55 g, crude) in DCM (40 mL) was added DIEA (5.31 g, 41.11 mmol) dropwise at -40 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 hour at -40 °C. The mixture was diluted with 10% citric solution (50 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (Intermediate 3, 4 g, crude) as a light-yellow solid. MS: m / z = 329.00, 331.00 [M + H]+.

[0305] Intermediate 4 & 5: (1R,7S)-6-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane & (1S,7R)-6-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octaneAttorney Docket No.62619-726601Step 1: 6-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane To a stirred solution of Intermediate 3 (4 g, crude) in DMSO (40 mL) under nitrogen atmosphere were added KF (2.47 g, 42.53 mmol) and Intermediate 17 (3.13 g, 19.44 mmol) at room temperature. The resulting mixture was heated at 100 °C for 16 hours. The mixture was cooled to room temperature, diluted with water (50 mL), and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with CH2Cl2 / MeOH (10 : 1) to afford the title compound (1.5 g, 20% yield for three steps) as a light yellow solid. MS: m / z = 454.15 [M + H]+. Step 2: (1R,7S)-6-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane & (1S,7R)-6-(7- chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane The mixture of 6-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane (1.5 g, 3.30 mmol) was separated by Prep-SFC with the following conditions: Column: JW-Lux Cellulose-3, 4.6 x 50 mm, 3 μm; Mobile Phase A: CO2; Mobile Phase B: MeOH; Flow rate: 100 mL / min; Gradient: isocratic 15% B; Back Pressure (bar): 100; RT1: 5.13 min; RT2: 7.47 min. The first eluting peak (RT1: 5.13 min) was concentrated and lyophilized to give the title compound (Intermediate 4, 495 mg, 33% yield) as a light yellow solid1H NMR (400 MHz, Chloroform-d) δ 9.10 (s, 1H), 5.36 - 5.23 (m, 1H), 4.68 - 4.65 (m, 1H), 4.02 - 3.99 (m, 1H), 3.78 - 3.72 (m, 2H), 3.55 - 3.49 (m, 1H), 3.36 - 3.22 (m, 3H), 3.13 - 2.99 (m, 2H), 2.43 - 2.17 (m, 4H), 1.99 - 1.70 (m, 4H), 1.39 - 1.33 (m, 1H), 0.79 - 0.75 (m, 1H). The second eluting peak (RT2: 7.47 min) was concentrated and lyophilized to give the title compound (Intermediate 5, 510 mg, 34% yield) as a light yellow solid.1H NMR (400 MHz, Chloroform-d) δ 9.10 (s, 1H), 5.35 - 5.22 (m, 1H), 4.68 - 4.65 (m, 1H), 4.03 - 4.00 (m, 1H), 3.78 - 3.72 (m, 2H), 3.55 - 3.49 (m, 1H), 3.31 - 3.18 (m, 3H), 3.14 - 3.09 (m, 1H), 3.02 - 2.96 (m, 1H), 2.44 - 2.15 (m, 4H), 1.99 - 1.87 (m, 4H), 1.39 - 1.29 (m, 1H), 0.79 - 0.75 (m, 1H).Attorney Docket No.62619-726601

[0306] Intermediate 6: 4-(4-Azabicyclo[5.1.0]octan-4-yl)-2,7-dichloro-8-fluoropyrido[4,3- d]pyrimidineStep 1: tert-Butyl 8,8-dichloro-4-azabicyclo[5.1.0]octane-4-carboxylate To a solution of tert-butyl 2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (1 g, 5.07 mmol), benzyl(triethyl)ammonium chloride (23 mg, 101 μmol) in CHCl3(12 mL) was added a solution of NaOH (661 mg, 16.5 mmol) in H2O (1.3 mL). The mixture was stirred at 35 °C for 16 h under N2 atmosphere. The mixture was diluted with H2O (20 mL) and extracted with CH2Cl2 (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 3% of EtOAc in petroleum ether) to give the title compound (0.87 g, 88% yield) as a yellow oil.1H NMR (400 MHz, Chloroform-d) δ 4.07 - 3.81 (m, 2H), 3.02 - 2.82 (m, 2H), 2.35 - 2.25 (m, 2H), 1.87 - 1.74 (m, 2H), 1.67 - 1.60 (m, 2H), 1.44 (s, 9H). Step 2: tert-Butyl 4-azabicyclo[5.1.0]octane-4-carboxylate To a suspension of sodium debris (1.7 g, 76 mmol) in THF (15 mL) was degassed and purged with N2three times. A solution of tert-butyl 8,8-dichloro-4-azabicyclo[5.1.0]octane-4- carboxylate (330 mg, 1.18 mmol) in MeOH (6 mL) and THF (6 mL) was added dropwise to the mixture at 25 °C to 40 °C under N2. The reaction mixture was stirred at 25 °C for 2 h under N2 atmosphere. The reaction mixture was quenched slowly with sat. NH4Cl aq. (50 mL) at 0 °C and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with saturate brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 4% of EtOAc in petroleum ether) to give the title compound (204 mg, 82% yield) as a colorless oil.1H NMR (400 MHz, Chloroform-d) δ 3.52 (s, 2H), 3.22 - 3.13 (m, 2H), 2.21 (s, 2H), 1.43 (s, 9H), 1.41 - 1.31 (m, 2H), 1.00 - 0.89 (m, 2H), 0.68 - 0.61 (m, 1H), 0.25 - 0.19 (m, 1H). Step 3: 4-Azabicyclo[5.1.0]octane To a solution of tert-butyl 4-azabicyclo[5.1.0]octane-4-carboxylate (204 mg, 965 μmol) in HCl (2M in EtOAc, 4 mL) was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give the title compound (143 mg, crude, HCl) as a white solid, which was used in the next step without further purification. Step 4: 4-(4-Azabicyclo[5.1.0]octan-4-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidineAttorney Docket No.62619-726601 To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (245 mg, 969 μmol), DIPEA (674.80 μL, 3.87 mmol) in CH2Cl2(5 mL) was added 4-azabicyclo[5.1.0]octane (143 mg, 969 μmol, HCl) at -40 °C under N2atmosphere. The reaction mixture was stirred at -40 °C for 0.5 h under N2 atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the compound title compound (Intermediate 6, 253 mg, crude) as a yellow solid, which was used in the next step without further purification. MS: m / z = 327.0 [M + H]+.

[0307] Intermediate 7: tert-Butyl 2,3,4,5-tetrahydro-1H-azepine-1-carboxylateStep 1: tert-Butyl 2-oxoazepane-1-carboxylate To a solution of azepan-2-one (40 g, 353 mmol) and (Boc)2O (84.9 g, 389 mmol) in dry THF (400 mL) was added DMAP (47.5 g, 389 mmol). The mixture was stirred at 25 °C for 3 h. TLC indicated that azepan-2-one was consumed completely and one new spot formed (PE / EA=3:1, Rf=0.5, color developing reagent: ninhydrin). The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (300 mL × 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 ~ 30% EtOAc in Petroleum ether) to give the title compound (75 g, 99% yield) as an off-white oil.1H NMR (400 MHz, CDCl3) δ 3.76 (s, 2H), 2.67 - 2.60 (m, 2H), 1.80 - 1.68 (m, 6H), 1.51 (s, 9H). Step 2: tert-Butyl 7-((diphenoxyphosphoryl)oxy)-2,3,4,5-tetrahydro-1H-azepine-1-carboxylate To a solution of tert-butyl 2-oxoazepane-1-carboxylate (68 g, 319 mmol) in THF (1500 mL) were added dropwise TMEDA (44.5 g, 383 mmol) and LDA (2 M, 191 mL) at -78 °C under N2. The mixture was stirred at this temperature for 2 h. Diphenyl phosphorochloridate (103 g, 383 mmol) was added dropwise at -78 °C under N2. The resulting mixture was stirred at -78 °C for 3 h. TLC indicated that tert-butyl 2-oxoazepane-1-carboxylate was consumed completely and one new spot formed (PE / EA=5:1, Rf=0.76, color developing reagent: ninhydrin). The reaction mixture was diluted with sat. NH4Cl aq. (500 mL) and extracted with EtOAc (300 mL × 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 ~ 10% EtOAc in Petroleum ether) to give the title compound (85 g, 60% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 7.41 - 7.28 (m, 4H), 7.27 - 7.15 (m,Attorney Docket No.62619-726601 6H), 5.42 (t, J = 2.8, 6.4 Hz, 1H), 3.93 - 3.07 (m, 2H), 2.14 - 1.99 (m, 2H), 1.73 (dd, J = 5.6, 11.2 Hz, 2H), 1.58 - 1.48 (m, 2H), 1.41 (s, 9H). Step 3: tert-Butyl 2,3,4,5-tetrahydro-1H-azepine-1-carboxylate To a solution of tert-butyl 7-((diphenoxyphosphoryl)oxy)-2,3,4,5-tetrahydro-1H-azepine-1- carboxylate (58 g, 130 mmol) in DME (600 mL) were added triphenylphosphane (2.73 g, 10.4 mmol) and Pd(OAc)2(1.17 g, 5.21 mmol) at 25 °C under N2. TEA (39.5 g, 391 mmol) and formic acid (5.99 g, 130 mmol) in DME (400 mL) were added dropwise to the mixture at 25 °C under N2. The mixture was stirred at 84 °C for 40 min under N2. TLC indicated one new spot formed (PE / EA=5:1, Rf=0.81, color developing reagent: ninhydrin). The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (300 mL × 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 ~ 10% EtOAc in Petroleum ether) to give the title compound (Intermediate 7, 20 g, 78% yield) as an off-white oil.1H NMR (400 MHz, CDCl3) δ 6.65 - 6.26 (m, 1H), 5.05 - 4.81 (m, 1H), 3.61 (s, 2H), 2.22 - 2.07 (m, 2H), 1.77 - 1.63 (m, 4H), 1.45 (s, 9H).

[0308] Intermediate 8: 4-(2-Azabicyclo[5.1.0]octan-2-yl)-2,7-dichloro-8-fluoropyrido[4,3- d]pyrimidineStep 1: tert-Butyl 2-azabicyclo[5.1.0]octane-2-carboxylate To a solution of Intermediate 7 (160 mg, 760 μmol) in CH2Cl2 (3 mL) was added diethylzinc (1 M in n-hexane, 1.52 mL). The mixture was stirred at 0 °C for 0.5 h under N2. A solution of CH2I2 (815 mg, 3.04 mmol) in CH2Cl2 (1.5 mL) was added to the mixture dropwise at 0 °C under N2. The mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with sat NH4Cl aq (10 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 10% EtOAc in Petroleum ether) to give the title compound (120 mg, 75% yield) as a colorless oil.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 3.86 - 3.72 (m, 1H), 2.92 - 2.76 (m, 2H), 2.22 - 2.11 (m, 1H), 1.72 - 1.58 (m, 2H), 1.38 (s, 11H), 0.99 - 0.88 (m, 3H), 0.55 ( d, J = 3.2 Hz, 1H) Step 2: 2-Azabicyclo[5.1.0]octane To a solution of tert-butyl 2-azabicyclo[5.1.0]octane-2-carboxylate (120 mg, 568 μmol) in CH2Cl2 (2 mL) was added TFA(2 mL) at 0 °C. The mixture was stirred at 20 °C for 0.5 h. TheAttorney Docket No.62619-726601 mixture was concentrated under reduced pressure to give the title compound (100 mg, TFA salt) as a yellow oil, which was used in the next step without further purification. Step 3: 4-(2-Azabicyclo[5.1.0]octan-2-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (228 mg, 899 μmol) in CH2Cl2 (2 mL) were added DIPEA (581 g, 783 μL) and 2-azabicyclo[5.1.0]octane (100 mg, 899 μmol) at -40 °C under N2. The mixture was stirred at -40 °C for 1 h. The reaction mixture was diluted with water (30 mL) and extracted with CH2Cl2 (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (Intermediate 8, 150 mg, crude) as a yellow oil, which was used in the next step without further purification. MS: m / z = 327.0 [M+H]+.

[0309] Intermediate 9: 7-Chloro-4-(8,8-difluoro-2-azabicyclo[5.1.0]octan-2-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidineStep 1: tert-Butyl 8,8-difluoro-2-azabicyclo[5.1.0]octane-2-carboxylate To a solution of Intermediate 7 (100 mg, 507 μmol) in THF (2 mL) were added NaI (760 mg, 5.07 mmol) and trimethyl(trifluoromethyl)silane (721 mg, 5.07 mmol). The mixture was stirred at 55°C for 3 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 10% EtOAc in Petroleum ether) to give the title compound (120 mg, 96% yield) as a colorless oil.1H NMR (400 MHz, Chloroform-d) δ 4.01 (d, J = 11.2 Hz, 1H), 3.08 - 2.77 (m, 2H), 2.12 - 1.95 (m, 1H), 1.88 - 1.69 (m, 3H), 1.60 - 1.52 (m, 3H), 1.49 - 1.43 (m, 9H).19F NMR (376 MHz, Chloroform-d) δ -127.71, -128.14, -149.06, - 149.49. Step 2: 8,8-Difluoro-2-azabicyclo[5.1.0]octane TFA salt To a solution of tert-butyl 8,8-difluoro-2-azabicyclo[5.1.0]octane-2-carboxylate (600 mg, 2.43 mmol) in CH2Cl2(15 mL) was added TFA(15 mL) at 0 °C. The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give the title compoundAttorney Docket No.62619-726601 (600 mg, TFA, salt) as a yellow oil, which was used in the next step without further purification.1H NMR (400 MHz, Chloroform-d) δ 9.89 - 9.38 (m, 2H), 3.67 ( d, J = 13.2 Hz, 1H), 3.41 (t, J = 10.0 Hz, 1H), 3.11 (t, J = 12.8 Hz, 1H), 2.39 - 2.26 (m, 1H), 2.20 - 2.00 (m, 3H), 1.99 - 1.84 (m, 1H), 1.76 - 1.51 (m, 2H).19F NMR (376 MHz, Chloroform-d) δ -126.76, -127.22, -148.98, - 149.44. Step 3: 2,7-Dichloro-4-(8,8-difluoro-2-azabicyclo[5.1.0]octan-2-yl)-8-fluoropyrido[4,3- d]pyrimidine To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (580 mg, 2.30 mmol) in CH2Cl2(10 mL) were added DIPEA (1.48 g, 2 mL) and 8,8-difluoro-2-azabicyclo[5.1.0]octane (600 mg, 2.30 mmol) at -40 °C under N2. The mixture was stirred at -40 °C for 1 h. The reaction mixture was diluted with water (30 mL) and extracted with CH2Cl2 (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (1 g, crude) as a yellow solid, which was used into the next step without further purification. MS: m / z = 363.0 [M+H]+.1H NMR (400 MHz, Chloroform-d) δ 9.20 (s, 1H), 4.54 ( d, J = 13.6 Hz, 1H), 3.86 (t, J = 10.4 Hz, 1H), 3.44 - 3.33 (m, 1H), 2.33 - 2.15 (m, 2H), 2.07 - 2.04 (m, 1H), 1.90 - 1.84 (m, 1H), 1.68 - 1.51 (m, 2H), 1.50 - 1.46 (m, 1H). Step 4: 7-Chloro-4-(8,8-difluoro-2-azabicyclo[5.1.0]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine To a solution of 2,7-dichloro-4-(8,8-difluoro-2-azabicyclo[5.1.0]octan-2-yl)-8-fluoropyrido[4,3- d]pyrimidine (1 g, 2.75 mmol) in 1,4-dioxane (10 mL) were added DIPEA (1.07 g, 1.44 mL) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (1.10 g, 6.88 mmol). The mixture was stirred at 110°C for 16hr. The mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 10% MeOH in CH2Cl2) to give the title compound (Intermediate 9, 880 mg, 62% yield over 3 steps) as a yellow solid. MS: m / z = 486.2 [M+H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.11 (s, 1H), 5.39 - 5.17 (m, 1H), 4.38 - 4.24 (m, 2H), 4.20 - 4.07 (m, 2H), 3.23 - 2.97(m, 3H), 2.86 - 2.77 (m, 1H), 2.36 - 2.27 (m, 1H), 2.18 - 2.09 (m, 2H), 2.06 - 1.95 (m, 3H), 1.95 - 1.68 (m, 6H), 1.64 - 1.53 (m, 1H), 1.40 - 1.29 (m, 1H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -125.11, -136.40, - 138.02, -145.97, -172.16.Attorney Docket No.62619-726601

[0310] Intermediate 10: 4-(3-Azabicyclo[5.1.0]octan-3-yl)-2,7-dichloro-8-fluoropyrido[4,3- d]pyrimidineStep 1: tert-Butyl allyl(but-3-en-1-yl)carbamate To a solution of NaH (3.82 g, 95.4 mmol, 60% purity) in DMF (65 mL) was added tert-butyl allylcarbamate (10 g, 63.6 mmol) in DMF (135 mL) dropwise at 0°C under N2. The mixture was stirred at 25 °C for 30 minutes, and 4-bromobut-1-ene (11.38 g, 76.3 mmol) in DMF (135 mL) was added dropwise to the mixture at 0 °C. The reaction mixture was warmed to 25 °C and stirred at 25 °C for 0.5 h. The reaction mixture was quenched with sat. NH4Cl aq. (100 mL) at 0 °C, warmed to 25 °C and stirred at 25 °C for 30 min. The reaction mixture was diluted with H2O (60 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (400 mL), dried over Na2SO4, 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 (15.6 g, 98% yield) as a colorless oil.1H NMR (400 MHz, Chloroform-d) δ 5.93 - 5.68 (m, 2H), 5.17 - 4.92 (m, 4H), 3.80 (s, 2H), 3.17 (s, 2H), 2.03 (q, J = 6.8 Hz, 2H), 1.65 - 1.57 (m, 2H), 1.45 (s, 9H). Step 2: tert-butyl 2,3,4,7-tetrahydro-1H-azepine-1-carboxylate To a solution of tert-butyl allyl(but-3-en-1-yl)carbamate (10 g, 44.4 mmol) in CH2Cl2 (1500 mL) was added Grubb’s II (3.77 g, 4.44 mmol) at 40 °C under N2. The mixture was stirred at 40 °C for 2 h under N2atmosphere. The reaction mixture was 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 (7.1 g, 81% yield) as a brown oil.1H NMR (400 MHz, Chloroform-d) δ 5.83 - 5.63 (m, 2H), 3.98 - 3.78 (m, 1H), 3.57 - 3.37 (m, 4H), 2.37 - 2.14 (m, 4H), 1.47 - 1.44 (m, 9H). Step 3: tert-Butyl 8,8-dichloro-3-azabicyclo[5.1.0]octane-3-carboxylate To a solution of tert-butyl 2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (500 mg, 2.53 mmol) and BnNEt3Cl (16 mg, 50.7 μmol) in CHCl3(10 mL) was added a solution of NaOH (1.27 g, 31.7 mmol) in H2O (2.43 mL) dropwise at 25 °C. The reaction mixture was stirred at 45 °C forAttorney Docket No.62619-726601 16 h. The mixture was diluted with sat. NH4Cl aq. (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent: 0 ~ 7% of EtOAc in petroleum ether) to give the title compound (780 mg, 60% yield) as a colorless oil.1H NMR (400 MHz, Chloroform-d) δ 4.09 - 3.76 (m, 2H), 3.03 - 2.79 (m, 2H), 2.40 - 2.20 (m, 2H), 1.88 - 1.75 (m, 2H), 1.73 - 1.58 (m, 2H), 1.44 (s, 9H). Step 4: tert-Butyl 3-azabicyclo[5.1.0]octane-3-carboxylate To a suspension of sodium debris (1.56 g, 67.9 mmol) in THF (10 mL) was addded a solution of tert-butyl 8,8-dichloro-3-azabicyclo[5.1.0]octane-3-carboxylate (250 mg, 892 μmol) in MeOH (1 mL) dropwise at 0 °C under N2 atmosphere. During the addition, the temperature was controlled between 0 °C and 25 °C. The mixture was stirred at 25 °C for 3 h under N2 atmosphere. MeOH was slowly added dropwise until the sodium metal disappearred completely while the temperature was controlled between 25 °C and 40 °C. The reaction mixture was quenched with sat. NH4Cl aq. (50 mL) slowly at 0 °C and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent: 0 ~ 6% of EtOAc in petroleum ether) to give the title compound (130 mg, 69% yield) as a colorless oil.1H NMR (400 MHz, Chloroform-d) δ 3.69 - 3.40 (m, 2H), 3.28 - 3.10 (m, 2H), 2.26 - 2.16 (m, 2H), 1.49 - 1.39 (m, 11H), 1.02 - 0.90 (m, 2H), 0.71 - 0.60 (m, 1H), 0.22 (q, J = 5.2 Hz, 1H). Step 5: 3-Azabicyclo[5.1.0]octane, TFA salt To a solution of tert-butyl 3-azabicyclo[5.1.0]octane-3-carboxylate (130 mg, 615 μmol) in CH2Cl2(3 mL) was added TFA (0.5 mL, 6.73 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound (138 mg, TFA salt) as a yellow gum. Step 6: 4-(3-Azabicyclo[5.1.0]octan-3-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine To solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (139 mg, 550 μmol, 0.9 eq) and DIPEA (320 μL, 1.83 mmol) in CH2Cl2 (5 mL) at -40° C was added 3-azabicyclo[5.1.0]octane (138 mg, 612 μmol, TFA salt). The mixture was stirred at -40 °C for 15 min. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (Intermediate 10, 170 mg, 62% yield over 2 steps) as a yellow solid. MS: m / z = 326.8 [M + H]+.

