KRAS modulators

Abstract

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

Description

KRAS MODULATORSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of US Patent Application No. 63 / 717,155, filed on November 6, 2024; US Patent Application No. 63 / 774,503, filed on March 19, 2025; and US Patent Application No. 63 / 825,192, filed on June 17, 2025, all of which are hereby incorporated by reference in their entirety.BACKGROUND

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

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

[0004] One embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate, thereofwherein: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;-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;(t) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; and (u) optionally substituted 8-methylene-5-oxa-2-azabicyclo[5.1.0]octan-2-yl; 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; andR1is selected from:

[0005] One embodiment provides a compound having the structure of Formula (II), 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;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,; and G is an optionally substituted 5- to 14-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;(t) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; and (u) optionally substituted 8-methylene-5-oxa-2-azabicyclo[5.1.0]octan-2-yl; 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; andAr is selected from:

[0006] One embodiment provides a compound having the structure of Formula (III), 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;-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;(t) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; and (u) optionally substituted 8-methylene-5-oxa-2-azabicyclo[5.1.0]octan-2-yl; 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;R1is selected from:

[0007] One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate, thereof, selected from the group consisting of:

[0008] One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate, thereof, selected from the group consisting of:

[0009] One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate, thereof, selected from the group consisting of:

[0010] One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate, thereof, selected from the group consisting of:

[0011] One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate, thereof, selected from the group consisting of:

[0012] One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate, thereof, selected from the group consisting of:

[0013] One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate, thereof, selected from the group consisting of:

[0014] One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate, thereof, selected from the group consisting of:

[0015] One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate, thereof, selected from the group consisting of:

[0016] One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate, thereof, selected from the group consisting of:

[0017] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (X), (Y), or Table 1, or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0018] One embodiment provides a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), (inc), (X), (Y), or Table 1, or pharmaceutically acceptable salt or solvate thereof.

[0019] One embodiment provides a method of inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), (inc), (X), (Y), or Table 1, wherein the KRAS protein is contacted in an in vitro setting.

[0020] One embodiment provides a method of inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (X), (Y), or Table 1, wherein the KRAS protein is contacted in an in vivo setting.BRIEF DESCRIPTION OF THE DRAWINGS

[0021] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0022] Figure 1 provides additional embodiments of compounds of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (X), (Y), or Table 1, or pharmaceutically acceptable salt or solvate thereof;

[0023] Figure 2 provides additional embodiments of compounds of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (X), (Y), or Table 1, or pharmaceutically acceptable salt or solvate thereof;

[0024] Figure 3 provides additional embodiments of compounds of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (X), (Y), or Table 1, or pharmaceutically acceptable salt or solvate thereof;

[0025] Figure 4 provides additional embodiments of compounds of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (X), (Y), or Table 1, or pharmaceutically acceptable salt or solvate thereof;

[0026] Figure 5 provides additional embodiments of compounds of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (X), (Y), or Table 1, or pharmaceutically acceptable salt or solvate thereof;

[0027] Figure 6 provides additional embodiments of compounds of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (X), (Y), or Table 1, or pharmaceutically acceptable salt or solvate thereof;

[0028] Figure 7 provides additional embodiments of compounds of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (X), (Y), or Table 1, or pharmaceutically acceptable salt or solvate thereof;

[0029] Figure 8 provides additional embodiments of compounds of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (X), (Y), or Table 1, or pharmaceutically acceptable salt or solvate thereof;

[0030] Figure 9 provides additional embodiments of compounds of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (X), (Y), or Table 1, or pharmaceutically acceptable salt or solvate thereof;

[0031] Figure 10 provides additional embodiments of compounds of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (X), (Y), or Table 1, or pharmaceutically acceptable salt or solvate thereof;

[0032] Figure 11 provides additional embodiments of compounds of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (X), (Y), or Table 1, or pharmaceutically acceptable salt or solvate thereof; and

[0033] Figure 12 provides additional embodiments of compounds of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (X), (Y), or Table 1, or pharmaceutically acceptable salt or solvate thereof.INCORPORATION BY REFERENCE

[0034] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein.DETAILED DESCRIPTION OF THE INVENTION

[0035] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statisticalexperimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, "consist of or "consist essentially of' the described features.Definitions

[0036] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0037] " Amino" refers to the -NH2 radical.

[0038] "Cyano" refers to the -CN radical.

[0039] "Nitro" refers to the -NO2 radical.

[0040] " Oxa" refers to the -O- radical.

[0041] " Oxo" refers to the =0 radical.

[0042] " Thioxo" refers to the =S radical.

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

[0044] " Oximo" refers to the =N-0H radical.

[0045] "Hydrazino" refers to the =N-NH2 radical.

[0046] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., Ci-Cs alkyl). In other embodiments, an alkyl comprises one to five carbon atoms e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms e.g., Ci-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms e.g., Cs-Cs alkyl). In other embodiments, an alkyl comprises two to five carbon atoms e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl ( / / -propyl), 1 -methylethyl ( / .w-propyl), 1 -butyl ( / / -butyl), 1 -methylpropyl ( ec-butyl), 2-m ethylpropyl ( / .w-butyl), 1,1 -dimethylethyl (tert-butyl), 1 -pentyl ( / / -pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one ormore 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, oxo or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, oxo or trifluoromethyl), or heteroaryl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). In certain embodiments, an optionally substituted alkyl is a haloalkyl. In other embodiments, an optionally substituted alkyl is a fluoroalkyl. In other embodiments, an optionally substituted alkyl is a -CF3 group.

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

[0048] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluorom ethyl).

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

[0050] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, -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-C8alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g.,C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C1alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C5-C8alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0051] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkenylene comprises two to eight carbon atoms (e.g., C2-C8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (e.g., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., Cs-Cs alkenylene). In other embodiments, an alkenylene comprises three to 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, 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 heteroaryl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0052] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C2-C8alkynylene). 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-C4alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C2-C3alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C2alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C5-C8alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C3-C5alkynylene). 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, ortrifluoromethyl), 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 heteroaryl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluorom ethyl).

[0053] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, , it contains a cyclic, delocalized (4n+2) π–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 heteroaryl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

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

[0055] "Aralkenyl" refers to a radical of the formula -Rd-aryl where Rdis an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

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

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

[0058] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds). A fully saturated carbocyclyl radical is also referred to as "cycloalkyl." Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbomyl (i.e., bicyclo[2.2.1]heptanyl), norbomenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, oxo, thioxo, cyano, nitro, -Rb-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 heteroaryl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

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

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

[0061] "Carbocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc-carbocyclyl where Rcis an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

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

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

[0064] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally 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[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

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

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

[0067] "Heterocyclylalkyl" refers to a radical of the formula — Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene 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.

[0068] "Heterocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0069] "Heteroaryl" refers to a radical derived from a 3 - to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, , it contains a cyclic, delocalized (4n+2) π–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 quatemized. 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 -benzodi oxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[][1,4]dioxepinyl, benzo[b][1,4]oxazinyl,1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5.6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1.6-naphthyri dinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1 -phenyl- 1 / f-pyrrolyl, phenazinyl,phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,5.6.7.8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6.7.8.9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, optionally substituted fluoroalkyl, optionally substituted haloalkenyl, optionally substituted haloalkynyl, oxo, thioxo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

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

[0071] " C-heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in theheteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

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

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

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

[0075] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0076] 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.

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

[0078] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,11C,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35C1,37C1,79Br,81Br,125I are all contemplated. In some embodiments, isotopic substitution with18F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0079] In certain embodiments, the compounds disclosed herein have some or all of 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.

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

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

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

[0083] Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAlD4), are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD4 is illustrated, by way of example only, in the reaction schemes below.

[0084] Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.

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

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

[0087] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S. M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared bycontacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0088] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N, N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, 7V-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

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

[0090] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0091] As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and / or a prophylactic benefit. By “therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement isobserved in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.KRAS Protein and Function

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

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

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

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

[0096] KRAS protein functions as a molecular switch in growth factor signaling pathways by regulating proliferation by alternating between a GDP -bound inactive form and a GTP -bound active form. The GTP -bound active form is capable of engaging downstream effector proteins to trigger a pro-proliferative response. This regulation cycle is impaired by mutations in codon 12 which disrupts association of GTPase activating proteins, which impairs the inactivation of KRAS, which leads to accumulation of the pro-proliferative form. Many growth factors such as but not limited to epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and fibroblast growth factors (FGF) can activate KRAS proteins through intermediary moleculesafter 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.

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

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

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

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

[0101] NMR studies have shown that MRTX849 can engage mutant KRAS proteins lacking the nucleophilic mutant cysteine 12, but that the engagement is selected for inactive GDP -loaded state of KRAS protein. AMG510 exhibits weak binding and relies on irreversiblereaction of the mutant cysteinel2 for KRAS (G12C) inhibitory activity (J. D. Vasta et al., Nature Chemical Biology, 2022, 18, 596-604).

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

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

[0104] One embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt 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;-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;(t) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; and (u) optionally substituted 8-methylene-5-oxa-2-azabicyclo[5.1.0]octan-2-yl; 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; andR1is selected from:

[0105] One embodiment provides a compound having the structure of Formula (la), 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;-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;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; andR1is selected from:

[0106] One embodiment provides a compound having the structure of Formula (lb), 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;-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;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; andR1is selected from:

[0107] 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, 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;-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; 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; andR1is selected from:

[0108] One embodiment provides a compound having the structure of Formula (II), 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;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,; and G is an optionally substituted 5- to 14-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;(t) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; and (u) optionally substituted 8-methylene-5-oxa-2-azabicyclo[5.1.0]octan-2-yl; 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; andAr is selected from:

[0109] One embodiment provides a compound having the structure of Formula (Ila), 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;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,; and G is an optionally substituted 5- to 14-membered heterocyclyl;-N(R2)R3form an optionally substituted heterocyclyl substituent selected from the group consisting of:(u) optionally substituted azabicyclo[3.1.0]hexane;(v) optionally substituted azabicyclo[4.1.0]heptane;(w) optionally substituted oxazabicyclo[4.1.0]heptane;(x) optionally substituted azabicyclo[5.1.0]octane;(y) optionally substituted oxazabicyclo[5.1.0]octane;(z) optionally substituted azabicyclo[6.1.0]nonane;(aa) optionally substituted oxazabicyclo[6.1.0]nonane;(bb) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl;(cc) optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl;(dd) optionally substituted azabicyclo[6.1.0]non-6-en-2-yl;(ee) optionally substituted azabicyclo[6.1.0]non-5-en-2-yl;(ff) optionally substituted azabicyclo[6.1.0]non-4-en-2-yl;(gg) optionally substituted 3-oxa-2,6-diazabicyclo[5.1.0]oct-1-en-6-yl; (hh) optionally substituted 2-oxa-3,6-diazabicyclo[5.1.0]oct-3-en-6-yl; (ii) optionally substituted 4-oxa-2,5-diazabicyclo[5.1.0]oct-5-en-2-yl;(jj) optionally substituted 3-oxa-2,7-diazabicyclo[6.1.0]non-1-en-7-yl;(kk) optionally substituted 2-oxa-3,7-diazabicyclo[6.1.0]non-3-en-7-yl; (11) optionally substituted 5-oxa-2,6-diazabicyclo[6.1.0]non-6-en-2-yl;(mm) optionally substituted 6-oxa-2,5-diazabicyclo[6.1.0]non-4-en-2-yl; and (nn) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; 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; andAr is selected from:

[0110] One embodiment provides a compound having the structure of Formula (IIb), 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;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,; and G is an optionally substituted 5- to 14-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;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; andAr is selected from:

[0111] One embodiment provides a compound having the structure of Formula (IIc), 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;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,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;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; andAr is selected from:

[0112] One embodiment provides a compound having the structure of Formula (III), 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;-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;(t) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; and (u) optionally substituted 8-methylene-5-oxa-2-azabicyclo[5.1.0]octan-2-yl; 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;R1is selected from:Ill

[0113] One embodiment provides a compound having the structure of Formula (IIIa), 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;-N(R2)R3form an optionally substituted heterocyclyl substituent selected from the group consisting of:(oo) optionally substituted azabicyclo[3.1.0]hexane;(pp) optionally substituted azabicyclo[4.1.0]heptane;(qq) optionally substituted oxazabicyclo[4.1.0]heptane;(rr) optionally substituted azabicyclo[5.1.0]octane;(ss) optionally substituted oxazabicyclo[5.1.0]octane;(tt) optionally substituted azabicyclo[6.1.0]nonane;(uu) optionally substituted oxazabicyclo[6.1.0]nonane;(vv) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl;(ww) optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl;(xx) optionally substituted azabicyclo[6.1.0]non-6-en-2-yl;(yy) optionally substituted azabicyclo[6.1.0]non-5-en-2-yl;(zz) optionally substituted azabicyclo[6.1.0]non-4-en-2-yl;(aaa) optionally substituted 3-oxa-2,6-diazabicyclo[5.1.0]oct-1-en-6-yl;(bbb) optionally substituted 2-oxa-3,6-diazabicyclo[5.1.0]oct-3-en-6-yl;(ccc) optionally substituted 4-oxa-2,5-diazabicyclo[5.1.0]oct-5-en-2-yl;(ddd) optionally substituted 3-oxa-2,7-diazabicyclo[6.1.0]non-1-en-7-yl;(eee) optionally substituted 2-oxa-3,7-diazabicyclo[6.1.0]non-3-en-7-yl;(fff) optionally substituted 5-oxa-2,6-diazabicyclo[6.1.0]non-6-en-2-yl;(ggg) optionally substituted 6-oxa-2,5-diazabicyclo[6.1.0]non-4-en-2-yl; and (hhh) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl;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;R1is selected from:Ar is selected from:

[0114] One embodiment provides a compound having the structure of Formula (IIIb), 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;-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; 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;R1is selected from:Ar is selected from:

[0115] One embodiment provides a compound having the structure of Formula (IIIc), 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;-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; 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;R1is selected from:L

[0116] One embodiment provides a compound, or a pharmaceutically acceptable salt or

[0117] One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate, thereof, selected from the group consisting of:

[0118] One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate, thereof, selected from the group consisting of:

[0119] One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate, thereof, selected from the group consisting of:

[0120] One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate, thereof, selected from the group consisting of:

[0121] One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate, thereof, selected from the group consisting of:

[0122] One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate, thereof, selected from the group consisting of:

[0123] One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate, thereof, selected from the group consisting of:

[0124] One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate, thereof, selected from the group consisting of:

[0125] One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate, thereof, selected from the group consisting of:

[0126] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is N.

[0127] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C-CN.

[0128] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein X2is N.

[0129] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein X2is C-H, C-F, or C-Cl.

[0130] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein X2is C-CH3.

[0131] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein X2is C-(optionally substituted C1-C6 alkyl).

[0132] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein X2is C-(C2-C6 optionally substituted alkenyl).

[0133] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein X2is C-(optionally substituted C3-C6 carbocyclyl).

[0134] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein X3is N.

[0135] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein X3is C-H, C-F, or C-Cl.

[0136] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein X3is C-F.

[0137] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein X3is C-CF3.

[0138] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is H.

[0139] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is optionally substituted C1-C4 alkoxy.

[0140] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is -OCH3.

[0141] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is -OCD3.

[0142] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), 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 heterocyclyl. In some embodiments, the optionally substituted 5-oxa-2-azabicyclo[5.1.0]octan-2-yl heterocyclyl is 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.

[0143] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted 2-azabicyclo[5.1.0]octan-2-yl heterocyclyl. In some embodiments, the optionally substituted 5-oxa-2-azabicyclo[5.1.0]octan-2-yl heterocyclyl is 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.

[0144] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl is selected from:

[0145] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl is selected from:

[0146] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl is selected from:

[0147] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl is selected from:

[0148] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl is selected from:

[0149] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl is selected from:

[0150] Another embodiment provides the compound of Formula (I), (la), (II), (Ila), (III), or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl is selected from:

[0151] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl is selected from:

[0152] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl is selected from:

[0153] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl is selected from:

[0154] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl is selected from:

[0155] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl is selected from:

[0156] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl. In some embodiments, the optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl is 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.

[0157] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl. In some embodiments, the optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl is substituted witha 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.

[0158] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted oxazabicyclo[5.1.0]octane. In some embodiments, the optionally substituted oxazabicyclo[5.1.0]octane is an optionally substituted 5-oxa-2-azabicyclo[5.1.0]octan-2-yl. In some embodiments, the optionally substituted oxazabicyclo[5.1.0]octane is an optionally substituted 2-oxa-6-azabicyclo[5.1.0]octan-6-yl. In some embodiments, the cyclopropyl of the optionally substituted oxazabicyclo[5.1.0]octane is substituted with halo. In some embodiments, the cyclopropyl of the optionally substituted oxazabicyclo[5.1.0]octane is substituted with fluoro. In some embodiments, the cyclopropyl of the optionally substituted oxazabicyclo[5.1.0]octane is substituted with chloro. In some embodiments, the cyclopropyl of the optionally substituted oxazabicyclo[5.1.0]octane is substituted with bromo. In some embodiments, the cyclopropyl of the optionally substituted oxazabicyclo[5.1.0]octane is substituted with oxo. In some embodiments, the cyclopropyl of the optionally substituted oxazabicyclo[5.1.0]octane is substituted with cyano. In some embodiments, the cyclopropyl of the optionally substituted oxazabicyclo[5.1.0]octane is substituted with optionally substituted C1-C6 alkyl. In some embodiments, the compound comprises a compound of Formula (I), (II), (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the cyclopropyl of the optionally substituted oxazabicyclo[5.1.0]octane is substituted with optionally substituted methylidene.

[0159] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted azabicyclo[5.1.0]octane. In some embodiments, the optionally substituted azabicyclo[5.1.0]octane is an optionally substituted 2-azabicyclo[5.1.0]octane. In some embodiments, the cyclopropyl of the optionally substituted azabicyclo[5.1.0]octane is substituted with halo. In some embodiments, the cyclopropyl of the optionally substituted azabicyclo[5.1.0]octane is substituted with fluoro. In some embodiments, the cyclopropyl of the optionally substituted azabicyclo[5.1.0]octane is substituted with chloro. In some embodiments, the cyclopropyl of the optionally substituted azabicyclo[5.1.0]octane is substituted with bromo. In some embodiments, the cyclopropyl of the optionally substituted azabicyclo[5.1.0]octane is substituted with oxo. In some embodiments, the cyclopropyl of the optionally substituted azabicyclo[5.1.0]octane is substituted with cyano. In some embodiments, the cyclopropyl of the optionally substituted azabicyclo[5.1.0]octane is substituted with optionally substituted C1-C6 alkyl. In some embodiments, the compound comprises a compoundof Formula (I), (II), (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the cyclopropyl of the optionally substituted azabicyclo[5.1.0]octane is substituted with optionally substituted methylidene.

[0160] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl. In some embodiments, the optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl is an optionally substituted 2-azabicyclo[5.1.0]oct-4-en-2-yl. In some embodiments, the cyclopropyl of the optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl is substituted with halo. In some embodiments, the cyclopropyl of the optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl is substituted with fluoro. In some embodiments, the cyclopropyl of the optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl is substituted with chloro. In some embodiments, the cyclopropyl of the optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl is substituted with bromo. In some embodiments, the cyclopropyl of the optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl is substituted with oxo. In some embodiments, the cyclopropyl of the optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl is substituted with cyano. In some embodiments, the cyclopropyl of the optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl is substituted with optionally substituted C1-C6 alkyl. In some embodiments, the compound comprises a compound of Formula (I), (II), (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the cyclopropyl of the optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl is substituted with optionally substituted methylidene.

[0161] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl. In some embodiments, the optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl is an optionally substituted 2-azabicyclo[5.1.0]oct-5-en-2-yl. In some embodiments, the cyclopropyl of the optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl is substituted with halo. In some embodiments, the cyclopropyl of the optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl is substituted with fluoro. In some embodiments, the cyclopropyl of the optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl is substituted with chloro. In some embodiments, the cyclopropyl of the optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl is substituted with bromo. In some embodiments, the cyclopropyl of the optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl is substituted with oxo. In some embodiments, the cyclopropyl of the optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl is substituted with cyano. In some embodiments, the cyclopropyl of the optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl is substituted with optionallysubstituted C1-C6 alkyl. In some embodiments, the compound comprises a compound of Formula (I), (II), (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the cyclopropyl of the optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl is substituted with optionally substituted methylidene.

[0162] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3is selected from the group consisting of:

[0163] Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3is:

[0164] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a monocyclic optionally substituted aryl. In some embodiments, the monocyclic optionally substituted aryl is an optionally substituted phenyl. In some embodiments, the optionally substituted phenyl is substituted with an -OH group at the meta-position. In some embodiments, the optionally substituted phenyl is

[0165] In some embodiments, the optionally substituted phenyl is selected from:

[0166] In some embodiments, the optionally substituted phenyl is substituted with an -NH2 group at the meta-position.

[0167] In some embodiments, the optionally substituted phenyl is selected from:

[0168] In some embodiments, the optionally substituted phenyl is selected from:

[0169] In some embodiments, the optionally substituted phenyl is a 2, 3, 5 -tri substituted phenyl. In some embodiments, the 2,3,5-trisubstituted phenyl is substituted with a 3-hydroxy group.

[0170] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a bicyclic optionally substituted aryl. In some embodiments, the bicyclic optionally substituted aryl is an optionally substituted naphthyl. In some embodiments, the optionally substituted 1 -naphthyl is further substituted at the 8-position.

[0171] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0172] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0173] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0174] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0175] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0176] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0177] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0178] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0179] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0180] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0181] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0182] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0183] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0184] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0185] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0186] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0187] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0188] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

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

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

[0191] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0192] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0193] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0195] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0196] Another embodiment provides the compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:[image]

[0197] Another embodiment provides the compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a bicyclic optionally substituted aryl 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; andR18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C≡CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

[0198] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a monocyclic optionally substituted heteroaryl.

[0199] In some embodiments, the monocyclic optionally substituted heteroaryl is an optionally substituted 2-pyridinyl.

[0200] In some embodiments, the optionally substituted 2-pyridinyl isIn some embodiments, the optionally substituted 2-pyridinyl is

[0202] In some embodiments, the monocyclic optionally substituted heteroaryl is an optionally substituted 4-pyridinyl. In some embodiments, the optionally substituted 4-pyridinyl is

[0203] In some embodiments, the optionally substituted 4-pyridinyl is

[0204] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a bicyclic optionally substituted heteroaryl.

[0205] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a bicyclic optionally substituted heteroaryl selected from:

[0206] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a bicyclic optionally substituted heteroaryl selected from:

[0207] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a bicyclic optionally substituted heteroaryl selected from:

[0208] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a bicyclic optionally substituted heteroaryl selected from:

[0209] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a bicyclic optionally substituted heteroaryl selected from:

[0210] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a bicyclic optionally substituted heteroaryl described by Formula (bl):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; andR18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C≡CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

[0211] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a bicyclic optionally substituted heteroaryl 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; andR18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C≡CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

[0212] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a bicyclic optionally substituted heteroaryl described by Formula (b3):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; andR18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C≡CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

[0213] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a bicyclic optionally substituted heteroaryl 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; andR18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C≡CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

[0214] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a bicyclic optionally substituted heteroaryl 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; andR18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C≡CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

[0215] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a bicyclic optionally substituted heteroaryl described by Formula (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; andR18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C≡CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

[0216] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a bicyclic optionally substituted heteroaryl 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; andR18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C≡CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

[0217] Another embodiment provides the compound of Formula (I), (la), (lb), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a bicyclic optionally substituted heteroaryl 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; andR18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C≡CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

[0218] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein L is optionally substituted Cl-C4 alkylene. In some embodiments, L is, is optionally substituted C1 alkylene.

[0219] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein G is an optionally substituted 5-to 10-membered heterocyclyl.

[0220] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:

[0221] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:

[0222] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:

[0223] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), 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.

[0224] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), 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; andR33is hydrogen, deuterium, F, or optionally substituted C1-C4 alkyl.

[0225] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:

[0226] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:

[0227] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:

[0228] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:

[0229] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0230] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0231] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0232] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0233] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0234] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

[0235] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0236] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0237] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0238] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0239] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0240] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0241] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0242] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0243] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is:

[0244] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0245] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0246] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0247] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0248] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0249] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0250] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0251] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0252] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0253] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0254] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0255] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0256] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0257] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0258] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0259] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0260] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0261] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0262] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0263] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0264] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0265] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0266] Another embodiment provides the compound of Formula (II), (Ila), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0267] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0268] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0269] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0270] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0271] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0272] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0273] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0274] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0275] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0276] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0277] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0278] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0279] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0280] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0281] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0282] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0283] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0284] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0285] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0286] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0287] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0288] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0289] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0290] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0291] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0292] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0293] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0294] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0295] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0296] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0297] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0298] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0299] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0300] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0301] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0302] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0303] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0304] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0305] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0306] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0307] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0308] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0309] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0310] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0311] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0312] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0313] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0314] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0315] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0316] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0317] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0318] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0319] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0320] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0321] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0322] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0323] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0324] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0325] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0326] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0327] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0328] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1isprovides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0330] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0331] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0332] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0333] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is:

[0334] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0335] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0336] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0337] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0338] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0339] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0340] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0341] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0342] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0343] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0344] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (inc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0345] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0346] Another embodiment provides the compound of Formula (I), (la), (lb), (Ic), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0347] Another embodiment provides a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0348] Another embodiment provides a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0349] Another embodiment provides a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0350] Another embodiment provides a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0351] Another embodiment provides a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0352] Another embodiment provides a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0353] Another embodiment provides a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0354] Another embodiment provides a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0355] Another embodiment provides a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

[0356] Another embodiment provides a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

[0357] Another embodiment provides a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

[0358] Another embodiment provides a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

[0359] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is:

[0360] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0361] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0362] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0363] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0364] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0365] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0366] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is:

[0367] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0368] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0369] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0370] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0371] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is:

[0372] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is:

[0373] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is:

[0374] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is:

[0375] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0376] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0377] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0378] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0379] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0380] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0381] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0382] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0383] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0384] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0385] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0386] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0387] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0388] Another embodiment provides the compound of Formula (II), (Ila), (IIb), (III), (IIIa), or (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0389] Another embodiment provides a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0390] Another embodiment provides a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0391] Another embodiment provides a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0392] Another embodiment provides a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0393] Another embodiment provides a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

[0394] Another embodiment provides a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is

[0395] Another embodiment provides a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is

[0396] Another embodiment provides a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is

[0397] Another embodiment provides a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is

[0398] Another embodiment provides a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is

[0399] Another embodiment provides a compound of Formula (I), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is N. In some embodiments, X2is C-H, C-F, or C-Cl. In some embodiments, X2is C-F. In some embodiments, X3is N. In some embodiments, R4is H. In some embodiments, -N(R2)R3form an optionally substituted 5-oxa-2-azabicyclo[5.1.0]octan-2-yl heterocyclyl. In some embodiments, the optionally substituted 5-oxa-2-azabicyclo[5.1.0]octan-2-yl heterocyclyl is substituted with a group selected from the group consisting of halogen, cyano, and hydroxyl. In some embodiments, the group is fluoro.

[0400] Another embodiment provides a compound of Formula (I), or (II), 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 heterocyclyl selected from:

[0401] Another embodiment provides a compound of Formula (II), 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 heterocyclyl selected from

[0402] Another embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is:

[0403] Another embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is:

[0404] Another embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is:

[0405] Another embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is:

[0406] Another embodiment provides a compound of Formula (X), 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;-N(R2)R3is selected fromR4is 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;R1is selected from:

[0407] Another embodiment provides a compound of Formula (Y), 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;-N(R2)R3is selected fromR4is 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;R1is selected from:

[0408] Another embodiment provides a compound of Formula (X), or (Y), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is N. In some embodiments, X2is C-H, C-F, or C-Cl. In some embodiments, X3is N. In some embodiments, R4is H or C1-C4 alkoxy.

[0409] One embodiment provides a KRAS inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 1.Table 1

[0410] Another embodiment provides a KRAS inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 2.Table 2\L1mIZ£t9£

[0411] Another embodiment provides a KRAS inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in any one of Figures 1-12.Preparation of Compounds

[0412] 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).

[0413] Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition(1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J. C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[0414] 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

[0415] 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)).

[0416] Provided herein is a pharmaceutical composition comprising at least one KRAS inhibitory compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or the patient) of the composition.

[0417] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), (la), (lb), (Ic), (II), (Ila),(IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (X), (Y), or a pharmaceutically acceptable salt or solvate thereof.

[0418] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (X), (Y), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0419] In certain embodiments, the KRAS inhibitory compound as described by Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (X), (Y), 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.

[0420] 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.

[0421] 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.

[0422] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 2, or a pharmaceutically acceptable salt or solvate thereof. One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of any of Figures 1-12, or a pharmaceutically acceptable salt or solvate thereof.

[0423] 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.

[0424] 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)).

[0425] In some embodiments, the KRAS inhibitory compound as described by Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (X), (Y), or Table 1, or pharmaceutically acceptable salt or solvate thereof, is formulated for administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a non-aqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like.

[0426] 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.

[0427] 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.

[0428] Oral doses typically range from about 0.01 mg to about 1000 mg, one to four times, or more, per day.Methods of Treatment

[0429] One embodiment provides a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (X), (Y), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0430] One embodiment provides a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (X), (Y), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer.

[0431] One embodiment provides a use of a compound of Formula (I), (la), (lb), (II), (Ila), (IIb), (III), (IIIa), (IIIb), (X), (Y), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer.

[0432] In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (X), (Y), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is provided a method of treating cancer, in a patient inneed thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (X), (Y), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0433] 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.

[0434] One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer.

[0435] 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.

[0436] In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a compound Table 1, or a pharmaceutically acceptable salt 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.

[0437] 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.

[0438] One embodiment provides a method of treating a cancer in a patient in need thereof, the method comprising administering to the patient a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), or Table 1, or pharmaceutically acceptable salt or solvate thereof.

[0439] One embodiment provides a method of treating a cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), or Table 1, or pharmaceutically acceptable salt or solvate thereof.

[0440] One embodiment provides a method of treating a cancer in a patient in need thereof, the method comprising administering to the patient a compound of Table 2, or any one of Figs. 1-12, or pharmaceutically acceptable salt or solvate thereof.

[0441] One embodiment provides a method of treating a cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising atleast one pharmaceutically acceptable excipient and a compound of Table 2, or any one of Figs.1-12, or pharmaceutically acceptable salt or solvate thereof.

[0442] One embodiment provides the method wherein the cancer is breast cancer.Another embodiment provides the method wherein the breast cancer is a hormone receptor positive (HR+) breast cancer. Another embodiment provides the method wherein the breast cancer is a HER2+ breast cancer. Another embodiment provides the method wherein the breast cancer is a triple negative breast cancer (TNBC). Another embodiment provides the method wherein the breast cancer is ductal carcinoma, lobular carcinoma, or inflammatory breast cancer.

[0443] One embodiment provides the method wherein the cancer is uterine cancer.Another embodiment provides the method wherein the cancer is uterine sarcoma.

[0444] One embodiment provides the method wherein the cancer is endometrial cancer. Another embodiment provides the method wherein the endometrial cancer is selected from endometrioid adenocarcinoma, serous adenocarcinoma (uterine papillary serous carcinoma), uterine carcinosarcoma, uterus sarcoma, endometrial undifferentiated carcinoma, endometrial squamous cell carcinoma, endometrial small cell carcinoma, endometrial transitional carcinoma, endometrial mucinous adenocarcinoma, or endometrial clear cell adenocarcinoma.

[0445] One embodiment provides the method wherein the cancer is cervical cancer. Another embodiment provides the method wherein the cervical cancer is a cervical squamous cell carcinoma, cervical adenocarcinoma, cervical adenosquamous carcinoma, cervical clear cell carcinoma, or cervical small cell carcinoma.

[0446] One embodiment provides the method wherein the cancer is fallopian tube cancer (FTC). Another embodiment provides the method wherein the fallopian tube cancer (FTC) cancer is FTC papillary serous adenocarcinoma, FTC endometrioid carcinoma, FTC clear cell carcinoma, FTC mucinous carcinoma, FTC transitional cell carcinoma, FTC sarcoma, or primary fallopian tube cancer.

[0447] One embodiment provides the method wherein the cancer is prostate cancer. Another embodiment provides the method wherein the cancer is prostate adenocarcinoma.Another embodiment provides the method wherein the cancer is prostate transitional cell carcinoma. Another embodiment provides the method wherein the cancer is prostate squamous cell carcinoma. Another embodiment provides the method wherein the cancer is prostate small cell carcinoma. Another embodiment provides the method wherein the cancer is prostate lymphoma. Another embodiment provides the method wherein the cancer is prostate sarcoma.

[0448] One embodiment provides the method wherein the cancer is bladder cancer. Another embodiment provides the method wherein the bladder cancer is urothelial carcinoma (transitional cell carcinoma), bladder squamous cell carcinoma, urachal adenocarcinoma, non-urachal adenocarcinoma, bladder small cell carcinoma, or bladder sarcoma. Another embodiment provides the method wherein the cancer is urothelial cancer. Another embodiment provides the method wherein the cancer is squamous cell cancer of the bladder. Another embodiment provides the method wherein the cancer is small cell cancer of the bladder. Another embodiment provides the method wherein the cancer is adenocarcinoma of the bladder.

[0449] One embodiment provides the method wherein the cancer is lung cancer.

[0450] One embodiment provides the method wherein the cancer is non-small cell lung cancer. Another embodiment provides the method wherein the cancer is non-small cell lung cancer, squamous cell cancer. Another embodiment provides the method wherein the cancer is non-small cell lung cancer, adenocarcinoma. Another embodiment provides the method wherein the cancer is non-small cell lung cancer, large cell carcinoma. Another embodiment provides the method wherein the cancer is non-small cell lung cancer, adenosquamous carcinoma. Another embodiment provides the method wherein the cancer is non-small cell lung cancer, adenosquamous carcinoma. Another embodiment provides the method wherein the cancer is small cell lung cancer. Another embodiment provides the method wherein the cancer is combined small cell lung cancer.

[0451] One embodiment provides the method wherein the cancer is rectal cancer.Another embodiment provides the method wherein the rectal cancer is adenocarcinoma. Another embodiment provides the method wherein the rectal cancer is quamous cell carcinoma. Another embodiment provides the method wherein the cancer is CRC, carcinoid. Another embodiment provides the method wherein the rectal cancer is gastrointestinal stromal. Another embodiment provides the method wherein the rectal cancer is lymphoma. One embodiment provides the method wherein the cancer is colon cancer (CRC). Another embodiment provides the method wherein the cancer is CRC, adenocarcinoma. Another embodiment provides the method wherein the cancer is CRC, squamous cell carcinoma. Another embodiment provides the method wherein the cancer is CRC, colon cancer. Another embodiment provides the method wherein the cancer is CRC, carcinoid. Another embodiment provides the method wherein the cancer is CRC, gastrointestinal stromal. Another embodiment provides the method wherein the cancer is CRC lymphoma.

[0452] One embodiment provides the method wherein the cancer is anal cancer. Another embodiment provides the method wherein the anal cancer is selected from squamous cell carcinoma anal cancer, or adenocarcinoma anal cancer.

[0453] One embodiment provides the method wherein the cancer is biliary cancer.Another embodiment provides the method wherein the biliary cancer is cholangiocarcinoma,extra-hepatic cholangiocarcinoma, perihilar bile duct cancer (Klatskin tumor), distal bile duct cancer, or intra-hepatic cholangiocarcinoma.

[0454] One embodiment provides the method wherein the cancer is a meningioma.

[0455] One embodiment provides the method wherein the cancer is a glioma.

[0456] One embodiment provides the method wherein the cancer is pancreatic cancer. Another embodiment provides the method wherein the cancer is pancreatic ductal adenocarcinoma (PDAC). Another embodiment provides the method wherein the cancer is PDAC, adenocarcinoma. Another embodiment provides the method wherein the cancer is PDAC, acinar cell carcinoma. Another embodiment provides the method wherein the cancer is exocrine pancreatic cancer. Another embodiment provides the method wherein the cancer is neuroendocrine pancreatic cancer. Another embodiment provides the method wherein the cancer is pancreatic cancer, squamous cell carcinoma. Another embodiment provides the method wherein the cancer is pancreatic cancer, adenosquamous carcinoma. Another embodiment provides the method wherein the cancer is pancreatoblastoma.

[0457] One embodiment provides the method wherein the cancer is thyroid cancer.Another embodiment provides the method wherein the thyroid cancer is selected from papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, or anaplastic thyroid cancer.

[0458] One embodiment provides the method wherein the cancer is parotid gland cancer.

[0459] One embodiment provides the method wherein the cancer is esophageal cancer, esophageal adenocarcinoma, or esophageal squamous cell carcinoma.

[0460] One embodiment provides the method wherein the cancer is stomach cancer or gastric cancer. Another embodiment provides the method wherein the stomach cancer or gastric cancer is selected from gastric adenocarcinoma, intestinal type gastric adenocarcinoma, diffuse type gastric adenocarcinoma, adenocarcinoma of the stomach, gastroesophageal junction adenocarcinoma (GEJ), gastrointestinal neuroendocrine tumor (GNET), gastrointestinal stromal tumor (GIST), gastric adenosquamous carcinoma, gastric carcinoid tumor, or primary gastric lymphoma.

[0461] One embodiment provides the method wherein the cancer is small bowel adenocarcinoma, small bowel sarcoma, small bowel lymphoma, small bowel neuroendocrine tumor, or small bowel carcinoid tumor.

[0462] One embodiment provides the method wherein the cancer is skin cancer. Another embodiment provides the method wherein the skin cancer is basal cell carcinoma, or squamous cell carcinoma. Another embodiment provides the method wherein the cancer is non-melanoma skin cancer, squamous non-melanoma skin cancer, or non-squamous non-melanoma skin cancer.

[0463] One embodiment provides the method wherein the cancer is melanoma. Another embodiment provides the method wherein the melanoma is superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral lentiginous melanoma, or desmoplastic melanoma.

[0464] One embodiment provides the method wherein the cancer is ovarian cancer. Another embodiment provides the method wherein the ovarian cancer is epithelial ovarian cancer, ovarian fibrosarcoma, ovarian mucinous carcinoma, neuroendocrine cancer of ovary.

[0465] One embodiment provides the method wherein the cancer is renal cell cancer.

[0466] One embodiment provides the method wherein the cancer is an appendiceal cancer. Another embodiment provides the method wherein the cancer is appendiceal carcinoid tumor. Another embodiment provides the method wherein the cancer is appendiceal mucinous neoplasm. Another embodiment provides the method wherein the cancer is appendix adenocarcinoma. Another embodiment provides the method wherein the cancer is appendiceal adenocarcinoid or goblet cell appendiceal carcinoma. Another embodiment provides the method wherein the cancer is signet ring cell appendiceal carcinoma, colonic-type appendiceal adenocarcinoma, appendiceal paraganglioma, epithelial appendiceal cancer, or neuroendocrine appendiceal cancer.

[0467] One embodiment provides the method wherein the cancer is a peritoneal cancer or primary peritoneal carcinoma.

[0468] One embodiment provides the method wherein the cancer is a bone cancer, osteosarcoma, chondrosarcoma, or chordoma.

[0469] One embodiment provides the method wherein the cancer is a sarcoma.

[0470] One embodiment provides the method wherein the cancer is a primary brain tumor. Another embodiment provides the method wherein the brain cancer is glioblastoma, astrocytoma, anaplastic astrocytoma, oligodendroglioma, ependymoma, meningioma, pituitary adenoma.

[0471] One embodiment provides the method wherein the cancer is gallbladder cancer. Another embodiment provides the method wherein the gallbladder cancer is gallbladder adenocarcinoma, nonpapillary adenocarcinoma, papillary adenocarcinoma, mucinous adenocarcinoma, gallbladder squamous cell carcinoma, gallbladder adenosquamous carcinoma, or gallbladder carcinosarcoma.

[0472] One embodiment provides the method wherein the cancer is soft tissue sarcoma, or undifferentiated pleomorphic sarcoma.

[0473] One embodiment provides the method wherein the cancer is germ cell tumor. Another embodiment provides the method wherein the germ cell tumor is testicular germ cell cancer, ovarian germ cell tumor, brain germ cell tumor, or endodermal sinus tumor.

[0474] One embodiment provides the method wherein the cancer is plasma cell neoplasm. Another embodiment provides the method wherein the plasma cell neoplasm is selected from isolated plasmacytoma of bone, extramedullary plasmacytoma, multiple myeloma, or monoclonal gammopathy of undetermined significance (MGUS).

[0475] One embodiment provides the method wherein the cancer is myelodysplastic / myeloproliferative neoplasms (MDS / MPN).

[0476] One embodiment provides the method wherein the cancer is myelodysplastic neoplasm, myeloproliferative neoplasm, chronic myelomonocytic leukemia, atypical chronic myeloid leukemia, or juvenile myelomonocytic leukemia.

[0477] One embodiment provides the method wherein the cancer is acute leukemia, acute lymphocytic leukemia, or acute myelogenous leukemia.

[0478] One embodiment provides the method wherein the cancer is neuroendocrine carcinoma

[0479] One embodiment provides the method wherein the cancer is cancer of unknown primary (CUP).

[0480] One embodiment provides the method wherein the cancer is locally advanced.

[0481] One embodiment provides the method wherein the cancer is metastatic.

[0482] One embodiment provides the method wherein the method is adjuvant therapy following surgical resection.

[0483] One embodiment provides the method wherein the method is neo-adjuvant therapy.

[0484] One embodiment provides the method wherein the method is first-line systemic therapy for locally advanced or metastatic disease.

[0485] One embodiment provides the method wherein the patient has relapsed after prior therapy.

[0486] One embodiment provides the method wherein the patient has acquired resistance to prior therapy.

[0487] One embodiment provides the method wherein the patient is refractory to therapy.

[0488] Another embodiment provides the method, wherein the oral administration occurs every other day, once per day, twice per day, or three times per day.

[0489] One embodiment provides the method wherein the cancer is characterized by existence of KRAS G12A mutation. One embodiment provides the method wherein the cancer is characterized by existence of KRAS G12D mutation. One embodiment provides the method wherein the cancer is characterized by existence of KRAS G12V mutation. One embodiment provides the method wherein the cancer is characterized by existence of KRAS G12C mutation.

[0490] One embodiment provides a method of inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (X), (Y), 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.

[0491] Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way.EXAMPLESI. Chemical Synthesis

[0492] 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 acetonitrile°C degrees CelsiusδH chemical shift in parts per million downfield from tetramethylsilaneDCM dichloromethane (CH₂Cl₂)DIAL) diisopropyl azodicarboxylateDIEA diisopropylethylamineDMF dimethylformamideDMSO dimethylsulfoxideEA ethyl acetateEtOAc ethyl acetateESI electrospray ionizationEt ethylg gram(s)h hour(s)HPLC high performance liquid chromatographyHz hertzJ coupling constant (in NMR spectrometry)LCMS liquid chromatography mass spectrometryμ microm multiplet (spectral); meter(s); milliM molarM+parent molecular ionMe methylMsCl methanesulfonyl chlorideMHz megahertzmin minute(s)mol mole(s); molecular (as in mol wt)mL milliliterMS mass spectrometrynm nanometer(s)NMR nuclear magnetic resonancepH potential of hydrogen; a measure of the acidity or basicity of an aqueous solutionPE petroleum etherRT room temperatures singlet (spectral)t triplet (spectral)SFC Supercritical fluid chromatographyT temperatureTFA trifluoroacetic acidTHF tetrahydrofuranTPP Triphenylphosphine

[0493] Intermediate 1 & 2: Benzyl 6,7-dihydro-5J / -l,4-oxazepine-4-carboxylate & benzyl 3,7-dihydro-2J / -l,4-oxazepine-4-carboxylateStep 1: Benzyl l,4-oxazepane-4-carboxylateTo an ice-cooled mixture of 1,4-oxazepane (20 g, 197.73 mmol) and K2CO3 (54.65 g, 395.45 mmol) in THF (200 mL) under N2 was added Cbz-Cl (40.47 g, 237.27 mmol) dropwise at room temperature. The ice bath was removed, and the resulting mixture was stirred at room temperature for 16 h. The resulting mixture was quenched with 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, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 35% EA in PE to afford the title compound (44 g, 94% yield) as a colorless oil. MS: m / z = 236.05 [M + H]+. 1HNMR (400 MHz, Chloroform-d) 87.39 - 7.29 (m, 5H), 5.15 (s, 2H), 3.75 - 3.56 (m, 8H), 1.93 - 1.79 (m, 2H).Step 2: Benzyl 3 -m ethoxy- l,4-oxazepane-4-carboxylate & benzyl 5 -methoxy- l,4-oxazepane-4-carb oxy lateTo a solution of benzyl l,4-oxazepane-4-carboxylate (40 g, 170.00 mmol) in MeOH (200 mL) was added tetraethyl ammonium tosylate (25.62 g, 85.00 mmol) at room temperature. The reaction mixture was electrolysis with C (+) I C(-) electrodes at constant current 200 mA. The resulting mixture was stirred at 20 °C for 72 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted 35% EA in PE to afford a mixture of the title compounds (37 g, 82.03%) as a light-yellow oil.1H NMR (400 MHz, Chloroform-d) <57.39 - 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-5J / -l,4-oxazepine-4-carboxylate & benzyl 3,7-dihydro-2J / -l,4-oxazepine-4-carboxylateTo an ice-cooled solution of benzyl 3 -methoxy- l,4-oxazepane-4-carboxylate and benzyl 5-methoxy-l,4-oxazepane-4-carboxylate (8.3 g, 31.28 mmol) in DCM (830 mL) were added DIEA (4.85 g, 37.54 mmol) and TMSOTf (8.34 g, 37.54 mmol 1.2) under N2. The reaction mixture was stirred in an ice bath for 0.5 h. The solid was filtered 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. 'H NMR (400 MHz, Chloroform- ) <57.40 - 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. 'H NMR (400 MHz, Chloroform^ / ) <57.42 - 7.28 (m, 5H), 5.26 - 4.85 (m, 4H), 4.22 - 4.20 (m, 2H), 3.93 - 3.70 (m, 4H).