[0311] Intermediate 11 & 12: tert-Butyl 8-fluoro-2-azabicyclo[5.1.0]octane-2-carboxylate (trans mixture) & tert-butyl 8-fluoro-2-azabicyclo[5.1.0]octane-2-carboxylate (cis mixture)Attorney Docket No.62619-726601Step 1: tert-Butyl 8-bromo-8-fluoro-2-azabicyclo[5.1.0]octane-2-carboxylate To a solution of NaOEt (7.93 g, 117 mmol) in CH2Cl2(50 mL) was added dropwise a solution of tert-butyl 2,3,4,5-tetrahydro-1H-azepine-1-carboxylate (10 g, 50.7 mmol) and ethyl 2,2- dibromo-2-fluoroacetate (26.8 g, 101 mmol) in CH2Cl2 (50 mL) at 0 °C under N2. The reaction mixture was stirred at 25 °C for 12 h. TLC indicated one new spot formed (PE / EA=5:1, Rf=0.60, color developing reagent: ninhydrin). The residue was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 10% EtOAc in Petroleum ether) to give the title compound (9 g, 58% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 4.02 - 3.79 (m, 1H), 3.03 - 2.82 (m, 2H), 2.29 - 2.07 (m, 1H), 1.84 - 1.69 (m, 3H), 1.58 - 1.42 (m, 12H).19F NMR (376 MHz, CDCl3) -127.11, -157.44. Step 2: tert-Butyl 8-fluoro-2-azabicyclo[5.1.0]octane-2-carboxylate (trans mixture) & tert-butyl 8-fluoro-2-azabicyclo[5.1.0]octane-2-carboxylate (cis mixture) To a suspension of sodium debris (8.59 g, 374 mmol) in THF (40 mL) was added a solution of tert-butyl 8-bromo-8-fluoro-2-azabicyclo[5.1.0]octane-2-carboxylate (4 g, 13 mmol) in THF (20 mL) and MeOH (20 mL) at 25 °C under N2 atmosphere. During the addition, the temperature was controlled between 25 °C and 40 °C. Then the suspension was stirred at 25 °C for 3 h. MeOH was added dropwise till the sodium metal disappeared completely while the temperature was controlled between 25 °C and 40 °C. TLC indicated two spots formed (PE: EA=10:1, Rf=0.60 with FNMR= -205 and Rf=0.55 with FNMR=-232, color developing reagent: ninhydrin). The reaction mixture was quenched slowly with sat. NH4Cl aq. (200 mL) at 0 °C and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 10% EtOAc in Petroleum ether) to give the title compound (trans mixture) (Intermediate 11, 1.2 g, 40% yield) as an off- white oil and the title compound (cis mixture) (Intermediate 12, 900 mg, 30% yield) as an off- white oil. Spectra for Intermediate 11:1H NMR (400 MHz, CDCl3) δ = 4.44 (s, 1H), 3.97 ( s, 1H), 2.81 (dd, J = 9.2, 18.8 Hz, 2H), 2.37 - 2.20 (m, 1H), 1.76 - 1.66 (m, 2H), 1.58 - 1.39 (m, 12H), 1.13 - 0.95 (m, 1H).19F NMR (376 MHz, CDCl3) δ -205.16. Spectra for Intermediate 12:1H NMR (400 MHz, CDCl3) δ 4.59 - 4.23 (m, 1H), 3.95 ( s, 1H), 3.02 - 2.83 (m, 1H), 2.42 ( s, 1H), 1.95 - 1.86 (m, 1H) 1.84 - 1.67 (m, 3H), 1.63 - 1.54 (m, 2H), 1.45 (s, 9H), 1.14 - 1.03 (m, 1H).19F NMR (376 MHz, CDCl3) δ -233.29.Attorney Docket No.62619-726601

[0312] Intermediate 13 & 14: 2,7-Dichloro-8-fluoro-4-((1R,7S,8R)-8-fluoro-2- azabicyclo[5.1.0]octan-2-yl)pyrido[4,3-d]pyrimidine & 2,7-dichloro-8-fluoro-4-((1S,7R,8S)-8- fluoro-2-azabicyclo[5.1.0]octan-2-yl)pyrido[4,3-d]pyrimidineStep 1: 8-Fluoro-2-azabicyclo[5.1.0]octane TFA salt (trans mixture) To a solution of tert-butyl 8-fluoro-2-azabicyclo[5.1.0]octane-2-carboxylate (trans mixture) (500 mg, 568 μmol) in CH2Cl2 (5 mL) was added TFA(5 mL) at 0 °C. The mixture was stirred at 20 °C for 0.5 h. The residue was concentrated under reduced pressure to give the title compound (500 mg, TFA salt) as a yellow oil, which was used in the next step without further purification. Step 2: 2,7-Dichloro-8-fluoro-4-((1R,7S,8R)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)pyrido[4,3- d]pyrimidine & 2,7-dichloro-8-fluoro-4-((1S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2- yl)pyrido[4,3-d]pyrimidine To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (586 mg, 2.32 mmol) in CH2Cl2 (5 mL) were added DIPEA (1.5 g, 2.02 mL) and 8-fluoro-2-azabicyclo[5.1.0]octane TFA salt (trans mixture) (500 mg, 2.32 mmol, TFA salt) at -40 °C under N2. The mixture was stirred at -40 °C for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with CH2Cl2 (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was separated by SFC (column: DAICEL CHIRALCEL OJ (250 mm × 30 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH3·H2O)]; B% : 40%, isocratic elution mode) to give the title compound (Intermediate 13, 200 mg, 25% yield, SFC peak 1: 1.126 min) as a yellow solid and the title compound (Intermediate 14, 200 mg, 25% yield, SFC peak 2: 1.546 min) as a yellow solid. Spectra for Intermediate 13: MS: m / z = 345.0 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 9.31 (s, 1H), 4.60 (d, J = 13.6 Hz, 1H), 4.23 - 3.94 (m, 1H), 3.76 - 3.62 (m, 1H), 3.42 - 3.28 (m, 1H), 2.49 - 2.35 (m, 1H), 2.12 - 1.90 (m, 3H), 1.85 - 1.72 (m, 1H), 1.64 - 1.59 (m, 1H), 1.12 - 0.94 (m, 1H).19F NMR (376 MHz, Chloroform-d) δ -132.27, -203.94, - 203.97. Spectra for Intermediate 14: MS: m / z = 345.0 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 9.30 (s, 1H), 4.60 (d, J = 13.6 Hz, 1H), 4.23 - 3.97 (m, 1H), 3.79 - 3.61 (m, 1H), 3.44 - 3.27 (m, 1H), 2.48 - 2.36 (m, 1H), 2.14 - 1.89 (m, 3H), 1.85 - 1.72 (m, 1H), 1.66 - 1.58 (m, 1H), 1.13 - 0.94 (m, 1H)19F NMR (376 MHz, Chloroform-d) δ -132.29, -203.891, - 203.951.Attorney Docket No.62619-726601

[0313] Intermediate 15 & 16: 2,7-Dichloro-8-fluoro-4-((1S,7R,8R)-8-fluoro-2- azabicyclo[5.1.0]octan-2-yl)pyrido[4,3-d]pyrimidine & 2,7-dichloro-8-fluoro-4-((1R,7S,8S)-8- fluoro-2-azabicyclo[5.1.0]octan-2-yl)pyrido[4,3-d]pyrimidineStep 1: 8-Fluoro-2-azabicyclo[5.1.0]octane TFA salt (cis mixture) To a solution of tert-butyl 8-fluoro-2-azabicyclo[5.1.0]octane-2-carboxylate (cis mixture) (500 mg, 2.18 mmol) in CH2Cl2(5 mL) was added TFA(486 μL, 6.54 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound (cis mixture, TFA salt) (280 mg, TFA salt) as a colorless oil, which was used in the next step without further purification. Step 2: 2,7-Dichloro-8-fluoro-4-((1S,7R,8R)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)pyrido[4,3- d]pyrimidine & 2,7-dichloro-8-fluoro-4-((1R,7S,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2- yl)pyrido[4,3-d]pyrimidine To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (547 mg, 2.17 mmol) in CH2Cl2 (10 mL) were added DIPEA (2.27 mL, 13.0 mmol) and 8-fluoro-2-azabicyclo[5.1.0]octane TFA salt (cis mixture) (280 mg, 2.17 mmol, TFA salt) at -40 °C under N2. The mixture was stirred at -40 °C for 0.5 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous Na2SO4, 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 a mixture. The mixture was separated by SFC: DAICEL CHIRALPAK IK (250mm × 30mm,10 μm); mobile phase: [CO2-i-PrOH (0.1% NH3H2O)]; B%: 40%, isocratic elution mode) to give the title compound (Intermediate 15, 150 mg, 20% yield over 2 steps, SFC Peak1: 1.898 min) as a white solid and the title compound (Intermediate 16, 150 mg, 20% yield over 2 steps, SFC Peak2: 2.263 min) as a white solid. Spectra for Intermediate 15: MS: m / z = 344.8 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.62 (s, 1H), 5.10 - 4.82 (m, 1H), 4.41 (d, J = 13.2 Hz, 1H), 3.68 - 3.60 (m, 1H), 3.46 (t, J = 12.4 Hz, 1H), 2.03 - 1.92 (m, 2H), 1.86 - 1.75 (m, 2H), 1.68 - 1.56 (m, 2H), 1.36 - 1.21 (m, 1H). Spectra for Intermediate 16: MS: m / z = 344.8 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.62 (s, 1H), 5.06 - 4.85 (m, 1H), 4.41 (d, J = 13.2 Hz, 1H), 3.70 - 3.61 (m, 1H), 3.46 (t, J = 12.4 Hz, 1H), 2.03 - 1.94 (m, 2H), 1.86 - 1.77 (m, 2H), 1.67 - 1.57 (m, 2H), 1.32 - 1.22 (m, 1H).

[0314] Intermediate 17: ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methan-d2-olAttorney Docket No.62619-726601Step 1: (2R,7aS)-2-Fluoro-hexahydropyrrolizine-7a-carboxylic acid To a stirred solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (500 mg, 3.141 mmol) and RuCl3.H2O (35.40 mg, 0.157 mmol) in CCl4(4 mL), MeCN (4 mL) and H2O (6 mL) under nitrogen atmosphere was added NaIO4(2686.99 mg, 12.564 mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 hours. The resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with CH2Cl2(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]+. Step 2: ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methan-d2-ol To an ice-cooled solution of (2R,7aS)-2-fluoro-hexahydropyrrolizine-7a-carboxylic acid (200 mg, 1.155 mmol) in Me-THF (2 mL) under nitrogen atmosphere was added LiAlD4 (2.43 mL, 2.425 mmol, 1M in THF) dropwise. The ice bath was removed, and the reaction mixture was heated at 90 °C for 2 hours. 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 dichloromethane to afford the title compound (Intermediate 17, 100 mg, 53% yield) as a yellow oil. MS: m / z = 162.15 [M + H]+.

[0315] Intermediate 18: N-(6,7-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-yl)-1,1-diphenylmethanimineStep 1: 5-(2-(3,4-Difluorophenyl)acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dioneAttorney Docket No.62619-726601 To an ice cooled mixture of (3,4-difluorophenyl)acetic acid (7 g, 40.667 mmol), DMAP (5.47 g, 44.734 mmol) and Meldrum's acid (5.86 g, 40.667 mmol) in DCM (71.79 mL) under nitrogen atmosphere was added DCC (9.23 g, 44.734 mmol) dropwise. The reaction mixture was stirred at 0 °C with an ice bath for 16 hours. The resulting mixture was filtered, and the filter cake was washed with DCM (3 x 100 mL). The resulting mixture was washed with 1 M NaHSO4 (3 x 100 mL) and brine (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (8 g, crude used through) as a yellow oil. MS: m / z = 297.10 [M - H]-. Step 2: tert-Butyl 4-(3,4-difluorophenyl)-3-oxobutanoate A solution 5-(2-(3,4-difluorophenyl)acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (8 g, crude) in t-BuOH (80 mL) under nitrogen atmosphere was heated at 88 °C for 5 hours. The resulting mixture was cooled to room temperature, concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 0-15% EA in PE to afford the title compound (7 g, 65% yield for two steps) as a light-yellow oil. MS: m / z = 269.05 [M - H]-.1H NMR (300 MHz, Chloroform-d) δ 7.26 - 7.00 (m, 2H), 6.93 - 6.91 (m, 1H), 3.80 (s, 2H), 3.40 (s, 2H), 1.47 (s, 9H). Step 3: 4-(3,4-Difluorophenyl)-3-oxobutanoic acid To an ice cooled solution of tert-butyl 4-(3,4-difluorophenyl)-3-oxobutanoate (7 g, 25.899 mmol) in DCM (70 mL) under nitrogen atmosphere was added TFA (70 mL, 863.994 mmol) dropwise. The ice bath was removed, and the resulting mixture was stirred at room temperature for 4 hours. The resulting mixture was co-evaporated with toluene (70 mL x 6) to give the title compound (6 g, crude used through) as a yellow solid. MS: m / z = 213.00 [M - H]-. Step 4: 6,7-Difluoronaphthalene-1,3-diol A solution of 4-(3,4-difluorophenyl)-3-oxobutanoic acid (6 g, crude) in CF3SO3H (180 mL) under nitrogen atmosphere was stirred at room temperature for 16 hours. The resulting mixture was diluted with EtOAc (800 mL), washed with water (4 x 300 mL) and brine (400 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 0-50% EA in PE to afford the title compound (1.7 g, 34% yield for two steps) as a black oil. MS: m / z = 195.10 [M - H]-.1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.71 (s, 1H), 7.78 - 7.72 (m, 1H), 7.63 - 7.58 (m, 1H), 6.62 - 6.53(m, 2H). Step 5: 6,7-Difluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol To a stirred solution of 6,7-difluoronaphthalene-1,3-diol (520 mg, 2.65 mmol) and (2- bromoethynyl)triisopropylsilane (761.91 mg, 2.91 mmol) in 1,4-dioxane (6 mL) under nitrogen atmosphere were added [Ru(p-cymene)Cl2]2 (162.34 mg, 0.26 mmol) and KOAc (520.35 mg,Attorney Docket No.62619-726601 5.30 mmol) at room temperature. The resulting mixture was heated at 110 °C for 2 hours. The resulting mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 0-50% EA in PE to afford the title compound (600 mg, 60% yield) as a brown solid. MS: m / z = 377.00 [M + H]+. Step 6: 6,7-Difluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diyl bis(trifluoromethanesulfonate) To a stirred solution of 6,7-difluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (1.8 g, 4.781 mmol) in DCM (18 mL) were added DIEA (3.7 g, 28.686 mmol) and Tf2O (4.4 g, 14.343 mmol) at -40 °C under nitrogen atmosphere. The resulting mixture was stirred at -40 °C for 3 hours. The resulting mixture was quenched with aq. NaHCO3 (50 mL), extracted with CH2Cl2 (3 x 100 mL), washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the title compound (3 g, crude used through) as a brown oil. MS: m / z = 638.95 [M - H]-. Step 7: 3-((Diphenylmethylene)amino)-6,7-difluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl trifluoromethanesulfonate To a stirred mixture of 6,7-difluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diyl bis(trifluoromethanesulfonate) (3 g, crude), Pd2(dba)3 (428.83 mg, 0.468 mmol), XantPhos (812.90 mg, 1.405 mmol) and Cs2CO3(3051.55 mg, 9.366 mmol) in toluene (30 mL) under nitrogen atmosphere was added diphenylmethanimine (933.59 mg, 5.151 mmol) at room temperature. The resulting mixture was heated at 100 °C for 2 hours. The resulting mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE / EA (10:1) to afford the title compound (3 g, 93% yield for two steps) as a yellow oil. MS: m / z = 672.20 [M + H]+. Step 8: N-(6,7-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-yl)-1,1-diphenylmethanimine To a stirred solution of 3-((diphenylmethylene)amino)-6,7-difluoro-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (2 g, 2.977 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (B2Pin2,1.512 g, 5.954 mmol) in 1,4- dioxane (20 mL) under nitrogen atmosphere were added KOAc (876.53 mg, 8.931 mmol) and Pd(dppf)Cl2.CH2Cl2 (12.13 mg, 0.015 mmol) at room temperature. The reaction mixture was heated at 110 °C for 3 hours. The 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 the title compound (Intermediate 18, 1.2 g, 62% yield) as a yellow solid. MS: m / z = 650.65 [M + H]+.1H NMR (400 MHz, DMSO-d6) δAttorney Docket No.62619-726601 7.86 - 7.83 (m, 1H), 7.70 - 7.68 (m, 2H), 7.59 - 7.55 (m, 1H), 7.51 - 7.48 (m, 2H), 7.31 - 7.29 (m, 4H), 7.19 - 7.17 (m, 2H), 7.09 - 7.08 (m, 1H), 1.27 (s, 12H), 1.13 - 1.07 (m, 21H).

[0316] Intermediate 19 & 20: N-(6-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-yl)-1,1-diphenylmethanimine & 6-Fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-amineStep 1: 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol To a solution of 7-fluoronaphthalene-1,3-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:1-isopropyl-4-methyl-benzene (17.2 g, 28.1 mmol). The mixture was stirred at 110 °C for 2 h under N2atmosphere. 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]+.1H NMR (400 MHz, Chloroform-d) δ 9.15 (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, Chloroform-d) δ -112.51. Step 2: 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diyl bis(trifluoromethanesulfonate) To a solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (140 g, 390 mmol) and DIPEA (408 mL, 2.34 mol) in CH2Cl2 (3.5 L) was added Tf2O (258 ml, 1.56 mol) dropwise under N2atmosphere at 0 °C. The mixture was stirred at 0 °C under N2atmosphere for 2 h. The reaction mixture was partitioned between CH2Cl2(500 mL) and H2O (2 L). The organic phase was separated, washed with brine (500 mL), dried over Na2SO4, 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.1H NMR (400 MHz, Chloroform-d) δ 7.87 (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).Attorney Docket No.62619-726601 Step 3: 3-((Diphenylmethylene)amino)-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate A mixture of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3- 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)3(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 atmosphere 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]+.1H NMR (400 MHz, Chloroform-d) δ 7.78 (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) δ -71.40, -104.22. Step 4: N-(6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-yl)-1,1-diphenylmethanimine & 6-Fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine A mixture of 3-((diphenylmethylene)amino)-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl trifluoromethanesulfonate (50 g, 76.5 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (39 g, 153 mmol), KOAc (30 g, 306 mmol), and Pd(dppf)Cl2(11.2 g, 15.3 mmol) in 1,4-dioxane (600 mL) was degassed, purged with N2three times, and stirred at 100 °C under N2atmosphere 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 19, 9 g, 14.3 mmol, 19% yield) as a yellow solid and the title compound (Intermediate 20, 10 g, 21.4 mmol, 28% yield) as a brown oil. Spectra for Intermediate 19: MS: m / z = 632.4 [M+ H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 7.86 - 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, Dimethylsulfoxide-d6) δ -106.71. Spectra for Intermediate 20: MS: m / z = 468.3 [M+ H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 7.67 - 7.57 (m, 1H), 7.27 (t, J = 9.0 Hz, 1H), 7.23 - 7.17 (m, 1H), 6.89 (d, J = 2.4 Hz, 1H), 5.48 (s, 2H), 1.33 (s, 12H), 1.17 - 1.11 (m, 21H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -112.20.Attorney Docket No.62619-726601

[0317] Intermediate 21 & 22: (1R,7R)-2-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8,8-difluoro-5-oxa-2- azabicyclo[5.1.0]octane & (1S,7S)-2-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8,8-difluoro-5-oxa-2- azabicyclo[5.1.0]octaneStep 1: Benzyl 8,8-difluoro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate To a stirred mixture of Intermediate 2 (5 g, 21.43 mmol) and NaI (1.61 g, 10.71 mmol) in THF (50 mL) was added trimethyl(trifluoromethyl)silane (12.19 g, 85.74 mmol) dropwise at room temperature under nitrogen atmosphere. The reaction mixture was heated at 65 °C for 16 hours. The resulting mixture was cooled to room temperature, diluted with water (100 mL) and extracted with EtOAc (3 x 200 mL). 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, eluted with PE / EA (10 : 1) to afford the title compound (5.1 g, 83% yield) as a light yellow solid. MS: m / z = 284.00 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 7.42 - 7.30 (m, 5H), 5.18 (s, 2H), 4.35 - 4.29 (m, 1H), 4.16 (d, J = 14.4 Hz, 1H), 3.97 (d, J = 12.8 Hz, 1H), 3.60 - 3.48 (m, 2H), 3.30 - 3.23 (m, 2H), 2.28 - 2.17 (m, 1H).19F NMR (376 MHz, Chloroform-d) δ -125.47 - -126.24 (m, 1F), -147.36 - - 148.73 (m, 1F). Step 2: 8,8-Difluoro-5-oxa-2-azabicyclo[5.1.0]octane hydrobromide A solution of benzyl 8,8-difluoro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate (2.3 g, 8.11 mmol) in 33wt% HBr in AcOH (23 mL) was stirred in an ice bath for 1 hour under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was triturated with hexane (3 x 50 mL) to afford the compound (1.5 g, crude used through) as a light yellow solid. Step 3: 2-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8,8-difluoro-5-oxa-2- azabicyclo[5.1.0]octaneAttorney Docket No.62619-726601 To a stirred solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.54 g, 10.05 mmol) and 8,8-difluoro-5-oxa-2-azabicyclo[5.1.0]octane hydrobromide (1.5 g, crude) in DCM (40 mL) was added DIEA (3.90 g, 30.17 mmol) dropwise at -40 °C under nitrogen atmosphere. The reaction mixture was stirred at -40 °C for 1 hour. The resulting mixture was diluted with 10% citric solution (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE / EA (1 : 1) to afford the title compound (1.9 g, 51% yield) as a light yellow solid. MS: m / z = 365.05, 367.05 [M + H]+. Step 4: 2-(7-Chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-8,8-difluoro-5-oxa-2- azabicyclo[5.1.0]octane To a stirred solution of 2-{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl}-8,8-difluoro-5- oxa-2-azabicyclo[5.1.0]octane (1.9 g, 5.20 mmol) in DMSO (40 mL) was added KF (604.61 mg, 10.40 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated at 80 °C for 16 hours. The resulting mixture was cooled to room temperature, diluted with water (100 mL), extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE / EA (1 : 1) to afford the title compound (1.6 g, 88% yield) as a light yellow solid. MS: m / z = 349.10 [M + H]+. Step 5: 2-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-4-yl)-8,8-difluoro-5-oxa-2-azabicyclo[5.1.0]octane To an ice-cooled stirred mixture of Intermediate 17 (443.86 mg, 2.75 mmol) in THF (8 mL) was added NaH (110.12 mg, 2.75 mmol, 60% dispersion in mineral oil) under nitrogen atmosphere. The mixture was stirred an an ice bath for 30 min. To the above mixture was added 2-(7-chloro- 2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-8,8-difluoro-5-oxa-2-azabicyclo[5.1.0]octane (800 mg, 2.29 mmol). The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with saturated aq. NH4Cl (50 mL) in an ice bath and extracted with CH2Cl2(3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with CH2Cl2 / MeOH (10 : 1) to afford the title compound (480 mg, 42% yield) as a light yellow solid. MS: m / z = 490.35 [M + H]+. Step 6: (1R,7R)-2-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8,8-difluoro-5-oxa-2-azabicyclo[5.1.0]octane &Attorney Docket No.62619-726601 (1S,7S)-2-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-4-yl)-8,8-difluoro-5-oxa-2-azabicyclo[5.1.0]octane 2-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-4-yl)-8,8-difluoro-5-oxa-2-azabicyclo[5.1.0]octane (480 mg, 0.98 mmol) was separated by Prep-CHIRAL-HPLC with the following conditions: Column: CHIRALPAK IF 2 x 25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2 M NH3-MeOH); Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: isocratic 30% B; Detector: UV 220 & 254 nm; RT1: 8.655 min; RT2: 11.221 min. The first eluting peak (RT1: 8.655 min) was concentrated and lyophilized to give the title compound (Intermediate 21, 180 mg, 37% yield, structure tentatively assigned) as a light yellow solid. MS: m / z = 490.15 [M + H]+. The second eluting peak (RT2: 11.221 min) was concentrated and lyophilized to give the title compound (Intermediate 22, 90 mg, 18% yield, structure tentatively assigned) as a light yellow solid. MS: m / z = 490.15 [M + H]+.