[0494] Intermediate 3 & 4: Benzyl 8-chloro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate (trans mixture) & benzyl 8-chloro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate (cis mixture)Step 1: Benzyl 8,8-dichloro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylateTo an ice-cooled solution of Intermediate 2 (20 g, 85.73 mmol) and TBAI (6.33 g, 17.14 mmol) in DCM (100 mL) and NaOH (200 mL, 50% aq.) under N2 was added chloroform (30.70 g, 257.21 mmol) dropwise. The ice bath was removed, and the reaction mixture was stirred at room temperature for 12 h. The resulting mixture was diluted with water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE / EA (3: 1) to afford the title compound (22 g, 73% yield) as a light yellow solid. MS: m / z = 316.00, 318.00 [M + H]+.'H NMR (400 MHz, Chloroform-^ 57.50 - 7.31 (m, 5H), 5.29 - 5.16 (m, 2H), 4.56 - 4.50 (m, 1H), 4.14 - 3.93 (m, 2H), 3.64 - 3.50 (m, 2H), 3.34 - 3.28 (m, 2H), 2.28 - 2.16 (m, 1H).Step 2: Benzyl 8-chloro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate (trans mixture) & benzyl 8-chloro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate (cis mixture)To a stirred mixture of benzyl 8,8-dichloro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate (10 g, 31.62 mmol) in EtOH (100 mL) under N2 were added ammonium chloride (15.23 g, 284.65 mmol) and Zn (18.61 g, 284.65 mmol) at room temperature. The reaction mixture was heated at 70 °C for 16 h. 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 (Intermediate 3, 4.8 g, 53% yield) as an off-white semi-solid. MS: m / z = 282.05 [M + H]+. 'H NMR (300 MHz, Chloroform-; / ) 57.46 - 7.29 (m, 5H), 5.29 - 5.14 (m, 2H), 4.40 - 4.34 (m, 1H), 4.05 - 3.78 (m, 2H), 3.51 - 3.06 (m, 5H), 1.87 - 1.78 (m, 1H). The second eluting mixtures were collected and concentrated under reduced pressure to give the other title compound (Intermediate 4, 2.2 g, 24% yield) as a yellow oil.1H NMR (300 MHz, Chloroform-; / ) 87.41 -7.30 (m, 5H), 5.23 - 5.08 (m, 2H), 4.43 - 4.36 (m, 1H), 4.14 - 3.97 (m, 2H), 3.77 - 3.57 (m, 2H) 3.40 - 3.32 (m, 2H), 2.97 - 2.92 (m, H), 1.74 - 1.63 (m, 1H).

[0495] Intermediate 5 & 6: Benzyl (lA,7A,8A)-8-chloro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate & Benzyl (15',75',85)-8-chloro-5-oxa-2-azabicyclo[5.1,0]octane-2-carboxylateIntermediate 3 (40 g) was purified by SFC (column: DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 pm); mobile phase: [CO2 - EtOH (0.1% NEE’lfeO)]; B%:25%, isocratic elution mode) to give the title compound (Intermediate 5, SFC peak 1: 1.240 min, 20.7 g, 51% yield) as a white solid and the other title compound (Intermediate 6, SFC peak 2: 1.442 min, 17.1 g, 42% yield) as a white solid. Spectra for Intermediate 5: MS: m / z = 282.1 [M + H]+.JH NMR (400 MHz, Chloroform-; / ) 87.51 - 7.29 (m, 5H), 5.30 - 5.12 (m, 2H), 4.42 - 4.32 (m, 1H), 4.11 - 3.93 (m, 1H), 3.85 - 3.76 (m, 1H), 3.50 - 3.42 (m, 1H), 3.36 - 3.18 (m, 3H), 3.13 - 3.02 (m, 1H), 1.88 -1.78 (m, 1H). Spectra for Intermediate 6: MS: m / z = 282.2 [M + H]+. 'H NMR (400 MHz, Chloroform-; / ) 87.50 - 7.28 (m, 5H), 5.27 - 5.10 (m, 2H), 4.41 - 4.32 (m, 1H), 4.09 - 3.94 (m, 1H), 3.86 - 3.77 (m, 1H), 3.51 - 3.42 (m, 1H), 3.37 - 3.17 (m, 3H), 3.12 - 3.00 (m, 1H), 1.89 -1.78 (m, 1H).

[0496] Intermediate 7: (l£,7£,85)-8-Chloro-2-(7-chloro-2-fluoro-8-methylpyrido[4,3-J]pyrimidin-4-yl)-5-oxa-2-azabicyclo[5.1.0]octaneStep 1: (15',75',85)-8-Chloro-5-oxa-2-azabicyclo[5.1.0]octaneTo a solution of Intermediate 6 (500 mg, 1.76 mmol) was added HBr (5 mL, 30% in AcOH). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound (402 mg, HBr salt) as a brown solid, which was used into the next step without further purification.Step 2: (l£,7£,85)-8-Chloro-2-(2,7-dichloro-8-methylpyrido[4,3-; / ]pyrimidin-4-yl)-5-oxa-2-azabicyclo[5.1.0]octaneA mixture of (15',75',85)-8-chloro-5-oxa-2-azabicyclo[5.1.0]octane (402 mg, 1.76 mmol, HBr salt), 2,4,7-trichloro-8-methylpyrido[4,3-; / ]pyrimidine (460 mg, 1.85 mmol) in CH2Ch(8 mL) was added DIPEA (1.61 mL, 9.26 mmol) at -78 °C under N2. The mixture was stirred at -78 °C for 1 h under N2. The reaction mixture was quenched with H2O (7 mL) at 0 °C and extracted with CH2CI2 (10 mL x 3). The combined organic layers were washed with brine (5 mL), driedover anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 30% of EtOAc in petroleum ether) to give the title compound (500 mg, 73% yield) as a yellow solid. MS: m / z = 358.9, 360.9 [M + H]+.Step 3: (15',75',85)-8-Chloro-2-(7-chloro-2-fluoro-8-methylpyrido[4,3- ]pyrimidin-4-yl)-5-oxa-2-azabicyclo[5.1.0]octaneTo a solution of (15',75',85)-8-chloro-2-(2,7-dichloro-8-methylpyrido[4,3- ]pyrimidin-4-yl)-5-oxa-2-azabicyclo[5.1.0]octane (400 mg, 1.09 mmol) in DMSO (4 mL) was added KF (315 mg, 5.43 mmol) under N2. The mixture was stirred at 100 °C for 6 h. The reaction mixture was added water (8 mL) at 25 °C and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 100% of CH2CI2) to give the title compound (Intermediate 7, 320 mg, 79% yield) as a yellow solid. MS: m / z = 342.9 [M + H]+.

[0497] Intermediate 8: (5 -(2 -Methylenetetrahydro- U / -pyrrolizin-7a(5J7)-yl)methan-t / 2-olStep 1: (5)-7a-(hydroxymethyl-t / 2)-6-methylenehexahydro-3J / -pyrrolizin-3-oneTo a solution of ethyl fS')-2-methylene-5-oxotetrahydro- l7 / -pyrrolizine-7a(57 / )-carboxylate (1 g, 4.78 mmol) in CD3OD (20 mL) was added NaBD4 (904 mg, 23.9 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with HC1 (0.8 mL, IM in H2O) at 25 °C and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 5% of MeOH in CH2CI2) to give the title compound (735 mg, 91% yield) as a yellow oil. MS: m / z = 170.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-tL) 35.07 - 4.93 (m, 3H), 4.10 - 3.99 (m, 1H), 3.56 - 3.45 (m, 1H), 2.69 -2.53 (m, 2H), 2.31 - 2.24 (m, 1H), 2.23 - 2.14 (m, 2H), 1.92 - 1.80 (m, 1H).Step 2: (5)-(2 -Methylenetetrahydro- U / -pyrrolizin-7a(5J7)-yl)methan-t / 2-olTo a solution of CS')-7a-(hydroxymethyl-t / 2)-6-methylenehexahydro-37 / -pyrrolizin-3-one (735 mg, 4.34 mmol) in THF (10 mL) was added LiAlH4 (8.69 mL, 2.5 M in THF) dropwise at 0 °C under N2. The mixture was stirred at 70 °C for 4 h. The reaction mixture was slowly quenched with Na2SO4*10H2O (15 g) at 0 °C. The organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 20% of MeOH in CH2Q2) to give the title compound (Intermediate8, 430 mg, 64% yield) as a yellow oil. MS: m / z = 156.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-tL) 4.89 - 4.80 (m, 2H), 3.49 - 3.48 (m, 1H), 3.16 - 3.11 (m, 1H), 2.95 - 2.87 (m, 1H), 2.53 - 2.52 (m, 1H), 2.49 - 2.46 (m, 1H), 2.21 - 2.12 (m, 1H), 1.89 - 1.82 (m, 1H), 1.81 - 1.73 (m, 1H), 1.72 - 1.60 (m, 1H), 1.53 - 1.43 (m, 1H).

[0498] Intermediate 9 & 10: A-(6-Fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)-l, 1-diphenylmethanimine & 6-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-amineStep 1: 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-l,3-diolTo 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 di chlororuthenium: l-isopropyl-4-methyl-benzene (17.2 g, 28.1 mmol). The mixture was stirred at 110 °C for 2 h under N2 atmosphere. 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, Chloroforms / ) 89.15 (s, 1H), 7.59 (dd, J= 5.6, 9.2 Hz, 1H), 7.17 (t, J= 8.8 Hz, 1H), 6.77 - 6.62 (m, 2H), 1.21 - 1.15 (m, 21H).19F NMR (376 MHz, Chloroform- ) 8 -112.51.Step 2: 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-l,3-diylbi s(trifluorom ethanesulfonate)To a solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-l,3-diol (140 g, 390 mmol) and DIPEA (408 mL, 2.34 mol) in CH2CI2 (3.5 L) was added Tf20 (258 ml, 1.56 mol) dropwise under N2 atmosphere at 0 °C. The mixture was stirred at 0 °C under N2 atmosphere for 2 h. The reaction mixture was partitioned between CH2Q2 (500 mL) and H2O (2 L). The organic phase was separated, washed with brine (500 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent: 0 ~ 3% of EtOAc in petroleum ether) to give the title compound (218 g, 340 mmol, 87% yield) as abrown solid. 'HNMR (400 MHz, Chloroform-^ 87.87 (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).Step 3: 3-((Diphenylmethylene)amino)-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl tri fluoromethanesulfonateA mixture of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-l,3-diylbis(trifluoromethanesulfonate) (94 g, 151 mmol), diphenylmethanimine (54.7 g, 302 mmol, 50.7 mL), (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (17.5 g, 30.2 mmol), Pd2(dba)s (6.91 g, 7.55 mmol) and CS2CO3 (148 g, 453 mmol) in toluene (1800 mL) was degassed, purged with N2 three times, and stirred at 100 °C under N2 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]+. 'H NMR (400 MHz, Chloroforms / ) 87.78 (d, J= 8.0 Hz, 2H), 7.57 - 7.51 (m, 2H), 7.48 - 7.41 (m, 2H), 7.27 (s, 2H), 7.26 - 7.19 (m, 2H), 7.17 - 7.01 (m, 4H), 1.22 - 1.13 (m, 21H).19F NMR (376 MHz, Dimethylsulfoxide-d6) 8 -71.40, -104.22.Step 4: A-(6-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)- 1,1 -diphenylmethanimine & 6-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-amineA mixture of 3-((diphenylmethylene)amino)-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl trifluoromethanesulfonate (50 g, 76.5 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (39 g, 153 mmol), KOAc (30 g, 306 mmol), and Pd(dppf)C12 (11.2 g, 15.3 mmol) in 1,4-dioxane (600 mL) was degassed, purged with N2 three times, and stirred at 100 °C under N2 atmosphere 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 9, 9 g, 14.3 mmol, 19% yield) as a yellow solid and the title compound (Intermediate 10, 10 g, 21.4 mmol, 28% yield) as a brown oil. Spectra for Intermediate 9: MS: m / z = 632.4 [M+ H]+. 'HNMR (400 MHz, DimethylsulfoxidesL) 87.86 - 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, Dimethyl sulfoxide-d6) 8 -106.71. Spectra for Intermediate 10: MS: m / z = 468.3 [M+ H]+. 'HNMR (400 MHz, DimethylsulfoxidesL) 87.67 - 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) 5 -112.20.

[0499] Intermediate 11: ((2 / 7aA')-2-fluorotetrahydro-l 7 / -pyrrolizin-7a(57 / )-yl)methan-tfe-olStep 1: (2A,7a5)-2-Fluoro-hexahydropyrrolizine-7a-carboxylic acidTo a stirred solution of ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)m ethanol (500 mg, 3.141 mmol) and RuCh. FbO (35.40 mg, 0.157 mmol) in CCU (4 mL), MeCN (4 mL) and H2O (6 mL) under N2 was added NaKL (2686.99 mg, 12.564 mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 h. The resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with CH2CI2 (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: ((2 / ,7aA')-2-Fluorotetrahydro- l7 / -pyrrolizin-7a(57 / )-yl)methan-t / 2-olTo an ice-cooled solution of (2A,7a5)-2-fluoro-hexahydropyrrolizine-7a-carboxylic acid (200 mg, 1.155 mmol) in Me-THF (2 mL) under N2 was added LiAHZL (2.43 mL, 2.425 mmol, IM in THF) dropwise. The ice bath was removed, and the reaction mixture was heated at 90 °C for 2 h. The reaction mixture was cooled and quenched with MeOH (5 mL) in an ice bath. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with 1-20% methanol in di chloromethane) to afford the title compound (Intermediate 11, 100 mg, 53% yield) as a yellow oil. MS: m / z = 162.15 [M + H]+.

[0500] Intermediate 12 & 13: (6A,7a5)-7a-(((tert-Butyldiphenylsilyl)oxy)methyl-t / 2)-6-fluorohexahydro-37 / -pyrrolizin-3-one & (2 / ,7aA')-7a-((( / c / 7-butyldiphenylsilyl)oxy)methyl-t / 2)-2-fluorohexahydro-3J / -pyrrolizin-3-oneStep 1: (2A,7a5)-7a-(((tert-butyldiphenylsilyl)oxy)methyl-t / 2)-2-fluorohexahydro-l 7 / -pyrrolizine To an ice-cooled solution of Intermediate 11 (30 g, 186.08 mmol) and Imidazole (25.34 g, 372.17 mmol) in DMF (300 mL) under N2 was added / c / 7-butyl(chloro)diphenylsilane (61.38 g, 223.30 mmol). The ice bath was removed, and the reaction mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with CH2CI2 (1000 mL), washed with water (3 x 300 mL) and brine (300 mL), dried over anhydrous Na2SC>4, filtered, andconcentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with 0-20% EA in PE) to afford the title compound (60 g, 80% yield) as a light-yellow oil. MS: m / z = 400.15 [M + H]+.JH NMR (400 MHz, Chloroform-; / ) 87.73 -7.65 (m, 4H), 7.44 - 7.35 (m, 6H), 5.26 - 5.11 (m, 1H), 3.15 - 3.08 (m, 2H), 2.95 - 2.88 (m, 3H), 2.15 - 1.63 (m, 5H), 1.07 (s, 9H).Step 2: (6 / 7ak)-7a-((( / c / 7-Butyldiphenylsilyl)oxy)methyl-; / 2)-6-fluorohexahydro-3 / / -pyrrolizin-3-one & (2 / ,7ak)-7a-((( / c77-butyldiphenylsilyl)oxy)methyl-; / 2)-2-tluorohexahydro-3 / 7-pyrrolizin-3-oneTo an ice-cooled solution of (2 / ,7ak)-7a-((( / c77-butyldiphenylsilyl)oxy)methyl-; / 2)-2-fluorohexahydro-l / Z-pyrrolizine (60 g, 150.14 mmol) and tri chlororuthenium hydrate (16.92 g, 75.07 mmol) in CCh (300 mL) and H2O (300 mL) was added NaIC (160.57 g, 750.71 mmol). The ice bath was removed, and the reaction mixture was stirred at room temperature for 30 min. The resulting mixture was filtered and extracted with DCM (3 x 100 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with 0-20% EA in PE) to afford a mixture of two isomers (60 g) as a light-yellow solid. The mixture was purified by re / ?-Achiral-SFC with the following conditions: Column: XA-GreenSep Naphthyl, 3 x 25 cm, 5 pm; Mobile Phase A: CO2; Mobile Phase B: IPA (0.1% 7 M NHsrMeOH); Flow rate: 200 mL / min; Gradient: isocratic 20% B; Detector: UV 220 nm; RT1 = 4.30 min; RT2: 6.07 min. The first eluting peak (RT1: 4.30 min) was concentrated and lyophilized to give the title compound (Intermediate 12, 40 g, 66% yield) as a yellow solid. MS: m / z = 414.30 [M + H]+. ‘HNMR (400 MHz, Chloroform-; / ) 87.64 - 7.61 (m, 4H), 7.47 - 7.38 (m, 6H), 5.34 - 5.20 (m, 1H), 4.23 - 4.07 (m, 1H), 3.19 - 2.99 (m, 1H), 2.81 - 2.65 (m, 1H), 2.43 - 2.12 (m, 3H), 2.05 -1.97 (m, 2H), 1.04 (s, 9H).19F NMR (376 MHz, Chloroform - ) <5 -173.04 (s, IF). The second eluting peak (RT2: 6.07 min) was concentrated and lyophilized to give the other title compound (Intermediate 13, 12 g, 20% yield) as a yellow solid. MS: m / z = 414.30 [M + H]+. 'H NMR (400 MHz, Chloroform-; / ) 87.65 - 7.58 (m, 4H), 7.47 - 7.37 (m, 6H), 5.74 - 5.51 (m, 1H), 3.84 -3.72 (m, 1H), 2.94 - 2.86 (m, 2H), 2.10 - 1.71 (m, 4H), 1.66 - 1.55 (m, 1H), 1.05 (s, 9H).19F NMR (376 MHz, Chloroform-; / ) <5 -184.21 (s, IF).

[0501] Intermediate 14 & 15: (2A,35',7a5)-7a-(((terLButyldiphenylsilyl)oxy)methyl-6?2)-2 -fluoro-3 -methylhexahydro- 1 / Z-pyrrolizine. & (2 / ,3 / ,7ak)-7a-((( / c77-butyldiphenylsilyl)oxy)methyl-6?2)-2-fluoro-3-methylhexahydro-U / -pyrrolizineIntermediate 13 Intermediate 14 Intermediate 15To a mixture of Intermediate 13 (3.6 g, 8.70 mmol) and chloroiridium; methanidylidyneoxidanium; bis(triphenylphosphane) (0.14 g, 0.17 mmol) in DCM (36 mL) under N2 was added 1,1,3,3-tetramethyldisiloxane (2.34 g, 17.40 mmol) at room temperature. The mixture was stirred at room temperature for 0.5 h. Methylmagnesium bromide (1.0 M in THF, 17.41 mL, 17.40 mmol) was added to the above mixture at -70 °C. The resulting mixture was stirred at room temperature for 4 h. The resulting mixture was quenched with sat. NH4CI aq. (100 mL) in an ice bath and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with PE / EA (7: 1)) to give two isomers. The first eluting isomer was concentrated to give the title compound (Intermediate 14, 0.6 g, 16% yield) as a light-yellow oil. MS: m / z = 414.20 [M + H]+.JH NMR (400 MHz, Chloroform^ / ) 87.71 - 7.57 (m, 4H), 7.43 - 7.35 (m, 6H), 4.78 - 4.63 (m, 1H), 3.16 -2.70 (m, 3H), 2.39 - 2.31 (m, 1H), 2.03 - 1.78 (m, 3H), 1.75 - 1.62 (m, 2H), 1.08 - 1.06 (m, 12H).19F NMR (376 MHz, Chloroform-t / ) 8 -182.46 (s, IF). The second eluting isomer was concentrated to give the other title compound (Intermediate 15, 1.8 g, 49% yield) as a lightyellow oil. MS: m / z = 414.25 [M + H]+. 'H NMR (400 MHz, Chloroform-t / ) 87.68 - 7.64 (m, 4H), 7.43 - 7.34 (m, 6H), 5.00 - 4.85 (m, 1H), 3.19 - 2.79 (m, 3H), 2.23 - 1.95 (m, 3H), 1.82 -1.63 (m, 3H), 1.32 (d, J= 7.2 Hz, 3H), 1.06 (s, 9H).19F NMR (376 MHz, Chloroform^ / ) 8 -187.10 (s, IF).