[0318] Intermediate 23 and 24: 8-Fluoro-2-oxa-6-azabicyclo[5.1.0]octane hydrobromide (trans mixture) & 8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane hydrobromide (cis mixture)Step 1: Benzyl 8-bromo-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane-6-carboxylate To an ice-cooled solution of Intermediate 1 (5.0 g, 21.45 mmol) and TBAI (1.62 g, 4.40 mmol) in DCM (50 mL) were added 50% aq. NaOH (50 mL) and dibromofluoromethane (12.35 g, 64.35 mmol) dropwise. The ice bath was removed, and the reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with iced water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, 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 (2.6 g, 35% yield) as an off-white semi-solid. MS: m / z = 361.10, 363.10 [M + NH4]+. Step 2: Benzyl 8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane-6-carboxylate (trans mixture) and benzyl 8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane-6-carboxylate (cis mixture) To a stirred mixture of benzyl 8-bromo-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane-6-carboxylate (2.6 g, 7.58 mmol) in EtOH (25 mL) under nitrogen atmosphere were added NH4Cl (2.10 g, 68.22 mmol) and Zn (2.53 g, 68.22 mmol) at room temperature. The reaction mixture wasAttorney Docket No.62619-726601 stirred at 10 °C for 16 hours. The resulting mixture was 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 mixtures. The first eluting peak was collected and concentrated under reduced pressure to give the title compound (trans mixture, F-NMR = -211) (233 mg, 12% yield) as an off-white semi-solid.1H-NMR (400 MHz, Chloroform-d) δ 7.32 - 7.24 (m, 5H), 5.16 - 5.12 (m, 2H), 4.66 - 4.55 (m, 1H), 4.10 - 3.65 (m, 4H), 3.00 - 2.90 (m, 1H), 2.87 - 2.80 (m, 1H), 1.79 - 1.48 (m, 2H).19F NMR (376 MHz, Chloroform-d) δ -211.30 (s, 1F). The second eluting peak was collected and concentrated under reduced pressure to give the title compound (cis mixture, F-NMR = -239) (1.0 g, 50% yield) as an off-white semi-solid.19F NMR (376 MHz, Chloroform-d) δ -239.8 (s, 1F) Step 3: 8-Fluoro-2-oxa-6-azabicyclo[5.1.0]octane hydrobromide (trans mixture) A solution of benzyl 8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane-6-carboxylate (trans mixture) (233 mg, 1.78 mmol) in 33wt% HBr in AcOH (2 mL) was stirred in an ice bath for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was triturated with hexane (3 x 8 mL) to afford the title compound (trans mixture, HBr salt) (Intermediate 23, 130 mg, crude used through) as a brown solid. MS: m / z =132.10 [M + H]+.1H NMR (300 MHz, Deuterium Oxide) δ 5.13 - 4.93 (m, 1H), 4.14 - 3.97 (m, 2H), 3.80 - 3.72 (m, 1H), 3.48 - 3.38 (m, 1H), 3.33 - 3.24 (m, 2H), 1.94 - 1.88 (m, 2H).19F NMR (282 MHz, Deuterium Oxide) δ - 211.86 (s, 1F). Step 4: 8-Fluoro-2-oxa-6-azabicyclo[5.1.0]octane hydrobromide (cis mixture) A solution of benzyl 8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane-6-carboxylate (cis mixture) (1.00 g, 7.63 mmol) in 33wt% HBr in AcOH (10 mL) was stirred in an ice bath for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was triturated with hexane (3 x 20 mL) to afford the title compuond (cis mixture) (Intermediate 24, 600 mg, HBr salt, crude used through) as a brown solid. MS: m / z = 132.10 [M + H]+.1H NMR (300 MHz, Deuterium Oxide) δ 4.85 - 4.65 (m, 1H), 4.14 - 3.86 (m, 2H), 3.65 - 3.35 (m, 3H), 2.94 - 2.89 (m, 1H), 2.16 - 1.99 (m, 2H).19F NMR (282 MHz, Deuterium Oxide) δ -240.77 (s, 1F)

[0319] Intermediate 25 & 26: (1S,7R,8R)-6-(7-Chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2- oxa-6-azabicyclo[5.1.0]octane & (1R,7S,8S)-6-(7-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2- oxa-6-azabicyclo[5.1.0]octaneAttorney Docket No.62619-726601Step 1: 6-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2-oxa-6- azabicyclo[5.1.0]octane (cis mixture) A solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (481 mg, 1.90 mmol) and 4A molecular sieves in DCM (34 mL) was stirred at room temperature for 30 min, and then DIEA (738.77 mg, 5.71 mmol) and Intermediate 24 (340 mg, crude) were added at -40 °C. The reaction mixture was stirred at -40 °C for 1 hour. The resulting mixture was diluted with 10% citric solution (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with DCM / EA (5 : 1) to afford the title compound (cis mixture) (530 mg, 80% yield) as a light yellow solid. MS: m / z = 347.00, 349.00 [M + H]+. Step 2: 6-(7-Chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2-oxa-6- azabicyclo[5.1.0]octane (cis mixture) To a stirred solution of 6-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2-oxa-6- azabicyclo[5.1.0]octane (cis mixture) (460 mg, 1.32 mmol) in DMSO (28 mL) was added KF (153.97 mg, 2.65 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 16 hours. The resulting mixture was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with DCM / EA (5 : 1) to afford the title compound (cis mixture) (180 mg, 41% yield) as a light yellow solid. MS: m / z = 330.65 [M + H]+. Step 3: 6-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane (cis mixture)Attorney Docket No.62619-726601 To an ice-cooled stirred mixture of Intermediate 17 (105.30 mg, 0.65 mmol) in THF (18 mL) was added NaH (26.12 mg, 0.65 mmol, 60% dispersion in mineral oil) under nitrogen atmosphere. After stirring in an ice bath for 30 min, Intermediate 17 (cis mixture) (180 mg, 0.54 mmol) was added to the above mixture. The ice bath was removed, and the resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with sat. aq. NH4Cl (100 mL), extracted with CH2Cl2(3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with CH2Cl2 / MeOH (10 : 1) to afford the title compound (cis mixture) (100 mg, 38% yield) as a light yellow solid. MS: m / z = 471.80 [M + H]+. Step 4: (1S,7R,8R)-6-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane & (1R,7S,8S)-6-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane 6-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane (cis mixture) (100 mg, 0.21 mmol) was separated by Prep-CHIRAL-HPLC with the following conditions: Column: CHIRAL ART Cellulose-SZ 250 x 20 mm, 5 μm; Mobile Phase A: Hex (0.5% 2 M NH3- MeOH); Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: isocratic 30%; Detector: UV 220 & 254 nm; RT1: 10.147 min; RT2: 15.476 min. The first eluting peak (RT1: 10.147 min) was concentrated and lyophilized to give the title compound (Intermediate 25, 40 mg, 40% yield) as a light yellow solid. MS: m / z = 472.20 [M + H]+. The second eluting peak (RT2: 15.476 min) was concentrated and lyophilized to give the title compound (Intermediate 26, 40 mg, 40% yield) as a light yellow solid. MS: m / z = 472.20 [M + H]+.

[0320] Intermediate 27 & 28: (1S,7R,8S)-6-(7-Chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2- oxa-6-azabicyclo[5.1.0]octane & (1R,7S,8R)-6-(7-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2- oxa-6-azabicyclo[5.1.0]octaneAttorney Docket No.62619-726601Step 1: 6-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2-oxa-6- azabicyclo[5.1.0]octane (trans mixture) A solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (260 mg, 1.03 mmol) and 4A molecular sieves in DCM (13 mL) was stirred at room temperature for 30 min, and then DIEA (399.34 mg, 3.09 mmol) and Intermediate 23 (trans mixture) (130 mg, crude) were added at -40 °C. The reaction mixture was stirred at -40 °C for 1 hour. The resulting mixture was diluted with 10% citric solution (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with DCM / EA (5 : 1) to afford the title compound (trans mixture) (160 mg, 44% yield) as a light yellow solid. MS: m / z = 346.95, 348.95 [M + H]+. Step 2: 6-(7-Chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2-oxa-6- azabicyclo[5.1.0]octane (trans mixture) To a stirred solution of 6-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2-oxa-6- azabicyclo[5.1.0]octane (trans mixture) (250 mg, 0.72 mmol) in DMSO (25 mL) was added KF (83.68 mg, 1.44 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated at 80 °C for 16 hours. The resulting mixture was cooled to room temperature, diluted with water (100 mL), extracted with EtOAc (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 DCM / EA (5 : 1) to afford the title compound (trans mixture) (100 mg, 41% yield) as a light yellow solid. MS: m / z = 331.00 [M + H]+. Step 3: 6-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane (trans mixture) To an ice-cooled stirred mixture of Intermediate 17 (58.50 mg, 0.36 mmol) in THF (9 mL) was added NaH (14.51 mg, 60% dispersion in mineral oil) under nitrogen atmosphere. After stirringAttorney Docket No.62619-726601 with an ice bath for 30 min, 6-(7-chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2- oxa-6-azabicyclo[5.1.0]octane (trans mixture) (100 mg, 0.30 mmol) was added to the above mixture. The ice bath was removed, and the reaction mixture was stirred at room temperature for an hour. The resulting mixture was quenched with sat. aq. NH4Cl (50 mL) and extracted with CH2Cl2 (3 x 50 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 CH2Cl2 / MeOH (10 : 1) to afford the title compound (trans mixture) (65 mg, 45% yield) as a light yellow solid. MS: m / z = 472.10 [M + H]+. Step 3: (1S,7R,8S)-6-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane & (1R,7S,8R)-6-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane 6-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane (trans mixture) (65 mg, 0.14 mmol) was separated by Prep-CHIRAL-HPLC with the following conditions: Column: CHIRALPAK IF, 2*25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: isocratic 25; Wave Length: 220 / 254 nm; RT1: 14.707 min; RT2: 18.946 min. The first eluting peak (RT1: 14.707 min) was concentrated and lyophilized to give the title compound (Intermediate 27, 26 mg, 40% yield) as a light yellow solid. The second eluting peak (RT2: 18.946 min) was concentrated and lyophilized to give the title compound (Intermediate 28, 27 mg, 41% yield) as a light yellow solid.

[0321] Intermediate 29 & 30: (1S,7R)-6-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6- azabicyclo[5.1.0]octane-5,5-d2 & (1R,7S)-6-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6- azabicyclo[5.1.0]octane-5,5-d2Attorney Docket No.62619-726601Step 1: 4-[(4-Methoxyphenyl)methyl]-1,4-oxazepan-5-one To an ice-cooled solution of 1,4-oxazepan-5-one (30 g, 260.57 mmol) in DMF (300 mL) was added NaH (12.51 g, 312.68 mmol, 60% dispersion in mineral oil) under nitrogen atmosphere. After stirring with an ice bath for 15 min, PMBCl (44.89 g, 286.63 mmol) was added dropwise. The ice bath was removed, and the reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was quenched with sat. aq. NH4Cl (1000 mL) and extracted with EA (4 x 800 mL). The combined organic layers were washed with brine (800 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 4% MeOH in DCM to the title compound(52 g, 84% yield) as a colorless oil.1H-NMR (300 MHz, DMSO-d6) δ 7.21 - 7.16 (m, 2H), 6.91 - 6.86 (m, 2H), 4.44 (s, 2H), 3.73 (s, 3H), 3.66 - 3.63 (m, 2H), 3.50 - 3.38 (m, 4H), 2.73 - 2.67 (m, 2H). Step 2: 4-(4-Methoxybenzyl)-1,4-oxazepane-5,5-d2To an ice-cooled solution of 4-[(4-methoxyphenyl)methyl]-1,4-oxazepan-5-one (24 g, 102.00 mmol) in THF (240 mL) under nitrogen atmosphere was added LiAlD4(306.01 mL, 306.01 mmol, 1 M in THF) dropwise. The ice bath was removed, and the reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was quenched with water (11.6 mL), 15% aq. NaOH (34.8 mL) and water (11.6 mL) with an ice bath. The resulting mixture was stirred at room temperature for 15 min, then filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 3% MeOH in DCM to afford the title compound (18.9 g, 82% yield) as a colorless oil.1H-NMR (400 MHz, Chloroform-d) δ 7.26 - 7.24 (m, 2H), 6.88 - 6.84 (m, 2H), 3.83 - 3.76 (m, 5H), 3.74 - 3.70 (m, 2H), 3.60 (s, 2H), 2.68 - 2.63 (m, 2H), 1.89 - 1.86 (m, 2H). Step 3: 1,4-oxazepane-5,5-d2 hydrochlorideAttorney Docket No.62619-726601 To an ice-cooled solution of 4-(4-methoxybenzyl)-1,4-oxazepane-5,5-d2 (18.9 g, 84.63 mmol) in DCE (380 mL) under nitrogen atmosphere was added 1-chloroethyl carbonochloridate (30.25 g, 211.59 mmol). The ice bath was removed, and the reaction mixture was heated at 85 °C for 16 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in MeOH (190 mL) and heated at 65 °C for 3 hours. The resulting mixture was cooled to room temperature and HCl (4 N in 1,4-dioxane, 21.16 mL, 84.64 mmol) was added. The resulting mixture was concentrated under reduced pressure. The residue was triturated with Et2O (3 x 50 mL) to afford the title compound (11.2 g, crude) as a yellow solid. Step 4: Benzyl 1,4-oxazepane-4-carboxylate-5,5-d2 To an ice-cooled mixture of 1,4-oxazepane-5,5-d2 hydrochloride (10 g, 71.62 mmol) and K2CO3 (27.77 g, 214.87 mmol) in THF (100 mL) under nitrogen atmosphere was added Cbz-Cl (14.66 g, 85.95 mmol) dropwise. The ice bath was removed, and the resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was quenched with H2O (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 benzyl 1,4-oxazepane-4-carboxylate-5,5-d2 (13 g, 76% yield) as a colorless oil.1H NMR (400 MHz, Chloroform-d) δ 7.37 - 7.29 (m, 5H), 5.15 (s, 2H), 3.81 - 3.69 (m, 4H), 3.62 - 3.56 (m, 2H), 1.93 - 1.86 (m, 2H). Step 5: Benzyl 3-methoxy-1,4-oxazepane-4-carboxylate-5,5-d2 & benzyl 5-methoxy-1,4- oxazepane-4-carboxylate-5-d To a solution of benzyl 1,4-oxazepane-4-carboxylate-5,5-d2(13 g, 54.78 mmol) in MeOH (150 mL) was added tetraethylammonium tosylate (8.26 g, 27.39 mmol) at room temperature. The reaction mixture was electrolyzed at room temperature for 20 hours using C (+) / C(-) electrodes at constant current 200 mA. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted 35% EA in PE to afford the title compounds (12 g, 82% yield) as a light-yellow oil.1H-NMR (400 MHz, Chloroform-d) δ crude H-NMR showed two isomers. Step 6: Benzyl 6,7-dihydro-1,4-oxazepine-4(5H)-carboxylate-5,5-d2 To an ice-cooled solution of benzyl 3-methoxy-1,4-oxazepane-4-carboxylate-5,5-d2 & benzyl 5- methoxy-1,4-oxazepane-4-carboxylate-5-d (11.7 g, 43.76 mmol) in DCM (120 mL) were added DIEA (5.26 g, 40.66 mmol) and TMSOTf (8.34 g, 37.54 mmol) under nitrogen atmosphere. The resulting mixture was stirred in an ice bath for 30 min, quenched with saturated aq. NaHCO3 (100 mL), and extracted with ethyl acetate (3 x 100 mL). The combined organic layersAttorney Docket No.62619-726601 were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 42% EA in PE to afford two isomers. The first eluting peak was collected and concentrated under reduced pressure to afford the title compound (5.0 g, 48% yield) as a yellow oil.1H NMR (300 MHz, Chloroform-d) δ 7.41 - 7.29 (m, 5H), 5.94 - 5.74 (m, 2H), 5.18 (s, 2H), 4.10 - 4.07 (m, 2H), 2.04 - 1.96 (m, 2H). Step 7: Benzyl 2-oxa-6-azabicyclo[5.1.0]octane-6-carboxylate-5,5-d2 To a solution of benzyl 6,7-dihydro-1,4-oxazepine-4(5H)-carboxylate-5,5-d2 (5.0 g, 21.25 mmol) in DCM (50 mL) was added ZnEt2(53.13 mL, 53.13 mmol, 1 M in n-hexane) at room temperature. After stirring at room temperature for 0.5 hour, a solution of CH2I2 (22.77 g, 85.00 mmol) in DCM (12 mL) was added to the mixture dropwise with an ice bath. The reaction mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into cold sat. aq. NH4Cl (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried with anhydrous Na2SO4, 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 (4.0 g, 75% yield) as a yellow oil. MS: m / z = 250.10 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 7.39 - 7.29 (m, 5H), 5.20 - 5.10 (m, 2H), 3.97 - 3.92 (m, 1H), 3.69 - 3.63 (m, 1H), 3.43 - 3.39 (m, 1H), 2.45 - 2.42 (m, 1H), 1.91 - 1.64 (m, 2H), 1.26 - 1.10 (m, 2H). Step 8: 2-Oxa-6-azabicyclo[5.1.0]octane-5,5-d2 To an ice-cooled solution of benzyl 2-oxa-6-azabicyclo[5.1.0]octane-6-carboxylate-5,5-d2 (2 g, 8.02 mmol) in MeOH (100 mL) was added Pd / C (667 mg, 10wt%) under nitrogen atmosphere. The reaction mixture was stirred in an ice bath for 40 min under hydrogen atmosphere. The resulting mixture was filtered and concentrated under reduced pressure to afford the title compound (580 mg, crude used through) as a light yellow oil. Step 9: 6-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane- 5,5-d2 To a stirred solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1.27 g, 5.03 mmol) and 2-oxa-6-azabicyclo[5.1.0]octane-5,5-d2(580 mg, crude) in DCM (13 mL) was added DIEA (1.95 g, 15.10 mmol) dropwise at -40 °C under nitrogen atmosphere. The reaction mixture was stirred at -40 °C for 1 hour. The resulting mixture was quenched with 10% citric solution (50 mL) and extracted with DCM (3 x 80 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (1.1 g, crude used through) as a light yellow solid. MS: m / z = 331.10, 333.10 [M + H]+.Attorney Docket No.62619-726601 Step 10: 6-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane-5,5-d2To a stirred solution of 6-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6- azabicyclo[5.1.0]octane-5,5-d2 (1.1 g, 3.32 mmol) in DMSO (11 mL) under nitrogen atmosphere were added KF (675.40 mg, 11.62 mmol) and Intermediate 17 (856.79 mg, 5.31 mmol) at room temperature. The reaction mixture was heated at 100 °C for 16 hours. The resulting mixture was cooled to room temperature, diluted with water (60 mL), and extracted with DCM (3 x 60 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with CH2Cl2 / MeOH (10 : 1) to afford the title compound (670 mg, 29% yield for two steps) as a light yellow solid. MS: m / z = 456.30 [M + H]+. Step 11: (1S,7R)-6-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane-5,5-d2& (1R,7S)- 6-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane-5,5-d2 6-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane-5,5-d2 (900 mg, 1.97 mmol) was separated by Prep-SFC with the following conditions: Column: Enantiocel C9-5, 30 x 250 mm, 5.0 um; Mobile Phase A: CO2, Mobile Phase B: IPA; Flow rate: 100 mL / min; Gradient: isocratic 50% B; Back Pressure (bar): 100; Detector: UV 220 nm; RT1: 3.9 min; RT2: 6.4 min; Sample Solvent: MeOH : DCM = 2: 1. The first eluting peak (RT1: 3.9 min) was concentrated and lyophilized to give the title compound (Intermediate 29, 350 mg, 38% yield) as a light yellow solid. MS: m / z = 456.30 [M + H]+. The second eluting peak (RT2: 6.4 min) was concentrated and lyophilized to give the title compound (Intermediate 30, 350 mg, 38% yield) as a light yellow solid. MS: m / z = 456.30 [M + H]+.

[0322] Intermediate 31 & 32: 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)Step 1: Benzyl 8-bromo-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate 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 nitrogen atmosphere were added 33wt% aq. NaOH solution (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 hours. The resulting mixture was diluted withAttorney Docket No.62619-726601 iced water (50 mL), extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, 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]+. 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) 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 nitrogen atmosphere were added NH4Cl (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 hours. The 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 mixtures. The first eluting mixtures were collected and concentrated under reduced pressure to give the title compound (trans mixture) (Intermediate 31, 700 mg, 38% yield) as an off-white semi-solid. MS: m / z = 283.20 [M + NH4]+.1H NMR (300 MHz, Chloroform-d) δ 7.39 - 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, Chloroform-d) δ - 207.85 (s, 1F). The second eluting mixtures were collected and concentrated under reduced pressure to give the title compound (cis mixture) (Intermediate 32, 360 mg, 19% yield) as a yellow oil. MS: m / z = 283.20 [M + NH4]+.1H NMR (300 MHz, Chloroform-d) δ 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-d) δ -232.23 (s, 1F).

[0323] Intermediate 33 & 34: (1R,7R,8R)-2-(7-Chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5- oxa-2-azabicyclo[5.1.0]octane & (1S,7S,8S)-2-(7-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5- oxa-2-azabicyclo[5.1.0]octaneAttorney Docket No.62619-726601Step 1: 8-Fluoro-5-oxa-2-azabicyclo[5.1.0]octane hydrobromide (trans mixture) Intermediate 31 (trans mixture) (2.6 g, 9.81 mmol) in 33wt% HBr in AcOH (26 mL) under nitrogen atmosphere was stirred in an ice bath for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was trituration with hexane (3 x 50 mL) to afford the title compound (trans mixture, HBr salt) (1.9 g, crude used through) as a light yellow solid. Step 2: 2-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2- azabicyclo[5.1.0]octane (trans mixture) To a stirred solution of 8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane hydrobromide (trans mixture) (600 mg, crude) and 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1154.94 mg, 4.57 mmol) in DCM (11 mL) was added DIEA (1773.88 mg, 13.72 mmol) dropwise at -40 °C under nitrogen atmosphere. The reaction mixture was stirred at -40 °C for 1 hour. The resulting mixture was diluted with 10% citric solution (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4,filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with CH2Cl2 / EA (5 : 1) to afford the title compound (trans mixture) (800 mg, 50% yield) as a light yellow solid. MS: m / z = 347.10, 349.10 [M + H]+. Step 3: 2-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (trans mixture) To a stirred solution of 2-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2- azabicyclo[5.1.0]octane (trans mixture) (800 mg, 2.30 mmol) in DMSO (8 mL) under nitrogen atmosphere were added KF (468.59 mg, 8.06 mmol) and Intermediate 17 (594.43 mg, 3.68 mmol) at room temperature. The resulting mixture was heated at 100 °C for 16 hours. The resulting mixture was cooled to room temperature, diluted with water (50 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (50 mL), driedAttorney Docket No.62619-726601 over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with CH2Cl2 / MeOH (10 : 1) to afford the title compound (trans mixture) (400 mg, 36% yield) as a light yellow solid. MS: m / z = 472.25 [M + H]+. Step 4: (1R,7R,8R)-2-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane & (1S,7S,8S)-2-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane 2-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (trans mixture) (400 mg, 0.84 mmol) was separated by Prep-SFC with the following conditions: Column: (S, S)- Whelk-O 15μm Kromasil, 3 x 25 cm, 5 μm; Mobile Phase A: CO2; Mobile Phase B: MeCN: MeOH = 1 : 1 (1% 2 M NH3-MeOH); Flow rate: 100 mL / min; Gradient: isocratic 50% B; Back Pressure (bar): 100; Detector: UV 220 nm; RT1: 3.3 min; RT2: 6.1 min; Sample Solvent: MeOH. The first eluting peak (RT1: 3.3 min) was concentrated and lyophilized to give the title compound (Intermediate 33, 150 mg, 37%) as a light yellow solid. MS: m / z = 472.10 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 9.21 (s, 1H), 5.41 - 5.16 (m, 1H), 4.69 - 4.55 (m, 1H), 4.50 - 4.21 (m, 2H), 4.03 - 3.79 (m, 3H), 3.70 - 3.55 (m, 1H), 3.33 - 3.15 (m, 3H), 3.05 - 2.94 (m, 1H), 2.40 - 1.74 (m, 8H).19F NMR (376 MHz, CDCl3) δ -134.22 (s, 1F), -173.15 (s, 1F), - 207.66 (s, 1F). The second eluting peak (RT2: 6.1 min) was concentrated and lyophilized to give the title compound (Intermediate 34, 200 mg, 50%) as a light yellow solid. MS: m / z = 472.10 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 9.22 (s, 1H), 5.37 - 5.16 (m, 1H), 4.68 - 4.58 (m, 1H), 4.49 - 4.22 (m, 2H), 4.02 - 3.81 (m, 3H), 3.71 - 3.57 (m, 1H), 3.31 - 3.12 (m, 3H), 3.05 - 2.91 (m, 1H), 2.40 - 1.77 (m, 8H).19F NMR (376 MHz, CDCl3) δ -134.20 (s, 1F), - 173.11 (s, 1F), -207.61 (s, 1F).

[0324] Intermediate 35 & 36: (1R,7R,8S)-2-(7-Chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5- oxa-2-azabicyclo[5.1.0]octane & (1S,7S,8R)-2-(7-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5- oxa-2-azabicyclo[5.1.0]octaneAttorney Docket No.62619-726601Step 1: 8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane hydrobromide (cis mixture) A solution of Intermediate 32 (600 mg, 2.26 mmol) in 33wt% HBr in AcOH (6 mL) under nitrogen atmosphere was stirred in an ice bath for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with hexane (3 x 50 mL) to afford the title compound (cis mixture, HBr salt) (470 mg, crude used through) as a light yellow solid. Step 2: 2-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2- azabicyclo[5.1.0]octane (cis mixture) To a stirred solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (866.20 mg, 3.43 mmol) and 8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane hydrobromide (cis mixture) (450 mg, crude) in DCM (18 mL) was added DIEA (1.33 g, 10.29 mmol) dropwise at -40 °C under nitrogen atmosphere. The reaction mixture was stirred at -40 °C for 1 hour. The resulting mixture was diluted with 10% citric solution (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE / EA (1 : 1) to afford the title compound (cis mixture) (260 mg, 21% yield) as a light yellow solid. MS: m / z = 347.05, 349.05 [M + H]+. Step 3: 2-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (cis mixture) To a stirred solution of 2-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2- azabicyclo[5.1.0]octane (cis mixture) (250 mg, 0.72 mmol) in DMSO (2.5 mL) under nitrogen atmosphere were added KF (146.43 mg, 2.52 mmol) and Intermediate 17 (185.76 mg, 1.15 mmol) at room temperature. The reaction mixture was heated at 100 °C for 16 hours. The resulting mixture was cooled to room temperature, diluted with water (20 mL), extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue wasAttorney Docket No.62619-726601 purified by silica gel flash chromatography, eluted with CH2Cl2 / MeOH (10 : 1) to afford 2-(7- chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (cis mixture) (100 mg, 29% yield) as a light yellow solid. MS: m / z = 472.30 [M + H]+. Step 4: (1R,7R,8S)-2-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane & (1S,7S,8R)-2-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane 2-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (cis mixture) (100 mg, 0.21 mmol) was separated by Prep-CHIRAL-HPLC with the following conditions: Column: CHIRALPAK IF, 2 x 25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2 M NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: isocratic 20%; Detector: UV 220 & 254 nm; RT1: 14.255 min; RT2: 16.335 min. The first eluting peak (RT1: 14.225 min) was concentrated and lyophilized to give the title compound (Intermediate 35, 35 mg, 35% yield) as a light yellow solid. MS: m / z = 471.85 [M + H]+. The second eluting peak (RT2: 16.335 min) was concentrated and lyophilized to give the title compound (Intermediate 36, 35 mg, 35% yield) as a light yellow solid. MS: m / z = 471.80 [M + H]+.

[0325] Intermediate 37 & 38: (1R,6S)-5-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-5- azabicyclo[4.1.0]heptane. & (1S,6R)-5-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-5- azabicyclo[4.1.0]heptaneStep 1: 5-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[4.1.0]heptane To a mixture of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (2 g, 7.92 mmol) and 2-oxa-5- azabicyclo[4.1.0]heptane hydrochloride (1.07 g, 7.92 mmol) in DCM (40 mL) under nitrogenAttorney Docket No.62619-726601 atmosphere was added DIEA (3.07 g, 23.76 mmol) dropwise at -40 °C. The reaction mixture was stirred at -40 °C for 1 hour. The resulting mixture was diluted with water (150 mL) 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 5% methanol in dichloromethane to afford the title compound (2 g, 80% yield) as a yellow solid. MS: m / z = 314.95, 316.95 [M + H]+. Step 2: 5-(7-Chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[4.1.0]heptane To a stirred solution of 5-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-2-oxa-5- azabicyclo[4.1.0]heptane (2 g, 6.34 mmol) in DMSO (40 mL) under nitrogen atmosphere was added KF (0.66 g, 11.42 mmol) at room temperature. The reaction mixture was heated at 80 °C for 16 hours. The resulting mixture was cooled to room temperature, diluted with EtOAc (300 mL), and washed with brine (3 x 80 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 5% methanol in dichloromethane to afford the title compound (1.5 g, 79% yield) as a yellow solid. MS: m / z = 299.00 [M + H]+. Step 3: 5-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[4.1.0]heptane To an ice-cooled solution of Intermediate 17 (0.97 g, 6.02 mmol) in THF (40 mL) under nitrogen atmosphere was added NaH (0.24 g, 6.02 mmol, 60% dispersion in mineral oil). After stirring in an ice bath for 0.5 hours, 5-(7-chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-2-oxa- 5-azabicyclo[4.1.0]heptane (1.5 g, 5.02 mmol) was added to the above mixture. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with saturated aq. NH4Cl (100 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by RP-Flash directly with the following conditions: Column, C18; Mobile phase A: 5 mM aq. NH4HCO3; Mobile phase B: MeCN; Gradient: 5% B - 95% B in 40 min, 57% B hold 3 mins; Flow rate: 40 mL / min; Detector UV: 254 & 210 nm. The collected fractions were combined, concentrated and then lyophilized overnight to give the title compound (500 mg, 22% yield) as a yellow solid. MS: m / z = 440.25 [M + H]+. Step 4: (1R,6S)-5-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[4.1.0]heptane. & (1S,6R)-5-(7- chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[4.1.0]heptaneAttorney Docket No.62619-726601 5-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[4.1.0]heptane (500 mg, 1.13 mmol) was separated by Prep-Chiral-HPLC with following conditions: Column: CHIRALPAK IF, 2 x 25 cm, 5 μm; Mobile Phase A: MTBE (0.5% 2 M NH3-MeOH)-HPLC; Mobile Phase B: EtOH- HPLC; Flow rate: 20 mL / min; Gradient: isocratic 30%; Detected: UV 220 & 254 nm; RT1: 7.032 min; RT2: 8.72 min. The first eluting isomer (RT1: 7.032 min) was concentrated and lyophilized overnight to give the title compound (Intermediate 37, 150 mg, 30% yield) as a yellow lyophilized powder. MS: m / z = 440.20 [M + H]+. The second eluting isomer (RT2: 8.72 min) was concentrated and lyophilized overnight to give the title compound (Intermediate 38, 190 mg, 38% yield) as a yellow lyophilized powder. MS: m / z = 440.15 [M + H]+.

[0326] Intermediate 39 & 40: (1R,7S)-6-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy-d2)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6- azabicyclo[5.1.0]octane & (1S,7R)-6-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy-d2)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6- azabicyclo[5.1.0]octaneStep 1: 6-(2,7-Dichloro-8-fluoro-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6- azabicyclo[5.1.0]octane To a stirred solution of 2,4,7-trichloro-8-fluoro-5-methoxypyrido[4,3-d]pyrimidine (1.0 g, 3.54 mmol, refer to Intermediate 132 for detail procedures) and 2-oxa-6-azabicyclo[5.1.0]octane (0.40 g, 3.54 mmol, refer to Intermediate 3 for detail procedures) in DCM (20 mL) was added DIEA (0.92 g, 7.08 mmol) dropwise at -40 °C under nitrogen atmosphere. The reaction mixture was stirred at -40 °C for 1 hour. The resulting mixture was diluted with 10% citric acid solution (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (0.9 g, crude used through) as a light yellow solid. MS: m / z = 359.10, 361.10 [M + H]+.Attorney Docket No.62619-726601 Step 2: 6-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy- d2)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane To a stirred solution of 6-(2,7-dichloro-8-fluoro-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-2-oxa- 6-azabicyclo[5.1.0]octane (0.9 g, crude) in DMSO (9 mL) under nitrogen atmosphere were added KF (0.51 g, 8.77 mmol) and Intermediate 17 (0.65 g, 4.01 mmol) at room temperature. The reaction mixture was heated at 100 °C for 16 hours. The resulting mixture was cooled to room temperature, diluted with water (30 mL), extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with CH2Cl2 / MeOH (10 : 1) to afford the title compound (440 mg, 25% yield for two steps) as a light yellow solid. MS: m / z = 484.20 [M + H]+. Step 3: (1R,7S)-6-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy-d2)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane & (1S,7R)-6-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy- d2)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane 6-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d2)-5- methoxypyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane (440 mg, 0.81 mmol) was separated by Prep-CHIRAL-HPLC with the following conditions: Column: CHIRALPAK IF 2 x 25 cm, 5 μm; Mobile Phase A: Hexane (0.5% 2 M NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: isocratic 30% B; Detector: UV 220 nm & 254 nm; RT1: 10.889 min; RT2: 14.542 min. The first eluting peak (RT1: 10.889 min) was concentrated and lyophilized to give the title compound (Intermediate 39, 120 mg, 30% yield) as an off-white solid. MS: m / z = 484.25[M + H]+. The second eluting peak (RT2: 14.542 min) was concentrated and lyophilized to give the title compound (Intermediate 40, 120 mg, 30% yield) as an off-white solid. MS: m / z = 484.2[M + H]+.

[0327] Intermediate 41 & 42: Benzyl-7-fluoro-2-oxa-5-azabicyclo[4.1.0]heptane-5-carboxylate (trans mixture) & benzyl 7-fluoro-2-oxa-5-azabicyclo[4.1.0]heptane-5-carboxylate (cis mixture)Step 1: Benzyl morpholine-4-carboxylateAttorney Docket No.62619-726601 To an ice-cooled mixture of morpholine (5 g, 57.39 mmol) and K2CO3 (23.80 g, 172.17 mmol) in THF (50 mL) under nitrogen atmosphere was added CbzCl (11.75 g, 68.86 mmol) dropwise. The ice bath was removed, and the reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was quenched with sat. aq. NaHCO3 (500 mL) and extracted with EA (3 x 300 mL). The combined organic layers were washed with brine (200 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 (11 g, 86% yield) as a colorless oil.1H-NMR (400 MHz, Chloroform-d) δ 7.39 - 7.31 (m, 5H), 5.15 (s, 2H), 3.66 - 3.49 (m, 8H). Step 2: Benzyl 3-methoxymorpholine-4-carboxylate To a solution of benzyl morpholine-4-carboxylate (10 g, 45.19 mmol) in MeOH (200 mL) was added tetraethylammonium tosylate (6.81 g, 22.59 mmol) at room temperature. The reaction mixture was electrolyzed at 20 °C for 28 hours using C (+) / C(-) electrodes at constant current 200 mA. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted 35% EA in PE to afford the title compound (8 g, 70% yield) as a light-yellow oil.1H-NMR (400 MHz, Chloroform-d) δ 7.40 - 7.32 (m, 5H), 5.34 - 5.04 (m, 3H), 4.20 - 3.16 (m, 10H). Step 3: Benzyl 2,3-dihydro-4H-1,4-oxazine-4-carboxylate To an ice-cooled solution of benzyl 3-methoxymorpholine-4-carboxylate (8 g, 31.83 mmol) in DCM (90 mL) were added DIEA (5.35 g, 41.38 mmol) and TMSOTf (8.49 g, 38.20 mmol) under nitrogen atmosphere. The reaction mixture was stirred in an ice bath for 0.5 hour. The resulting mixture was diluted with hexane (200 mL), filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 42% EA in PE to afford the title compound (5 g, 71% yield).1H-NMR (400 MHz, Chloroform-d) δ 7.57 - 7.32 (m, 5H), 6.34 - 6.20 (m, 1H), 6.03 - 5.75 (m, 1H), 5.19 (d, J = 4.0 Hz, 2H), 4.10 - 4.02 (m, 2H), 3.84 - 3.73 (m, 2H). Step 4: Benzyl 7-bromo-7-fluoro-2-oxa-5-azabicyclo[4.1.0]heptane-5-carboxylate To an ice-cooled solution of benzyl 2,3-dihydro-4H-1,4-oxazine-4-carboxylate (5 g, 22.80 mmol) in DCM (15 mL) were added NaOH (25 mL, 50% aq.) and dibromofluoromethane (13124.32 mg, 68.41 mmol). The ice bath was removed, and the reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with water (100 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (70 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 38% EA in PE to affordAttorney Docket No.62619-726601 the title compound (6 g, 79% yield) as a yellow oil.1H-NMR (300 MHz, Chloroform-d) δ 7.45 - 7.33 (m, 5H), 5.31 - 5.19 (m, 2H), 4.26 - 3.79 (m, 2H), 3.75 - 3.60 (m, 1H), 3.50 - 3.29 (m, 3H). Step 5: Benzyl-7-fluoro-2-oxa-5-azabicyclo[4.1.0]heptane-5-carboxylate (trans mixture) & benzyl 7-fluoro-2-oxa-5-azabicyclo[4.1.0]heptane-5-carboxylate (cis mixture) To a stirred solution of benzyl 7-bromo-7-fluoro-2-oxa-5-azabicyclo[4.1.0]heptane-5- carboxylate (5 g, 15.14 mmol) and NH4Cl (7290.71 mg, 136.29 mmol) in EtOH (23 mL) was added Zn (8911.32 mg, 136.29 mmol) at room temperature. The reaction mixture was stirred at 10 °C for 20 hours. The resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 43% EA in PE to give two mixtures. The first eluting peak was concentrated to give the title compound (trans mixture) (Intermediate 41, 2.02 g, 53% yield) as a light yellow oil.1H NMR (400 MHz, Chloroform-d) δ 7.42 - 7.31 (m, 5H), 5.28 - 5.16 (m, 2H), 4.59 - 4.43 (m, 1H), 4.06 - 3.96 (m, 1H), 3.73 - 3.61 (m, 2H), 3.34 - 3.19 (m, 3H).19F-NMR (376 MHz, Chloroform-d) δ -215.72 - - 216.69 (m, F). The second eluting peak was concentrated to give the title compound (cis mixture) (Intermediate 42, 1.28 g, 33% yield) as a yellow oil.1H-NMR (400 MHz, Chloroform- d) δ 7.40 - 7.32 (m, 5H), 5.30 - 5.17 (m, 2H), 4.45 - 4.19 (m, 1H), 3.94 - 3.79 (m, 1H), 3.70 - 3.30 (m, 4H), 2.90 - 2.80 (m, 1H).19F-NMR (376 MHz, Chloroform-d) δ -240.93 - -242.11 (m, 1F).

[0328] Intermediate 43 & 44: (1S,6R,7S)-5-(7-Chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-7-fluoro-2- oxa-5-azabicyclo[4.1.0]heptane & (1R,6S,7R)-5-(7-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-7-fluoro-2- oxa-5-azabicyclo[4.1.0]heptaneStep 1: 7-Fluoro-2-oxa-5-azabicyclo[4.1.0]heptane (trans mixture) To an ice-cooled solution of Intermediate 41 (2.0 g, 7.96 mmol) in MeOH (100 mL) was added Pd / C (771.01 mg, 10% wt) under nitrogen atmosphere. The reaction mixture was stirred in anAttorney Docket No.62619-726601 ice bath for 40 min under hydrogen atmosphere using a hydrogen balloon. The resulting mixture was filtered through a Celite pad and concentrated under reduced pressure to afford the title compound (trans mixture) (750 mg, 80% yield, assumed 100% purity) as a light yellow oil. Step 2: 5-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-7-fluoro-2-oxa-5- azabicyclo[4.1.0]heptane (trans mixture) To a stirred solution of 7-fluoro-2-oxa-5-azabicyclo[4.1.0]heptane (trans mixture) (750 mg, crude) and 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1616.57 mg, 6.40 mmol) in DCM (16 mL) was added DIEA (2482.91 mg, 19.21 mmol) dropwise at -40 °C under nitrogen atmosphere. The reaction mixture was stirred at -40 °C for 1 hour. The resulting mixture was diluted with 10% citric solution (50 mL) and extracted with DCM (3 x 60 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE / EA (1:1) to afford the title compound (trans mixture) (1.1 g, 51% yield) as a light yellow solid. MS: m / z = 332.65 [M + H]+. Step 2: 5-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-4-yl)-7-fluoro-2-oxa-5-azabicyclo[4.1.0]heptane (trans mixture) To a stirred solution of 5-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-7-fluoro-2-oxa-5- azabicyclo[4.1.0]heptane (trans mixture) (1.1 g, 3.30 mmol) in DMSO (11 mL) under nitrogen atmosphere were added KF (671.45 mg, 11.55 mmol) and Intermediate 17 (532.36 mg, 3.30 mmol) at room temperature. The reaction mixture was heated at 100 °C for 16 hours. The resulting mixture was cooled to room temperature, diluted with water (80 mL), and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with CH2Cl2 / MeOH (10 : 1) to afford the title compound (trans mixture) (600 mg, 39% yield) as a light yellow solid. MS: m / z = 457.80 [M + H]+. Step 3: (1S,6R,7S)-5-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-7-fluoro-2-oxa-5-azabicyclo[4.1.0]heptane & (1R,6S,7R)-5-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-7-fluoro-2-oxa-5-azabicyclo[4.1.0]heptane 5-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-4-yl)-7-fluoro-2-oxa-5-azabicyclo[4.1.0]heptane (trans mixture) (600 mg, 1.31 mmol) was separated by Prep-SFC Column: CHIRAL ART Cellulose-SJ, 3 x 25 cm, 5 μm; Mobile Phase A: CO2; Mobile Phase B: IPA (0.1% DEA); Flow rate: 100 mL / min; Gradient: isocratic 45% B; Back Pressure (bar): 100; Detector: UV 220 nm; RT1: 2.8 min; RT2:Attorney Docket No.62619-726601 4.7 min. The first eluting peak (RT1: 2.8 min) was concentrated and lyophilized to give the title compound (Intermediate 43, 110 mg, 18% yield) as a light yellow solid. MS: m / z = 458.20 [M + H]+. The second eluting peak (RT2: 4.7 min) was concentrated and lyophilized to give the title compound (Intermediate 44, 110 mg, 18% yield) as a light yellow solid. MS: m / z = 458.20 [M + H]+.

[0329] Intermediate 45: ((2,3-Difluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalen-1-yl)ethynyl)triisopropylsilaneStep 1: 6,7-Difluoro-1,4-dihydro-1,4-epoxynaphthalene To a stirred solution of 1-bromo-2,4,5-trifluorobenzene (1.0 g, 4.74 mmol) in anhydrous Et2O (10 mL) was added n-BuLi (2.5 M in n-hexane, 2.27 mL, 5.69 mmol) dropwise at -78 °C. The reaction mixture was stirred at -78 °C for 0.5 hours. To the above mixture was added furan (3.2 g, 47.40 mmol) at -78 °C, then stirred at -78 °C for 2 hours and additional 16 hours at room temperature. The resulting mixture was quenched with water (20 mL), extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with EA / PE (1 / 5) to afford the title compound (300 mg, 34% yield) as a yellow oil. MS: m / z = 180.95 [M + H]+.1H NMR (300 MHz, CD3CN) δ 7.21 - 7.13 (m, 2H), 7.05 - 7.03 (m, 2H), 5.70 - 5.69 (m, 2H).19F NMR (282 MHz, CD3CN) δ -144.99 (s, 2F). Step 2: 6,7-Difluoronaphthalen-1-ol To an ice-cooled solution of 6,7-difluoro-1,4-dihydro-1,4-epoxynaphthalene (1.3 g, 7.22 mmol) in anhydrous DCM (15 mL) was added boron trifluoride diethyl etherate (1.07 g, 7.58 mmol). The ice bath was removed, and the reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by RP-Flash with the following conditions: column: C-18; Mobile phase A: Water; Mobile phase B: MeCN; Gradient: 10% B to 50% B in 20 min; Detector: UV 254 nm. The collected fractions were combined, concentrated, and then lyophilized overnight to afford the title compound (1.0 g,Attorney Docket No.62619-726601 76% yield) as a light yellow solid. MS: m / z = 179.04 [M - H]+.1H NMR (400 MHz, Chloroform-d) δ 7.96 - 7.91 (m, 1H), 7.54 - 7.52 (m, 1H), 7.36 - 7.37 (m, 2H), 6.80 - 6.78 (m, 1H), 5.24 (bs, 1H).19F NMR (376 MHz, Chloroform-d) δ -136.83 - -137.48 (m, 2F). Step 3: 6,7-Difluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol To a stirred solution of 6,7-difluoronaphthalen-1-ol (1.0 g, 5.55 mmol) in anhydrous 1,4-dioxane (10 mL) were added dichloro(p-cymene)ruthenium(II) dimer (336.80 mg, 0.55 mmol), (2- bromoethynyl)triisopropylsilane (1.52 g, 5.83 mmol) and KOAc (1.08 g, 11.10 mmol) at room temperature under argon atmosphere. The reaction mixture was heated at 110 °C for 2 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with EA / PE (1 / 5) to afford the title compound (1.3 g, 65% yield) as a light yellow solid. MS: m / z = 359.10 [M - H]+.1H NMR (300 MHz, Chloroform-d) δ 8.98 (s, 1H), 7.55 - 7.49 (m, 1H), 7.41 - 7.38 (m, 1H), 7.35 - 7.27 (m, 1H), 7.00 - 6.97 (m, 1H), 1.29 - 1.16 (m, 21H).19F NMR (282 MHz, Chloroform-d) δ -131.53 - -131.67 (m, 1F), -137.55 - -137.63 (m, 1F). Step 4: 6,7-Difluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate To a stirred solution of 6,7-difluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (1.57 g, 4.36 mmol) in DCM (16 mL) were added N-ethyl-N-isopropylpropan-2-amine (2.25 g, 17.44 mmol) and trifluoromethanesulfonic anhydride (1.84 g, 6.54 mmol) at - 40 °C under argon atmosphere. The reaction mixture was stirred at - 40 °C for 1 hour. The resulting mixture was quenched with saturated aq. NaHCO3 (80 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 0-30% ethyl acetate in petroleum ether to afford the title compound (1.6 g, 0.65 mmol, 76% yield) as a light yellow solid.1H NMR (300 MHz, Chloroform-d) δ 7.79 - 7.76 (m, 1H), 7.62 - 7.46 (m, 3H), 1.25 - 1.15 (m, 21H).19F NMR (282 MHz, Chloroform-d) δ -71.20 (s, 3F), -124.63 - -124.71(d, 1F), -134.16 - -134.24 (d, 1F). Step 5: ((2,3-Difluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1- yl)ethynyl)triisopropylsilane To a stirred mixture of 6,7-difluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (2.2 g, 4.46 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.40 g, 13.39 mmol) in 1,4-dioxane (44 mL) were added Pd(dppf)Cl2•CH2Cl2(363.83 mg, 0.44 mmol) and KOAc (1.75 g, 17.86 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated at 110°C for 16 hours. The resulting mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 0-10% ethylAttorney Docket No.62619-726601 acetate in petroleum ether to afford the title compound (Intermediate 45,1.2 g, 57% yield) as a light yellow solid.1H NMR (400 MHz, Chloroform-d) δ 7.78 - 7.74 (m, 2H), 7.54 - 7.42 (m, 2H), 1.43 (s, 12H), 1.27 - 1.13 (m, 21H).