[0502] Intermediate 16: ((2A,3A,7a5)-2-fluoro-3-methyltetrahydro-17 / -pyrrolizin- 7a(57 / )-yl)methan-t / 2-olTo a solution of Intermediate 15 (400 mg, 0.97 mmol) in methanol (4.0 mL) was added NH4F (1.43 g, 38.61 mmol) at room temperature. The reaction mixture was heated at 65 °C for 4 h. The resulting mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by rep-TLC (DCM: MeOH = 10: 1) to afford the title compound (Intermediate 16, 110 mg, 64% yield) as a yellow oil. MS: m / z = 176.05 [M + H]+. 'HNMR (400 MHz, DMSO-t / 6) 85.11 - 4.96 (m, 1H), 3.26 - 2.24 (m, 1H), 3.17 - 2.87 (m, 2H), 2.18 - 1.54 (m, 6H), 1.25 - 1.19 (m, 3H).19F NMR (376 MHz, DMSO-t / 6) 8 -186.00 (s, IF).

[0503] Intermediate 17 & 18: Ethyl (5)-6'-methylene-3'-oxotetrahydrospiro[cyclopropane-l,l'-pyrrolizine]-7a'(577)-carboxylate & ethyl (R)-&-methylene-3'-oxotetrahydrospiro[cyclopropane-l,l'-pyrrolizine]-7a'(577)-carboxylateStep 1: Ethyl 2-(l-(2-ethoxy-2-oxoethyl)cyclopropyl)-2-nitroacetateA mixture of ethyl 2-cyclopropylideneacetate (150 g, 1.19 mol), ethyl 2-nitroacetate (152 mL, 1.37 mol) and K2CO3 (189 g, 1.37 mol) in THF (3000 mL) was degassed, purged with N2 three times, and stirred at 80 °C for 3 h under N2. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (1000 mL). The pH of the mixture was adjusted to around 3 with HC1 (1 L, 6 M in H2O). The mixture was extracted with CH2Q2 (1000 mL x 3). The combined organic layers were washed with brine (1000 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (308 g, crude) as a yellow liquid, which was used in the next step without further purification. 'HNMR (400 MHz, Chloroforms / ) 55.02 (s, 1H), 4.30 - 4.20 (m, 2H), 4.15 - 4.06 (m, 2H), 2.64 - 2.53 (m, 1H), 1.32 - 1.27 (m, 3H), 1.27 - 1.20 (m, 3H), 1.07 - 0.99 (m, 1H), 0.94 - 0.77 (m, 3H).Step 2: Ethyl 6-oxo-5-azaspiro[2.4]heptane-4-carboxylateTo a solution of ethyl 2-(l-(2-ethoxy-2-oxoethyl)cyclopropyl)-2-nitroacetate (39.5 g, 152 mmol) in AcOH (400 mL) and EtOH (800 mL) was added Zn (99 g, 1.52 mol) in batches at 25 °C under N2. The mixture was stirred at 100 °C for 16 h under N2. The reaction mixture was filtered, and concentrated under reduced pressure. The residue was diluted with sat. NaHCO₃ aq. (500 mL) (pH was adjusted to around 8) and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 1% of MeOH in CH2Q2) to give the title compound (31.6 g, 56% yield) as a white solid. MS: m / z = 184.0 [M + H]+. 'H NMR (400 MHz, Dimethyl sulfoxide-t / r,) 58.11 (s, 1H), 4.16 - 4.09 (m, 2H), 3.70 (s, 1H), 2.42 (d, J= 16.8 Hz, 1H) 2.01 - 1.95 (m, 1H), 1.20 (t, J= 7.2 Hz, 3H), 0.84 - 0.77 (m, 1H), 0.74 - 0.66 (m, 1H), 0.66 - 0.58 (m, 2H).Step 3: Ethyl 6'-methylene-3'-oxotetrahydrospiro[cyclopropane-l,l'-pyrrolizine]-7a'(577)-carboxylateTo a solution of ethyl 6-oxo-5-azaspiro[2.4]heptane-4-carboxylate (20 g, 109 mmol, refer to Intermediate 17 & 18 for detail procedures) and 3-chloro-2-(chloromethyl)prop-l-ene (51 mL,437 mmol) in THF (1000 mL) was added LiHMDS (229 mL, 1 M in THF) dropwise over 50 min at -40 °C under N2. The mixture was stirred at this temperature for 30 min, and continued to stirr at 25 °C for 15.5 h under N2. The reaction mixture was quenched with sat. NH4CI aq. (1000 mL) at 25 °C and extracted with EtOAc (lOOOmL x 3). The combined organic layers were washed with brine (2000 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 35% of EtOAc in petroleum ether) to give the title compound (6.5 g, 25% yield). MS: m / z = 236.1 [M + H]+.Step 4: Ethyl (5)-6'-methylene-3'-oxotetrahydrospiro[cyclopropane-l,l'-pyrrolizine]-7a'(577)-carboxylate & ethyl (A)-6'-methylene-3'-oxotetrahydrospiro[cyclopropane-l,l'-pyrrolizine]-7a'(577)-carboxylateEthyl 6'-methylene-3'-oxotetrahydrospiro[cyclopropane-l,l'-pyrrolizine]-7a'(5'H)-carboxylate (30 g) was separated by SFC (column: DAICEL CHIRALPAK AS (250 mm x 50 mm, 10 pm); mobile phase: [CO2-i-PrOH (0.1% NEE FLO)]; gradient: 45% ~ 50% B over 2.5 min) to give the title compound (Intermediate 17, 13.77 g, 46% yield, SFC peak 1, retention time: 1.216 min) as a yellow oil and the other title compound (Intermediate 18, 14.4 g, 48% yield, SFC peak 2, retention time: 1.542 min) as a yellow oil. Spectra for Intermediate 17: MS: m / z = 236.0 [M + H]+. ‘HNMR (400 MHz, Chloroform-; / ) 85.10 - 4.98 (m, 2H), 4.34 (br d, J= 16 Hz, 1H), 4.28 -4.13 (m, 2H), 3.65 (br d, J= 15.6 Hz, 1H), 3.07 (d, J= 16.8 Hz, 1H), 2.84 (br d, J= 14.8 Hz, 1H), 2.36 (br d, J= 14.8 Hz, 1H), 2.20 (d, J= 16.8 Hz, 1H), 1.27 (t, J= 7.2 Hz, 3H), 0.92 - 0.77 (m, 2H), 0.71 - 0.60 (m, 2H). Spectra for Intermediate 18: MS: m / z = 236.0 [M + H]+. 'H NMR (400 MHz, Chloroform-; / ) 85.09 - 4.98 (m, 2H), 4.34 (br d, J= 15.6 Hz, 1H), 4.27 - 4.13 (m, 2H), 3.70 - 3.60 (m, 1H), 3.07 (d, J= 16.8 Hz, 1H), 2.84 (dd, J= 0.8, 14.4 Hz, 1H), 2.40 - 2.32 (m, 1H), 2.19 (d, J= 16.8 Hz, 1H), 1.26 (t, J= 7.2 Hz, 3H), 0.91 - 0.78 (m, 2H), 0.70 - 0.61 (m, 2H).

[0504] Intermediate 19: (A)-(6'-Methylenetetrahydrospiro[cyclopropane-l, l'-pyrrolizin]-7a'(5'J7)-yl)methan-6?2-olStep 1: (A)-7a'-(Hydroxymethyl-6?2)-6'-methylenetetrahydrospiro[cyclopropane-l,l'-pyrrolizin]-3'(277)-oneTo a solution of Intermediate 18 (500 mg, 2.13 mmol) in CD3OD (10 mL) was added NaBD4 (402 mg, 10.6 mmol) under N2. The mixture was stirred at 25 °C for 16 h under N2. The reaction mixture was quenched with HC1 (5 mL, 1 M in H2O) and concentrated under reducedpressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 8% MeOH in CH2CI2) to give the title compound (390 mg, 94% yield) as an off-white solid. MS: m / z = 196.2 [M + H]+.Step 2: ( / )-(6'-Methylenetetrahydrospiro[cyclopropane-l, l'-pyrrolizin]-7( '(5' / / )-yl)methan-t / ?-ol To a solution of ( / )-7a'-(hydroxymethyl-t / ?)-6'-methylenetetrahydrospiro[cyclopropane-l, l'-pyrrolizin]-3'(2 7)-one (340 mg, 1.74 mmol) in THF (15 mL) was added LiAlTLj (3.48 mL, 2.5 M in THF) at 0 °C under N2. The mixture was stirred at 70 °C for 3 h under N2, quenched with Na2SO4*10H2O (3 g) at 0 °C under N2, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 30% MeOH in CH2CI2) to give the title compound (Intermediate 19, 230 mg, 69% yield) as a yellow oil. MS: m / z = 182.2 [M + H]+. 'H NMR (400 MHz, Chloroform^ / ) 84.98 - 4.83 (m, 2H), 3.74 (d, J= 14.4 Hz, 1H), 3.37 (d, J= 14.8 Hz, 1H), 3.24 - 3.15 (m, 1H), 2.80 - 2.70 (m, 1H), 2.26 - 2.17 (m, 2H), 2.05 -1.95 (m, 1H), 1.78 - 1.69 (m, 1H), 0.65 - 0.55 (m, 2H), 0.54 - 0.45 (m, 2H).

[0505] Intermediate 20 & 21: 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-carboxylateTo an ice-cooled solution of Intermediate 2 (2.0 g, 8.58 mmol) and TBAI (0.65 g, 1.76 mmol) in DCM (10 mL) under N2 were added 33 wt% 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 h. The resulting mixture was diluted with iced water (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 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 N2 were added NH4CI (3.37 g, 63.00 mmol) and Zn (4.12 g, 63.00 mmol) at room temperature. The reaction mixture was heated at 70 °C for 16 h. The resulting mixture was cooled to room temperature, filtered, and concentrated under reducedpressure. 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 20, 700 mg, 38% yield) as an off-white semi-solid. MS: m / z = 283.20 [M + NEU]+.JH NMR (300 MHz, Chloroform-6?) 87.39 - 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-6?) 8 -207.85 (s, IF). The second eluting mixtures were collected and concentrated under reduced pressure to give the title compound (cis mixture) (Intermediate 21, 360 mg, 19% yield) as a yellow oil. MS: m / z = 283.20 [M + ISEU]. 'HNMR (300 MHz, Chloroform-6?) 87.38 - 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) 8 -232.23 (s, IF).

[0506] Intermediate 22: (15',75',85)-8-Fluoro-5-oxa-2-azabicyclo[5.1.0]octaneA mixture of benzyl (l£,7£,85)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate (2.0 g, 102 mmol, refer to Intermediate 20 and 21 for detail procedures) and HBr (10 mL, 30% in AcOH) was stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound (Intermediate 22, 1.6 g, HBr salt) as a yellow solid, which was used in the next step without further purification.

[0507] Intermediate 23: (l£,7£,85)-2-(2,7-Dichloro-8-iodopyrido[4,3-6?]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octaneStep 1: Ethyl 4-amino-6-chloro-5-iodonicotinateTo a stirred solution of ethyl 4-amino-6-chloronicotinate (80 g, 398.76 mmol) and Ag2SC>4 (198.93 g, 638.02 mmol) in MeOH (768 mL) and H2O (640 mL) was added a solution of iodine(323.8 g, 1.27 mol) in THF (768 mL) at room temperature. The reaction mixture was heated at 65 °C for 16 h. The resulting mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting mixture was diluted with DCM (600 mL), poured into cold sat. NaHSCh aq. (1800 mL) and extracted with DCM (3 x 800 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was triturated with EA (80 mL). The precipitate was collected by filtration and washed with EA (3 x 20 mL) to give the title compound (80 g, 245.0 mmol, 61% yield) as a light yellow solid. MS: m / z = 326.85 [M + H]+. 'H NMR (400 MHz, Chloroforms / ) 58.48 (s, 1H), 4.35 - 4.29 (m, 2H), 1.32 (t, J= 7.2 Hz, 3H). Step 2: Ethyl 6-chloro-5-iodo-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinateTo a stirred solution of ethyl 4-amino-6-chloro-5-iodonicotinate (10 g, 30.62 mmol) in THF (100 mL) under N2 was added tri chloroethanecarbonyl isocyanate (5.77 g, 30.62 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 min. The resulting mixture was concentrated under reduced pressure. The residue was triturated with MTBE (80 mL). The precipitate was filtrated and washed with MTBE (20 mL) to give the title compound (12 g, 76% yield) as an off-white solid. MS: m / z = 513.95, 515.95 [M + H]+.Step 3: 7-Chloro-8-iodopyrido[4,3s / ]pyrimidine-2,4-diolTo a stirred solution of ethyl 6-chloro-5-iodo-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate (12 g, 23.30 mmol) in methanol (180 mL) was added NHs^MeOH (7 M in MeOH, 9.32 mL, 65.25 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was triturated with MTBE (150 mL) to give the title compound (10 g, crude) as an off-white solid. 'H NMR (400 MHz, DMSO ) 88.35 (s, 1H).Step 4: 2,4,7-Trichloro-8-iodopyrido[4,3-t / ]pyrimidineTo an ice-cooled stirred solution of POCI3 (100 mL) and DIEA (19.98 g, 154.57 mmol) was added 7-chloro-8-iodopyrido[4,3s / ]pyrimidine-2,4-diol (10 g, crude) under N2. The ice bath was removed, and the reaction mixture was heated at 110 °C for 16 h. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted EA (50 mL), poured slowly into cold sat. NaHCO₃ aq. (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed water (100 mL) and brine (100 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with PE / EA (25: 1)) to afford the title compound (6.5 g, 77% yield for two steps) as a light yellow solid. 'H NMR (400 MHz, Chloroforms / ) 89.32 (s, 1H).Step 5: (15,75,85)-2-(2,7-Dichloro-8-iodopyrido[4,3s / ]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octaneTo a stirred solution of 2,4,7-trichloro-8-iodopyrido[4,3-6?]pyrimidine (2.5 g, 6.93 mmol) and DIEA (2.689g, 20.81 mmol) in DCM (30 mL) was added Intermediate 22 (1.471g, 6.93 mmol) dropwise at -40 °C under N2. The reaction mixture was stirred at -40 °C for 1 h. 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 20% DCM in EA) to afford the title compound (Intermediate 23, 2.1 g, 66% yield) as a light yellow solid. MS: m / z = 454.85, 456.85 [M + H]+.

[0508] Intermediate 24: 6-Fluoro-5-(fluoromethoxy-6?2)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-2-amineStep 1: 4-Bromo-6-fluoro-5-methoxynaphthalen-2-olTo a solution of 8-bromo-2-fluoronaphthalene-l,6-diol (5 g, 19.5 mmol) and K2CO3 (8.06 g, 58.4 mmol) in DMF (50 mL) was added CH3I (1.21 mL, 19.5 mmol) dropwise at 0 °C under N2. The mixture was stirred at 0 °C for 2 h under N2. The reaction mixture was quenched with H2O (200 mL) at 0 °C and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 8% of EtOAc in petroleum ether) to give the title compound (4.7 g, 88% yield) as a brown oil. MS: m / z = 268.9, 270.9 [M - H]'. 'HNMR (400 MHz, Chloroform^ / ) 8 10.29 - 9.98 (m, 1H), 7.58 (dd, J= 5.4, 9.2 Hz, 1H), 7.53 - 7.38 (m, 2H), 7.25 - 7.19 (m, 1H), 3.87 (s, 3H).19F NMR (400 MHz, Chloroform-6?) 8 -134.77.Step 2: A-(4-Bromo-6-fluoro-5-methoxynaphthalen-2-yl)-2-hydroxy-2-methylpropanamide To a solution of 4-bromo-6-fluoro-5-methoxynaphthalen-2-ol (4.6 g, 17.0 mmol) in DMA (10 mL) was added 2-bromo-2-methylpropanamide (8.45 g, 50.9 mmol) and NaOH (6.11 g, 152.7 mmol) at 20 °C under N2. The mixture was stirred at 50 °C for 6 h. The reaction mixture was quenched with H2O (200 mL) at 0 °C and extracted with EtOAc (100 mL x 3). The combinedorganic layers were washed with brine (200 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 20% of EtOAc in petroleum ether) to give the title compound (5.96 g, 87% yield) as a yellow oil. MS: m / z = 354.0, 356.0 [M - H]’. 'H NMR (400 MHz, Dimethylsulfoxide-t / e) 89.95 (s, 1H), 8.51 - 8.25 (m, 2H), 7.70 (dd, J= 5.6, 9.2 Hz, 1H), 7.57 - 7.51 (m, 1H), 5.78 (s, 1H), 3.90 (s, 3H), 1.38 (s, 6H).19F NMR (376 MHz, Dimethyl sulfoxide^) 8 -131.96.Step 3: A-(4-Bromo-6-fluoro-5-hydroxynaphthalen-2-yl)-2-hydroxy-2-methylpropanamide To a solution of 7V-(4-bromo-6-fluoro-5-methoxynaphthalen-2-yl)-2-hydroxy-2-methylpropanamide (5.86 g, 16.5 mmol) in CH2CI2 (0.5 mL) was added BBr? (10 mL, 2 M in CH2CI2) at 0 °C under N2. The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with H2O (100 mL) at 0 °C and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 100% of EtOAc in petroleum ether) to give the title compound (3.03 g, 54% yield) as an off-white solid. MS: m / z = 342.1, 344.1 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-tL) 10.04 (s, 1H), 9.85 (s, 1H), 8.32 (s, 1H), 8.20 (s, 1H), 7.43 (t, J= 9.6 Hz, 1H), 7.37 - 7.30 (m, 1H), 5.75 (s, 1H), 1.37 (s, 6H).19F NMR (376 MHz, Dimethylsulfoxide-t / e) 8 -138.38, -139.06. Step 4: A-(4-Bromo-6-fluoro-5-(fluoromethoxy-t / 2)naphthalen-2-yl)-2-hydroxy-2-methylpropanamideTo a solution of fl uorom ethyl -t / 24-methylbenzenesulfonate (1.22 g, 5.9 mmol) and A-(4-bromo-6-fluoro-5-hydroxynaphthalen-2-yl)-2-hydroxy-2-methylpropanamide (3.03 g, 8.9 mmol) in DMF (25 mL) was added K2CO3 (2.45 g, 17.7 mmol). The mixture was stirred at 80 °C for 4 h. The reaction mixture was quenched with H2O (100 mL) at 0 °C and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 30% of EtOAc in petroleum ether) to give the title compound (2.35 g, 99% yield) as a light yellow solid. MS: m / z = 376.0, 378.0 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-tL) 89.99 (s, 1H), 8.50 (d, J= 2.0 Hz, 1H), 8.37 (d, J= 2.0Hz, 1H), 7.83 (dd, J= 5.6, 9.2 Hz, 1H), 7.64 - 7.55 (m, 1H), 5.79 (s, 1H), 1.38 (s, 6H).19F NMR (376 MHz, Dimethylsulfoxide-tL) 8 -129.42, -152.72, -152.74.Step 5: 4-Bromo-6-fluoro-5-(fluoromethoxy-t / 2)naphthalen-2-amineTo a solution of N-(4-bromo-6-fluoro-5-(fluoromethoxy-t / 2)naphthalen-2-yl)-2-hydroxy-2-methylpropanamide (2.35 g, 6.25 mmol) in EtOH (10 mL) was added NaOH (8.45 mL, 5 M in H2O). The mixture was stirred at 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 15%of EtOAc in petroleum ether) to give the title compound (1.42 g, 75% yield) as a yellow solid. MS: m / z = 289.9, 290.9 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-t / e) 87.50 (dd, J= 5.6, 9.2 Hz, 1H), 7.43 - 7.34 (m, 2H), 6.90 (d, J= 2.0 Hz, 1H), 5.64 (s, 2H).19F NMR (376 MHz, Dimethylsulfoxide-tL) 8 -134.98, -152.39.Step 6: 6-Fluoro-5-(fluorornethoxy-t / 2)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-2-amineA mixture of 4-bromo-6-fluoro-5-(fluoromethoxy-t / 2)naphthalen-2-amine (1.4 g, 4.83 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (3.68 g, 14.5 mmol), CysPPdG3 (471 mg, 724 pmol), and K3PO4 (3.07 g, 14.5 mmol) in 1,4-dioxane (10 mL) was degassed and purged with N2 three times. The mixture was stirred at 100 °C for 16 h under N2. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 35% of EtOAc in petroleum ether) to give the title compound (Intermediate 24, 681 mg, 71% yield) as a yellow solid. MS: m / z = 337.9 [M + H]+. 'H NMR (400 MHz, Dimethyl sulfoxide-tL) 87.38 (dd, J= 5.2, 9.2 Hz, 1H), 7.32 - 7.25 (m, 1H), 7.02 (d, J= 2.0 Hz, 1H), 6.85 (d, J= 2.4 Hz, 1H), 5.44 (s, 2H), 1.34 (s, 12H).19F NMR (376 MHz, Dimethylsulfoxide-tL) 8 -139.70, -149.68, -149.72.

[0509] Intermediate 25 & 26: (lA,7A,8A)-2-(7-Chloro-2,8-difluoropyrido[4,3-J]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane & (15,75,85)-2-(7-chloro-2,8-difluoropyrido[4,3-J]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octaneStep 1: 8-Fluoro-5-oxa-2-azabicyclo[5.1.0]octane hydrobromide (trans mixture)A mixture of Intermediate 20 (trans mixture) (2.6 g, 9.81 mmol) in 33 wt% HBr in AcOH (26 mL) under N2 was stirred in an ice bath for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was triturated 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-J]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-J]pyrimidine (1154.94 mg, 4.57 mmol) inDCM (11 mL) was added DIEA (1773.88 mg, 13.72 mmol) dropwise at -40 °C under N2. The reaction mixture was stirred at -40 °C for 1 h. 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 Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with CH2CI2 / 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-2,8-difluoropyrido[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) (4.8 g, 13.82 mmol) in DMSO (96 mL) was added KF (1.45 g, 24.88 mmol) at room temperature under N2. The reaction mixture was stirred at 80 °C for 16 h. The resulting mixture was cooled to room temperature, diluted with water (300 mL), and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (3 x 300 mL), dried over anhydrous Na2SC>4, 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 (2 g, 43% yield) as a light-yellow solid. MS: m / z = 331.05 [M + H]+. Step 4: (lA,7A,8A)-2-(7-chloro-2,8-difluoropyrido[4,3- ]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane & (kS',7k,8k)-2-(7-chloro-2,8-difluoropyrido[4,3-t / ]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane2-(7-Chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5. L0]octane (trans mixture) (2.7 g, 8.16 mmol, two batches) was separated by Prep-SFC with the following conditions: Column: CHIRAL ART Cellulose-SB 5 x 25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MeOH (0.1% 2 MNH3-MeOH); Flow rate: 140 mL / min; Gradient: isocratic 40% B; RT1: 8 min; RT2: 9.5 min. The first eluting peak (RT1: 8 min) was concentrated and lyophilized to give the title compound (Intermediate 25, 1 g, 37% yield) as a light yellow solid. MS: m / z = 331.10 [M + H]+. The second eluting peak (RT2: 9.5 min) was concentrated and lyophilized to give the title compound (Intermediate 26, 970 mg, 35% yield) as a light yellow solid. MS: m / z = 331.10 [M + H]+.

[0510] Intermediate 27: (15',75',85)-2-(7-Bromo-2,6-difluoro-8-methylquinazolin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octaneStep 1: Methyl 2-amino-4-bromo-5-fluoro-3-iodobenzoateTo a stirred solution of methyl 2-amino-4-bromo-5-fluorobenzoate (4.5 g, 18.14 mmol) and Ag2SO4(9.05 g, 29.02 mmol) in methanol (43.2 mL) and H2O (36 mL) was added dropwise a solution of iodine (7.37 g, 29.02 mmol) in THF (43.2 mL) at room temperature. The reaction mixture was stirred at room temperature for 0.5 h. The resulting mixture was concentrated under reduced pressure to remove MeOH & THF, filtered and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with PE / EA (15: 1)) to afford the title compound (6.2 g, 91% yield) as an off-white solid. MS: m / z =373.95, 375.95 [M + H]+. 'H NMR (400 MHz, Chloroform-; / ) d 7.72 - 7.75 (m, 1H), 3.90 (s, 3H).19F NMR (376 MHz, Chloroform-; / ) 5 -111.95 (s, IF).Step 2: Methyl 2-amino-4-bromo-5-fluoro-3-methylbenzoateTo a stirred solution of methyl 2-amino-4-bromo-5-fluoro-3-iodobenzoate (6 g, 16.04 mmol) and methylboronic acid (5762.73 mg, 96.27 mmol) in 1,2-dimethoxy ethane (87.6 mL) and H2O (15 mL) were added Pd(PPh3)2Cl2(1126.20 mg, 1.60 mmol) and K2COs (4.43 g, 32.09 mmol) at room temperature under N2. The reaction mixture was heated at 90 °C for 16 h. The resulting mixture was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (3 x 60 mL). 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 (eluted with PE / EA (15: 1)) to afford the title compound (2.2 g, 52% yield) as an off-white solid. MS: m / z = 261.95, 263.95 [M + H]+. 'H NMR (400 MHz, Chloroform-^ 57.55 - 7.53 (m, 1H), 3.88 (s, 3H), 2.33 (s, 3H).19F NMR (376 MHz,Chloroform-t / ) 8 -118.82 (s, IF).Step 3: Methyl 4-bromo-5-fluoro-3-methyl-2-(3-(2,2,2-trichloroacetyl)ureido)benzoateTo a stirred solution of methyl 2-amino-4-bromo-5-fluoro-3 -methylbenzoate (2 g, 7.63 mmol) in THF (25 mL) was added tri chloroethanecarbonyl isocyanate (2.16 g, 11.44 mmol) at room temperature under N2. The reaction mixture was stirred at room temperature for 30 min. The resulting mixture was concentrated under reduced pressure. The residue was triturated with MTBE (3 x 25 mL) to give the title compound (3.5 g, crude) as an off-white solid. MS: m / z = 470.75 and 472.75 [M + Na]+.Step 4: 7-Bromo-6-fluoro-8-methylquinazoline-2,4-diolTo a stirred solution of methyl 4-bromo-5-fluoro-3-methyl-2-(3-(2,2,2-trichloroacetyl)ureido)benzoate (3.5 g, crude) in methanol (120 mL) was added NFL^MeOH (7 M in MeOH, 3.11 mL, 21.75 mmol) dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was triturated with MTBE (3 x 40 mL) to give the title compound (1.9 g, crude) as an off-white solid. MS: m / z = 272.85, 274.85 [M + H]+.Step 5: 7-Bromo-2,4-dichloro-6-fluoro-8-methylquinazolineTo a stirred solution of POCI3 (665.36 mg, 4.33 mmol) and DIEA (3.08 g, 23.80 mmol) was added 7-bromo-6-fluoro-8-methylquinazoline-2,4-diol (1.3 g, crude) in an ice bath under N2. The reaction mixture was heated at 110 °C for 16 h. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was quenched with sat. NaHCO3aq. (15 mL) in an ice bath, diluted with water (100 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SC>4, 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 (700 mg, 43% yield for three steps) as an off-white solid.JH NMR (300 MHz, Chloroform-t / ) 87.82 -7.79 (m, 1H), 2.89 (d, J= 0.6 Hz, 3H).19F NMR (282 MHz, Chloroform^ / ) 8 -97.76 (s, IF). Step 6: (15',75',85 -2-(7-Bromo-2-chloro-6-fluoro-8-methylquinazolin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octaneTo a stirred solution of 7-bromo-2,4-dichloro-6-fluoro-8-methylquinazoline (300 mg, 0.96 mmol) and Intermediate 22 (205.25 mg, 0.96 mmol) in DCM (5 mL) was added DIEA (375.29 mg, 2.90 mmol) dropwise at room temperature under N2. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by E / v -TLC (PE / EA 5: 1) to afford the title compound (300 mg, 76% yield) as an off-white solid. MS: m / z = 403.90, 405.90 [M + H]+. 'H NMR (300 MHz, Chloroforms / ) 87.94 - 7.91 (m, 1H), 4.54 - 4.39 (m, 2H), 4.29 - 4.08 (m, 1H), 3.99 - 3.96 (m,2H), 3.89 - 3.80 (m, 1H), 3.66 - 3.57 (m, 1H), 3.23 - 3.07 (m, 1H), 2.82 (s, 3H), 2.35 - 2.23 (m, 1H).19F NMR (282 MHz, Chloroform-6?) 5 -104.30 (s, IF), -207.16 (s, IF).Step 7: (15',75',85)-2-(7-Bromo-2,6-difluoro-8-methylquinazolin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octaneTo a solution of (15',75',85 -2-(7-bromo-2-chloro-6-fluoro-8-methylquinazolin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (320 mg, 0.79 mmol) in DMSO (0.5 mL) under N2 was added KF (321.61 mg, 5.53 mmol) at room temperature. The reaction mixture was heated at 120 °C for 16 h. The resulting mixture was cooled to room temperature, diluted with water (10 mL), and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by E / v -TLC (PE / EA 6: 1) to afford the title compound (Intermediate 27, 170 mg, 55% yield) as an off-white solid. MS: m / z = 388.00, 390.00 [M + H]+.1H NMR (400 MHz, Chloroform-6?) 58.00 - 7.98 (m, 1H), 4.53 - 4.41 (m, 2H), 4.30 - 4.15 (m, 1H), 3.98 - 3.83 (m, 3H), 3.67 - 3.60 (m, 1H), 3.23 - 3.07 (m, 1H), 2.80 (s, 3H), 2.35 - 2.26 (m, 1H).19F NMR (376 MHz, Chloroform-6?) 8 -46.78 (s, IF), -106.04 (s, IF), -207.06 (s, IF).

[0511] Intermediate 28: (A)-(dihydro-5 / -dispiro[cyclopropane- 1, 1 '-pyrrolizine-61, 1 "-cyclopropan]-7a'(7'Z / )-yl)methan-6?2-olTo a solution of Intermediate 19 (100 mg, 552 pmol) in CH2CI2 (2.5 mL) was added dropwise diethylzinc (2.76 mL, 1 M in toluene) at -30 °C and stirred at -30 °C for 0.5 h under N2. A solution of CH2I2 (1.01 mL, 203 pmol) in CH2Q2 (1 mL) was added dropwise to the mixture at -30 °C. The mixture was stirred at 25 °C for 2 h under N2. The reaction mixture was quenched with sat. NaHCOs aq. (2 mL) at 25 °C, dried over MgSCU, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 7% MeOH in CH2Q2) to give (A)-(dihydro-5 / -dispiro[cyclopropane-l,l'-pyrrolizine-6',l"-cyclopropan]-7a'(7'Z / )-yl)methan-6?2-ol (170 mg, HI salt) as a yellow oil. To a solution of (R)-(dihydro-5'J / -dispiro[cyclopropane- 1,1 '-pyrrolizine-6', l"-cy cl opropan]-7a'(7'Z / )-yl)methan-6?2-ol (170 mg, HI salt, 552 pmol) in THF (2 mL) was added LiAlH4 (21 mg, 552 pmol) at 0 °C under N2. The mixture was stirred at 0 °C for 10 min under N2. The reaction mixture was quenched with H2O (20 pL), NaOH (20 pL, 15wt%), and water (60 pL) slowly at 0 °C. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 7% MeOH in CH2CI2) to give the title compound (Intermediate 28, 105 mg, 58% yield) as a yellow oil. MS: m / z = 196.2 [M + H]+.

[0512] Intermediate 29: (15',75',85)-2-(7-Chloro-2-fluoro-8-methylpyrido[4,3- J]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octaneStep 1: (15',75',85)-2-(2,7-Dichloro-8-methylpyrido[4,3- ]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octaneTo a solution of Intermediate 22 (1.62 g, 7.65 mmol, HBr salt) in CH2CI2 (20 mL) were added DIPEA (5.61 mL, 32.2 mmol) and 2,4,7-trichloro-8-methylpyrido[4,3-J]pyrimidine (2 g, 8.05 mmol) at -78 °C under N2. The mixture was stirred at -78 °C for 0.5 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 15% of EtOAc in petroleum ether) to give the title compound (2.7 g, 98% yield) as a yellow solid. MS: m / z = 342.9 [M + H]+. 'H NMR (400 MHz, Chloroform-; / ) 59.40 (s, 1H), 4.70 -4.61 (m, 1H), 4.47 - 4.19 (m, 2H), 4.00 - 3.84 (m, 3H), 3.70 - 3.60 (m, 1H), 3.41 - 3.14 (m, 1H), 2.67 (s, 3H), 2.39 - 2.25 (m, 1H).Step 2: (15',75',85)-2-(7-chloro-2-fluoro-8-methylpyrido[4,3- ]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octaneTo a solution of (15',75',85)-2-(2,7-dichloro-8-methylpyrido[4,3- ]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (2.6 g, 7.58 mmol) in DMSO (26 mL) was added KF (1.32 g, 22.7 mmol) under N2 at 25 °C. The mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with H2O (300 mL) and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (300 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 (Intermediate 29, 2 g, 81% yield) as a yellow solid. MS: m / z = 327.1 [M + H]+. 'H NMR (400 MHz, Chloroform-^ 59.42 (s, 1H), 4.72 - 4.54 (m, 1H), 4.48 - 4.22 (m, 2H), 4.03 - 3.83 (m, 3H), 3.72 - 3.60 (m, 1H), 3.45 - 3.13 (m, 1H), 2.64 (s, 3H), 2.44 - 2.25 (m, 1H).

[0513] Intermediate 30: 7-Chloro-4-((15',7A,85')-8-chloro-2-azabicyclo[5.1.0]octan-2-yl)-2,8-difluoropyrido[4,3-J]pyrimidineStep 1: (15,7A,85)-8-chloro-2-azabicyclo[5.1.0]octane hydrobromideA solution of benzyl (15,7A,85)-8-chloro-2-azabicyclo[5.1.0]octane-2-carboxylate (1 g, 3.57 mmol) in hydrogen bromide-acetic acid solution (10 mL) under N2 was stirred in an ice bath for 1 h. The resulting mixture was concentrated under reduced pressure to afford the title compound (806 mg, crude) as a yellow solid. MS: m / z = 146.61 [M + H]+.Step 2: 2,7-Dichloro-4-((15,7A,85)-8-chloro-2-azabicyclo[5. L0]octan-2-yl)-8-fluoropyrido[4,3- ]pyrimidineTo a mixture of (15,7A,85)-8-chloro-2-azabicyclo[5.1.0]octane hydrobromide (806 mg, crude) and 2,4,7-trichloro-8-fluoropyrido[4,3-J]pyrimidine (988.00 mg, 3.91 mmol) in DCM (8 mL) was added DIEA (1379.53 mg, 10.67 mmol) dropwise at - 40 °C under N2. The reaction mixture was stirred at - 40 °C for 1 h. The resulting mixture was quenched with water (20 mL) and extracted with CH2Q2 (3 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with 10% EA in PE) to afford the title compound (1.0 g, 77% yield for two steps) as a light yellow solid. MS: m / z = 361.00, 363.00 [M + H]+.Step 3: 7-Chloro-4-((15',7A,85 -8-chloro-2-azabicyclo[5.1.0]octan-2-yl)-2,8-difluoropyrido[4,3- ]pyrimidineTo a stirred solution of 2,7-dichloro-4-((15,7A,85)-8-chloro-2-azabicyclo[5.1.0]octan-2-yl)-8-fhioropyrido[4,3- ]pyrimidine (1 g, 2.76 mmol) in DMSO (10 mL) was added KF (240.98 mg, 4.14 mmol) at room temperature under N2. The reaction mixture was heated at 80 °C for 16 h. The resulting mixture was cooled to room temperature, diluted with EA (100 mL), and washed with water (3 x 30 mL) and brine (30 mL). The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with PE / EA (10: 1)) to afford the title compound (Intermediate 30, 630 mg, 66% yield) as a yellow solid. MS: m / z = 345.00, 347.00 [M + H]+.

[0514] Intermediate 31: 6-Fluoro-5-(fluoromethoxy-d2)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-2-olStep 1: 4-Bromo-6-fluoro-5-(fluoromethoxy-d2)naphthalen-2-olTo a solution of fluoromethyl-ch 4-methylbenzenesulfonate (700 mg, 3.39 mmol,) in DMF (20 mL) were added K2CO3 (938 mg, 6.79 mmol) and 8-bromo-2-fluoronaphthalene-l,6-diol (872 mg, 3.39 mmol). The mixture was stirred at 50 °C for 16 h under N2. The reaction mixture was partitioned between H2O (500 mL) and CH₂Cl₂ (300 mL). The organic phase was separated, washed with CH₂Cl₂ (500 mL x 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 9% of EtOAc in petroleum ether) to give the title compound (400 mg, 38% yield over 2 steps, confirmed by 2D-NMR) as a white solid. MS: m / z = 290.7 [M - H]+.JH NMR (400 MHz, Dimethylsulfoxide-tZ6) 8 10.24 (s, 1H), 7.75 - 7.68 (m, 1H), 7.56 - 7.46 (m, 2H), 7.29 - 7.23 (m, 1H).19F NMR (376 MHz, Dimethylsulfoxide-tL) 8 -132.22, -132.26, -152.63, -152.65.Step 2: 6-Fluoro-5-(fluoromethoxy-d2)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-2-olA mixture of 4-bromo-6-fluoro-5-(fluoromethoxy-d2)naphthalen-2-ol (70 mg, 240.48 pmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (122 mg, 480 pmol), K3PO4 (153 mg, 721 pmol), and CysP Pd G3 (31 mg, 48.1 pmol) in dioxane (3 mL) was degassed and purged with N2 three times. The mixture was stirred at 100 °C for 16 h under N2. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 11% of EtOAc in petroleum ether) to give the title compound (Intermediate 31, 67 mg, 81% yield) as a white solid. MS: m / z = 336.8 [M - H]+. *HNMR (400 MHz, Dimethylsulfoxide-tL) 89.83 (s, 1H), 7.62 - 7.55 (m, 1H), 7.45 - 7.37 (m, 1H), 7.20 - 7.09 (m, 2H), 1.35 (s, 12H).19F NMR (376 MHz, Dimethyl sulfoxide-t / 6) 8 -137.18, -137.23, -149.87.

[0515] Intermediate 32: 2-(7-Fluoro-3-(methoxymethoxy)-8-vinylnaphthalen-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolaneStep 1: 2-(8-Ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolaneTo a solution of ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l-yl)ethynyl)triisopropylsilane (10.0 g, 19.5 mmol) in DMSO (100 mL) was added CsF (29.6 g, 195 mmol). The mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into ice-water (300 mL), filtered, and washed with water (500 mL). The filter cake was dried and washed with petroleum ether (80 mL) to give the title compound (6.90 g, 99% yield) as an off-white solid. MS: m / z = 356.8 [M + H]+.JH NMR (400 MHz, Dimethylsulfoxide-tL) 87.97 (dd, J= 6.0, 9.2 Hz, 1H), 7.58 (d, J= 2.4 Hz, 1H), 7.49 (t, J= 8.8 Hz, 1H), 7.34 (d, J= 2.4 Hz, 1H), 5.32 (s, 2H), 5.03 (s, 1H), 3.44 - 3.39 (m, 3H), 1.37 (s, 12H).19F NMR (376 MHz, Dimethylsulfoxide-6) 8 -110.39.Step 2: 2-(7-Fluoro-3-(methoxymethoxy)-8-vinylnaphthalen-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolaneTo a solution of 2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (13.0 g, 36.5 mmol), quinoline (6.00 g, 46.5 mmol, 5.48 mL) in methanol (50.0 mL) was added Lindlar catalyst (7.80 g, 37.8 mmol). The mixture was stirred at 40 °C for 1 h under H2 (30 psi). The reaction mixture was filtered and washed with methanol (100 mL x 3). The filtrate was concentrated and purified by prep-HPLC (column: Daisogel C18 250 x 70 mm x 10 pm; mobile phase: [water (NH3H2O) - ACN]; gradient: 55% - 85% B over 15 min) to give the title compound (Intermediate 32, 6.67 g, 50% yield) as a yellow solid. MS: m / z = 359.0 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide r,) 87.83 (dd, J= 5.6, 8.8 Hz, 1H), 7.53 (d, J= 2.4 Hz, 1H), 7.40 (t, J= 9.6 Hz, 1H), 7.28 (d, J= 2.8 Hz, 1H), 7.00 (dd, J= 11.2, 17.6 Hz, 1H), 5.72 (dd, J= 1.6, 11.6 Hz, 1H), 5.56 (d, J= 17.6 Hz, 1H), 5.31 (s, 2H), 3.42 (s, 3H), 1.34 (s, 12H).19F NMR (376 MHz, Dimethylsulfoxide r,) 8 -117.39.

[0516] Intermediate 33: 4,7-Dichloro-8-fluoro-5-(methoxy-t / 3)-2-(methylthio)pyrido[4,3- ]pyrimidineStep 1: 7-Chloro-8-fluoro-5-(methoxy-t / 3)-2-(methylthio)pyrido[4,3- ]pyrimidin-4-olA mixture of CD3OD (218 pL, 5.36 mmol) in THF (10 mL) was degassed and purged with N2 three times. Sodium hydride (714 mg, 17.9 mmol, 60% purity) was added to the mixture at 0°C under N2. The mixture was stirred at 0 °C for 1 h under N2. 5,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-J]pyrimidin-4-ol (1 g, 3.57 mmol) was added to the mixture at 0 °C under N2. The mixture was stirred at 25 °C for 2 h under N2. The reaction mixture was quenched with sat. NH4CI. aq. (50 mL) at 0 °C under N2 and filtered. The filtrate was extracted with EtOAc (50mL x 3). The combined organic layers were washed with brine (50mL), driedover Na2SC>4, and filtered. The filtrate was combined with the filter cake and concentrated under reduced pressure. The residue was triturated with Petroleum ether (40 mL) and filtered to give the title compound (980 mg, 98% yield) as an off-white solid. MS: m / z = 279.0, 281.0 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-6) 82.35 (s, 3H).19F NMR (376 MHz, Dimethylsulfoxide-tL) 8 -147.48.Step 2: 4,7-Dichloro-8-fluoro-5-(methoxy-t / 3)-2-(methylthio)pyrido[4,3- ]pyrimidineTo a solution of 7-chloro-8-fluoro-5-(methoxy-t / 3)-2-(methylthio)pyrido[4,3- ]pyrimidin-4-ol (880 mg, 3.16 mmol) in CH₂Cl₂ (10 mL) were added DIPEA (2.75 mL, 15.8 mmol) and POCI3 (0.88 mL, 9.47 mmol). The mixture was stirred at 20 °C for 1 h under N2. The 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 (Intermediate 33, 660 mg, 68% yield) as an off-white solid. MS: m / z = 297.0, 299.0 [M + H]+.1H NMR (400 MHz, Di methyl sulfoxide r,) 82.64 (s, 3H).19F NMR (376 MHz, Dimethylsulfoxide- e) 8 -144.91, -145.14.

[0517] Intermediate 34: (lS,7S,8S)-2-(7-Chloro-8-fluoro-5-(methoxy-t / 3)-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octaneStep 1: (1 S,7S,8S)-2-(7-Chloro-8-fluoro-5-(methoxy-t / 3)-2-(methylthio)pyrido[4,3- ]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octaneTo a solution of Intermediate 33 (300 mg, 1.01 mmol) and DIPEA (0.88 mL, 5.05 mmol) in CH2CI2 (5 mL) was added Intermediate 22 (428 mg, 2.02 mmol, HBr salt) at -40 °C under N2.The reaction mixture was stirred at -40 °C for 1 h under N2. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (60 mL x 2). The combined organic layers were washed with brine (40 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 50% of di chloromethane in petroleum ether) to give the title compound (375 mg, 94% yield) as a light yellow solid. MS: m / z = 392.1 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) 8 4.67 - 4.40 (m, 2H), 4.30 (dd, J= 6.0, 13.6 Hz, 1H), 4.01 - 3.88 (m, 2H), 3.67 - 3.49 (m, 2H), 2.85 - 2.72 (m, 1H), 2.52 - 2.51 (m, 3H), 2.26 - 2.08 (m, 1H).19F NMR (376 MHz, Dimethylsulfoxide-d6) 8 -147.80, -206.61.Step 2: (1 S,7S,8S)-2-(7-Chloro-8-fluoro-5-(methoxy-t / 3)-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octaneA mixture of (15',75',85)-2-(7-chloro-8-fluoro-5-(methoxy-t / 3)-2-(methylthio)pyrido[4,3-t / ]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (360 mg, 919 pmol) and m-CPBA (205 mg, 1.01 mmol, 85% purity) in CH2CI2 (5 mL) was stirred at 25 °C for 0.5 h. The reaction mixture was quenched with Na2S20s aq. (50 mL) at 0°C and extracted with CH2CI2 (50 mL x 2). The combined organic layers were washed with Na2S20s aq. (50 mL) and brine (50 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 5 % of MeOH in CH2CI2) to give the title compound (Intermediate 34, 420 mg, 98% yield) as a colorless oil. MS: m / z = 407.9 [M + H]+.