[0330] Intermediate 46: 2-(7-Fluoro-8-(methoxy-d3)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolaneStep 1: 8-Bromo-2-fluoronaphthalen-1-ol To a stirred solution of 7-bromo-2,3-dihydro-1H-inden-1-one (3.5 g, 16.58 mmol) and TBAB (534.5 mg, 1.65 mmol) in toluene (40 mL) was added (bromodifluoromethyl)trimethylsilane (10.1 g, 49.74 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated at 110 °C for 16 hours. To the above solution was added TBAF (1 M in THF, 3.31 mL, 3.31 mmol) at room temperature, and then the mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with H2O (50 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with water (80 mL) and brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE / EA (5 : 1) to afford the title compound (2.8 g, 70% yield) as an off-white solid. MS: m / z = 238.65, 240.65 [M - H]+.1H NMR (300 MHz, DMSO-d6) δ 10.11 - 10.10 (m, 1H), 7.90 - 7.86 (m, 1H), 7.78 - 7.75 (m, 1H), 7.54 - 7.45 (m, 2H), 7.30 - 7.24 (m, 1H).19F NMR (282 MHz, DMSO-d6) δ -135.81 - -136.21 (m,1 F). Step 2: 8-Bromo-2-fluoro-1-(methoxy-d3)naphthalene To a solution of 8-bromo-2-fluoronaphthalen-1-ol (1.5 g, 6.22 mmol) in acetone (20 mL) were added K2CO3(1.28 g, 9.33 mmol) and iodomethane-d3(1.35 g, 9.33 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated at 80 °C for 2 hours. The resulting mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE / EA (5 : 1) to afford the title compound (1.5 g, 93% yield) as a yellow semi-solid.1H NMR (300 MHz, DMSO-d6) δ 8.02 - 7.99 (m, 1H), 7.90 - 7.83 (m, 2H), 7.65 - 7.58 (m, 1H), 7.39 - 7.34 (m, 1H).19F NMR (282 MHz, DMSO-d6) δ -129.64 (s, 1F). Step 3: 2-(7-Fluoro-8-(methoxy-d3)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a stirred solution of 8-bromo-2-fluoro-1-(methoxy-d3)naphthalene (500 mg, 1.93 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (983.86 mg, 3.87 mmol) in 1,4-Attorney Docket No.62619-726601 dioxane (5 mL) were added Pd(dppf)Cl2.DCM (155.16 mg, 0.19 mmol) and KOAc (570.29 mg, 5.811 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated at 80 °C for 3 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE / EA (7 : 1) to afford the title compound (Intermediate 46, 510 mg, 86% yield) as a yellow solid.1H NMR (300 MHz, DMSO - d6) δ 7.96 - 7.93 (m, 1H), 7.74 - 7.69 (m, 1H), 7.54 - 7.45 (m, 3H), 1.37 (s, 12H).19F NMR (282 MHz, DMSO-d6) δ -132.64 (s, 1F).

[0331] Intermediate 47: 6-Amino-1-(methoxy-d3)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-2-naphthonitrileStep 1: 8-Bromo-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one To a solution of 8-bromo-6-methoxy-3,4-dihydronaphthalen-1(2H)-one (30 g, 117 mmol) in toluene (400 mL) was added AlCl3 (39.2 g, 293 mmol). The mixture was stirred at 100 °C for 1 hr. After the reaction was cooled to 25 °C, the mixture was poured into cold water (500 mL), and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0 ~ 30% EtOAc in petroleum ether), the title compound (27.3 g, yield: 92%) was obtained as a yellow solid. MS: m / z = 240.8, 242.8 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 10.67 (br s, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.69 (d, J = 2.4 Hz, 1H), 2.86 (t, J = 6.0 Hz, 2H), 2.55 - 2.51 (m, 2H), 1.98 - 1.87 (m, 2H). Step 2: 6-Amino-8-bromo-3,4-dihydronaphthalen-1(2H)-one To a solution of 8-bromo-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one (27.3 g, 113 mmol) in DMA (300 mL) was added NaOH (13.5 g, 339 mmol). The mixture was stirred at 20 °C for 1 hr. 2-Bromo-2-methylpropanamide (56.4 g, 339 mmol) was added, and the reaction mixture was stirred at 20 °C for 16 hr. Then NaOH (45.2 g, 1.13 mol) was added, and the resulting mixture was stirred at 50 °C for 3 hr. Then H2O (170 mL, 9.44 mol) was added, and theAttorney Docket No.62619-726601 reaction mixture was stirred at 100 °C for another 2 hr. After the reaction was cooled to 25 °C, the mixture was diluted with H2O (400 mL) and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with H2O (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0 ~ 50% EtOAc in petroleum ether), the title compound (30 g, yield: 68%) was obtained as a yellow oil. MS: m / z = 239.9, 241.9 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 6.73 (s, 1H), 6.36 (s, 1H), 6.22 (br s, 2H), 2.77 - 2.73 (m, 2H), 2.43 (t, J = 6.4 Hz, 2H), 1.90 - 1.85 (m, 2H). Step 3: tert-Butyl N-(8-bromo-1-oxo-tetralin-6-yl)-N-tert-butoxycarbonyl-carbamate To a solution of 6-amino-8-bromo-3,4-dihydronaphthalen-1(2H)-one (30 g, 124 mmol) in THF (500 mL) were added DMAP (1.53 g, 12.4 mmol) and Boc2O (86 mL, 374 mmol). The mixture was stirred at 65 °C for 16 hr. The mixture was diluted with H2O (200 mL) and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with H2O (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0 ~ 5% EtOAc in petroleum ether), the title compound (16.2 g, yield: 28%) was obtained as a yellow oil. MS: m / z = 461.9, 463.9 [M + Na]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 7.47 (d, J = 1.6 Hz, 1H), 7.26 (d, J = 1.6 Hz, 1H), 2.96 (t, J = 6.0 Hz, 2H), 2.64 (t, J = 6.4 Hz, 2H), 2.02 - 1.97 (m, 2H), 1.42 (s, 18H). Step 4: tert-Butyl N-[(2E)-8-bromo-2-(hydroxymethylene)-1-oxo-tetralin-6-yl]-N-tert- butoxycarbonyl-carbamate To a solution of tert-butyl N-(8-bromo-1-oxo-tetralin-6-yl)-N-tert-butoxycarbonyl-carbamate (5 g, 11.3 mmol) in THF (80 mL) was added NaH (908 mg, 22.7 mmol, 60% purity in oil) at 0 °C. The mixture was stirred at 0 °C for 1 hr. Then HCOOEt (8 mL, 99.4 mmol) was added dropwise. The resulting mixture was stirred at 45 °C for 3 hr. The reaction mixture was quenched with saturated NH4Cl (30 mL) at 0 °C. The resulting mixture was carefully neutralized with HCl (3 M) and the pH was adjusted to about 7. The mixture was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The title compound (5 g, crude) was obtained as a yellow solid. MS: m / z = 367.9, 369.9 [M - 100 + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.86 - 9.73 (m, 1H), 7.77 - 7.65 (m, 2H), 7.42 - 7.36 (m, 1H), 2.76 – 2.72 (m, 2H), 2.58 - 2.50 (m, 2H), 1.48 (s, 18H). Step 5: 9-Bromo-4,5-dihydronaphtho[2,1-d]isoxazol-7-amine To a solution of tert-butyl N-[(2E)-8-bromo-2-(hydroxymethylene)-1-oxo-tetralin-6-yl]-N-tert- butoxycarbonyl-carbamate (5.5 g, 11.7 mmol) in AcOH (50 mL) was added NH2OH•HCl (1.63 g, 23.4 mmol). The mixture was stirred at 80 °C for 2 hr. The pH of the reaction was adjustedAttorney Docket No.62619-726601 to about 7 with saturated NaHCO3. The mixture was extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated under reduced pressure. The title compound (4 g, crude) was obtained as a brown solid. MS: m / z = 264.8, 266.8 [M + H]+. Step 6: 6-Amino-8-bromo-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carbonitrile To a solution of 9-bromo-4,5-dihydronaphtho[2,1-d]isoxazol-7-amine (4 g, 7.54 mmol) in THF (30 mL) was added MeONa (1.63 g, 30.1 mmol). The mixture was stirred at 25 °C for 1 hr. The pH of the reaction mixture was adjusted to about 7 with HCl (1M). The mixture was extracted with EtOAc (40 mL x 2). The combined organic layers were washed with brine (30 mL x 2) and dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0 ~ 70% EtOAc in petroleum ether), the title compound (1.7 g, yield: 42 % for three steps) was obtained as a yellow solid. MS: m / z = 264.8, 266.8 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 6.79 (d, J = 2.0 Hz, 1H), 6.50 (s, 2H), 6.36 (d, J = 2.0 Hz, 1H), 4.29 – 4.23 (m, 1H), 2.97 - 2.87 (m, 1H), 2.86 - 2.78 (m, 1H), 2.37 - 2.29 (m, 1H), 2.26 - 2.14 (m, 1H). Step 7: 6-Amino-2,8-dibromo-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carbonitrile To a solution of 6-amino-8-bromo-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carbonitrile (1.7 g, 6.41 mmol) in ACN (90 mL) was added PyBr3 (2.26 g, 7.05 mmol). The mixture was stirred at 70 °C for 0.5 hrs. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (60 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The title compound (2.2 g, crude) was obtained as a brown solid. MS: m / z = 342.6, 344.6, 346.6[M + H]+. Step 8: 6-Amino-8-bromo-1-hydroxy-2-naphthonitrile To a solution of 6-amino-2,8-dibromo-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carbonitrile (2.2 g, 6.40 mmol) in DMF (30 mL) was added LiBr (1.22 g, 14 mmol). The mixture was stirred at 100 °C for 1 hr. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (60 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0 ~ 30% EtOAc in petroleum ether), the title compound (320 mg, yield: 18% for two steps) was obtained as a yellow solid. MS: m / z = 262.8, 264.8 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 10.66 (br s, 1H), 7.31 - 7.23 (m, 2H), 7.12 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 2.4 Hz, 1H), 6.03 (br s, 2H). Step 9: 6-Amino-8-bromo-1-(methoxy-d3)-2-naphthonitrile To a solution of 6-amino-8-bromo-1-hydroxy-2-naphthonitrile (300 mg, 1.14 mmol) in DMF (5 mL) was added K2CO3 (315 mg, 2.28 mmol) and CD3I (85.2 mL, 1.37 mmol) at 0 °C. TheAttorney Docket No.62619-726601 mixture was stirred at 20 °C for 1 hr. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (60 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0 ~ 17% EtOAc in petroleum ether), the title compound (267 mg, yield: 78%) was obtained as a yellow solid. MS: m / z = 279.8, 281.8 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 7.47 - 7.38 (m, 3H), 6.86 (d, J = 2.0 Hz, 1H), 6.18 (br s, 2H). Step 10: 6-Amino-1-(methoxy-d3)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- naphthonitrile To a solution of 6-amino-8-bromo-1-(methoxy-d3)-2-naphthonitrile (257 mg, 917 μmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (349 mg, 1.38 mmol) in 1,4-dioxane (4 mL) were added Cy3PPdG3 (67.4 mg, 92 μmol) and KOAc (270 mg, 2.75 mmol). The mixture was degassed and purged with N2three times. The mixture was stirred at 100 °C for 1 hr under N2. The mixture was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 100% CH2Cl2), the title compound (Intermediate 47, 145 mg, yield: 46%) was obtained. MS: m / z = 328.0 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 7.37 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 2.0 Hz, 1H), 6.81 (d, J = 2.0 Hz, 1H), 5.99 (br s, 2H), 1.35 (s, 12H).

[0332] Intermediate 48: 6-((Diphenylmethylene)amino)-3-fluoro-1-(methoxy-d3)-8-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthonitrileStep 1: 4-Bromo-2-fluoro-6-(methoxy-d3)benzonitrileAttorney Docket No.62619-726601 To a solution of 4-bromo-2-fluoro-6-hydroxybenzonitrile (7 g, 32.4 mmol) in MeCN (70 mL) were added K2CO3(8.9 g, 64.8 mmol) and CD3I (9.2 g, 64.8 mmol) at 25 °C. The mixture was stirred at 50 °C for 3 hr under N2. The reaction mixture was filtered concentrated under reduced pressure. The title compound (7 g, yield: 93%) was obtained as a white solid. MS: m / z = 232.9, 234.9 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 7.48 (dd, J = 8.8, 1.6 Hz, 1H), 7.40 (d, J = 1.6 Hz, 1H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -106.22. Step 2: 4-Allyl-2-fluoro-6-(methoxy-d3)benzonitrile To a solution of 4-bromo-2-fluoro-6-(methoxy-d3)benzonitrile (10 g, 42.9 mmol) and 2-allyl- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.6 g, 51.5 mmol) in THF (750 mL) were added Pd(PPh3)4 (5.0 g, 4.3 mmol) and CsF (20.0 g, 129 mmol). The mixture was degassed and purged with N2 three times and stirred at 75 °C for 16 hr under N2. The reaction mixture was concentrated under reduced pressure. After purification by silica gel flash chromatography (eluent of 0 ~ 5% of EtOAc in petroleum ether), the title compound (5.77 g, yield: 69%) was obtained as an off white solid.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 6.97 (s, 1H), 6.91 (d, J = 10.0 Hz, 1H), 6.02 - 5.90 (m, 1H), 5.20 - 5.04 (m, 2H), 3.45 (d, J = 6.8 Hz, 2H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -108.36. Step 3: 2-(4-Cyano-3-fluoro-5-(methoxy-d3)phenyl)acetic acid To a solution of 4-allyl-2-fluoro-6-(methoxy-d3)benzonitrile (5 g, 25.7 mmol) in ACN (100 mL), H2O (150 mL) and EtOAc (100 mL) was added RuCl3(0.5 g, 2.6 mmol) at 0 °C. Then NaIO4(8.3 g, 38.6 mmol) was added in batches at 0 °C over 0.5 hr. The reaction mixture was stirred at 0 °C for 0.5 hr under N2 atmosphere. The reaction mixture was poured into H2O (100 mL). The resulting mixture washed with EtOAc (500 mL x 2). The pH of the combined aqueous phase was adjusted to 6 with 2 M HCl. The mixture was extracted with EtOAc (100 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The title compound (1.0 g, yield: 18%) was obtained as an off white solid. MS: m / z = 423.1 [2M - H]^.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 12.63 ( s, 1H), 7.06 (s, 1H), 7.01 (d, J = 10.0 Hz, 1H), 3.72 (s, 2H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ - 108.78. Step 4: 2-(2-Bromo-4-cyano-3-fluoro-5-(methoxy-d3)phenyl)acetic acid To a solution of 2-(4-cyano-3-fluoro-5-(methoxy-d3)phenyl)acetic acid (1 g, 4.7 mmol) and KBr (2.8 g, 23.6 mmol) in H2O (10 mL) was added Br2(0.6 mL, 11.8 mmol). The mixture was stirred at 50 °C for 2 hr. The reaction mixture was filtered, and the filter cake was washed with water (50 mL) and dried under reduced pressure. The title compound (900 mg, yield: 63%) was obtained as an off white solid. MS: m / z = 579.0, 581.0, 583.0 [2M - H]^.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 7.24 (s, 1H), 3.76 (s, 2H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δAttorney Docket No.62619-726601 -99.87, -99.94. Step 5: 3-Bromo-4-(2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-2-hydroxyethyl)-2-fluoro- 6-(methoxy-d3)benzonitrile To a solution of 2-(2-bromo-4-cyano-3-fluoro-5-(methoxy-d3)phenyl)acetic acid (850 mg, 2.9 mmol) in ACN (8 mL) were added 2,2-dimethyl-1,3-dioxane-4,6-dione (463 mg, 3.2 mmol), DMAP (36 g, 293 µmol) and DIPEA (1.1 mL, 6.4 mmol). Then t-BuCOCl (0.36 mL, 2.9 mmol) was added dropwise at 0 °C under N2. The resulting mixture was stirred at 25 °C for 1 hr under N2. The reaction mixture was quenched with 2M HCl (10 mL) at 0 °C, and the precipitate was filtered and washed with water and dried under reduced pressure. The title compound (1.01 g, yield: 69%) was obtained as an off white solid. MS: m / z = 414.9, 416.9 [M - H]^.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 7.23 (s, 1H), 4.56 (s, 2H), 4.03 - 3.95 (m, 1H), 1.65 (s, 6H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -99.76. Step 6: tert-Butyl 4-(2-bromo-4-cyano-3-fluoro-5-(methoxy-d3)phenyl)-3-oxobutanoate A solution of 3-bromo-4-(2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-2-hydroxyethyl)-2- fluoro-6-(methoxy-d3)benzonitrile (1.0 g, 2.4 mmol) in t-BuOH (25 mL) was stirred at 90 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to afford the title compound (950 mg, yield: 88%) as an off white solid. MS: m / z = 386.8, 388.8 [M - H]^.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 7.20 (s, 1H), 4.19 (s, 2H), 3.64 (s, 2H), 1.42 (s, 9H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -99.35. Step 7: 4-(2-Bromo-4-cyano-3-fluoro-5-(methoxy-d3)phenyl)-3-oxobutanoic acid To a solution of tert-butyl 4-(2-bromo-4-cyano-3-fluoro-5-(methoxy-d3)phenyl)-3-oxobutanoate (950 mg, 2.4 mmol) in CH2Cl2(3 mL) was added TFA (3.6 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (800 mg crude) as an off white solid. MS: m / z = 330.9, 332.9 [M - H]^.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 7.20 (s, 1H), 4.22 (s, 2H), 3.65 (s, 2H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -99.35. Step 8: 4-Bromo-3-fluoro-6,8-dihydroxy-1-(methoxy-d3)-2-naphthonitrile A solution of 4-(2-bromo-4-cyano-3-fluoro-5-(methoxy-d3)phenyl)-3-oxobutanoic acid (800 mg, 2.4 mmol) in CF3SO3H (8 mL) was stirred at 25 °C for 16 hr. The reaction mixture was poured into ice water (10 mL). The precipitate was filtered, and the filter cake was washed with water (50 mL) and dried under reduced pressure. The title compound (410 mg, yield: 47%) was obtained as a yellow solid. MS: m / z = 313.0, 315.0 [M - H]^.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 11.57 - 9.97 (m, 2H), 6.97 (d, J = 2.0 Hz, 1H), 6.60 (d, J = 2.0 Hz, 1H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -102.48. Step 9: 3-Fluoro-6,8-dihydroxy-1-(methoxy-d3)-2-naphthonitrileAttorney Docket No.62619-726601 To a solution of 4-bromo-3-fluoro-6,8-dihydroxy-1-(methoxy-d3)-2-naphthonitrile (400 mg, 1.27 mmol) in MeOH (10 mL) was added Pd / C (135 mg, 10% purity). The mixture was degassed and purged with H2three times, and the mixture was stirred at 25 °C for 2 hr under H2atmosphere (15 psi). The mixture was filtered, and the filter cake was washed with MeOH (100 mL). The filtrate was concentrated under reduced pressure to give the title compound (300 mg) as an off white solid. MS: m / z = 235.0 [M - H]^.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 10.46 (s, 1H), 10.35 (s, 1H), 7.37 (d, J = 11.2 Hz, 1H), 6.67 (d, J = 2.0 Hz, 1H), 6.53 (d, J = 2.0 Hz, 1H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -114.93. Step 10: 7-Cyano-6-fluoro-8-(methoxy-d3)naphthalene-1,3-diyl bis(trifluoromethanesulfonate) To a solution of 3-fluoro-6,8-dihydroxy-1-(methoxy-d3)-2-naphthonitrile (270 mg, 1.1 mmol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (837 mg, 2.3 mmol) in DMF (6 mL) were added DMAP (4 mg, 34 µmol) and TEA (256 mg, 2.5 mmol) at 0 °C. The mixture was stirred at 0 °C under N2for 0.5 hr. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The title compound (450 mg crude) was obtained as an off white solid. MS: m / z = 498.9 [M - H]^.1H NMR (400 MHz, Dimethylsulfoxide-d6) 8.47 (d, J = 2.0 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 8.09 (d, J = 10.0 Hz, 1H). Step 11: 7-Cyano-3-((diphenylmethylene)amino)-6-fluoro-8-(methoxy-d3)naphthalen-1-yl trifluoromethanesulfonate To a solution of 7-cyano-6-fluoro-8-(methoxy-d3)naphthalene-1,3-diyl bis(trifluoromethanesulfonate) (450 mg, 899 µmol) in 1,4-dioxane (40 mL) were added diphenylmethanimine (163 mg, 899 µmol), Cs2CO3 (879 mg, 2.7 mmol) and XantPhosPdG3 (85 mg, 90 µmol). The mixture was stirred at 90 °C under N2 for 2 hr. The reaction mixture was concentrated under reduced pressure. After purification by silica gel flash chromatography (eluent of 0 ~ 20% EtOAc in petroleum ether), the title compound (300 mg, yield: 45%) was obtained as a yellow oil. MS: m / z = 532.0 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide- d6) δ 7.79 - 7.64 (m, 3H), 7.64 - 7.45 (m, 4H), 7.43 – 7.39 (m, 1H), 7.37 - 7.27 (m, 3H), 7.25 – 7.19 (m, 2H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -73.03, -110.67. Step 12: 6-((Diphenylmethylene)amino)-3-fluoro-1-(methoxy-d3)-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2-naphthonitrile To a solution of 7-cyano-3-((diphenylmethylene)amino)-6-fluoro-8-(methoxy-d3)naphthalen-1- yl trifluoromethanesulfonate (280 mg, 527 µmol) in 1,4-dioxane (6 mL) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (160 mg, 632 µmol), KOAc (155 mg, 1.6 mmol) and Cy3PPdG3(34 mg, 52.7 µmol). The mixture was stirred at 100 °C under N2for 1Attorney Docket No.62619-726601 hr. The reaction mixture was concentrated under reduced pressure. After purification by silica gel flash chromatography (eluent of 0 ~ 15% EtOAc in petroleum ether), the title compound (Intermediate 48, 135 mg, yield: 34%) was obtained as an off white solid. MS: m / z = 510.2 [M + H]+.

[0333] Intermediate 49: 4-(2-Azabicyclo[4.1.0]heptan-2-yl)-7-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidineStep 1: tert-Butyl 2-azabicyclo[4.1.0]heptane-2-carboxylate To a solution of tert-butyl 3,4-dihydropyridine-1(2H)-carboxylate (5.4 g, 29.5 mmol) in CH2Cl2(80 mL) was added diethylzinc (59.0 mL, 1 M in n-hexane) at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 h under N2. A solution of CH2I2 (31.6 g, 39.2 mmol) in CH2Cl2 (30 mL) was added dropwise to the mixture at 0 °C under N2,and the mixture was stirred at 20 °C for 3.5 h. The reaction mixture was quenched with sat. NH4Cl aq. (200 mL). The organic phase was separated and extracted with EtOAc (200 mL × 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 ~ 6% EtOAc in Petroleum ether) to give the title compound (3 g, 52% yield) as a colorless oil.1H NMR (400 MHz, Chloroform-d) δ 3.82 - 3.55 (m, 1H), 2.90 - 2.70 (m, 1H), 2.68 - 2.44 (m, 1H), 1.87 - 1.71 (m, 2H), 1.60 - 1.52 (m, 1H), 1.52 - 1.42 (m, 9H), 1.30 - 1.12 (m, 2H), 0.89 - 0.69 (m, 1H), 0.34 - 0.18 (m, 1H). Step 2: 2-Azabicyclo[4.1.0]heptane (HCl salt) To a solution of tert-butyl 2-azabicyclo[4.1.0]heptane-2-carboxylate (1.4 g, 568 μmol) in CH2Cl2 (20 mL) was added HCl (10 mL, 2M in EtOAc) at 0 °C. The mixture was stirred at 20 °C for 0.5 h. The mixture was concentrated under reduced pressure to give the title compound (900 mg, HCl salt) as a white solid, which was used in the next step without further purification. Step 3: 4-(2-Azabicyclo[4.1.0]heptan-2-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (1.70 g, 6.74 mmol) and DIPEA (3.52 mL, 20.21 mmol) in CH2Cl2(20 mL) was added 2-azabicyclo[4.1.0]heptane (900Attorney Docket No.62619-726601 mg, 6.74 mmol, HCl salt) at -40 °C under N2. The mixture was stirred at -40 °C for 0.5 h under N2. The reaction mixture was diluted with water (30 mL) and extracted with CH2Cl2(30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (2.1 g, crude) as a yellow solid, which was used in the next step without further purification. MS: m / z = 313.0 [M+H]+. Step 4: 4-(2-Azabicyclo[4.1.0]heptan-2-yl)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidine To a solution of 4-(2-azabicyclo[4.1.0]heptan-2-yl)-2,7-dichloro-8-fluoropyrido[4,3- d]pyrimidine (1.2 g, 3.83 mmol) and DIPEA (2.00 mL, 11.5 mmol) in 1,4-dioxane (15 mL) was added Intermediate 17 (1.11 g, 6.9 mmol). The mixture was stirred at 110 °C for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 5% MeOH in CH2Cl2) to give the title compound (Intermediate 49, 1.57 g, 89% yield over 3 steps) as a yellow solid. MS: m / z = 438.1 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 9.64 - 9.58 (m, 1H), 5.53 - 5.21 (m, 2H), 4.68 (d, J = 14.0 Hz, 1H), 4.04 - 3.93 (m, 1H), 3.29 - 3.10 (m, 4H), 2.04 - 1.92 (m, 5H), 1.70 - 1.57 (m, 5H), 1.27 - 1.13 (m, 2H), 0.78 - 0.73 (m, 1H).