[0518] Intermediate 35: 5,7-Dichloro-8-methyl-2-(methylthio)pyrido[4,3-J]pyrimidin-4-Step 1: tert-Butyl 4-((te / 7-butoxycarbonyl)amino)-2,6-dichloronicotinateA mixture of tert-butyl (ter / -butoxycarbonyl)(2,6-dichloropyridin-4-yl)carbamate (20 g, 55.1 mmol) in THF (200 mL) was degassed and purged with N2 three times. LDA (66.1 mL, IM in THF) was added dropwise to the mixture at -78 °C under N2. The mixture was stirred at -78 °C under N2.for 2 h. The reaction mixture was quenched with sat. NH4CI aq. (500 mL) and extracted with EtOAc (250 mL x 2). The combined organic layers were washed with brine (300 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 (21 g, 93% purity, 99% yield) as a brown solid. MS: m / z = 363.2 [M + H]+.1HNMR (400 MHz, Chloroform^ / ) 88.97 (s, 1H), 8.33 (s, 1H), 1.62 (s, 9H), 1.52 (s, 9H).Step 2: tert-Butyl 4-((te / 7-butoxycarbonyl)amino)-2,6-dichloro-5-iodonicotinateA mixture of tert-butyl 4-((ter / -butoxycarbonyl)amino)-2,6-dichloronicotinate (21 g, 57.8 mmol) in THF (300 mL) was degassed and purged with N2 three times. LDA (69.4 mL, IM in THF)was added dropwise to the mixture at -78 °C under N2. The mixture was stirred at -78 °C for 1 h. A solution of I2 (17.6 g, 69.4 mmol) in THF (50 mL) was added, and the mixture was stirred at this temperature for another 1 h under N2. The reaction mixture was quenched with sat. NH4CI aq. (500 mL) and extracted with EtOAc (250 mL x 3). The combined organic layers were washed with brine (500 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 (13 g, 35.4 mmol). MS: m / z = 489.1 [M + H]+.1HNMR (400 MHz, Chloroform^ / ) 36.92 (s, 1H), 1.60 (s, 9H), 1.50 (s, 9H).Step 3: / c / V-Butyl 4-amino-2,6-dichloro-5-iodonicotinateA mixture of / crt-butyl 4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-iodonicotinate (2 g, 4.09 mmol) in HC1 (20 mL, 2M in EtOAc) was stirred at 25 °C under N2 for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound (1.74 g, HC1 salt) as a white solid. MS: m / z = 388.9 [M + H]+.Step 4: / c / V-Butyl 4-amino-2,6-dichloro-5-methylnicotinateA mixture of terLbutyl 4-amino-2,6-dichloro-5-iodonicotinate (1.74 g, 4.09 mmol, HC1 salt), 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (1.14 mL, 8.17 mmol), K2CO3 (2.26 g, 16.4 mmol) and Pd(dppf)C12 (299 mg, 409 pmol) in 1,4 -dioxane (15 mL) and H2O (3 mL) was degassed and purged with N2 three times. The mixture was stirred at 80 °C for 1 h under N2. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (20 mL x 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 ~ 8% of EtOAc in Petroleum ether) to give the title compound (1.07 g, 93 % yield over 2 steps) as a white solid. MS: m / z = 277.1 [M + H]+.1HNMR (400 MHz, Chloroforms / ) 85.79 (s, 2H), 2.18 (s, 3H), 1.60 (s, 9H).Step 5: 4-Amino-2,6-dichloro-5-methylnicotinic acidTo a solution of tert-butyl 4-amino-2,6-dichloro-5-methylnicotinate (1.07 g, 3.86 mmol) in CH2CI2 (9 mL) was added TFA (9 mL). The reaction was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound (1.3 g, TFA salt) as a brown solid. MS: m / z = 221.1 [M + H]+.Step 6: 5,7-Dichloro-2-mercapto-8-methylpyrido[4,3-t / ]pyrimidin-4-olA mixture of 4-amino-2,6-dichloro-5-methylnicotinic acid (1.3 g, 3.88 mmol) in SOCI2 (10 mL) was stirred at 80 °C under N2 for 2 h. The mixture was concentrated. The residue was triturated with / / -hexane (20 mL) at 25 °C for 5 min and filtered. The filter cake was dissolved in acetone (10 mL). The above mixture was added dropwise to a solution of NH4SCN (1.10 g, 14.4 mmol) in acetone (5 mL) at 25 °C. The mixture was stirred at 25 °C for 1 h. The mixture wasquenched with H2O (20 mL) at 25 °C and filtered. The filter cake was washed with water and dried under reduced pressure to give the title compound (900 mg, 88% yield over 2 steps) as a yellow solid. MS: m / z = 262.0 [M + H]+.Step 7: 5,7-Dichloro-8-methyl-2-(methylthio)pyrido[4,3-J]pyrimidin-4-olTo a solution of 5,7-dichloro-2-mercapto-8-methylpyrido[4,3-J]pyrimidin-4-ol (900 mg, 3.43 mmol) in MeOH (10 mL) were added NaOH (5.15 mL, IM in H2O) and Mel (321 pL, 5.15 mmol). The reaction was stirred at 25 °C for 2 h. The reaction mixture was quenched with sat. NH4CI aq. (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with Petroleum ether / EtOAc = 5:1 (30 mL) to give the title compound (Intermediate 35, 900 mg, 95% yield) as a yellow solid. MS: m / z = 276.0 [M + H]+.

[0519] Intermediate 36: 4,7-Dichloro-5-(methoxy-t / 3)-8-methyl-2- (methy Ithi o)py rido [4, 3 - d\ py rimi dineStep 1: 7-Chloro-5-(methoxy-t / 3)-8-methyl-2-(methylthio)pyrido[4,3- ]pyrimidin-4-olA mixture of NaH (623 mg, 16 mmol, 60% purity) in THF (10 mL) was degassed and purged with N2 three times. Methanol -d (677 mg, 4.7 mmol, 190 pL) was added to the mixture at 0°C under N2. The mixture was stirred at 0 °C for 0.5 h. A solution of Intermediate 35 (860 mg, 3.1 mmol) in THF (10 mL) was added at 0 °C, and the mixture was stirred at 25°C for 1 h. The reaction mixture was quenched with sat. NH4CI r / c / .(IO mL) at 0°C and extracted with EtOAc (45 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was treated with Petroleum ether (20 mL). The mixture was stirred at 25°C for 1 h and filtered. The filter cake was dried under reduced pressure to give the title compound (820 mg, 96% yield) as a yellow solid. MS: m / z = 275.1 [M + H]+. 'H NMR (400 MHz, Chloroform^ / ) 89.15 (s, 1H), 2.70 (s, 3H), 2.55 (s, 3H).Step 2: 4,7-Dichloro-5-(methoxy-t / 3)-8-methyl-2-(methylthio)pyrido[4,3- ]pyrimidineTo a solution of 7-chloro-5-(methoxy-t / 3)-8-methyl-2-(methylthio)pyrido[4,3-t / ]pyrimidin-4-ol (820 mg, 3 mmol) in CH2CI2 (20 mL) were added DIPEA (1.9 g, 15 mmol, 2.6 mL) and POCI3 (834 pl, 9 mmol) at 25 °C. The mixture was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent of 0 ~ 36% CH2CI2 in Petroleum ether) to give the title compound(Intermediate 36, 200 mg, 22% yield) as a white solid. MS: m / z = 293.0, 295.0 [M + H]+. 'H NMR (400 MHz, Chloroform-; / ) 52.65 (s, 3H), 2.55 (s, 3H).

[0520] Intermediate 37: (15',75',85)-2-(7-Bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octaneTo an ice-cooled solution of 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (1 g, 3.18 mmol) and DIEA (1235.20 mg, 9.55 mmol) in DCM (10 mL) under N2 was added Intermediate 22 (675.55 mg, 3.18 mmol). The reaction mixture was stirred in an ice bath for 1 h. The resulting mixture was quenched with water (20 mL) in an ice bath and extracted with DCM (3 x 30 mL). 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 (eluted with PE / EA (3: 1) to afford the title compound (Intermediate 37, 1 g, 76% yield). MS: m / z = 407.85, 409.85 [M + H]+. 'H NMR (400 MHz, Chloroform-; / ) 57.96 -7.94 (m, 1H), 4.58 - 4.54 (m, 1H), 4.42 - 4.20 (m, 2H), 3.96 - 3.84 (m, 3H), 3.64 (bs, 1H), 3.30 -3.20 (m, 1H), 2.40 - 2.20 (m, 1H).19F NMR (376 MHz, Chloroform-^ 5 -106.59 (s, IF), -111.46 (s, IF).

[0521] Intermediate 38: (15',75',85)-2-(7-Bromo-6-iodo-8-methyl-2-(methylthio)quinazolin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5. L0]octaneStep 1: 2-Amino-4-bromo-5-iodo-3-methylbenzoic acidTo a stirred solution of 2-amino-4-bromo-3 -methylbenzoic acid (10 g, 43.47 mmol) in DMF (90 mL) was added NIS (1.47 g, 65.20 mmol) at room temperature under N2. The reaction mixture was heated at 80 °C for 2 h. The mixture was cooled to room temperature and poured into water (200 mL). The resulting mixture was filtered and washed with water and MeCN to afford the title compound (15 g), which was used in the next step without further purification. MS: m / z = 353.85, 355.85 [M -H]’.Step 2: 7-Bromo-6-iodo-2-mercapto-8-methylquinazolin-4-olA solution of 2-amino-4-bromo-5-iodo-3-methylbenzoic acid (12 g, 33.71 mmol) in SOCh (204 mL) was heated 50 °C for 3 h. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in acetone (60 mL). The mixture was added to a solution of ammonium sulfurothioate (5.50 g, 37.11 mmol) in acetone (60 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was filtered, and the filter cake was washed with water. The filter cake was dissolved in 10% aq. NaOH (200 mL) and filtered. The pH of the filtrate was adjusted to about 2 with HC1 aq. (1 M). The resulting mixture was filtered again and the collected solid was washed with methanol to afford the title compound (9 g). MS: m / z = 396.75 [M + H]+. 'H NMR (400 MHz, DMSO-t / 6) 8 12.73 - 12.72 (m, 1H), 11.66 (s, 1H), 8.23 (s, 1H), 2.51 (s, 3H). Step 3: 7-Bromo-6-iodo-8-methyl-2-(methylthio)quinazolin-4-olTo a solution of 7-bromo-6-iodo-2-mercapto-8-methylquinazolin-4-ol (9 g, 22.67 mmol) in methanol (234 mL) was added a solution of NaOH (1.8 g, 45.34 mmol) in H2O (180 mL) and CH3I (6.4 g, 45.34 mmol). The reaction mixture was stirred at room temperature for 2 hr. The resulting mixture was filtered, and the filter cake was washed with water and dissolved in 10% NaOH. The resulting mixture was filtered. The pH of the filtrate was adjusted to about 6 with HC1 aq. (IM). The resulting mixture was filtered again and the filter cake was triturated with methanol to afford the title compound (6.4 g). MS: m / z = 410.85, 412.85 [M + H]+.Step 4: 7-Bromo-4-chloro-6-iodo-8-methyl-2-(methylthio)quinazolineTo a solution of 7-bromo-6-iodo-8-methyl-2-(methylthio)quinazolin-4-ol (6.4 g, 15.57 mmol) in POCI3 (48 mL) was added DIEA (6.4 mL) at room temperature. The reaction mixture was heated at 100 °C for 2 h. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate (200 mL), washed with sat. NaHCO₃ aq. (3 x 50 mL) and brine (50 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to afford the title compound (6.0 g). MS: m / z = 428.90, 430.90 [M + H]+.Step 5: (15',75',85)-2-(7-Bromo-6-iodo-8-methyl-2-(methylthio)quinazolin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octaneTo a stirred solution of 7-bromo-4-chloro-6-iodo-8-methyl-2-(methylthio)quinazoline (6.0 g, 13.97 mmol) in DMSO (60 mL) were added DIEA (3.61 g, 27.94 mmol) and Intermediate 22 (4.44 g, 20.96 mmol) at room temperature under N2. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with H2O (100 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purifiedby silica gel flash chromatography (eluted with 22% EA in PE) to afford the title compound (Intermediate 38, 1.3 g, 17% yield two steps). MS: m / z = 523.75, 525.75 [M + H]+.

[0522] Intermediate 39 & 40: ((2 / ,5A',7aA')-5-Ethyl-2-fluorotetrahydro-l / / -pyrrolizin-7a(57 / )-yl)methan-t / 2-ol & ((2 / ,5 / ,7aA')-5-ethyl-2-fluorotetrahydro-l / / -pyrrolizin-7a(5 / / )-yl)methan-t / 2-olStep 1: (2 / ,5A',7aA')-7a-((( / c / 7-Butyldiphenylsilyl)oxy)methyl-t / 2)-5-ethyl-2-fluorohexahydro-17 / -pyrrolizine & (2A,5A,7a5)-7a-(((terLbutyldiphenylsilyl)oxy)methyl-t / 2)-5-ethyl-2-fluorohexahy dro- I / / -pyrrol i zi neTo a mixture of Intermediate 12 (10 g, 24.17 mmol) and chloroiridium; methanidylidyneoxidanium; bis(triphenylphosphane) (377.30 mg, 0.48 mmol) in DCM (100 mL) under N2 was added 1,1,3,3-tetramethyldisiloxane (6.50 g, 48.35 mmol) at room temperature. The mixture was stirred at room temperature for 0.5 h before ethylmagnesium bromide (48.36 mL, 48.35 mmol, 1.0 M in THF) was added to the above mixture at -78 °C. The resulting mixture was stirred at -78 °C for 10 min. The reaction mixture was stirred at room temperature for 4 h. The resulting mixture was quenched with sat. NH4CI aq. (50 mL) in an ice bath and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with PE / EA (7: 1)) to give two isomers. The first eluting isomer was concentrated to give the title compound (1 g, 9% yield). MS: m / z = 428.35 [M + H]+.1H NMR (400 MHz, CDCh-t / ) 87.73 - 7.67 (m, 4H), 7.44 - 7.34 (m, 6H), 5.30 - 5.14 (m, 1H), 3.25 - 3.82 (m, 3H), 2.12 - 1.93 (m, 3H), 1.90 - 1.74 (m, 2H), 1.30 - 1.20 (m, 2H), 1.32 - 1.20 (m, 1H), 1.05 - 0.90 (m, 9H), 0.90 - 0.86 (m, 3H).19F NMR (376 MHz, CDCL- ) 8 -172.46 (s, IF). The second eluting isomer was concentrated to give the other title compound (1.7 g, 16% yield). MS: m / z = 428.15 [M + H]+. *HNMR (400 MHz, CDCh-t / ) 8 7.73 - 7.68 (m, 4H), 7.44 - 7.34 (m, 6H), 5.22 - 5.05 (m, 1H), 3.25 - 3.75 (m, 3H), 2.45 - 2.35(m, 1H), 1.94 - 1.25 (m, 7H), 1.06 (s, 9H), 1.00 - 0.96 (m, 3H).19F NMR (376 MHz, CDCh-tZ) 5 -180.53 (s, IF).Step 2: ((2 / ,5 7aA -5-Ethyl-2-fluorotetrahydro- l7 / -pyrrolizin-7a(57 / )-yl)rnethan-t / 2-olTo a stirred solution of (2A,55',7a5 -7a-(((tert-butyldiphenylsilyl)oxy)methyl-t / 2)-5-ethyl-2-fluorohexahydro-UT-pyrrolizine (1.0 g, 2.33 mmol) in MeOH (10 mL) was added NH4F (3.46 g, 93.52 mmol) at room temperature under N2. The reaction mixture was heated at 65 °C for 16 h. 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 CH2CI2 / MeOH (15: 1)) to afford the title compound (Intermediate 39, 340 mg, 76% yield). MS: m / z = 190.15 [M + H]+.Step 3: ((2 / ,5 / d7aA')-5-Ethyl-2-tluorotetrahydro- l 7 / -pyrrolizin-7a(57 / )-yl)methan-t / 2-olTo a stirred solution of (2 / ,5 / ,7aA')-7a-((( / c / 7-butyldiphenylsilyl)oxy)methyl-t / 2)-5-ethyl-2-fluorohexahydro-UT-pyrrolizine (1.8 g, 4.20 mmol) in MeOH (20 mL) was added NH4F (6.24 g, 168.36 mmol) at room temperature under N2. The reaction mixture was heated at 65 °C for 16 h. 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 CH2CI2 / MeOH (15: 1) to afford the title compound (Intermediate 40, 600 mg, 75% yield). MS: m / z = 190.15 [M + H]+.

[0523] Intermediate 41: 4-(2,8-Difluoro-4-((15',75',85)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)pyrido[4,3-J]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-amineA mixture of Intermediate 26 (12 g, 36.28 mmol), Intermediate 10 (36.58 g, 72.58 mmol, HC1), Ad2nBuP-Pd-G3(cataCXiumAPdG3) (5.28 g, 7.26 mmol), andK3PO4(23.1 g, 108.86 mmol) in THF (240 mL) and H2O (48 mL) was degassed, purged with N2 three times, and stirred under N2 at 80 °C for 5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 5% of MeOH in CH2Q2) to give the crude product. The crude was purified by / c -HPLC (column: XPT Cl 8250 x 70 x 7 pm; mobile phase: [water (ammonia hydroxide v / v)-ACN]; gradient: 65% ~ 95% B over 23 min) to give the title compound (Intermediate 41, 13.239 g, 60% purity). MS: m / z = 636.3 [M + H]+ 1HNMR (400 MHz, Dimethylsulfoxide-tL) 59.56 (s, 1H),7.84 - 7.76 (m, 1H), 7.41 - 7.32 (m, 1H), 7.15 - 6.97 (m, 2H), 5.69 (s, 2H), 5.14 - 4.87 (m, 1H), 4.50 - 4.27 (m, 3H), 4.07 - 3.96 (m, 1H), 3.75 - 3.59 (m, 2H), 3.26 - 3.07 (m, 1H), 2.48 -2.29 (m, 1H), 0.85 - 0.79 (m, 18H), 0.53 - 0.36 (m, 3H).19F NMR (376 MHz, Dimethylsulfoxide-tZe) 8 -41.05, -41.78, -110.77, -111.09, -138.96, -207.86.

[0524] Intermediate 42: ((6?,7a'5)-6'-Fluorotetrahydrospiro[cyclopropane-l,3'-pyrrolizin]-7a'(5' / / )-yl)methan-t / 2-olStep 1: (6'7?,7a'5)-7a'-(((ter / -butyldiphenylsilyl)oxy)methyl-t / 2)-6'-fluorohexahydrospiro[cyclopropane-l,3'-pyrrolizine]To a mixture of tetrakis(propan-2-yloxy)titanium (27.49 g, 96.71 mmol) in THF (50 mL) was added ethylmagnesium bromide (1.0 M in THF) (193.42 mL, 193.42 mmol) dropwise at - 40 °C under N2. The mixture was stirred at - 40 °C for 5 min before Intermediate 12 (5 g, 12.08 mmol) was added dropwise to the above mixture at -40 °C. The reaction mixture was stirred at -40 °C for 20 min. The resulting mixture was stirred at room temperature for 16 h. The mixture was quenched with sat. NaHCO3aq. (100 mL) in an ice bath and extracted with EA (5 x 50 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SC>4. filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with PE / EA (3: 1) to afford the title compound (3 g, 58% yield). MS: m / z = 426.25 [M + H]+.Step 2: ((67?,7a'5)-6'-Fhiorotetrahydrospiro[cyclopropane-l,3'-pyrrolizin]-7a'(577)-yl)methan-tfe-olTo a stirred solution of (67 7a\S')-7a'-((( / c / 7-butyldiphenylsilyl)oxy)methyl-t / 2)-6'-fluorohexahydrospiro[cyclopropane-l,3'-pyrrolizine] (3 g, 7.04 mmol) in MeOH (30 mL) was added NH4F (10441.29 mg, 281.92 mmol) at room temperature under N2. The reaction mixture was heated at 60 °C for 16 h. The resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with CH2CI2 / MeOH (10: 1)) to afford the title compound (Intermediate 42, 1.0 g, 75% yield). MS: m / z = 188.10 [M + H]+. ‘HNMR (300 MHz, DMSO-t / 6) 85.19 - 5.00 (m, 1H), 4.58 - 4.19 (bs, 1H), 3.27 - 2.82 (m, 2H), 2.33 - 2.16 (m, 2H), 2.00 - 1.76 (m, 3H), 1.26 - 1.22 (m, 1H), 0.76 - 0.71(m, 1H), 0.56 - 0.32 (m, 3H).19F NMR (282 MHz, DMSO-tL) 8-174.93 (s, IF).