[0334] Intermediate 50 & 51: tert-Butyl 7-fluoro-2-azabicyclo[4.1.0]heptane-2-carboxylate (cis mixture) & tert-butyl 7-fluoro-2-azabicyclo[4.1.0]heptane-2-carboxylate (trans mixture)Step 1: tert-Butyl 7-bromo-7-fluoro-2-azabicyclo[4.1.0]heptane-2-carboxylate To a solution of NaOEt (854 mg, 12.6 mmol) in CH2Cl2 (10 mL) were added tert-butyl 3,4- dihydropyridine-1(2H)-carboxylate (1 g, 5.46 mmol) and ethyl 2,2-dibromo-2-fluoroacetate (2.88 g, 10.9 mmol). The mixture was stirred at 25 °C for 16 h under N2. The reaction mixture was diluted with H2O (50 mL) and extracted with CH2Cl2 (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 6% of EtOAc in petroleum ether) to give the title compound (1.15 g, 74% yield) as a light- yellow oil.1H NMR (400 MHz, Chloroform-d) δ 3.86 - 3.53 (m, 1H), 3.37 - 3.17 (m, 1H), 2.85 - 2.56 (m, 1H), 2.02 - 1.81 (m, 3H), 1.80 - 1.59 (m, 2H), 1.52 (d, J = 2.4 Hz, 9H).19F NMR (376 MHz, Chloroform-d) δ -130.36, -161.24. Step 2: tert-Butyl 7-fluoro-2-azabicyclo[4.1.0]heptane-2-carboxylate (cis mixture) & tert-butyl 7-fluoro-2-azabicyclo[4.1.0]heptane-2-carboxylate (trans mixture)Attorney Docket No.62619-726601 To a suspension of Na (1.80 g, 78.2 mmol) in THF (15 mL) was added a solution of tert-butyl-7- bromo-7-fluoro-2-azabicyclo[4.1.0]heptane-2-carboxylate (1.15 g, 3.91 mmol) in MeOH (5 mL) slowly at 0 °C under N2.During the addition, the reaction temperature was kept between 25 °C and 40 °C. And the mixture was stirred at 25 °C for 2 h under N2. The reaction was quenched slowly with MeOH until the sodium metal disappeared completely. The temperature was maintained between 25 °C and 40 °C. The reaction mixture was quenched with sat. NH4Cl aq. (50 mL) slowly at 0 °C and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 4% of EtOAc in petroleum ether) to give the title compound (cis mixture) (Intermediate 50, 220 mg, 26% yield) as a colorless oil and the title compound (trans mixture) (Intermediate 51, 388 mg, 46% yield) as a colorless oil. Spectra for Example 50:1H NMR (400 MHz, Chloroform-d) δ 4.33 - 4.07 (m, 1H), 3.78 - 3.54 (m, 1H), 3.29 - 3.09 (m, 1H), 2.64 - 2.36 (m, 1H), 1.94 - 1.87 (m, 1H), 1.64 - 1.59 (m, 3H), 1.51 - 1.47 (m, 9H), 1.10 - 0.99 (m, 1H).19F NMR (376 MHz, Chloroform-d) δ -208.77. Spectra for Intermediate 51:1H NMR (400 MHz, Chloroform-d) δ 4.67 - 4.30 (m, 1H), 3.81 - 3.49 (m, 1H), 2.65 (s, 2H), 1.95 - 1.69 (m, 2H), 1.55 - 1.49 (m, 2H), 1.48 (s, 9H), 1.27 - 1.09 (m, 1H).19F NMR (376 MHz, Chloroform-d) δ -236.05, -236.30.

[0335] Intermediate 52 & 53: 2,7-Dichloro-8-fluoro-4-((1R,6S,7R)-7-fluoro-2- azabicyclo[4.1.0]heptan-2-yl)pyrido[4,3-d]pyrimidine & 2,7-dichloro-8-fluoro-4-((1S,6R,7S)-7- fluoro-2-azabicyclo[4.1.0]heptan-2-yl)pyrido[4,3-d]pyrimidineStep 1: 7-Fluoro-2-azabicyclo[4.1.0]heptane (trans mixture) To a solution of Intermediate 51 (trans mixture) (388 mg, 1.80 mmol) in CH2Cl2 (2 mL) was added HCl (2 mL, 2M in EtOAc). The mixture was stirred at 20 °C for 2 h under N2. The reaction mixture was concentrated under reduced pressure to give the title compound (trans mixture) (200 mg, 96% yield) as a yellow oil. Step 2: 2,7-Dichloro-8-fluoro-4-((trans)-7-fluoro-2-azabicyclo[4.1.0]heptan-2-yl)pyrido[4,3- d]pyrimidine To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (482 mg, 1.91 mmol) and DIPEA (1.2 mL, 898 mmol) in CH2Cl2 (5 mL) was added 7-fluoro-2-azabicyclo[4.1.0]heptane (trans mixture) (200 mg, 1.74 mmol) at -40 °C under N2. The mixture was stirred at -40 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purifiedAttorney Docket No.62619-726601 by silica gel flash chromatography (eluent: 0 ~ 20% of EtOAc in petroleum ether) to give the title compound (trans mixture) (450 mg, 74% yield) as a yellow solid. MS: m / z = 330.7 [M + H]+. Step 3: 2,7-Dichloro-8-fluoro-4-((1R,6S,7R)-7-fluoro-2-azabicyclo[4.1.0]heptan-2- yl)pyrido[4,3-d]pyrimidine & 2,7-Dichloro-8-fluoro-4-((1S,6R,7S)-7-fluoro-2- azabicyclo[4.1.0]heptan-2-yl)pyrido[4,3-d]pyrimidine 2,7-Dichloro-8-fluoro-4-(7-fluoro-2-azabicyclo[4.1.0]heptan-2-yl)pyrido[4,3-d]pyrimidine (400 mg, 1.21 mmol) was separated by SFC (column: DAICEL CHIRALCEL OJ (250 mm x 30 mm, 10 μm); mobile phase: [CO2- MeOH (0.1% NH3H2O)]; B%: 25%, isocratic elution mode) to give the title compound (Intermediate 52, 150 mg, 37% yield, SFC Peak1: 1.524 min) as a yellow solid and the title compound (Intermediate 53, 120 mg, 30% yield, SFC Peak2: 1.631 min) as a yellow solid. Spectra for Intermediate 52: MS: m / z =330.7 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.51 (s, 1H), 4.72 (d, J = 13.2 Hz, 1H), 4.68 - 4.49 (m, 1H), 3.61 (t, J = 10.4 Hz, 1H), 2.81 (t, J = 12.8 Hz, 1H), 2.19 - 1.83 (m, 4H), 1.31 - 1.24 (m, 1H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -131.70, -209.75. Spectra for Intermediate 53: MS: m / z = 330.8[M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.51 (s, 1H), 4.72 (d, J = 13.2 Hz, 1H), 4.67 - 4.49 (m, 1H), 3.62 (t, J = 10.4 Hz, 1H), 2.87 - 2.76 (m, 1H), 2.17 - 1.90 (m, 4H), 1.32 - 1.25 (m, 1H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -131.69, -209.73.

[0336] Intermediate 54: 4-(2-Azabicyclo[6.1.0]nonan-2-yl)-2,7-dichloro-8-fluoropyrido[4,3- d]pyrimidineStep 1: tert-Butyl 2-oxoazocane-1-carboxylate To a solution of azocan-2-one (15 g, 118 mmol) and (Boc)2O (28.3 g, 130 mmol) in dry THF (200 mL) was added DMAP (15.9 g, 130 mmol). The mixture was stirred at 25 °C for 3 h. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (300 mL × 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 ~ 30% EtOAc in petroleum ether) to give the title compound (18 g, 67% yield) as a yellow oil.1H NMR (400 MHz, Chloroform-d) δ 3.84 - 3.70 (m, 2H), 2.64 -Attorney Docket No.62619-726601 2.50 (m, 2H), 1.82 - 1.78(m, 2H), 1.77 - 1.67 (m, 2H), 1.61 - 1.43 (m, 13H). Step 2: tert-Butyl (E)-8-((diphenoxyphosphoryl)oxy)-3,4,5,6-tetrahydroazocine-1(2H)- carboxylate To a solution of tert-butyl 2-oxoazocane-1-carboxylate (18 g, 79.2 mmol) and diphenyl phosphorochloridate (31.92 g, 118.8 mmol) in THF (200 mL) was added dropwise KHMDS (95.04 mL, 1 M in THF) at -78 °C under N2. After addition, the mixture was stirred at -78 °C for 1 h under N2. The reaction mixture was diluted with sat. NH4Cl aq. (100 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 10% EtOAc in petroleum ether) to give the title compound (31 g, 85% yield) as a yellow oil.1H NMR (400 MHz, Chloroform-d) δ 7.37 - 7.30 (m, 4H), 7.26 - 7.15 (m, 6H), 5.65 - 5.45 ( m, 1H), 2.10 - 2.04 (m, 2H), 1.70 - 1.55 (m, 7H), 1.49 - 1.38 (m, 10H). Step 3: tert-Butyl (Z)-3,4,5,6-tetrahydroazocine-1(2H)-carboxylate To a solution of tert-butyl (E)-8-((diphenoxyphosphoryl)oxy)-3,4,5,6-tetrahydroazocine-1(2H)- carboxylate (20 g, 43.5 mmol) in DME (100 mL) were added triphenylphosphane (913 mg, 3.48 mmol) and Pd(OAc)2 (391 mg, 1.74 mmol) at 25 °C under N2, and then a solution of TEA (13.2 g, 131 mmol) and formic acid (2.0 g, 43.5 mmol) in DME (60 mL) was added dropwise to the mixture at 25 °C under N2. The mixture was stirred at 85 °C for 40 min under N2. The reaction mixture was diluted with water (300 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 10% EtOAc in petroleum ether) to give the title compound (8 g, 87% yield) as a brown oil.1H NMR (400 MHz, Chloroform-d) δ 6.78 - 6.51 (m, 1H), 4.85 - 4.63 (m, 1H), 3.78 - 3.68 (m, 2H), 2.35 - 2.27 (m, 2H), 1.81 - 1.72 (m, 2H), 1.66 - 1.55 (m, 4H), 1.47 (s, 9H). Step 4: tert-Butyl 2-azabicyclo[6.1.0]nonane-2-carboxylate To a solution of tert-butyl (Z)-3,4,5,6-tetrahydroazocine-1(2H)-carboxylate (1 g, 4.73 mmol) in CH2Cl2 (18 mL) was added diethylzinc (9.47 mL, 1 M in n-hexane). The mixture was stirred at 0 °C for 0.5 h under N2. A solution of CH2I2 (5.07 g, 18.9 mmol) in CH2Cl2 (9 mL) was added to the mixture dropwise at 0 °C under N2. The mixture was stirred at 20 °C for 2 h under N2. The reaction mixture was diluted with sat. NH4Cl aq. (50 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 10% EtOAc in petroleum ether) to give the title compoundAttorney Docket No.62619-726601 (160 mg, 15% yield) as a colorless oil.1H NMR (400 MHz, Chloroform-d) 4.09 - 3.95 (m, 1H), 2.80 - 2.67 (m, 1H), 2.22 - 2.13 (m, 1H), 2.03 -1.93 (m, 1H), 1.83 - 1.70 (m, 1H), 1.69 - 1.63 (m, 1H), 1.61 ( d, J = 3.6 Hz, 1H), 1.50 - 1.41 (m, 12H), 1.04 - 0.97 (m, 1H), 0.92 - 0.77 (m, 2H), 0.72 - 0.62 (m, 1H). Step 5: 2-Azabicyclo[6.1.0]nonane TFA, salt To a solution of tert-butyl 2-azabicyclo[6.1.0]nonane-2-carboxylate (160 mg, 710 μmol) in CH2Cl2 (2 mL) was added TFA (2 mL) at 0 °C. The mixture was stirred at 20 °C for 0.5 h. The mixture was concentrated under reduced pressure to give the title compound (90 mg, TFA salt) as a yellow oil, which was used in the next step without further purification. Step 6: 4-(2-Azabicyclo[6.1.0]nonan-2-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (181 mg, 719 μmol) in CH2Cl2 (2 mL) was added DIPEA (626 μL, 3.59 mmol) and 2-azabicyclo[6.1.0]nonane (90 mg, 719 μmol) at -40 °C under N2. The mixture was stirred at -40 °C for 1 h. The reaction mixture was diluted with water (30 mL) and extracted with CH2Cl2 (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (Intermediate 54, 270 mg, crude) as a yellow solid, which was used in the next step without further purification. MS: m / z = 341.0 [M+H]+.

[0337] Intermediate 55 & 56: tert-Butyl 9-fluoro-2-azabicyclo[6.1.0]nonane-2-carboxylate (trans mixture) & tert-butyl 9-fluoro-2-azabicyclo[6.1.0]nonane-2-carboxylate (cis mixture)Step 1: tert-Butyl 9-bromo-9-fluoro-2-azabicyclo[6.1.0]nonane-2-carboxylate A mixture of NaOEt (3.70 g, 54.4 mmol) in CH2Cl2 (70 mL) was degassed and purged with N2 three times, then a solution of tert-butyl (Z)-3,4,5,6-tetrahydroazocine-1(2H)-carboxylate (5 g, 23.7 mmol) in CH2Cl2(15 mL) was added dropwise into the reaction vessel at 0 °C under N2. Then a solution of ethyl 2,2-dibromo-2-fluoroacetate (6.56 g, 24.9 mmol) in CH2Cl2 (15 mL) was added dropwise into the reaction vessel at 0°C under N2, and then the mixture was stirred at 25 °C for 4 h under N2atmosphere. The reaction mixture was quenched with sat. NH4Cl aq. (200 mL) at 0 °C and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 5% of EtOAc in Petroleum ether) to give the title compound (4.3 g, 51% yield) as a yellow oil.1H NMR (400 MHz, Chloroform-d) δ 3.52 - 3.38 (m, 2H), 3.17 - 3.02 (m, 1H), 1.71 - 1.59 (m, 6H), 1.52 - 1.50 (m, 9H), 1.48 - 1.47 (m, 2H), 0.91 - 0.79Attorney Docket No.62619-726601 (m, 1H).19F NMR (376 MHz, Chloroform-d) δ -116.52, -117.00, -126.14, -126.25, -126.36, - 126.38, -126.50, -156.61. Step 2: tert-Butyl 9-fluoro-2-azabicyclo[6.1.0]nonane-2-carboxylate (trans mixture) & tert-butyl 9-fluoro-2-azabicyclo[6.1.0]nonane-2-carboxylate (cis mixture) To a solution of Na (8.81 g, 383 mmol) in THF (100 mL) was added dropwise tert-butyl 9- bromo-9-fluoro-2-azabicyclo[6.1.0]nonane-2-carboxylate (3.8 g, 11.8 mmol) in THF (20 mL) and MeOH (20 mL) at 25 °C under N2. Then MeOH (20 mL) was added dropwise at 35 °C under N2. The mixture was stirred at 40 °C for 2 h under N2. The reaction mixture was quenched with sat. NH4Cl aq. (200 mL) at 0 °C and extracted with EtOAc (300 mL x 2). 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 ~ 5% of EtOAc in Petroleum ether) to give the title compound (trans mixture) (Intermediate 55, 1.2 g, 42% yield) as a yellow oil and the title compound (cis mixture) (Intermediate 56, 980 mg, 34% yield) as a yellow oil. Spectra for Intermediate 55:1H NMR (400 MHz, Chloroform-d) δ 4.78 - 4.51 (m, 1H), 4.01 - 3.89 (m, 1H), 2.78 - 2.68 (m, 1H), 2.61 - 2.48 (m, 1H), 2.10 - 1.98 (m, 1H), 1.80 - 1.58 (m, 3H), 1.56 - 1.52 (m, 1H), 1.50 - 1.48 (m, 1H), 1.47 (s, 9H), 1.43 - 1.38 (m, 1H), 1.30 - 1.19 (m, 1H), 0.93 - 0.78 (m, 1H).19F NMR (376 MHz, Chloroform-d) δ -206.13, -206.23, -206.26. Spectra for Intermediate 56:1H NMR (400 MHz, Chloroform-d) δ 5.33 - 5.03 (m, 1H), 4.04 - 3.89 (m, 1H), 3.51 - 3.34 (m, 1H), 3.03 - 2.95 (m, 1H), 2.25 - 2.10 (m, 1H), 1.81 - 1.74 (m, 3H), 1.60 - 1.54 (m, 3H), 1.45 - 1.43 (m, 9H), 1.40 - 1.39 (m, 1H), 0.91 - 0.76 (m, 1H).19F NMR (376 MHz, Chloroform-d) δ -233.86.

[0338] Intermediate 57 & 58: 2,7-Dichloro-8-fluoro-4-((1R,8S,9R)-9-fluoro-2- azabicyclo[6.1.0]nonan-2-yl)pyrido[4,3-d]pyrimidine & 2,7-dichloro-8-fluoro-4-((1S,8R,9S)-9-Step 1: 9-Fluoro-2-azabicyclo[6.1.0]nonane TFA salt (trans mixture) To a solution of tert-butyl 9-fluoro-2-azabicyclo[6.1.0]nonane-2-carboxylate (trans mixture) (1.1 g, 4.52 mmol) in CH2Cl2(15 mL) was added TFA (6 mL, 81.4 mmol) at 0 °C. The mixture was stirred at 20 °C for 0.1 h. The residue was concentrated under reduced pressure to give the title compound (trans mixture) (1.1 g, TFA salt) as a yellow oil, which was used in the next step without further purification.1H NMR (400 MHz, Chloroform-d) δ 4.79 - 4.41 (m, 1H), 3.43 - 3.28 (m, 1H), 3.18 - 3.03 (m, 1H), 2.98 - 2.80 (m, 1H), 2.44 - 2.34 (m, 1H), 2.00 - 1.78 (m, 3H),Attorney Docket No.62619-726601 1.77 - 1.64 (m, 2H), 1.61 - 1.43 (m, 2H), 1.26 - 1.10 (m, 1H).19F NMR (376 MHz, Chloroform- d) δ -76.00, -209.31. Step 2: 2,7-Dichloro-8-fluoro-4-(9-fluoro-2-azabicyclo[6.1.0]nonan-2-yl)pyrido[4,3- d]pyrimidine To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (1.08 g, 4.28 mmol) in CH2Cl2 (6 mL) were added DIPEA (3.72 mL, 21.4 mmol) and 9-fluoro-2-azabicyclo[6.1.0]nonane (trans mixture) (1.1 g, 4.28 mmol, TFA salt) at -40 °C under N2. The mixture was stirred at -40 °C for 1 h under N2. The reaction mixture was diluted with water (60 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, 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 (865 mg, 54% yield). Step 3: 2,7-Dichloro-8-fluoro-4-((1R,8S,9R)-9-fluoro-2-azabicyclo[6.1.0]nonan-2-yl)pyrido[4,3- d]pyrimidine & 2,7-dichloro-8-fluoro-4-((1S,8R,9S)-9-fluoro-2-azabicyclo[6.1.0]nonan-2- yl)pyrido[4,3-d]pyrimidine 2,7-Dichloro-8-fluoro-4-(9-fluoro-2-azabicyclo[6.1.0]nonan-2-yl)pyrido[4,3-d]pyrimidine (trans mixture) (300 mg) was separated by SFC (column: DAICEL CHIRALCEL OJ (250 mm × 30 mm, 10 μm); mobile phase: [CO2-i-PrOH (0.1% NH3·H2O)]; B% : 35%, isocratic elution mode) to give the title compound (Intermediate 57, 123 mg, SFC peak 1: 1.253 min) as a yellow solid and the title compound (Intermediate 58, 122 mg, SFC peak 2: 1.618 min) as a yellow solid. Spectra for Intermediate 57: MS: m / z = 359.0 [M + H]+. Spectra for Intermediate 57: MS: m / z = 358.9 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.19 (s, 1H), 4.49 - 4.31 (m, 2H), 3.96 - 3.77 (m, 1H), 3.32 - 3.28 (m, 1H), 2.00 - 1.48 (m, 7H), 1.43 - 1.33 (m, 1H), 0.84 - 0.69 (m, 1H).19F NMR (376 MHz, Dimethylsulfoxide-d6) -135.87, -208.10. Spectra for Intermediate 58: MS: m / z = 359.0 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.19 (s, 1H), 4.51 - 4.38 (m, 1H), 4.34 - 4.27 (m, 1H), 3.93 - 3.81 (m, 1H), 3.31 - 3.26 (m, 1H), 1.96 - 1.51 (m, 7H), 1.43 - 1.31 (m, 1H), 0.84 - 0.68 (m, 1H).19F NMR (376 MHz, Dimethylsulfoxide-d6) -135.87, - 208.09.

[0339] Intermediate 59 & 60: 2,7-Dichloro-8-fluoro-4-((1S,6R,7R)-7-fluoro-2- azabicyclo[4.1.0]heptan-2-yl)pyrido[4,3-d]pyrimidine & 2,7-Dichloro-8-fluoro-4-((1R,6S,7S)-7- fluoro-2-azabicyclo[4.1.0]heptan-2-yl)pyrido[4,3-d]pyrimidineAttorney Docket No.62619-726601 Step 1: 7-fluoro-2-azabicyclo[4.1.0]heptane (cis mixture) To a mixture of tert-butyl 7-fluoro-2-azabicyclo[4.1.0]heptane-2-carboxylate (cis mixture) (220 mg, 1.02 mmol) in CH2Cl2(2 mL) was added HCl (2 mL, 2M in EtOAc). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give the title compound (cis mixture) (117 mg, HCl salt) as a white solid, which was used in the next step without further purification. Step 2: 2,7-Dichloro-8-fluoro-4-((cis)-7-fluoro-2-azabicyclo[4.1.0]heptan-2-yl)pyrido[4,3- d]pyrimidine (cis mixture) To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (282 mg, 1.12 mmol) and DIPEA (708 μL, 4.06 mmol) in CH2Cl2 (5 mL) was added 7-fluoro-2-azabicyclo[4.1.0]heptane (cis mixture) (117 mg, 1.02 mmol) at -40 °C under N2. The mixture was stirred at -40 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 24% of EtOAc in petroleum ether) to give the title compound (cis mixture) (260 mg, 77% yield over 2 steps) as a yellow solid. MS: m / z = 331.0 [M + H]+. Step 3: 2,7-Dichloro-8-fluoro-4-((1S,6R,7R)-7-fluoro-2-azabicyclo[4.1.0]heptan-2- yl)pyrido[4,3-d]pyrimidine & 2,7-Dichloro-8-fluoro-4-((1R,6S,7S)-7-fluoro-2- azabicyclo[4.1.0]heptan-2-yl)pyrido[4,3-d]pyrimidine 2,7-Dichloro-8-fluoro-4-(7-fluoro-2-azabicyclo[4.1.0]heptan-2-yl)pyrido[4,3-d]pyrimidine (cis mixture) (260 mg, 785 μmol) was separated by SFC (column: DAICEL CHIRALPAK AD (250mm x 30 mm, 10 μm); mobile phase: [CO2 - MeOH (0.1% NH3·H2O)]; B%: 40%, isocratic elution mode) to give the title compound (Intermediate 59, 90 mg, 35% yield, SFC Peak 1: 1.819 min) as a yellow solid and the title compound (Intermediate 60, 70 mg, 27% yield, SFC Peak 2: 2.174 min) as a yellow solid. Spectra for Intermediate 59: MS: m / z = 330.9 [M + H]+.1HNMR (400 MHz, Dimethylsulfoxide-d6) δ 9.74 (s, 1H), 5.19 - 4.92 (m, 1H), 4.73 - 4.57 (m, 1H), 3.81 - 3.64 (m, 1H), 3.14 - 2.94 (m, 1H), 2.17 - 2.02 (m, 1H), 1.84 - 1.63 (m, 3H), 1.50 - 1.35 (m, 1H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -134.36, -232.37. Spectra for Intermediate 60: MS: m / z = 330.8[M + H]+.1HNMR (400 MHz, Dimethylsulfoxide-d6) δ 9.74 (s, 1H), 5.17 - 4.94 (m, 1H), 4.74 - 4.55 (m, 1H), 3.81 - 3.65 (m, 1H), 3.13 - 2.94 (m, 1H), 2.17 - 1.99 (m, 1H), 1.84 - 1.66 (m, 3H), 1.51 - 1.36 (m, 1H).19F NMR (376 MHz, Dimethylsulfoxide- d6) δ -134.36, -232.38.