[0525] Intermediate 43: (l,7,85)-2-(7-Bromo-8-fluoro-6-methyl-2-(methylthio)quinazolin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5. L0]octaneStep 1: 2-Amino-4-bromo-3-fluoro-5-iodobenzoic acidTo a stirred solution of 2-amino-4-bromo-3-fluorobenzoic acid (15 g, 64.09 mmol) in DMF (150 mL) was added NIS (21.63 g, 96.14 mmol) at room temperature under N2. The reaction mixture was heated at 80 °C for 2 h. The resulting mixture was cooled to room temperature and poured into water (200 mL). The precipitate was collected and washed with water and MeCN to afford the title compound (10 g, 43% yield). MS: m / z = 359.90, 361.90 [M + H]+.Step 2: 7-Bromo-8-fluoro-6-iodo-2-mercaptoquinazolin-4-olA solution of 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (10 g, 27.78 mmol) in SOCh (170 mL) was heated at 50 °C for 3 h. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in acetone (100 mL). The solution was added dropwise to a solution of ammonium sulfurothioate (4.53 g, 30.56 mmol) in acetone (100 mL). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was filtered. The filter cake was washed with water and dissolved in 10% NaOH. The resulting mixture was filtered. The pH of the filtrate was adjusted to about 2 with HC1 (1 M). The resulting mixture was filtered, and the filter cake was triturated with methanol to afford the title compound (8 g, crude). MS: m / z = 400.90, 402.90 [M + H]+.Step 3: 7-Bromo-8-fluoro-6-iodo-2-(methylthio)quinazolin-4-olTo a solution of 7-bromo-8-fluoro-6-iodo-2-mercaptoquinazolin-4-ol (10 g, 24.94 mmol) in methanol (260 mL) were added a solution of NaOH (1.9 g, 49.88 mmol) in H2O (200 mL) and Mel (7.0 g, 49.88 mmol). The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was filtered. The filter cake was washed with water and dissolved in 10% NaOH. The resulting mixture was filtered. The pH of the filtrate was adjusted to about 6 with HC1 (I M). The resulting mixture was filtered, and the filter cake was triturated with methanol to afford the title compound (6 g, crude).Step 4: 7-Bromo-4-chloro-8-fluoro-6-iodo-2-(methylthio)quinazolineTo an ice-cooled stirred solution of phosphoryl trichloride (72 mL) in DIEA (6.99 mL, 40.14 mmol) was added 7-bromo-8-fluoro-6-iodo-2-(methylthio)quinazolin-4-ol (7 g, crude) under Ar. The ice bath was removed, and the reaction mixture was heated at 100 °C for 3 h. The resultingmixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EtOAc (500 mL), washed with sat. NaHCO3aq. (200 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with 15% EA in PE) to afford the title compound (2.4 g, 19% yield for two steps). MS: m / z = 432.90, 434.90 [M + H]+.Step 5: (15',75',85 -2-(7-Bromo-8-fluoro-6-iodo-2-(methylthio)quinazolin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octaneTo a stirred solution of 7-bromo-4-chloro-8-fluoro-6-iodo-2-(methylthio)quinazoline (1.2 g, 2.77 mmo) in DCM (15 mL) were added DIEA (894.53 mg, 6.92 mmol) and Intermediate 22 (880.62 mg, 4.15 mmol) at room temperature under N2. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with H2O (100 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with 22% EA in PE) to afford the title compound (1.0 g, 68% yield). MS: m / z = 527.90, 529.90 [M + H]+.Step 6: (15',75',85 -2-(7-Bromo-8-fluoro-6-methyl-2-(methylthio)quinazolin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octaneTo a stirred solution of (15',75',85)-2-(7-bromo-8-fluoro-6-iodo-2-(methylthio)quinazolin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (600 mg, 1.14 mmol) and methylboronic acid (204.01 mg, 3.40 mmol) in 1,2-dimethoxy ethane (7.5 mL) and H2O (1.5 mL) were added dichlorobis(triphenylphosphine)palladium(II) (79.74 mg, 0.11 mmol) andK^CCL (314.01 mg, 2.2 mmol) at room temperature under N2. The reaction mixture was heated at 90 °C for 16 h. The resulting mixture was cooled to room temperature, diluted with water (100 mL) and extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with PE / EA (15: 1)) to afford the title compound (Intermediate 43, 300 mg, 63% yield) as an yellow solid. MS: m / z = 416.10, 418.10 [M + H]+.

[0526] Intermediate 44: ((2A,3A,7a5 -2-Fluoro-3-(methyl-t / 3)tetrahydro-l / / -pyrrolizin-7a(57 / )-yl)methan-t / 2-olStep 1: (2 / <3 A7aA')-7a-((( / c / 7-Butyldiphenylsilyl)oxy)methyl-t / 2)-2-fluoro-3-(methyl-tAjhexahydro- IT / -pyrrolizineTo a mixture of Intermediate 13 (3 g, 7.25 mmol) and chloroiridium; methanidylidyneoxidanium; bis(triphenylphosphane) (113.19 mg, 0.14 mmol) in DCM (30 mL) under N2 was added 1,1,3,3-tetramethyldisiloxane (1948.60 mg, 14.50 mmol) at room temperature. The mixture was stirred at room temperature for 0.5 h before (methyl-t / 3)magnesium iodide (2455.43 mg, 14.50 mmol) was added to the above mixture at -70 °C. The reaction mixture was warmed to room temperature and stirred for 4 h. The resulting mixture was quenched with sat. NH4CI aq. (50 mL) in an ice bath and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with PE / EA (7: 1)) to give the title compound (1.85 g, 61% yield). MS: m / z = 417.30 [M + H]+. 'H NMR (300 MHz, CD₃Cl) <57.70 - 7.64 (m, 1H), 7.44 - 7.33 (m, 1H), 5.03 - 4.82 (m, 1H), 3.17 - 2.70 (m, 3H), 2.21 - 1.80 (m, 3H), 170 - 1.50 (m, 3H), 1.06 (s, 9H).Step 2: ((2 / ,3 / ,7aA')-2-Fluoro-3-(methyl-t / )tetrahydro- l7 / -pyrrolizin-7a(57 / )-yl)methan-t / 2-ol To a solution of (2A,3A,7a5 -7a-(((terLbutyldiphenylsilyl)oxy)methyl-t / 2)-2-fluoro-3-(methyl-t / )hexahydro- IT / -pyrrolizine (1.85 g, 4.44 mmol) in MeOH (18 mL) was added NH4F (6.58 g, 177.60 mmol) at room temperature. The reaction mixture was heated at 60 °C for 16 h. The resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with 10% MeOH in CH2CI2) to afford the title compound (Intermediate 44, 600 mg, 75% yield). MS: m / z = 179.00 [M + H]+.1H NMR (300 MHz, DMSO ) b 5.09 - 4.89 (m, 1H), 3.20 - 2.70 (m, 3H), 2.13 - 1.86 (m, 2H), 1.86 -1.50 (m, 3H).

[0527] Intermediate 45 & 46: ((2A,35,7a5)-3-Ethyl-2-fluorotetrahydro-U / -pyrrolizin-7a(57 / )-yl)methan-t / 2-ol & ((2 / ,3 / ,7aA')-3-ethyl-2-fluorotetrahydro- l7 / -pyrrolizin-7a(57 / )-yl)methan-t / 2-olStep 1: (27?,35',7a5)-7a-(((tert-Butyldiphenylsilyl)oxy)methyl-t / 2)-3-ethyl-2-fluorohexahydro-UT-pyrrolizine & (2 / ,3 / ,7aA')-7a-((( / c / 7-butyldiphenylsilyl)oxy)methyl-t / 2)-3-ethyl-2-fluorohexahy dro- 17 / -py rrol i zi neTo a mixture of Intermediate 13 (3 g, 7.25 mmol) and chloroiridium; methanidylidyneoxidanium; bis(triphenylphosphane) (113.19 mg, 0.14 mmol) in DCM (30 mL) under N2 was added 1,1,3,3-tetramethyldisiloxane (1948.60 mg, 14.50 mmol) at room temperature. The mixture was stirred at room temperature for 0.5 h before ethylmagnesium bromide (14.51 mL, 14.50 mmol) was added to the above mixture at -70 °C. The reaction mixture was stirred at room temperature for 4 h. The resulting mixture was quenched with sat. NH4CI aq. (20 mL) in an ice bath and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with PE / EA (7: 1)) to give two isomers. The first eluting isomer was concentrated to give the title compound (900 mg, 29% yield). MS: m / z = 428.35 [M + H]+. 'H NMR (400 MHz, DMSO-tL) <57.70 - 7.65 (m, 4H), 7.47 - 7.41 (m, 6H), 4.94 - 4.79 (m, 1H), 2.95 - 2.93 (m, 1H), 2.78 - 2.73 (m, 2H), 2.28 - 2.19 (m, 1H), 1.95 - 1.58 (m, 5H), 1.35 - 1.24 (m, 2H), 1.00 (s, 9H), 0.89 - 0.86 (m, 3H). The second eluting isomer was concentrated to give the other title compound (1.5 g, 48% yield). MS: m / z = 428.15 [M + H]+. 'H NMR (400 MHz, DMSO-tL) <57.70 - 7.65 (m, 4H), 7.48 - 7.40 (m, 6H), 5.16 - 5.00 (m, 1H), 2.96 - 2.78 (m, 3H), 2.15 - 1.80 (m, 3H), 1.75 -1.49 (m, 5H), 0.99 - 0.88 (m, 12H).Step 2: ((2A,35,7aS -3-Ethyl-2-fluorotetrahydro-U / -pyrrolizin-7a(5J7)-yl)methan-t / 2-olTo a solution of (2 / ,3A',7aA')-7a-((( / c / 7-butyldiphenylsilyl)oxy)methyl-t / 2)-3-ethyl-2-fluorohexahydro-UT-pyrrolizine (200 mg, 0.49 mmol) in MeOH (9 mL) was added NH4F (3.12 g, 84.16 mmol) at room temperature. The reaction mixture was heated at 60 °C for 16 h. Theresulting mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with 2% MeOH in CH2CI2) to afford the title compound (Intermediate 45, 60 mg, 72% yield).JH NMR (400 MHz, DMSO-tL) <54.94 - 4.81 (m, 1H), 4.45 (bs, 1H), 3.07 - 2.61 (m, 3H), 2.30 - 2.04 (m, 1H), 1.96 - 1.47 (m, 5H), 1.48 - 1.17 (m, 2H), 0.91 - 0.86 (m, 3H).Step 3: ((2 / ,3 / f 7aA')-3-Ethyl-2-fluorotetrahydro- l 7 / -pyrrolizin-7a(57 / )-yl)methan-t / 2-olTo a solution of (2 / f3 / f7aA')-7a-((( / c77-butyldiphenylsilyl)oxy)methyl-t / 2)-3-ethyl-2-fluorohexahydro-l / 7-pyrrolizine (1.5 g, 3.50 mmol) in MeOH (15 mL) was added NH4F (5.20 g, 140.28 mmol) at room temperature. The reaction mixture was heated at 60 °C for 16 h. The resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with 2% MeOH in CH2CI2) to afford the title compound (Intermediate 46, 550 mg, 82% yield).1H NMR (400 MHz, DMSO-tL) <55.19 - 5.03 (m, 1H), 3.00 - 2.75 (m, 3H), 2.10 - 1.86 (m, 2H), 1.86 - 1.52 (m, 6H), 1.00 - 0.80 (m, 3H).

[0528] Intermediate 47: (2 / f 7aA')-7a-((( / c77-Butyldiphenylsilyl)oxy)methyl-t / 2)-2-fluorohexahy dro- lZZ-pyrrolizine-3, 3, 5, 5 -da,Step 1: ((27?,7a5)-2-Fluorotetrahydro-l / / -pyrrolizin-7a(5J7)-yl-5,5-t / 2)methan-t / 2-olTo an ice-cooled stirred solution of Intermediate 12 (40 g, 96.71 mmol) in 2-methyltetrahydrofuran (400 mL) were added LiAlD4 (1.0M in THF, 193.42 mL, 193.42 mmol) dropwise under N2. The ice bath was removed, and the reaction mixture was heated at 80 °C for 2 h. The resulting mixture was cooled to 0 °C and quenched with MeOH (200 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with CH2CI2 / MeOH (10: 1)) to afford the title compound (14 g, crude). MS: m / z = 164.25 [M + H]+.Step 2: (27?,7a5)-7a-(((terLButyldiphenylsilyl)oxy)methyl-t / 2)-2-fluorohexahydro-lZ7-pyrrolizine-5,5-t / 2To an ice-cooled stirred solution of ((2A,7a5)-2-fluorotetrahydro-lZ7-pyrrolizin-7a(5J7)-yl-5,5-tCfmethan-tC-ol (14 g, crude) and imidazole (17.52 g, 257.30 mmol) in DMF (42 mL) were added terLbutyl(chloro)diphenylsilane (35.36 g, 128.65 mmol) dropwise under N2. The reaction mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with EA (500 mL), washed with brine (5 x 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 (3: 1)) to afford the title compound (18 g, 46% yield for two steps). MS: m / z = 402.15 [M + H]+.Step 3: (6 / 7aA')-7a-((( / c / 7-Butyldiphenylsilyl)oxy)methyl-t / 2)-6-fluorohexahydro-37 / -pyrrolizin-3-one & (2A,7a5)-7a-(((terLbutyldiphenylsilyl)oxy)methyl-t / 2)-2-fluorohexahydro-3J / -pyrrolizin-3 -one-5, 5 -diTo an ice-cooled solution of (27?, 7 aS)-7 a-((( / c / 7-butyldiphenylsilyl)oxy)methyl-t / 2)-2-fluorohexahydro-lJT-pyrrolizine-5,5-7 / 2 (24 g, 59.75 mmol) and tri chlororuthenium hydrate (6.74 g, 29.87 mmol) in CCI4 (120 mL) and water (120 mL) was added NaICU (63.91 g, 298.78 mmol) under N2. The ice bath was removed, and the reaction mixture was stirred at room temperature for 30 min. 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 a mixture of the title compounds (19.8 g mixture.Step 4: (6A,7a5)-7a-(((terLbutyldiphenylsilyl)oxy)methyl-T / 2)-6-fluorohexahydro-3J / -pyrrolizin-3-one & (2 / ?,7a5)-7a-(((terLbutyldiphenylsilyl)oxy)methyl-t 2)-2-fluorohexahydro-3Z7-pyrrolizin-3 -one-5, 5 -t / 2The mixture of (6 / ?,7a5)-7a-(((terLbutyldiphenylsilyl)oxy)methyl-t 2)-6-fluorohexahydro-3Z7-pyrrolizin-3-one & (2 / ?,7a5)-7a-(((terLbutyldiphenylsilyl)oxy)methyl-t 2)-2-fluorohexahydro-3J / -pyrrolizin-3-one-5, 5-7 / 2 (19.8g mixture) was separated by Prep-SFC with the following conditions: Column: (R, / )-Whelk 3.5 pm. 6 x 50 mm; Mobile Phase A: CO2; Mobile Phase B: IPA (0.1% 7 M NH3-MeOH); Flow rate: 100 mL / min; Gradient: isocratic 20% B%; Back Pressure (bar): 100; Detector: UV 220 nm; RTE5.55 min; RT2: 7.17 min. The first eluting peak (RTL5.55 min) was concentrated to give the title compound (8 g, 32% yield for two steps). MS: m / z = 414.05 [M + H]+. 'H NMR (300 MHz, CDCI3) <57.65 - 7.61 (m, 4H), 7.45 - 7.37 (m, 6H), 5.41 - 5.15 (m, 1H), 4.26 - 4.04 (m, 1H), 3.09 - 3.00 (m, 1H), 2.87 - 2.62 (m, 1H), 2.52 -1.90 (m, 5H), 1.04 (s, 9H).19F NMR (282 MHz, CDCI3) <5 -172.83, -173.04, -173.10, -173.27, -173.46, -173.48 (m, IF). The second eluting peak (RT2: 7.17 min) was concentrated to give the other title compound (9 g, 36% yield for two steps). MS: m / z = 416.30 [M + H]+. 'H NMR (300 MHz, CDCI3) <57.66 - 7.58(m, 4H), 7.47 - 7.37 (m, 6H), 5.70 - 5.52 (m, 1H), 3.00 - 2.80 (m,1H), 2.15 - 1.62 (m, 5H), 1.05 (s,9H).19F NMR (282 MHz, CDC13) 6 -184.30 (s, IF).Step 5: ((2 / ,7aA -2-Fluorotetrahydro- l / / -pyrrolizin-7a(5 / / )-yl-3,3,5,5-t / 4)rnethan-t / 2-olTo a stirred solution of (2A,7a5)-7a-(((terLbutyldiphenylsilyl)oxy)methyl-t / 2)-2-fluorohexahydro-3J / -pyrrolizin-3-one-5,5-t / 2 (4 g, 9.91 mmol) in 2-methoxyfuran (40 mL) were added LiAlD4 (1.0M in THF, 19.82 mL, 19.82 mmol) in portions at room temperature under N2. The reaction mixture was heated at 80 °C for 2 h. The resulting mixture was cooled to 0 °C and quenched with MeOH (40 mL) in an ice bath. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with CH2CI2 / MeOH (10: 1)) to afford the title compound (1.3 g, crude). MS: m / z = 166.10 [M + H]+.Step 6: (2A,7a5)-7a-(((terLButyldiphenylsilyl)oxy)methyl-t / 2)-2-fluorohexahydro-UT-pyrrolizine-3, 3, 5, 5 -cTo an ice-cooled stirred solution of ((2A,7a5)-2-fluorotetrahydro-lJ / -pyrrolizin-7a(5J7)-yl-3,3,5,5-t / 4)methan-t / 2-ol (1.3 g, crude) and imidazole (1.34 g, 19.66 mmol) in DMF (3 mL) were added terLbutyl(chloro)diphenylsilane (2.81 g, 10.22 mmol) dropwise under N2. The reaction mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with EA (100 mL), washed with brine (5 x 30 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with PE / EA (3: 1)) to afford the title compound (1 g, 25% yield two steps). MS: m / z = 404.40 [M + H]+.Step 7: ((2 / ?,7aA')-2-Fluorotetrahydro- l / 7-pyrrolizin-7a(5 / 7)-yl-3,3,5,5-t / 4)methan-t / 2-olTo a stirred solution of (27?, 7 aS)-7 a-((( / c / 7-butyldiphenylsilyl)oxy)methyl-t / 2)-2-fluorohexahydro-U / -pyrrolizine-3,3,5,5-t / 4 (1 g, 2.47 mmol) in MeOH (10 mL) was added NH4F (3.67 g, 99.08 mmol) at room temperature under N2. The reaction mixture was heated at 60 °C for 16 h. 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 CH2CI2 / MeOH (10: 1)) to afford the title compound (Intermediate 47, 300 mg, 73% yield). MS: m / z = 166.10 [M + H]+.

[0529] Intermediate 48 & 49: Ethyl (5',£)-2-(fluoromethylene)-5-oxotetrahydro-UT-pyrrolizine-7a(5 / 7)-carboxylate & ethyl GS', Z)-2-(fluoromethylene)-5-oxotetrahydro- l H-pyrrolizine-7a(5J7)-carboxylateStep 1: Ethyl (5)-2-(fluoromethylene)-5-oxotetrahydro-U / -pyrrolizine-7a(5J7)-carboxylateTo a solution of 2-fluoromethanesulfonylpyridine (4.40 g, 25.09 mmol) in THF (200 mL) was added KHMDS (1 M in THF, 29.83 mL, 29.83 mmol) dropwise at -78 °C under Ar. The mixture was stirred at -78 °C for 0.5 h before a solution of ethyl (7a5)-2,5-dioxo-tetrahydropyrrolizine-7a-carboxylate (5 g, 23.67 mmol) in THF (20 mL) was added dropwise to the above mixture at -78 °C. The resulting mixture was warmed to room temperature and stirred for 16 h. The resulting mixture was quenched with sat. NH4CI aq. (200 mL) and extracted with ethyl acetate (3 x 200 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 0-60% ethyl acetate in petroleum ether) to afford the title compound (2 g, 18% yield). MS: m / z = 228.00 [M + H]+. 'H NMR (300 MHz, Chloroform- ) 36.70 - 6.45 (m, 1H), 4.40 - 4.32 (m, 1H), 4.23 - 4.21 (m, 2H), 3.91 - 3.70 (m, 1H), 3.33 - 3.01 (m, 1H), 2.86 - 2.56 (m, 2H), 2.52 - 2.40 (m, 2H), 2.18 - 2.10 (m, 1H), 1.31 - 1.27 (m, 3H).Step 2: Ethyl (A / )-2-(fluoromethylene)-5-oxotetrahydro-IT / -pyrrolizine-7a(57 / )-carboxylate & ethyl (5, Z)-2-(fluoromethylene)-5-oxotetrahydro-U / -pyrrolizine-7a(5J7)-carboxylate Ethyl (5)-2-(fluoromethylene)-5-oxotetrahydro-U / -pyrrolizine-7a(5J7)-carboxylate (550 mg) was separated by Achiral-prep-SFC with the following conditions: Column: GreenSep Nitro, 30 x 150 mm 5 um; Mobile Phase A: CO2; Mobile Phase B: IPA (20 mM NH3); Flow rate: 60 mL / min; Gradient: isocratic 12% B; Column Temperature (°C): 35; Back Pressure (bar): 100;Detector: UV 220 nm; RT1: 3.22 min; RT2: 4.50 min. The first eluting peak (RT1: 3.22 min) was combined and concentrated under reduced pressure to give the title compound (Intermediate 48, 164 mg, 29% yield). MS: m / z = 228.00 [M + H]+.1H NMR (300 MHz, Chloroform-6?) 5 6.74 - 6.45 (m, 1H), 4.36 - 4.31 (m, 1H), 4.26 - 4.19 (m, 2H), 3.74 - 3.69 (m, 1H), 3.33 - 3.28 (m, 1H), 2.82 - 2.62 (m, 2H), 2.51 - 2.40 (m, 2H), 2.19 - 2.08 (m, 1H), 1.29 (t, J= 7.2 Hz, 3H).19F NMR (282 MHz, Chloroform-6?) <5 -128.69 (s, IF). The second eluting peak (RT1: 4.50 min) was combined and concentrated under reduced pressure to give the other title compound (Intermediate 49, 140 mg, 25% yield). MS: m / z = 228.00 [M + H]+. 'H NMR (300 MHz, Chloroform-6?) 86.69 - 6.41 (m, 1H), 4.41 - 4.36 (m, 1H), 4.26 - 4.18 (m, 2H), 3.91 - 3.86 (m, 1H), 3.05 - 3.00 (m, 1H), 2.84 - 2.75 (m, 1H), 2.63 - 2.34 (m, 3H), 2.20 - 2.01 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H).19F NMR (282 MHz, Chloroform-6?) 3 -127.96 (s, IF).

[0530] Intermediate 50: (5, E)-(2-(Fluoromethylene)tetrahydro-l / 7-pyrrolizin-7a(5 / 7)-yl- 5, 5 -6?2)methan-6?2-olTo an ice-cooled stirred solution of Intermediate 48 (1 g, 4.40 mmol) in THF (10 mL) was added LiAlD4 (1 M in THF, 6.60 mL, 6.60 mmol) dropwise under N2. The ice bath was removed, and the reaction mixture was heated at 70 °C for 2 h. The resulting mixture was cooled and quenched with MeOH (7 mL) in an ice bath and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with CH2Q2 / MeOH (10: 1)) to afford The title compound (Intermediate 50, 700 mg, 90% yield). MS: m / z = 176.20 [M + H]+.