[0340] Intermediate 61: 6,7-Difluoro-5-(fluoromethoxy)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-2-amineAttorney Docket No.62619-726601Step 1: 5-Allyl-1,2-difluoro-3-methoxybenzene To a solution of 5-bromo-1,2-difluoro-3-methoxybenzene (20 g, 89.7 mmol), 2-allyl-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (30.1 g, 179 mmol) in THF (2 L) were added Pd(PPh3)4(10.36 g, 8.97 mmol) and CsF (40.9 g, 269 mmol). The mixture was degassed, purged with N2 three times, and stirred at 75 °C for 16 h under N2. The reaction mixture 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 (35 g, 71% yield) as a colorless oil.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 6.65 - 6.53 (m, 2H), 5.97 - 5.82 (m, 1H), 5.17 - 5.03 (m, 2H), 3.91 - 3.88 (m, 3H), 3.32 (d, J = 6.4 Hz, 2H). Step 2: 2-(3,4-Difluoro-5-methoxyphenyl)acetic acid To a solution of 5-allyl-1,2-difluoro-3-methoxybenzene (28 g, 152 mmol) in ACN (380 mL), H2O (540 mL) and EtOAc (380 mL) was added RuCl3(6.31 g, 30.4 mmol) at 0 °C under N2atmosphere. Then NaIO4(130 g, 608 mmol) was added in batches at 0 °C under N2atmosphere over 1 h. The reaction mixture was stirred at 0 °C for 1 h under N2 atmosphere, filtered and the filter cake was washed with EtOAc (500 mL). The filtrate was extracted with EtOAc (500 mL x 3). The combined organic phases were washed with Na2S2O3(100 mL) and brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (21 g, 68% yield) as a brown solid.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 12.57 - 12.26 (m, 1H), 6.97 - 6.81 (m, 2H), 3.85 (s, 3H), 3.58 (s, 2H). Step 3: 2-(2-Bromo-3,4-difluoro-5-methoxyphenyl)acetic acidAttorney Docket No.62619-726601 To a solution of 2-(3,4-difluoro-5-methoxyphenyl)acetic acid (21 g, 104 mmol) in acetic acid (80 mL) was added bromine (7.49 mL, 145.3 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (300 mL) and quenched with sat. Na2S2O3aq. (50 mL). The precipitate was filtered. The filter cake was washed with water (300 mL) and dried under reduced pressure to give the title compound (28.59 g, 98% yield) as a light yellow solid.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 12.6 (br s, 1H), 7.27 - 7.16 (m, 1H), 3.87 (s, 3H), 3.75 (s, 2H). Step 4: 5-(2-(2-Bromo-3,4-difluoro-5-methoxyphenyl)-1-hydroxyethylidene)-2,2-dimethyl-1,3- dioxane-4,6-dione To a solution of 2-(2-bromo-3,4-difluoro-5-methoxyphenyl)acetic acid (28.6 g, 101.7 mmol) in ACN (200 mL) were added 2,2-dimethyl-1,3-dioxane-4,6-dione (16.1 g, 111.9 mmol), DMAP (1.24 g, 10.1 mmol) and DIPEA (39.0 mL, 223.8 mmol). Then t-BuCOCl (12.5 mL, 101.7 mmol) was added dropwise at 0 °C under N2. The mixture was stirred at 25 °C for 3 h under N2. The reaction mixture was quenched with 2N HCl (400 mL), and the precipitate was filtered and washed with water and dried under reduced pressure to give the title compound (28.5 g, 69% yield) as a brown solid.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 7.23 - 7.15 (m, 1H), 4.52 (s, 2H), 3.87 (s, 3H), 1.69 (s, 6H). Step 5: tert-Butyl 4-(2-bromo-3,4-difluoro-5-methoxyphenyl)-3-oxobutanoate A solution of 5-(2-(2-bromo-3,4-difluoro-5-methoxyphenyl)-1-hydroxyethylidene)-2,2- dimethyl-1,3-dioxane-4,6-dione (28.5 g, 70.0 mmol) in t-BuOH (300 mL) was stirred at 90 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound (26 g, crude) as a brown solid. MS: m / z = 377.0 [M - H]-. Step 6: 4-(2-Bromo-3,4-difluoro-5-methoxyphenyl)-3-oxobutanoic acid To a solution of tert-butyl 5-(2-(2-bromo-3,4-difluoro-5-methoxyphenyl)-1-hydroxyethylidene)- 2,2-dimethyl-1,3-dioxane-4,6-dione (26 g, 68.6 mmol) in CH2Cl2 (50 mL) was added TFA (50 mL). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound (22 g, crude) as a brown solid.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 12.9 (br s, 1H), 7.11 (d, J = 7.2 Hz, 1H), 4.08 (s, 2H), 3.86 (s, 3H), 3.60 (s, 2H). Step 7: 5-Bromo-6,7-difluoro-8-methoxynaphthalene-1,3-diol A solution of 4-(2-bromo-3,4-difluoro-5-methoxyphenyl)-3-oxobutanoic acid (22 g, 68.1 mmol) in CF3SO3H (50 mL) was stirred at 25 °C for 16 h. The reaction mixture was poured into ice water (500 mL). The precipitate was filtered. The filter cake was washed with water (200 mL) and dried under reduced pressure to give the title compound (19 g, crude) as a brown solid.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 10.11 (s, 1H), 10.03 (s, 1H), 6.91 (d, J = 2.0 Hz, 1H),Attorney Docket No.62619-726601 6.54 (d, J = 2.4 Hz, 1H), 3.96 (s, 3H). Step 8: 6,7-Difluoro-8-methoxynaphthalene-1,3-diol To a solution of 5-bromo-6,7-difluoro-8-methoxynaphthalene-1,3-diol (19 g, 62.28 mmol) in MeOH (100 mL) was added Pd / C (2.65 g, 12.46 mmol, 10% purity). The mixture was degassed, purged with H2 three times, and stirred at 25 °C for 2 h under H2 atmosphere (15psi). The mixture was filtered, and the filter cake was washed with EtOAc (200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 13% EtOAc in Petroleum ether) to give the title compound (10 g, 67% yield over 4 steps) as a white solid. MS: m / z = 224.9 [M - H]-.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.70 (d, J = 14 Hz, 2H), 7.36 (dd, J = 7.6, 12 Hz, 1H), 6.62 - 6.42 (m, 2H), 3.96 (s, 3H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -137.25, -137.31, -162.68, - 162.74. Step 9: 6,7-Difluoro-8-methoxynaphthalene-1,3-diyl bis(trifluoromethanesulfonate) To a solution of 6,7-difluoro-8-methoxynaphthalene-1,3-diol (5 g, 22.1 mmol) and DIPEA (17.1 g, 132 mmol) in CH2Cl2 (50 mL) was added Tf2O (24.9 g, 88.4 mmol) at 0 °C. The mixture was stirred at 0 °C under N2for 0.5 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 1% EtOAc in petroleum ether) to give the title compound (9.65 g, 88% yield) as a white solid. MS: m / z = 489.0 [M - H]-.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.39 (d, J = 2.4 Hz, 1H), 8.13 - 8.08 (m, 1H), 8.01 (s, 1H), 4.07 (d, J = 2.0 Hz, 3H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -72.38, -72.87, -130.44, -130.49, - 149.38, -149.43. Step 10: 3-((Diphenylmethylene)amino)-6,7-difluoro-8-methoxynaphthalen-1-yl trifluoromethane...

Claims

Attorney Docket No.62619-726601 CLAIMS We claim:

1. A compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate, thereof:wherein: X1is N or C-CN; X2is N, C-H, C-F, C-CH3, C-Cl, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C2-C6 alkenyl), or C-(optionally substituted C3-C6 carbocyclyl); X3is N, C-H, C-F, C-Cl, C-CN, or C-CF3; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; R1is L-G; wherein L is optionally substituted C1-C4 alkylene,and G is an optionally substituted 5- to 10-membered heterocyclyl; -N(R2)R3form an optionally substituted heterocyclyl substituent selected from the group consisting of : (a) optionally substituted azabicyclo[3.1.0]hexane; (b) optionally substituted azabicyclo[4.1.0]heptane; (c) optionally substituted oxazabicyclo[4.1.0]heptane; (d) optionally substituted azabicyclo[5.1.0]octane; (e) optionally substituted oxazabicyclo[5.1.0]octane; (f) optionally substituted azabicyclo[6.1.0]nonane; (g) optionally substituted oxazabicyclo[6.1.0]nonane; (h) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl; (i) optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl; (j) optionally substituted azabicyclo[6.1.0]non-6-en-2-yl; (k) optionally substituted azabicyclo[6.1.0]non-5-en-2-yl; (l) optionally substituted azabicyclo[6.1.0]non-4-en-2-yl; (m) optionally substituted 3-oxa-2,6-diazabicyclo[5.1.0]oct-1-en-6-yl;Attorney Docket No.62619-726601 (n) optionally substituted 2-oxa-3,6-diazabicyclo[5.1.0]oct-3-en-6-yl; (o) optionally substituted 4-oxa-2,5-diazabicyclo[5.1.0]oct-5-en-2-yl; (p) optionally substituted 3-oxa-2,7-diazabicyclo[6.1.0]non-1-en-7-yl; (q) optionally substituted 2-oxa-3,7-diazabicyclo[6.1.0]non-3-en-7-yl; (r) optionally substituted 5-oxa-2,6-diazabicyclo[6.1.0]non-6-en-2-yl; (s) optionally substituted 6-oxa-2,5-diazabicyclo[6.1.0]non-4-en-2-yl; and (t) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; and R4is selected from H, -OH, -CN, halogen, optionally substituted C1-C4 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 cycloalkyl, or C1-C6 cycloalkylalkyl. A compound having the structure of Formula (Ia), or a pharmaceutically acceptable salt or solvate, thereof:wherein: X1is N or C-CN; X2is N, C-H, C-F, C-CH3, or C-Cl; X3is N, C-H, C-F, C-Cl, C-CN, or C-CF3; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; R1is L-G; wherein L is optionally substituted C1-C4 alkylene,and G is an optionally substituted 5- to 10-membered heterocyclyl; -N(R2)R3form an optionally substituted heterocyclyl substituent selected from the group consisting of : (a) optionally substituted azabicyclo[3.1.0]hexane; (b) optionally substituted azabicyclo[4.1.0]heptane; (c) optionally substituted oxazabicyclo[4.1.0]heptane; (d) optionally substituted azabicyclo[5.1.0]octane; (e) optionally substituted oxazabicyclo[5.1.0]octane; (f) optionally substituted azabicyclo[6.1.0]nonane;Attorney Docket No.62619-726601 (g) optionally substituted oxazabicyclo[6.1.0]nonane; (h) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl; (i) optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl; (j) optionally substituted azabicyclo[6.1.0]non-6-en-2-yl; (k) optionally substituted azabicyclo[6.1.0]non-5-en-2-yl; (l) optionally substituted azabicyclo[6.1.0]non-4-en-2-yl; (m) optionally substituted 3-oxa-2,6-diazabicyclo[5.1.0]oct-1-en-6-yl; (n) optionally substituted 2-oxa-3,6-diazabicyclo[5.1.0]oct-3-en-6-yl; (o) optionally substituted 4-oxa-2,5-diazabicyclo[5.1.0]oct-5-en-2-yl; (p) optionally substituted 3-oxa-2,7-diazabicyclo[6.1.0]non-1-en-7-yl; (q) optionally substituted 2-oxa-3,7-diazabicyclo[6.1.0]non-3-en-7-yl; (r) optionally substituted 5-oxa-2,6-diazabicyclo[6.1.0]non-6-en-2-yl; (s) optionally substituted 6-oxa-2,5-diazabicyclo[6.1.0]non-4-en-2-yl; and (t) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; and R4is selected from H, optionally substituted C1-C4 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 cycloalkyl, C1-C6 cycloalkylalkyl, cyano, or halogen. A compound having the structure of Formula (Ib), or a pharmaceutically acceptable salt or solvate, thereof:wherein: X1is N or C-CN; X2is N, C-H, C-F, C-CH3, or C-Cl; X3is N, C-H, C-F, C-Cl or C-CF3; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; R1is L-G; wherein L is optionally substituted C1-C4 alkylene,and G is an optionally substituted 5- to 10-membered heterocyclyl; -N(R2)R3form an optionally substituted heterocyclyl substituent selected from the group consisting of :Attorney Docket No.62619-726601 (a) optionally substituted azabicyclo[3.1.0]hexane; (b) optionally substituted azabicyclo[4.1.0]heptane; (c) optionally substituted oxazabicyclo[4.1.0]heptane; (d) optionally substituted azabicyclo[5.1.0]octane; (e) optionally substituted oxazabicyclo[5.1.0]octane; (f) optionally substituted azabicyclo[6.1.0]nonane; (g) optionally substituted oxazabicyclo[6.1.0]nonane; (h) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl; (i) optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl; (j) optionally substituted azabicyclo[6.1.0]non-6-en-2-yl; (k) optionally substituted azabicyclo[6.1.0]non-5-en-2-yl; (l) optionally substituted azabicyclo[6.1.0]non-4-en-2-yl; (m) optionally substituted 3-oxa-2,6-diazabicyclo[5.1.0]oct-1-en-6-yl; (n) optionally substituted 2-oxa-3,6-diazabicyclo[5.1.0]oct-3-en-6-yl; (o) optionally substituted 4-oxa-2,5-diazabicyclo[5.1.0]oct-5-en-2-yl; (p) optionally substituted 3-oxa-2,7-diazabicyclo[6.1.0]non-1-en-7-yl; (q) optionally substituted 2-oxa-3,7-diazabicyclo[6.1.0]non-3-en-7-yl; (r) optionally substituted 5-oxa-2,6-diazabicyclo[6.1.0]non-6-en-2-yl; (s) optionally substituted 6-oxa-2,5-diazabicyclo[6.1.0]non-4-en-2-yl; and (t) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; and R4is selected from H, optionally substituted C1-C4 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 cycloalkyl, C1-C6 cycloalkylalkyl, cyano, or halogen. A compound having the structure of Formula (Ic), or a pharmaceutically acceptable salt or solvate, thereof:wherein: X1is N or C-CN; X2is N, C-H, C-F, or C-Cl; X3is N, C-H, C-F, C-Cl or C-CF3; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system;Attorney Docket No.62619-726601 R1is L-G; wherein L is optionally substituted C1-C4 alkylene,and G is an optionally substituted 5- to 10-membered heterocyclyl; -N(R2)R3form an optionally substituted heterocyclyl substituent selected from the group consisting of : (a) optionally substituted azabicyclo[3.1.0]hexane; (b) optionally substituted azabicyclo[4.1.0]heptane; (c) optionally substituted oxazabicyclo[4.1.0]heptane; (d) optionally substituted azabicyclo[5.1.0]octane; (e) optionally substituted oxazabicyclo[5.1.0]octane; (f) optionally substituted azabicyclo[6.1.0]nonane; (g) optionally substituted oxazabicyclo[6.1.0]nonane; (h) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl; (i) optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl; (j) optionally substituted azabicyclo[6.1.0]non-6-en-2-yl; (k) optionally substituted azabicyclo[6.1.0]non-5-en-2-yl; (l) optionally substituted azabicyclo[6.1.0]non-4-en-2-yl; (m) optionally substituted 3-oxa-2,6-diazabicyclo[5.1.0]oct-1-en-6-yl; (n) optionally substituted 2-oxa-3,6-diazabicyclo[5.1.0]oct-3-en-6-yl; (o) optionally substituted 4-oxa-2,5-diazabicyclo[5.1.0]oct-5-en-2-yl; (p) optionally substituted 3-oxa-2,7-diazabicyclo[6.1.0]non-1-en-7-yl; (q) optionally substituted 2-oxa-3,7-diazabicyclo[6.1.0]non-3-en-7-yl; (r) optionally substituted 5-oxa-2,6-diazabicyclo[6.1.0]non-6-en-2-yl; (s) optionally substituted 6-oxa-2,5-diazabicyclo[6.1.0]non-4-en-2-yl; and (t) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; and R4is selected from H or optionally substituted C1-C4 alkoxy. A compound having the structure of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof:wherein:Attorney Docket No.62619-726601 X1is N or C-CN; X2is N, C-H, C-F, or C-Cl; X3is N, C-H, C-F, or C-Cl; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; R1is L-G; wherein L is optionally substituted C1-C4 alkylene,and G is an optionally substituted 5- to 10-membered heterocyclyl; -N(R2)R3form an optionally substituted heterocyclyl selected from: (a) optionally substituted azabicyclo[4.1.0]heptane; (b) optionally substituted oxazabicyclo[4.1.0]heptane; (c) optionally substituted azabicyclo[5.1.0]octane; (d) optionally substituted oxazabicyclo[5.1.0]octane; (e) optionally substituted azabicyclo[6.1.0]nonane; (f) optionally substituted oxazabicyclo[6.1.0]nonane; or (g) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl; and R4is selected from H or optionally substituted C1-C4 alkoxy. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt or solvate thereof, wherein X1is N. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C-CN. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, wherein X2is N. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, wherein X2is C-H, C-F, or C-Cl. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, wherein X2is C-CH3. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, wherein X2is C-(optionally substituted C1-C6 alkyl). The compound of any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, wherein X2is C-(C2-C6 optionally substituted alkenyl). The compound of any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, wherein X2is C-(optionally substituted C3-C6 carbocyclyl).Attorney Docket No.62619-726601 14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt or solvate thereof, wherein X3is N.

15. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt or solvate thereof, wherein X3is C-H, C-F, or C-Cl.

16. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt or solvate thereof, wherein X3is C-F.

17. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt or solvate thereof, wherein X3is C-CF3.

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

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

20. The compound of claim 19, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl is substituted with an -OH group at the meta-position.

21. The compound of claim 19, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl.

22. The compound of claim 19, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl is selected from:.

23. The compound of claim 19, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl is substituted with an -NH2 group at the meta-position.Attorney Docket No.62619-726601 24. The compound of claim 19, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl is selected from:.

25. The compound of claim 19, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl is selected from:.

26. The compound of claim 19, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl is a 2,3,5-trisubstituted phenyl.

27. The compound of claim 26, or a pharmaceutically acceptable salt or solvate thereof, wherein the 2,3,5-trisubstituted phenyl is substituted with a 3-hydroxy group.

28. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a bicyclic optionally substituted aryl.

29. The compound of claim 28, or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted aryl is an optionally substituted naphthyl.

30. The compound of claim 29, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted naphthyl is an optionally substituted 1-naphthyl.

31. The compound of claim 30, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 1-naphthyl is further substituted at the 8-position.

32. The compound of any one of claims 28-30, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:Attorney Docket No.62619-72660133. The compound of any one of claims 28-30, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:.

34. The compound of any one of claims 28-30, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:.

35. The compound of any one of claims 28-30, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:Attorney Docket No.62619-726601The compound of any one of claims 28-30, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:. The compound of any one of claims 28-30, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:Attorney Docket No.62619-726601.

38. The compound of any one of claims 28-30, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

39. The compound of any one of claims 28-30, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:.

40. The compound of any one of claims 28-30, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:Attorney Docket No.62619-726601.

41. The compound of any one of claims 28-30, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

42. The compound of any one of claims 28-30, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:.

43. The compound of any one of claims 28-30, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:.

44. The compound of any one of claims 28-30, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:Attorney Docket No.62619-726601.

45. The compound of any one of claims 28-30, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:.

46. The compound of any one of claims 28-30, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:.

47. The compound of any one of claims 28-30, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:Attorney Docket No.62619-726601. The compound of any one of claims 28-30, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:. The compound of any one of claims 28-30, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:Attorney Docket No.62619-72660150. The compound of any one of claims 28-30, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:.

51. The compound of any one of claims 28-30, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:.

52. The compound of any one of claims 28-30, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:Attorney Docket No.62619-726601.

53. The compound of any one of claims 28-30, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:.

55. The compound of claim 28, or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted aryl is described by Formula (a):wherein: R12is hydrogen, deuterium, or F; R13is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me; R14is hydrogen, deuterium, F, Cl, or Br; R15is hydrogen, deuterium, F, Cl, or Br; R16is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3; R17is hydrogen, deuterium, F, Cl, or -CN; and R18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C≡CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.Attorney Docket No.62619-726601 56. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a monocyclic optionally substituted heteroaryl.

57. The compound of claim 56, or a pharmaceutically acceptable salt or solvate thereof, wherein the monocyclic optionally substituted heteroaryl is an optionally substituted 2-pyridinyl.

58. The compound of claim 57, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 2-pyridinyl59. The compound of claim 57, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 2-pyridinyl is.

60. The compound of claim 57, or a pharmaceutically acceptable salt or solvate thereof, wherein the monocyclic optionally substituted heteroaryl is an optionally substituted 4-pyridinyl.

61. The compound of claim 60, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 4-pyridinyl is.

62. The compound of claim 60, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 4-pyridinyl is .

63. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a bicyclic optionally substituted heteroaryl.

64. The compound of claim 63, or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted heteroaryl is selected from:Attorney Docket No.62619-726601. The compound of claim 63, or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted heteroaryl is selected from:The compound of claim 63, or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted heteroaryl is selected from:Attorney Docket No.62619-726601.