[0531] Intermediate 51: (S, Z)-(2-(Fluoromethylene)tetrahydro-l / / -pyrrolizin-7a(5 / 7)-yl-5, 5 -t / 2 )m eth an -t / 2-olIntermediate 51 was prepared in a similar manner to Intermediate 50. MS: m / z = 176.30 [M + H]+. ‘HNMR (400 MHz, DMSO r,) 86.96 - 6.65 (m, 1H), 4.97 - 4.59 (m, 1H), 3.75 - 3.70 (m, 1H), 3.44 - 3.40 (m, 1H), 2.54 - 2.51 (m, 1H), 2.26 - 2.20 (m, 1H), 1.92 - 1.54 (m, 4H).19F NMR (376 MHz, DMSO r,) 8 -130.53 (s, IF).

[0532] Intermediate 52 & 53: Benzyl 8-fluoro-6-azaspiro[bicyclo[5.1.0]octane-3,2'-[l,3]dioxolane]-6-carboxylate (trans mixture) & benzyl 8-fluoro-6-azaspiro[bicyclo[5.1,0]octane-3,2'-[l,3]dioxolane]-6-carboxylate (cis mixture)Step 1: l,4-Dioxaspiro[4.5]decan-8-one oximeTo a solution of l,4-dioxaspiro[4.5]decan-8-one (190 g, 1.22 mol) and hydroxylamine hydrochloride (338 g, 4.86 mol) in H2O (2000 mL) was added ISfeCCL (387 g, 3.65 mol) in portions. The mixture was stirred at 25 °C for 1 h. The reaction mixture was extracted with EtOAc (1000 mL x 3). The combined organic layers were washed with brine (500 mL x 3), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give the title compound (200 g, crude), which was used in the next step without further purification.1H NMR (400 MHz, Chloroform- ) 83.98 (d, J= 1.6 Hz, 4H), 2.72 - 2.63 (m, 2H), 2.46 - 2.34 (m, 2H), 1.84 - 1.74 (m, 4H).Step 2: l,4-Dioxa-8-azaspiro[4.6]undecan-9-oneTo a solution of l,4-dioxaspiro[4.5]decan-8-one oxime (180 g, 1.05 mol) in acetone (1.8 L) was added NaOH (525 mL, 4 M in H2O) before 4-methylbenzenesulfonyl chloride (200 g, 1.05 mol) in acetone (1.8 L) was added dropwise to the mixture at 25 °C under N2. The resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (200 mL). The pH of the mixture was adjusted to around 7 with HC1 (4 M aq.). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was extracted with CH2CI2 (5 x 200 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was dissolved with toluene (100 mL), and / / -hexane (200 mL) was added to give a precipitate. The precipitate was filtered. The filter cake was washed with / / -hexane (100 mL), dried under reduced pressure to give the title compound (43 g, 20% yield over 2 steps). MS: m / z = 171.9 [M + H]+.Step 3: Benzyl 9-oxo-l,4-dioxa-8-azaspiro[4.6]undecane-8-carboxylateTo a solution of l,4-dioxa-8-azaspiro[4.6]undecan-9-one (43 g, 251 mmol) in THF (1100 mL) was added / / -BuLi (100 mL, 2.5 M in hexanes) dropwise at -78 °C under N2. The mixture was stirred -78 °C for 1 h before CbzCl (35 ml, 251 mmol) in THF (110 mL) was added dropwise at -78 °C under N2. The resulting mixture was stirred under N2 at 20 °C for 2 h. The reaction mixture was quenched with sat. NH4CI aq. (500 mL) at 0 °C and extracted with EtOAc (300 mL x 2). The combined organic layers were washed with brine (200 mL x 2), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 50% EtOAc in petroleum ether) to give the title compound (66 g, 87% yield). 'H NMR (400 MHz, Chloroform -tZ) 87.45 - 7.28 (m, 5H), 5.28 (s, 2H), 3.96 (s, 4H), 3.94 - 3.88 (m, 2H), 2.79 - 2.72 (m, 2H), 1.94 - 1.85 (m, 4H).Step 4: Benzyl l,4-dioxa-8-azaspiro[4.6]undec-9-ene-8-carboxylateTo a solution of benzyl 9-oxo-l,4-dioxa-8-azaspiro[4.6]undecane-8-carboxylate (66 g, 216 mmol) in toluene (1.2 L) was added Lithium triethylborohydride (238 mL, 1 M in THF) dropwise at -70 °C under N2. The mixture was stirred at -70 °C for 1 h before DMAP (264 mg, 2.16 mmol) was added in one portion. DIPEA (215 mL, 1.23 mol) and TFAA (45 mL, 324 mmol) were added dropwise in sequence while the reaction temperature was maintained below -55 °C under N2. The cooling bath was removed, and the reaction mixture was allowed to warm to 25 °C and stirred for 2 h under N2. The reaction mixture was quenched with water (600 mL) slowly at 0 °C while the reaction temperature was maintained below 15 °C. The combined organic layers were washed with brine (300 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 20% EtOAc in petroleum ether) to give the title compound (33.6 g,58% yield). MS: m / z = 289.9 [M + H]+. 'H NMR (400 MHz, Chloroform-^ 87.39 - 7.34 (m, 5H), 86.72 - 6.49 (m, 1H), 5.18 (s, 2H), 5.02 - 4.87 (m, 1H), 3.92 (s, 4H), 3.80 - 3.73 (m, 2H), 2.46 (d, J= 6.4 Hz, 2H), 2.08 - 2.01 (m, 2H).Step 5: Benzyl 8-bromo-8-fluoro-6-azaspiro[bicyclo[5.1.0]octane-3,2'-[l,3]dioxolane]-6-carb oxy lateA solution of benzyl l,4-dioxa-8-azaspiro[4.6]undec-9-ene-8-carboxylate (30 g, 104 mmol), BU4NI (128 mg, 10.4 mmol) in CH2Q2 (36 mL) and 50% (w%) NaOH aqueous (36 mL) was degassed and purged with N2 three times before dibromofluoromethane (60 g, 311 mmol) was added. The mixture was stirred under N2 at 35 °C for 7 h. The reaction mixture was quenched with sat. NH4CI aq. (600 mL) and extracted with EtOAc (400 mL x 2). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (37.2 g, crude), which was used in the next step without further purification. MS: m / z = 421.8, 423.8 [M + Na]+. 'H NMR (400 MHz, Chloroform-; / ) 87.45 - 7.21 (m, 5H), 85.25 - 5.03 (m, 2H), 3.94 - 3.82 (s, 4H), 3.64 -2.98 (m, 3H), 2.34 - 2.09 (m, 1H), 1.89 - 1.69 (m, 4H).19F NMR (376 MHz, Chloroform-; / ) 8 -128.56, -157.95.Step 6: Benzyl 8-fluoro-6-azaspiro[bicyclo[5. L0]octane-3,2'-[l,3]dioxolane]-6-carboxylate (trans mixture) and benzyl 8-fluoro-6-azaspiro[bicyclo[5.1.0]octane-3,2'-[l,3]dioxolane]-6-carb oxy late (cis mixture)To a solution of benzyl 8-bromo-8-fluoro-6-azaspiro[bicyclo[5.1.0]octane-3,2'-[l,3]dioxolane]-6-carboxylate (28 g, 70 mmol)...

Claims

CLAIMSWe 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;-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;(t) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; and (u) optionally substituted 8-methylene-5-oxa-2-azabicyclo[5.1.0]octan-2-yl; 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; andR1is selected from:OIL2. A compound having the structure of Formula (la), 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;-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; 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; andR1is selected from:6\L3. A compound having the structure of Formula (lb), 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;-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;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; andR1is selected from:

4. A compound having the structure of Formula (II), 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;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,; and G is an optionally substituted 5- to 14-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;(t) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; and (u) optionally substituted 8-methylene-5-oxa-2-azabicyclo[5.1.0]octan-2-yl; 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; andAr is selected from:

5. A compound having the structure of Formula (Ila), 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;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,; and G is an optionally substituted 5- to 14-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;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; andAr is selected from:

6. A compound having the structure of Formula (IIb), 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;R1is L-G; wherein L is optionally substituted C1-C4 alkylene,; and G is an optionally substituted 5- to 14-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;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; and7. A compound having of Formula (III), 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;-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;(t) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; and (u) optionally substituted 8-methylene-5-oxa-2-azabicyclo[5.1.0]octan-2-yl; 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;R1is selected from:Ar is selected from:

8. A compound having the structure of Formula (IIIa), 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;-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; 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;R1is selected from:

9. A compound having the structure of Formula (IIIb), 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;-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;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;R1is selected from:11m10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein X1is N.

11. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C-CN.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvate thereof, wherein X2is N.

13. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvate thereof, wherein X2is C-H, C-F, or C-Cl.

14. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvate thereof, wherein X2is C-CH3.

15. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvate thereof, wherein X2is C-(optionally substituted C1-C6 alkyl).

16. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvate thereof, wherein X2is C-(C2-C6 optionally substituted alkenyl).

17. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvate thereof, wherein X2is C-(optionally substituted C3-C6 carbocyclyl).

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

19. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt or solvate thereof, wherein X3is C-H, C-F, or C-Cl.

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

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

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein R4is H.

23. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein R4is optionally substituted C1-C4 alkoxy.

24. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein R4is -OCH3.

25. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein R4is -OCD3.

26. The compound of any one of claims 1-25, 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 heterocyclyl.

27. The compound of claim 26, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 5-oxa-2-azabicyclo[5.1.0]octan-2-yl heterocyclyl is substituted with a group selected from the group consisting of halogen, cyano, and hydroxyl.

28. The compound of claim 27, or a pharmaceutically acceptable salt or solvate thereof, wherein the group is chloro.

29. The compound of claim 27, or a pharmaceutically acceptable salt or solvate thereof, wherein the group is fluoro.

30. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted 2-azabicyclo[5.1.0]octan-2-yl heterocyclyl.

31. The compound of claim 30, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 5-oxa-2-azabicyclo[5.1.0]octan-2-yl heterocyclyl is substituted with a group selected from the group consisting of halogen, cyano, and hydroxyl.

32. The compound of claim 31, or a pharmaceutically acceptable salt or solvate thereof, wherein the group is chloro.

33. The compound of claim 31, or a pharmaceutically acceptable salt or solvate thereof, wherein the group is fluoro.

34. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl is selected from:

35. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl is selected from:

36. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl is selected from:

37. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl is selected from:

38. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl is selected from:

39. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl is selected from:

40. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl is selected from:

41. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl is selected from:

42. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl is selected from:

43. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl is selected from:

44. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl.

45. The compound of claim 44, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl is substituted with a group selected from the group consisting of halogen, cyano, and hydroxyl.

46. The compound of claim 45, or a pharmaceutically acceptable salt or solvate thereof, wherein the group is chloro.

47. The compound of claim 45, or a pharmaceutically acceptable salt or solvate thereof, wherein the group is fluoro.

48. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt or solvate thereof, wherein -N(R2)R3form an optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl.

49. The compound of claim 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl is substituted with a group selected from the group consisting of halogen, cyano, and hydroxyl.

50. The compound of claim 49, or a pharmaceutically acceptable salt or solvate thereof, wherein the group is chloro.

51. The compound of claim 49, or a pharmaceutically acceptable salt or solvate thereof, wherein the group is fluoro.

52. The compound of any one of claims 1-3 and 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a monocyclic optionally substituted aryl.

53. The compound of claim 52, or a pharmaceutically acceptable salt or solvate thereof, wherein the monocyclic optionally substituted aryl is an optionally substituted phenyl.

54. The compound of claim 53, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl is substituted with an -OH group at the meta-position.

55. The compound of claim 54, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl is56. The compound of claim 54, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl is selected from:

57. The compound of claim 53, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl is substituted with an -NH2 group at the meta-position.

58. The compound of claim 53, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl is selected from:

59. The compound of claim 53, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl is selected from:

60. The compound of claim 53, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl is a 2,3,5-trisubstituted phenyl.

61. The compound of claim 60, or a pharmaceutically acceptable salt or solvate thereof, wherein the 2,3,5-trisubstituted phenyl is substituted with a 3-hydroxy group.

62. The compound of claims 1-3 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a bicyclic optionally substituted aryl.

63. The compound of claim 62, or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted aryl is an optionally substituted naphthyl.

64. The compound of claim 63, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted naphthyl is an optionally substituted 1-naphthyl.

65. The compound of claim 64, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 1-naphthyl is further substituted at the 8-position.

66. The compound of any one of claims 62-64, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

67. The compound of any one of claims 62-64, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

68. The compound of any one of claims 62-64, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

69. The compound of any one of claims 62-64, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

70. The compound of any one of claims 62-64, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

71. The compound of any one of claims 62-64, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

72. The compound of any one of claims 62-64, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

73. The compound of any one of claims 62-64, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

74. The compound of any one of claims 62-64, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

75. The compound of any one of claims 62-64, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

76. The compound of any one of claims 62-64, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

77. The compound of any one of claims 62-64, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

78. The compound of any one of claims 62-64, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

79. The compound of any one of claims 62-64, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

80. The compound of any one of claims 62-64, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

81. The compound of any one of claims 62-64, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

82. The compound of any one of claims 62-64, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

83. The compound of any one of claims 62-64, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

84. The compound of any one of claims 62-64, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

85. The compound of any one of claims 62-64, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

86. The compound of any one of claims 62-64, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

87. The compound of any one of claims 62-64, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

88. The compound of any one of claims 62-64, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

89. The compound of claim 62, 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; andR18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C=CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

90. The compound of any one of claims 1-3 and 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a monocyclic optionally substituted heteroaryl.

91. The compound of claim 90, or a pharmaceutically acceptable salt or solvate thereof, wherein the monocyclic optionally substituted heteroaryl is an optionally substituted 2-pyridinyl.

92. The compound of claim 91, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 2-pyridinyl is93. The compound of claim 91, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 2-pyridinyl isCF3wY F NH294. The compound of claim 90, or a pharmaceutically acceptable salt or solvate thereof, wherein the monocyclic optionally substituted heteroaryl is an optionally substituted 4-pyridinyl.

95. The compound of claim 94, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 4-pyridinyl is96. The compound of claim 94, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 4-pyridinyl is97. The compound of any one of claims 1-3 and 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a bicyclic optionally substituted heteroaryl.

98. The compound of claim 97, or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted heteroaryl is selected from:

99. The compound of claim 97, or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted heteroaryl is selected from:

100. The compound of claim 97, or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted heteroaryl is selected from:

101. The compound of claim 97, or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted heteroaryl is selected from:

102. The compound of claim 97, or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted heteroaryl is103. The compound of claim 97, or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted heteroaryl is selected from:

104. The compound of claim 97, or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted heteroaryl is described by Formula (bl):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; andR18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C≡CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

105. The compound of claim 97, 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; andR18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C≡CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

106. The compound of claim 97, or a pharmaceutically acceptable salt or solvate thereof, wherein 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;R15is hydrogen, deuterium, F, Cl, or Br;R16is hydrogen, deuterium, F, Cl, Br, -CN, or -CH3;R17is hydrogen, deuterium, F, Cl, or -CN; andR18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C≡CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

107. The compound of claim 97, 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; andR18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C≡CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

108. The compound of claim 97, 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; andR18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C≡CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

109. The compound of claim 97, or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted heteroaryl is described by Formula (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; andR18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C≡CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

110. The compound of claim 97, 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; andR18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C≡CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

111. The compound of claim 97, or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted heteroaryl 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; andR18is hydrogen, deuterium, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C≡CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

112. The compound of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein L is optionally substituted C1-C4 alkylene.

113. The compound of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein L is.0.j,- X*114. The compound of claim 112, or a pharmaceutically acceptable salt or solvate thereof, wherein L is115. The compound of claim 112, or a pharmaceutically acceptable salt or solvate thereof, wherein L iis optionally substituted C1 alkylene.

116. The compound of any one of claims 112-115, or a pharmaceutically acceptable salt or solvate thereof, wherein G is an optionally substituted 5- to 14-membered heterocyclyl.

117. The compound of any one of claims 112-115, or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:

118. The compound of any one of claims 112-115, or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:

119. The compound of any one of claims 112-115, or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:

120. The compound of any one of claims 112-115, 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.

121. The compound of any one of claims 112-115, 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; andR33is hydrogen, deuterium, F, or optionally substituted C1-C4 alkyl.

122. The compound of any one of claims 112-115, or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:

123. The compound of any one of claims 112-115, or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:

124. The compound of any one of claims 112-115, or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:

125. The compound of any one of claims 112-115, or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:

126. The compound of any one of claims claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

127. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

128. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

129. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

130. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

131. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is132. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

134. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

135. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

136. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

137. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

138. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

139. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

140. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

141. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

142. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

143. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

144. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

145. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

146. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

147. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

148. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

149. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

150. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

151. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

152. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

153. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

154. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

155. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

156. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

157. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

158. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

159. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

160. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

161. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

162. The compound of any one of claims 4-6 or claims 10-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

163. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

164. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

165. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

166. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

167. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

168. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

169. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

170. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

171. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

172. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

173. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

174. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

175. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

176. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

177. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

178. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

179. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

180. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

181. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

182. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

183. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

184. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

185. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

186. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

187. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

188. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

189. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

190. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

191. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

192. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

193. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

194. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

195. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

196. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

197. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is:

198. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

199. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

200. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

201. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

202. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

203. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

204. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

205. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

206. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

207. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

208. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

209. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

210. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

211. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

212. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

213. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

214. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

215. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

216. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

217. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

218. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

219. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

220. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

221. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

222. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

223. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

224. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

225. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

226. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

227. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

228. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

229. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is:

230. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

231. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

232. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

233. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

234. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

235. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

236. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

237. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

238. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

239. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

240. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

241. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

242. The compound of any one of claims 1-3 or claims 7-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from:

243. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is:

244. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

245. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

246. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

247. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

248. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

249. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

250. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is:

251. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

252. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

253. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

254. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

255. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is:

256. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is:

257. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is:

258. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is:

259. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

260. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

261. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

262. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

263. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

264. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

265. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

266. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

267. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

268. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

269. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

270. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

271. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

272. The compound of any one of claims 4-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:A compound, or a pharmaceutically acceptable salt or solvate, thereof, selected from the274. A compound, or a pharmaceutically acceptable salt or solvate, thereof, selected from the group consisting of:

275. A compound, or a pharmaceutically acceptable salt or solvate, thereof, selected from the group consisting of:

276. A compound, or a pharmaceutically acceptable salt or solvate, thereof, selected from the group consisting of:

277. A compound, or a pharmaceutically acceptable salt or solvate, thereof, selected from the group consisting of:

278. A compound, or a pharmaceutically acceptable salt or solvate, thereof, selected from the group consisting of:

279. A compound, or a pharmaceutically acceptable salt or solvate, thereof, selected from the280. A compound, or a pharmaceutically acceptable salt or solvate, thereof, selected from the group consisting of:

281. A compound, or a pharmaceutically acceptable salt or solvate, thereof, selected from the group consisting of:

282. A compound, or a pharmaceutically acceptable salt or solvate, thereof, selected from the group consisting of:

283. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X1is N.

284. The compound of claim 4, or a pharmaceutically acceptable salt or solvate thereof, wherein X1is N.

285. The compound of claim 283 or 284, or a pharmaceutically acceptable salt or solvate thereof, wherein X2is C-H, C-F, or C-Cl.

286. The compound of claim 285, or a pharmaceutically acceptable salt or solvate thereof, wherein X2is C-F.

287. The compound of any one of claims 283-286, or a pharmaceutically acceptable salt or solvate thereof, wherein X3is N.

288. The compound of any one of claims 283-287, or a pharmaceutically acceptable salt or solvate thereof, wherein R4is H.

289. The compound of any one of claims 283-288, 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 heterocyclyl.

290. The compound of claim 289, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 5-oxa-2-azabicyclo[5.1.0]octan-2-yl heterocyclyl is substituted with a group selected from the group consisting of halogen, cyano, and hydroxyl.

291. The compound of claim 290, or a pharmaceutically acceptable salt or solvate thereof, wherein the group is fluoro.

292. The compound of any one of claims 283-291, 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 heterocyclyl selected from:

293. The compound of any one of claims 284-291, 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 heterocyclyl selected from:

294. The compound of any one of claims 283 or 285-292, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is:

295. The compound of any one of claims 283, 285-292, or 294 or a pharmaceutically acceptable salt or solvate thereof, wherein R1is:

296. The compound of any one of claims 284-293, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is297. The compound of any one of claims 284-294, or 296 or a pharmaceutically acceptable salt or solvate thereof, wherein R1is:

298. A compound having the structure of Formula (X), 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;-N(R2)R3is selected fromR4is 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;R1is selected from:Ar is:

299. A compound having the structure of Formula (Y), 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;-N(R2)R3is selected fromR4is 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;R1is selected from:

300. The compound of claim 298 or 299, or a pharmaceutically acceptable salt or solvate thereof, wherein X1is N.

301. The compound of any one of claims 298-300, or a pharmaceutically acceptable salt or solvate thereof, wherein X2is C-H, C-F, or C-Cl.

302. The compound of any one of claims 298-301, or a pharmaceutically acceptable salt or solvate thereof, wherein X3is N.

303. The compound of any one of claims 298-302, or a pharmaceutically acceptable salt or solvate thereof, wherein R4is H or C1-C4 alkoxy.

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

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

306. A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt or solvate thereof, as described in any one of claims 1-305 and a pharmaceutically acceptable excipient.

307. A method of preparing a pharmaceutical composition comprising mixing a compound, or pharmaceutically acceptable salt or solvate thereof, of any one of claims 1-305, and a pharmaceutically acceptable carrier.

308. A compound of any one of claims 1-305, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

309. A compound of any one of claims 1-305, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer.

310. Use of a compound of any one of claims 1-305, or pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer.

311. 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 1-305, or pharmaceutically acceptable salt or solvate thereof.

312. 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 1-305, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

313. A method of inhibiting KRAS comprising contacting the enzyme with a compound of any one of claims 1-305, wherein the KRAS is contacted in an in vitro setting.

314. A method of inhibiting KRAS comprising contacting the enzyme with a compound of any one of claims 1-305, wherein KRAS is contacted in an in vivo setting.

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