67. The compound of claim 63, or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted heteroaryl is selected from:.

68. The compound of claim 63, or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted heteroaryl is.

69. The compound of claim 63, or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted heteroaryl is selected from:.Attorney Docket No.62619-726601 70. The compound of claim 63, or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted heteroaryl is described by Formula (b1):wherein: R13is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me; R14is hydrogen, deuterium, F, Cl, or Br; R15is hydrogen, deuterium, F, Cl, or Br; R16is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3; R17is hydrogen, deuterium, F, Cl, or -CN; and R18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C≡CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

71. The compound of claim 63, or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted heteroaryl is described by Formula (b2):wherein: R12is hydrogen, deuterium, or F; R14is hydrogen, deuterium, F, Cl, or Br; R15is hydrogen, deuterium, F, Cl, or Br; R16is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3; R17is hydrogen, deuterium, F, Cl, or -CN; and R18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C≡CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

72. The compound of claim 63, or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted heteroaryl is described by Formula (b3):Attorney Docket No.62619-726601 wherein: R12is hydrogen, deuterium, or F; R13is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me; R15is hydrogen, deuterium, F, Cl, or Br; R16is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3; R17is hydrogen, deuterium, F, Cl, or -CN; and R18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C≡CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F. The compound of claim 63, or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted heteroaryl is described by Formula (b4):wherein: R12is hydrogen, deuterium, or F; R13is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me; R14is hydrogen, deuterium, F, Cl, or Br; R16is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3; R17is hydrogen, deuterium, F, Cl, or -CN; and R18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3,-CH=CH2, -C≡CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F. The compound of claim 63, or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted heteroaryl is described by Formula (b5):wherein: R12is hydrogen, deuterium, or F; R13is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me; R14is hydrogen, deuterium, F, Cl, or Br; R15is hydrogen, deuterium, F, Cl, or Br; R17is hydrogen, deuterium, F, Cl, or -CN; andAttorney Docket No.62619-726601 R18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C≡CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

75. The compound of claim 63, or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted heteroaryl is described by Formula (b6): (b6) wherein: R12is hydrogen, deuterium, or F; R13is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me; R14is hydrogen, deuterium, F, Cl, or Br; R15is hydrogen, deuterium, F, Cl, or Br; R16is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3; and R18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3,-CH=CH2, -C≡CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

76. The compound of claim 63, or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted heteroaryl is described by Formula (b7):wherein: R12is hydrogen, deuterium, or F; R13is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me; R16is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3; R17is hydrogen, deuterium, F, Cl, or -CN; and R18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3,-CH=CH2, -C≡CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

77. The compound of claim 63, or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted heteroaryl is described by Formula (b8):Attorney Docket No.62619-726601 wherein: R13is hydrogen, deuterium, -OH, -NH2, Cl, -CN, -OCONHMe, -NHCO2Me; R15is hydrogen, deuterium, F, Cl, or Br; R16is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3; R17is hydrogen, deuterium, F, Cl, or -CN; and R18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3,-CH=CH2, -C≡CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

78. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein L is optionally substituted C1-C4 alkylene.

79. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein.

80. The compound of claim 78, or a pharmaceutically acceptable salt or solvate thereof, wherein L.

81. The compound of any one of claims 1-78, or a pharmaceutically acceptable salt or solvate thereof, wherein L is optionally substituted C1 alkylene.

82. The compound of any one of claims 1-81, or a pharmaceutically acceptable salt or solvate thereof, wherein G is an optionally substituted 5- to 10-membered heterocyclyl.

83. The compound of any one of claims 1-82, or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:.

84. The compound of any one of claims 1-82, or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:.

85. The compound of any one of claims 1-82, or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:Attorney Docket No.62619-726601.

86. The compound of any one of claims 1-82, or a pharmaceutically acceptable salt or solvate thereof, wherein G is described by Formula (c):wherein, each R20-R30is independently selected from hydrogen or deuterium.

87. The compound of any one of claims 1-82, or a pharmaceutically acceptable salt or solvate 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; and R33is hydrogen, deuterium, F, or optionally substituted C1-C4 alkyl.

88. The compound of any one of claims 1-82, or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:

89. The compound of any one of claims 1-82, or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:Attorney Docket No.62619-72660190. The compound of any one of claims 1-82, or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:

91. The compound of any one of claims 1-82, or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:

92. The compound of any one of claims 1-82, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

93. The compound of any one of claims 1-82, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:Attorney Docket No.62619-726601.

94. The compound of any one of claims 1-82, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

95. The compound of any one of claims 1-82, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

96. The compound of any one of claims 1-82, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:Attorney Docket No.62619-726601.

97. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is.

98. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

99. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

100. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

101. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:Attorney Docket No.62619-726601.

102. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

103. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

104. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.Attorney Docket No.62619-726601 105. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

106. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

107. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.Attorney Docket No.62619-726601 108. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

109. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

110. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

111. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:Attorney Docket No.62619-726601.

112. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

113. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

114. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:Attorney Docket No.62619-726601.

115. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

116. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

117. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:Attorney Docket No.62619-726601.

118. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

119. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

120. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:Attorney Docket No.62619-726601.

121. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

122. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

123. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:Attorney Docket No.62619-726601.

124. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

125. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:.

126. The compound of any one of claims 1-125, or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted heterocyclyl selected from: (a) optionally substituted 2-azabicyclo[4.1.0]heptan-2-yl; (b) optionally substituted 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl; (c) optionally substituted 2-azabicyclo[5.1.0]octan-2-yl; (d) optionally substituted 2-oxa-6-azabicyclo[5.1.0]octan-6-yl (e) optionally substituted 5-oxa-2-azabicyclo[5.1.0]octan-2-yl;Attorney Docket No.62619-726601 (f) optionally substituted 2-azabicyclo[6.1.0]nonan-2-yl; (g) optionally substituted 2-oxa-7-azabicyclo[6.1.0]nonan-7-yl; (h) optionally substituted 6-oxa-2-azabicyclo[6.1.0]nonan-2-yl; (i) optionally substituted 5-oxa-2-azabicyclo[6.1.0]nonan-2-yl (j) optionally substituted 2-azabicyclo[5.1.0]oct-5-en-2-yl; (k) optionally substituted 2-azabicyclo[5.1.0]oct-4-en-2-yl; (l) optionally substituted 2-azabicyclo[3.1.0]hexan-2-yl; (m) optionally substituted 2-azabicyclo[6.1.0]non-4-en-2-yl; (n) optionally substituted 2-azabicyclo[6.1.0]non-5-en-2-yl; or (o) optionally substituted 2-azabicyclo[6.1.0]non-6-en-2-yl.

127. The compound of claim 126, or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted 2-azabicyclo[4.1.0]heptan-2-yl.

128. The compound of claim 126, or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl.

129. The compound of claim 126, or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted 2-azabicyclo[5.1.0]octan-2-yl.

130. The compound of claim 129, wherein the optionally substituted 2- azabicyclo[5.1.0]octan-2-yl is substituted with an oxo group.

131. The compound of claim 126, or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted 2-oxa-6-azabicyclo[5.1.0]octan-6-yl.

132. The compound of claim 126, or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted 5-oxa-2-azabicyclo[5.1.0]octan-2-yl.

133. The compound of claim 126, or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted 2-azabicyclo[6.1.0]nonan-2-yl.

134. The compound of claim 126, or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted 2-oxa-7-azabicyclo[6.1.0]nonan-7-yl.

135. The compound of claim 126, or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted 6-oxa-2-azabicyclo[6.1.0]nonan-2-yl.

136. The compound of claim 126, or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted 5-oxa-2-azabicyclo[6.1.0]nonan-2-yl.

137. The compound of claim 126, or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted 2-azabicyclo[5.1.0]oct-5-en-2-yl.

138. The compound of claim 126, or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted 2-azabicyclo[5.1.0]oct-4-en-2-yl.Attorney Docket No.62619-726601 139. The compound of claim 126, or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted 2-azabicyclo[3.1.0]hexan-2-yl.

140. The compound of claim 126, or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted 2-azabicyclo[6.1.0]non-4-en-2-yl.

141. The compound of claim 126, or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted 2-azabicyclo[6.1.0]non-5-en-2-yl 142. The compound of claim 126, or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted 2-azabicyclo[6.1.0]non-6-en-2-yl.

143. The compound of claim 126, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heterocyclyl is optionally substituted with a group selected from the group consisting of halogen, cyano, and hydroxyl.

144. The compound of claim 143, wherein the group is chloro.

145. The compound of claim 143, wherein the group is fluoro.

146. The compound of any one of claims 1-125, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.

147. The compound of any one of claims 1-125, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has a structure selected from:, wherein Z is halogen or cyano.

148. The compound of any one of claims 1-125, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.Attorney Docket No.62619-726601 149. The compound of any one of claims 1-125, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has a structure selected from:wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl.

150. The compound of claim 149, wherein the halogen is fluoro or chloro.

151. The compound of any one of claims 1-125, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has a structure selected from:wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl.

152. The compound of claim 151, wherein the halogen is fluoro or chloro.

153. The compound of any one of claims 1-125, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[4.1.0]heptane heterocyclyl has a structure selected from:wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl.

154. The compound of claim 153, wherein the halogen is fluoro or chloro.

155. The compound of any one of claims 1-125, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[4.1.0]heptane heterocyclyl has a structure selected from:wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl.

156. The compound of claim 155, wherein the halogen is fluoro or chloro.Attorney Docket No.62619-726601 157. The compound of any one of claims 1-125, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[3.1.0]hexane heterocyclyl has a structure selected from:wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl.

158. The compound of claim 157, wherein the halogen is fluoro or chloro.

159. The compound of any one of claims 1-125, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.

160. The compound of any one of claims 1-125, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.

161. The compound of any one of claims 1-125, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl is:.

162. The compound of any one of claims 1-125, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.Attorney Docket No.62619-726601 163. The compound of any one of claims 1-125, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl.

164. The compound of claim 163, wherein the halogen is fluoro or chloro.

165. The compound of any one of claims 1-125, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.

166. The compound of any one of claims 1-125, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.

167. The compound of any one of claims 1-125, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl.

168. The compound of claim 167, wherein the halogen is fluoro or chloro.

169. The compound of any one of claims 1-125, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.Attorney Docket No.62619-726601 170. The compound of any one of claims 1-125, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.

171. The compound of any one of claims 1-125, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[6.1.0]nonane heterocyclyl has a structure selected from:wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl.

172. The compound of claim 171, wherein the halogen is fluoro or chloro.

173. The compound of any one of claims 1-125, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[6.1.0]nonane heterocyclyl has a structure selected from:wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl.

174. The compound of claim 173, wherein the halogen is fluoro or chloro.

175. The compound of any one of claims 1-125, or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted azabicyclo[4.1.0]heptane heterocyclyl.

176. The compound of any one of claims 1-125, or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted oxazabicyclo[4.1.0]heptane heterocyclyl.

177. The compound of any one of claims 1-125, or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted azabicyclo[6.1.0]nonane heterocyclyl.

178. The compound of any one of claims 1-125, or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted oxazabicyclo[6.1.0]nonane heterocyclyl.Attorney Docket No.62619-726601 179. The compound of any one of claims 1-125, or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form a group selected from: optionally substituted 3-oxa-2,6-diazabicyclo[5.1.0]oct-1-en-6-yl; optionally substituted 2-oxa-3,6-diazabicyclo[5.1.0]oct-3-en-6-yl; optionally substituted 4-oxa-2,5-diazabicyclo[5.1.0]oct-5-en-2-yl; optionally substituted 3-oxa-2,7-diazabicyclo[6.1.0]non-1-en-7-yl; optionally substituted 2-oxa-3,7-diazabicyclo[6.1.0]non-3-en-7-yl; optionally substituted 5-oxa-2,6-diazabicyclo[6.1.0]non-6-en-2-yl; optionally substituted 6-oxa-2,5-diazabicyclo[6.1.0]non-4-en-2-yl; and optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl.

180. The compound of claim 179, or a pharmaceutically acceptable salt or solvate thereof, wherein the group is optionally substituted with a halogen.

181. The compound of claim 179 or 180, or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form a group selected from:

182. The compound of any one of claims 179-181, or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form a group selected from:wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl.

183. The compound of any one of claims 1-182, or a pharmaceutically acceptable salt or solvate thereof, wherein R4is H.

184. The compound of any one of claims 1-182, or a pharmaceutically acceptable salt or solvate thereof, wherein R4is optionally substituted C1-C4 alkoxy.Attorney Docket No.62619-726601 185. The compound of any one of claims 1-182, or a pharmaceutically acceptable salt or solvate thereof, wherein R4is -OCH3.

186. The compound of any one of claims 1-182, or a pharmaceutically acceptable salt or solvate thereof, wherein R4is optionally substituted C1-C6 alkyl.

187. The compound of any one of claims 1-182, or a pharmaceutically acceptable salt or solvate thereof, wherein R4is selected from optionally substituted C1-C6 cycloalkyl or C1-C6 cycloalkylalkyl.

188. The compound of any one of claims 1-182, or a pharmaceutically acceptable salt or solvate thereof, wherein R4is cyano.

189. The compound of any one of claims 1-182, or a pharmaceutically acceptable salt or solvate thereof, wherein R4is halogen.

190. The compound of any one of claims 1-182, or a pharmaceutically acceptable salt or solvate thereof, wherein R4is selected from H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 cycloalkyl, C1-C6 cycloalkylalkyl, cyano, or halogen.

191. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein.

192. The compound of claim 191, or a pharmaceutically acceptable salt or solvate thereof, wherein X1and X3are N, and X2is C-F.

193. The compound of claim 191, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:.

194. The compound of claim 191, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:.Attorney Docket No.62619-726601 195. The compound of claim 191, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:.

196. The compound of claim 191, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:.

197. The compound of any one of claims 191-196, or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form a group selected from:

198. The compound of any one of claims 191-196, or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form a group selected from:wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl.

199. The compound of claim 198, wherein the halogen is fluoro or chloro.

200. The compound of any one of claims 191-196, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:Attorney Docket No.62619-726601.

201. The compound of any one of claims 191-196, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.

202. The compound of any one of claims 191-196, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.

203. The compound of any one of claims 191-196, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.

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

205. A compound, or pharmaceutically acceptable salt or solvate thereof, as described in any one of Figures 1-26.

206. A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt or solvate thereof, as described in any one of claims 1-205 and a pharmaceutically acceptable excipient.

207. A method of preparing a pharmaceutical composition comprising mixing a compound, or pharmaceutically acceptable salt or solvate thereof, of any one of claims 1-205, and a pharmaceutically acceptable carrier.

208. A compound of any one of claims 1-205, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

209. A compound of any one of claims 1-205, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer.Attorney Docket No.62619-726601 210. Use of a compound of any one of claims 1-205, or pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer.

211. 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 1-205, or pharmaceutically acceptable salt or solvate thereof.

212. 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 1-205, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

213. A method of inhibiting KRAS comprising contacting the enzyme with a compound of any one of claims 1-205, wherein the KRAS is contacted in an in vitro setting.

214. A method of inhibiting KRAS comprising contacting the enzyme with a compound of any one of claims 1-205, wherein KRAS is contacted in an in vivo setting.

215. A compound having the structure of Formula (A), or a salt or stereoisomer thereof:Formula (A-1), wherein, X-Y are -CH=CH-; or X is CH2or O; and Y is CH2 or O; provided that both X and Y are not O; Rais halogen; Ra’is hydrogen or halogen; and Rbis hydrogen or an amine protecting group. .

216. The compound of claim 215, or a salt thereof, wherein the compound of Formula (A) is a compound of Formula (A-1):Formula (A-2).

217. The compound of claim 215, or a salt thereof, wherein the compound of Formula (A) is a compound of Formula (A-2):Attorney Docket No.62619-726601Formula (A-3).

218. The compound of any one of claims 215-217, or a salt or stereoisomer thereof, wherein: X is CH2 and Y is CH2.

219. The compound of any one of claims 215-217, or a salt or stereoisomer thereof, wherein: X is CH2and Y is O.

220. The compound of any one of claims 215-217, or a salt or stereoisomer thereof, wherein: X is O and Y is CH2.

221. A compound having the structure of Formula (A-4), or a salt or stereoisomer thereof:Formula (A-4), wherein: Rais halogen; Ra’is hydrogen or halogen; and Rbis hydrogen or an amine protecting group.

222. The compound of any one of claims 215-221, or a salt or stereoisomer thereof, wherein: Rais Cl or F.

223. The compound of any one of claims 215-221, or a salt or stereoisomer thereof, wherein: Rais Cl.

224. The compound of any one of claims 215-221, or a salt or stereoisomer thereof, wherein: Rais F.

225. The compound of any one of claims 215-221, or a salt or stereoisomer thereof, wherein: Ra’is Br.

226. The compound of any one of claims 215-221, or a salt or stereoisomer thereof, wherein: Ra’is H.

227. The compound of any one of claims 215-221, or a salt or stereoisomer thereof, wherein Rbis hydrogen, benzyloxycarbonyl (Cbz), tert-Butyloxycarbonyl (Boc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), 2-(trimethylsilyl)ethyloxycarbonyl (Teoc), trifluoroacetamide, 2,2,2- trichloroethyloxycarbonyl (Troc), or allyl (All).

228. The compound of any one of claims 215-221, or a salt or stereoisomer thereof, wherein:Attorney Docket No.62619-726601 Rbis hydrogen.

229. The compound of any one of claims 215-221, or a salt thereof, wherein: Rbis benzyloxycarbonyl (Cbz).

230. A compound having the structure of Formula (B1) or (B2), or a salt or stereoisomer thereof:Formula (B1) Formula (B2) wherein: X-Y are -CH=CH-; or X is CH2or O; and Y is CH2or O; provided that both X and Y are not O; Rais halogen; Rbis F or CH3; Rcis halogen, -SMe, -S(O)Me, -S(O)2Me, -OSO2CF3, or -OSO2C6H7CH3; and Rdis halogen,(alkyl)3, or -Zn(halide).

231. The compound of claim 230, or a salt thereof, wherein the compound of Formula (B1) is a compound of Formula (B3):Formula (B3).

232. The compound of claim 230, or a salt thereof, wherein the compound of Formula (B1) is a compound of Formula (B4):Attorney Docket No.62619-726601Formula (B4).

233. The compound of any one of claims 230-232, or a salt thereof, wherein: X is CH2 and Y is CH2.

234. The compound of any one of claims 230-232, or a salt thereof, wherein: X is CH2and Y is O.

235. The compound of any one of claims 230-232, or a salt thereof, wherein: X is O and Y is CH2.

236. The compound of claim 230, or a salt thereof, wherein the compound of Formula (B1) is a compound of Formula (B5):Formula (B5).

237. The compound of claim 230-236, or a salt thereof, wherein the compound of Formula (B1) is a compound of Formula (B6):Formula (B6).

238. The compound of any one of claims 230-237, or a salt thereof, wherein: Rais Cl or F.

239. The compound of any one of claims 230-237, or a salt thereof, wherein: Rais Cl.

240. The compound of any one of claims 230-237, or a salt thereof, wherein: Rais F.Attorney Docket No.62619-726601 241. The compound of any one of claims 230-237, or a salt thereof, wherein: Rcis halogen.

242. The compound of any one of claims 230-237, or a salt thereof, wherein: Rcis Cl.

243. The compound of any one of claims 230-237, or a salt thereof, wherein: Rdis halogen.

244. The compound of any one of claims 230-237, or a salt thereof, wherein: Rdis Cl.

245. The compound of any one of claims 230-237, or a salt thereof, wherein: Rbis F.

246. The compound of any one of claims 230-237, or a salt thereof, wherein: Rbis CH3.

247. A compound having the structure of Formula (C1) or (C2), or a salt or stereoisomer thereof:wherein: X-Y are -CH=CH-; or X is CH2or O; Y is CH2 or O; provided that both X and Y are not O; Rais halogen; Rbis F or CH3; L is -O-;, wherein: R3and R4are independently selected from H, D, halogen, -CN, optionally substituted C1- C4 alkoxy, optionally substituted C1-C4 alkyl; or R3and R4join to form an optionally substituted methylidene; orAttorney Docket No.62619-726601 R3and R4join to form an optionally substituted C3-C6 carbocyclyl; or R4and R5join to form a bond; or R4and R5join to form an optionally substituted C3-C6carbocylyl; R5and R6are independently selected from H, D, halogen, -CN, -OH, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkyl; or R5and R6join to form an optionally substituted methylidene; or R5and R6join to form an oxo; or R5and R6join to form an optionally substituted C3-C6 carbocyclyl; R7and R8are independently selected from H, D, optionally substituted C1-C4alkyl; or R7and R8join to form an optionally substituted C3-C6 carbocyclyl; R9and R10are independently selected from H, D, optionally substituted C1-C4 alkyl; or R9and R10join to form an optionally substituted C3-C6carbocyclyl; R11and R12are independently selected from H, D, halogen, optionally substituted C1-C4alkyl, optionally substituted C1-C4 alkoxy; or R11and R12join to form an optionally substituted methylidene; or R11and R12join to form an optionally substituted C3-C6carbocyclyl; R13or R14are independently selected from H, D, halogen, or optionally substituted C1-C4 alkyl; or R12and R13join to form a bond; R15is H or D; and48. The compound of claim 247, or a salt thereof, wherein the compound of Formula (C1) is a compound of Formula (C3):Formula (C3).Attorney Docket No.62619-726601 249. The compound of claim 247, or a salt thereof, wherein the compound of Formula (C1) is a compound of Formula (C4):Formula (C4).

250. The compound of any one of claims 247-249, or a salt or stereoisomer thereof, wherein: X is CH2 and Y is CH2.

251. The compound of any one of claims 247-249, or a salt or stereoisomer thereof, wherein: X is CH2 and Y is O.

252. The compound of any one of claims 247-249, or a salt or stereoisomer thereof, wherein: X is O and Y is CH2.

253. The compound of claim 247, or a salt thereof, wherein the compound of Formula (C2) is a compound of Formula (C5):Formula (C5).

254. The compound of claim 247, or a salt thereof, wherein the compound of Formula (C2) is a compound of Formula (C6):Formula (C6).

255. The compound of any one of claims 247-254, or a salt or stereoisomer thereof, wherein: Rais Cl or F.

256. The compound of any one of claims 247-254, or a salt or stereoisomer thereof, wherein: Rais Cl.Attorney Docket No.62619-726601 257. The compound of any one of claims 247-254, or a salt or stereoisomer thereof, wherein: Rais F.

258. The compound of any one of claims 247-254, or a salt or stereoisomer thereof, wherein: Rbis F.

259. The compound of any one of claims 247-254, or a salt or stereoisomer thereof, wherein: Rbis CH3.

260. The compound of any one of claims 247-254, or a salt or stereoisomer thereof, wherein: Rdis halogen.

261. The compound of any one of claims 247-254, or a salt or stereoisomer thereof, wherein: Rdis Cl.

262. The compound of any one of claims 247-254, or a salt or stereoisomer thereof, wherein:

263. The compound of any one of claims 247-254, or a salt or stereoisomer thereof, wherein:

264. The compound of any one of claims 247-254, or a salt or stereoisomer thereof, wherein:

265. The compound of any one of claims 247-254, or a salt or stereoisomer thereof, wherein:Attorney Docket No.62619-726601 266. The compound of any one of claims 247-254, or a salt or stereoisomer thereof, wherein:

267. The compound of any one of claims 247-254, or a salt or stereoisomer thereof, wherein:

268. The compound of any one of claims 247-254, or a salt or stereoisomer thereof, wherein:

269. The compound of any one of claims 247-254, or a salt or stereoisomer thereof, wherein:

270. The compound of any one of claims 247-254, or a salt or stereoisomer thereof, wherein:

271. A compound having the structure of Formula (D1) or (D2), or a salt thereof:Formula (D1) Formula (D2) wherein: X-Y are -CH=CH-; or X is CH2 or O; Y is CH2or O; provided that both X and Y are not O; and Rbis an amine protecting group.

272. The compound of claim 271, or a salt thereof, wherein: X is CH2and Y is CH2.Attorney Docket No.62619-726601 273. The compound of claim 271, or a salt thereof, wherein: X is CH2and Y is O.

274. The compound of claim 271, or a salt thereof, wherein: X is O and Y is CH2.

275. The compound of any one of claims 271-274, or a salt thereof, wherein Rbis benzyloxycarbonyl (Cbz), tert-Butyloxycarbonyl (Boc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), 2-(trimethylsilyl)ethyloxycarbonyl (Teoc), trifluoroacetamide, 2,2,2-trichloroethyloxycarbonyl (Troc), or allyl (All).

276. The compound of claim 275, or a salt thereof, wherein Rbis benzyloxycarbonyl (Cbz).

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